Office of Human Research
The Office of Human Research at Memorial Healthcare System was founded in
September 2011 in order to centralize the research performed at MHS and to
provide the infrastructure to conduct the research safely and efficiently. Our
vision is to offer a research study to any patient that walks through our doors and
to support and enable any physician who wants to perform research at MHS.
The goal of the Office of Human Research (OHR) is to provide a strong
foundation to enable and enhance human research at Memorial Healthcare
System. By providing educational and informational support, the OHR
strengthens the advancement of patient and community healthcare by ensuring
high quality, ethical, cost effective, research at the highest level of research
participant safety.
This manual provides guidelines for safe, effective, and efficient conduct of
clinical research, with attention to compliance with all relevant regulations and
Good Clinical Practice guidelines. It has been compiled to assist investigators,
coordinators, and other research team members throughout the course of a
research project – from study inception to study close-out.
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Abbreviations
ACRP Association of Clinical Research
Professionals
ADE Adverse Drug Experience
ADR Adverse Drug Reaction
AE Adverse Event
CBER Center for Biologics Evaluation and
Research
CDER Center for Drug Evaluation and
Research
CFR Code of Federal Regulations
CRA Clinical Research Associate
CRC Clinical Research Coordinator
ICH International Conference on
Harmonization
IDE Investigational Device Exemption
IEC Independent Ethics Committee
IND Investigational New Drug (application)
IRB Institutional Review Board/
Independent Review Board
IVRS Interactive Voice Response
System/Service
NDA New Drug Application
NIH National Institutes of Health
CRF Case Report Form
OHRP Office for Human Research
Protections
CRO Contract Research Organization
PHI Protected Health Information
DCF Data Clarification Form
PI Principal Investigator
DHHS Department of Health and Human
PMA Premarket Application
Services
PMN Premarket Notification [510(k)]
DIA Drug Information Association
PMS Postmarketing Surveillance
DSMB Data and Safety Monitoring Board
QA Quality Assurance
EC Ethics Committee
QI Quality Initiative
eCRF electronic Case Report Form
QOL Quality of Life
EDC Electronic Data Capture
RCT Randomized Controlled Trial
FDA Food and Drug Administration
SAE Serious Adverse Event
FWA Federalwide Assurance
SMO Site Management Organization
GCP Good Clinical Practice(s)
SoCRA Society of Clinical Research
Associates
GLP Good Laboratory Practice(s)
GMP Good Manufacturing Practice(s)
HIPAA Health Insurance Portability and
SOP Standard Operating Procedure
WMA World Medical Association
Accountability Act
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Chapter 1: Introduction
1. Defining Clinical Research
This manual was written for researchers who work with human subjects. Human subject
research encompasses a diverse array of activities, such as epidemiological studies,
evaluations of therapeutic interventions, behavioral investigations, translational research
etc. Human Research is defined as any activity that:
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Meets the Department of Health and Human Services (DHHS) definition of
“Research” and involves one or more “Human Subjects” as defined by DHHS
regulations
Or
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Meets the Food and Drug Administration (FDA) definition of “Research” and
involves one or more “Human Subjects” as defined by FDA regulations
1.1 Health and Human Services Definitions
Research
45 CFR 46.102(d) defines research as a systematic investigation, including research
development, and testing and evaluation, designed to develop or contribute to
generalizable knowledge.
Human Subject
45 CFR 102(f) defines a human subject as an individual about whom an investigator
conducting research obtains data through intervention or interaction with individual
and identifiable private information.
Intervention or Interaction includes physical procedures performed on an individual,
manipulation, communication, or interpersonal contact with an individual or manipulation
of an individual’s environment
Private information includes information that an individual can reasonable expect will not
be made public, and information about behavior that an individual can reasonably expect
will not be observed or recorded.
Identifiable means that the identity of the individual is or may be readily ascertained by
the investigator or associated with the information.
1.2 Food and Drug Administration Definitions
Research
21 CFR 50.3(c) defines research as an experiment that involves a test article and
one or more human subjects that is subject to IND or IDE regulations or which
collects data to be submitted to or held for inspection by FDA.
Research is subject to the IND regulations when it involves any use of a drug except
the use of a marketed drug in the course of medical practice (21 CFR §312.3).
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Human Subject
21 CFR 50.3(e) defines human subject as an individual who is or becomes a
participant in research, either as a recipient of a test article or as a control. In the
case of research involving a medical device, a human subject also includes an
individual on whose specimen a medical device is used.
Test Article
21 CFR 50.3 (j) defines test article as any drug (including a biological product) for
human use, medical device for human use, human food additive, color, adaptive,
electronic product, or any other article subject to regulation under the jurisdiction of
the FDA.
The Institutional Review Board (IRB) may provide additional guidance on determining
whether or not an activity meets the definition of human research.
2. Research Roles
This section contains information regarding the roles and responsibilities that each
position will have for the conduct and management of a research study.
2.1 Principal Investigator (PI)
The Principal Investigator (PI) conducts the investigation and is responsible for the study
at his/her site. The PI is responsible for following federal regulations and meeting Good
Clinical Practice (GCP) standards. The PI is ultimately responsible for the conduct of the
study, and is held accountable for his/her study team.
The PI’s responsibilities include the following:
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Ensure self and staff are qualified to conduct research
Have adequate resources
Comply with the protocol
Ensure that Informed Consent is obtained in the appropriate manner
Provide medical care and follow-up to subjects
Notify IRB and Sponsor of safety information
Communicate with the IRB and study Sponsor
Manage and maintain subject data
Inventory and dispense investigational product
Please refer to “Guidance for Industry: Investigator Responsibilities” to learn more (FDA
Guidance for Industry: Investigator Responsibilities)
2.2 Sponsor
The Sponsor is an individual, company, or organization who takes the responsibility for
the initiation, administration, and management of an investigation. A Sponsor is
responsible for assuring that the study is conducted in accordance with federal
regulations and GCP standards.
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The Sponsor’s responsibilities include the following:
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Design research project
Define and allocate study-related duties
Provide finances
Select and train qualified investigators
Assure protocol adherence by principal investigators
Monitor quality assurance and quality control
Confirm IRB approval
Notify regulatory authorities and study sites of safety information
Manage and maintain study data
Submit and maintain Investigational New Drug (IND) or Investigational Device
Exemption (IDE) applications to the FDA
Oversee manufacturing, packaging, labeling, and handling of investigational
agents
Please refer to General Responsibilities of Sponsors to learn more (Sponsor
Responsibilities)
A Sponsor-Investigator is an individual who would hold the same responsibilities as the
Sponsor in terms of upholding federal regulations and GCP standards, as well as those
of a PI, for study conduct at a site level. Sponsor-Investigators’ protocols are often
referred to as Investigator-initiated research.
2.3 Institutional Review Board (IRB)
The IRB is an independent group (either within MHS or external) responsible for
ensuring adequate protection of the rights and safety of human subjects. The IRB
encompasses national, local, and community ethical standards. A research project
cannot be implemented without IRB approval.
The IRB’s responsibilities include the following:
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Protect the rights and welfare of human research subjects
Review new and ongoing research
Obtain/maintain applicable regulatory documents
Review qualifications of investigators
Determine that research adequately addresses the ethical concerns
Determine that research meets regulatory requirements
Develop and evaluate institutional policies
Educate investigators and the community
2.4 Clinical Research Coordinator/Clinical Research Nurse
The Clinical Research Coordinator (CRC) or Clinical Research Nurse (CRN) is an
individual who assists the PI with the conduct of the study by overseeing day-to-day
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responsibilities of the study. The CRC helps ensure that the study is conducted in
accordance with federal regulations and GCP standards. Typically, a nurse specific to
the area of research under study fills this position.
The CRC’s responsibilities include the following:
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Organize and maintain regulatory documentation
Recruit subjects
Participate in the informed consent process
Conduct assessment and collect medical history
Coordinate study procedures and follow-up visits
Monitor patient care, assess patient status, monitor treatment effects
Serve as a liaison for subjects, investigators, IRB, sponsor, and other health care
providers
Coordinate activities in team in caring for patients
Maintain investigational drug/device accountability
Provide oversight of administration of medicines, study drugs, study interventions
Capture and report study data
Collect information on adverse events
2.5 Clinical Research Assistant (CRA)
A Clinical Research Assistant typically assists the CRC or CRN in performing routine
administrative activities. A CRA’s responsibilities may include:
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Assist in organizing and maintaining all documentation, case report forms and
study binders
Assist in obtaining appropriate signatures for regulatory forms
Assist in preparation of documents needed for initiation, monitoring, and closeout visits with sponsors and or clinical research organizations (CRO)
Assist in preparation and submission of regulatory documents (including
continuing review, amendments, and adverse event reporting) to the IRB
Maintain telephone follow-up with study patients
Screen for potential patients for research studies, in collaboration with the PI,
CRC or CRN
Processing and shipping of blood, urine, serum, and other specimens for clinical
trials
3. Regulations and Ethical Considerations
3.1 Federal Regulations
Clinical research is regulated by several federal agencies and must adhere to the
respective Code of Federal Regulations (CFR). The key regulations for human subject
research are:
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45 CFR 46 (Office of Human Research Protections – OHRP) (45 CFR 46)
The Office of Human Research Protections (OHRP) is the federal agency with
primary responsibility for the oversight of Institutional Review Boards (IRB) and for
ensuring compliance with the DHHS regulations (45 CFR 46). The OHRP grants the
IRBs the authority to review and approve research through a Federal-wide
Assurance. All research at MHS requiring IRB approval must, therefore, adhere to
the 45 CFR 46 regulations.
These regulations are divided into 4 subparts:
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Subpart A – Basic HHS Policy for Protection of Human Research Subjects
(IRB membership, function, operation & Informed consent requirements)
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Subpart B – Additional protections for Pregnant Women, Human Fetuses,
and Neonates
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Subpart C - Additional Protections Pertaining to Biomedical and Behavioral
Research Involving Prisoners as Subjects
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Subpart D - Additional Protections for Children Involved as Subjects in
Research
21 CFR (Food & Drug Administration – FDA) (21 CFR)
The FDA is the federal agency responsible for the review of research data on drugs
and devices. FDA regulations exist for the protection of human subjects and apply to
any studies that involve FDA-regulated products. The research-specific FDA
regulations include the following sections of the 21 CFR, and are collectively referred
to as “GCP Regulations”:
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Part 11 – Electronic Records; Electronic Signatures
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Part 50 – Protection of Human Subjects
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Part 54 – Financial Disclosure by Clinical Investigators
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Part 56 – Institutional Review Boards
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Part 312 – Investigational New Drug Application
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Part 314 – Applications for FDA Approval to Market a New Drug
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Part 601 – Licensing
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Part 812 – Investigational Device Exemptions
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Part 814 – Premarket Approval of Medical Devices
45 CFR 160 & 164 (Office of Civil Rights – OCR) (45 CFR 160 & 164)
Otherwise known as HIPAA regulations, 45 CFR 160 & 164 provide for the privacy of
patients and clinical research subjects. These regulations include restrictions for the
collection, use, and disclosure of protected health information.
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The Office of Human Research Protections has developed a comprehensive listing of
laws, regulations, and guidelines that govern human subjects’ research in many
countries around the world. This document can be downloaded from the OHRP website
at: International Compilation of Human Research Protections
4. Federal Agency Oversight
The nature of the study determines which federal agency will be involved. The study
may need to be submitted to and approved by any of the following agencies.
4.1 Food and Drug Administration (FDA)
If the study involves the use of an FDA-regulated product, the investigator may be
required to notify the FDA of the study. The investigator may also be required to notify
the FDA if the study involves any investigational agent to potentially cure, treat,
diagnose, prevent, or mitigate a disease, or otherwise affect a body structure or function.
The FDA uses two processes to ensure the protection of human subjects; if the safety of
the product under investigation is not known, the FDA may require the submission of an
application known as an Investigational New Drug (IND) application, or an
Investigational Device Exemption (IDE). These applications provide the FDA with
evidence that the investigational product is reasonably safe for human research.
Although the FDA is primarily a regulatory agency, it also serves as a funding agency for
an extremely small number of research projects.
4.2 Department of Health and Human Services (DHHS)
If the institution is engaged in human subjects research (not otherwise exempt, and is
supported by HHS), the institution must have an Office for Human Research Protectionsapproved assurance of compliance with the HHS regulations for the protection of human
subjects.
Protection of Human Subjects (Office for Human Research Protections, HHS)
45 CFR 46 – text of the federal regulation
Policy Guidance (Office for Human Research Protections, HHS)
Arranged by topic
Office for Human Research Protections (HHS)
Home page provides links to all aspects of the human research protections topic,
including registration of an Institutional Review Board (IRB) or Independent Ethics
Committee (IEC).
4.3 National Institutes of Health (NIH)
To obtain funding from NIH, researchers must submit their grant for scientific review.
Funding is based upon the quality and importance of the research.
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5. Ethical Considerations
Ethical considerations play a crucial role in conceptualizing, evaluating, and designing
clinical research studies. Past ethical violations have led to many of the current
regulations, guidelines and safeguards.
Several important documents exist to provide guidance on ethics in research:
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Declaration of Helsinki - WMA Declaration of Helsinki
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Belmont Report - NIH Belmont Report
The Belmont Report describes three basic ethical principles that should underlie
human research:
1. Respect for Persons – Respect centers upon two primary ethical convictions:
individuals are characterized as autonomous with respect to the decision to
participate in research, and individuals with diminished mental capacity are
dependent upon others to act on their behalf when deciding to participate in
research. Respect for persons imposes that participation is both voluntary and
informed, and that privacy should be protected.
Elements to consider:
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Informed Consent
Privacy and Confidentiality
Protection of Vulnerable Subjects
2. Beneficence – Beneficence is an obligation to make every effort to secure a
subject’s well-being during research participation. Two concepts express the
complementary convictions of beneficence: (1) do no harm, and (2) maximize the
possible benefits and minimize the possible harms.
Elements to consider:
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Risk-to-Benefit Ratio
Research Design (to minimize risks)
Investigator Qualifications
Conflicts of Interest
3. Justice – The concept of justice embodies an obligation to ensure that those
bearing the risks of the research study are selected fairly (i.e. are representative
of the reference population and not chosen simply because of their easy
availability for research), and are likely to have access to any benefit derived
from the research.
Elements to consider:
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Balance of Burdens/Benefits
Population of Inference
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Eligibility Criteria Representative of Population
Equitable Recruitment Methods
6. Vulnerable Populations
Some populations are considered vulnerable and deserving of additional research
protections. Vulnerable subjects are individuals who may be unduly influenced by the
expectation, whether or not justified, of the benefits of participation, or from fear of
retaliation from refusal to participate. There are specific federal regulations designed to
provide additional protection for pregnant women/fetuses/neonates (45 CFR 46 Subpart
B), prisoners (45 CFR 46 Subpart C), and children (45 CFR 46 Subpart D). Other
examples of vulnerable populations may include patients with incurable diseases,
subjects who are cognitively impaired, and employees or students of researchers.
Research in vulnerable populations can usually take place if they represent the
appropriate target population and the risks are minimized. However, the IRB often
requires additional safeguards to prevent coercion and to protect the integrity of the
informed consent process.
Please refer to the website for more information on vulnerable populations - Research
Involving Subjects with Questionable Capacity to Consent
6.1 Children/Minors
Federal regulations define “children” as persons who have not attained the legal age for
consent to treatments or procedures involved in the research, under the applicable law
of the jurisdiction in which the research will be conducted.
In Florida, the legal age of consent is 18 years of age. All under the age of 18 are
considered children or minors. Note the following exceptions:
Emancipated Minors - In Florida, the following categories of children are legally
authorized to consent to participation in research on their own behalf:
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Children who have had the "disability of nonage"(e.g. considered a child)
removed by a circuit court. (See Chapter 743, Florida Statutes).
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Children who are married or have been married may consent to medical care and
treatment, including participation in experimental procedures.
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An unwed pregnant child may consent to the performance of medical or surgical
care of services relating to her pregnancy by a hospital or clinic or by a licensed
physician. This category includes research relating to her pregnancy.
Except for emancipated minors, the IRB will not approve the enrollment in research of
persons under the age of 18 without parental permission unless the investigator can
demonstrate that enrollment is permissible under and consistent with Florida law and
meets the requirements set forth in 45 CFR 46, Subpart D and 21 CFR 50 Subpart D.
Individuals who are defined as “children” will be afforded the protections under the
regulations that protect children involved as subjects in research (Subpart D, 45 CFR
46.401 - 409 and 21 CFR 50.50 - 54). Additionally, the IRB may determine that minors
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who are not children (such as a person meeting one of the exceptions noted above) are
potentially vulnerable, at which point the IRB might apply additional protections.
Research involving children must fit into one of four categories:
1. Research not involving greater than minimal risk.
2. Research involving greater than minimal risk, but presenting the prospect of
direct benefit to an individual participant.
3. Research involving greater than minimal risk with no prospect of direct benefit,
but likely to yield generalizable knowledge.
4. Research that is not otherwise approvable, but which presents an opportunity to
understand, prevent, or alleviate a serious problem affecting the health or welfare
of children...(and) the research will be conducted in accordance with sound
ethical principles.
With children, emotional and psychological risks are given more consideration than
normally given to adult subjects. If possible, research involving greater than minimal risk
should be conducted first in adults and then in mature minors before young children are
involved. Consent is obtained from a parent or guardian and assent is obtained from the
child.
6.2 Limited Decision-Making Capacity
Decisionally impaired adults are individuals who have a diminished capacity for
judgment and reasoning due to a psychiatric, organic, developmental, or other disorder
that affects cognitive or emotional functions. Other individuals may be considered
decisionally impaired or have limited decision-making ability because they are under the
influence of or dependent on drugs or alcohol, suffering from degenerative diseases
affecting the brain, are terminally ill, or have severely disabling physical handicaps.
There are no universal criteria for determining competence. If competence is in question,
the subject’s decision-making capacity should be assessed in a manner appropriate for
that population.
The IRB takes special care to consider issues such as the selection of participants,
privacy and confidentiality, coercion and undue influence, and risk-benefit analysis.
Decisions should be made with the utmost deference to the ethical principles underlying
human research as set forth in the Belmont Report.
When designing a study that includes subjects with limited decision-making capacity, the
investigator should outline how the assessment process will be used to tailor informed
consent. It is suggested that consultation or collaboration be sought from departments
experienced in dealing with cognitive capacity issues in the population being studied.
The following criteria should be taken into consideration for adult participants with
impaired decision-making capacity involved in a research protocol:
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The objectives of the research cannot be met by conducting the research in a
population that does not have the disorder that may affect decision making
capacity.
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•
The research is designed for a disease or condition relevant to the vulnerable
population under study.
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The research is either minimal risk, more than minimal risk with a prospect of
direct benefit, or more than minimal risk without a prospect of direct benefit, but
of vital importance to the vulnerable population.
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Adequate provisions are made for obtaining consent from the participant’s legally
authorized representative.
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Adequate provisions are made for obtaining assent from the participant, unless
the IRB determines that assent is not appropriate as a condition of participation
or that some or all participants are not capable of providing assent.
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The protocol must describe when and how the participants will be assessed for
capacity for formal consent or assent and understanding of the proposed
research, and the process for a second confirming assessment. Competency
should be evaluated on an individual basis to avoid incorrect assumptions as to
an individual’s ability to make decisions. Criteria for determining competence
might vary according to the degree of risk or discomfort presented by the
research procedures and the extent to which therapeutic gain can be anticipated.
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The IRB will consider additional safeguards to protect participants. These
include:
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Requiring the involvement of participant advocates
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Requiring independent monitoring
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Requiring waiting periods
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Appointing a monitor to supervise the informed consent process
IRB decisions may be based on the amount of risk involved in the research and the
likelihood that participants will derive health benefits from their participation.
6.3 Pregnant Women, Fetuses, and Neonates
Pregnancy is the condition from conception to delivery, a fetus is the product of
conception from implantation until the time of delivery, and a neonate is a newborn up to
28 days.
Researchers studying women, fetuses, and neonates must not have any input in the
decisions as to the timing, method, or procedures used to terminate a pregnancy or in
determining the viability of a neonate.
Pregnant Women/Fetuses
Before approving research involving pregnant women, the following conditions must be
present:
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Where appropriate, preclinical and clinical studies (studies on pregnant animals
and non-pregnant women) have been conducted to assess potential risks.
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The research must fit into one of two categories:
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Risks are acceptable and the research offers the prospect of direct
benefit to the pregnant woman, the fetus, or both.
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Risks are minimal and the research purpose is to obtain knowledge that
cannot be obtained by any other means.
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No inducements will be offered to terminate a pregnancy.
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Informed consent will be obtained from:
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Only the pregnant woman: if there is possibility of direct benefit to the
pregnant woman -or- benefit both the pregnant woman and the fetus -orthe risk to fetus is minimal.
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Both the pregnant woman and the father: if the only potential benefit is to
the fetus (unless the father is unavailable, incompetent, temporarily
incapacitated, or the pregnancy is a result of rape or incest).
Neonates of Uncertain Viability
Before approving research involving neonates of uncertain viability, the following
conditions must be present:
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Where appropriate, preclinical and clinical studies have been conducted to
assess potential risks to neonates.
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The research must fit into one of two categories:
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Risks are minimized and the research has the potential to enhance the
probability of the neonate's survival to the point of viability.
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Research involves no additional risks and the purpose is to obtain
knowledge that cannot be obtained by any other means.
Informed consent will be obtained from:
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Either parent - If neither parent is able to consent because of
unavailability, incompetence, or temporary incapacity, informed consent
can be obtained from either parent's legally authorized representative.
Nonviable Neonates
Before approving research involving nonviable neonates, ALL of the following conditions
must be present:
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The research will not artificially maintain vital functions.
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The research will not terminate the heartbeat or respiration.
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The research must fit into one of two categories:
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Risks are minimized and the research has the potential to enhance the
probability of the neonate's survival to the point of viability.
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Research involves no additional risks and the purpose is to obtain
knowledge that cannot be obtained by any other means.
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Informed consent will be obtained from:
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Both parents - If one parent is unable to consent because of
unavailability, incompetence, or temporary incapacity, informed consent
can be obtained from only one parent. If the pregnancy is a result of rape
or incest only the mother's consent is necessary.
6.4 Prisoners
A prisoner is any individual involuntarily confined or detained in a penal institution.
Persons under house arrest and persons court-ordered to residential treatment facilities
are considered prisoners. Prisoners may only be used for research that is material to
their lives as prisoners or offers the prospect of therapeutic benefits.
An IRB reviewing this type of research must be specifically constituted to include at least
one member who has the appropriate background to serve as a prisoner representative.
The benefits and selection criteria of the research project must be carefully examined.
Incentives that would not entice non-prisoners could be coercive to this population due
to the limited choices available. Assurances should be established to prevent research
participation from influencing parole. Likewise, the selection criteria should be fair and
equitable. Subject selection criteria should not be subject to influence by prisoners or
prison authorities.
For DHHS-supported research involving prisoners, the Office of Human Research
Protection (OHRP) must also be involved prior to implementation of the project.
7. Risk to Subjects
Risk is the likelihood of harm occurring to research subjects. Risk can be social,
psychological, or physical. The amount of risk involved with a study will determine:
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What level of IRB (Institutional Review Board) review (Expedited vs. Full) is
required
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Whether the study qualifies for a waiver of consent or HIPAA Authorization
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How much oversight and safety monitoring is needed
An IRB uses the following categorizations to assess the level of risk.
7.1 Minimal Risk Eligible for Expedited IRB Review
Probability and magnitude of harm/discomfort no greater than daily life or routine
physical/psychological exams.
Examples
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Survey research
Venipuncture
Taste and observation studies
Contrast MRI studies
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Non-invasive procedures
7.2 Minimal Risk NOT Eligible for Expedited IRB Review
Generally includes studies that normally would be considered minimal risk, but involve:
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DEXA scans
Collection of >550mL of blood in an 8 week period or more than 2 venipunctures
within a 2-week period in healthy subjects
Phase IV studies
Biopsies
Catheter placement
Contrast MRI studies
7.3 Greater than Minimal Risk
Examples:
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HIV/AIDS and Hepatitis C studies
Most Phase III studies
Some studies that include a "washout" period or placebo use in an otherwise
treatable disease
Investigational drug/device utilizing invasive procedures
Phase I studies of new chemical entities or class of test article having unknown
expectations of toxicity
Gene transfer research
Emergency studies with waiver of informed consent
Xenotransplantation
The IRB will consider the following in determination of the risk level:
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That the risks to participants are minimized as much as possible
That the risks are reasonable in relation to the anticipated benefits
The adequacy of the informed consent process and documentation
Where appropriate, that the protocol contains provisions for monitoring
Where appropriate, that there are adequate provisions to protect the privacy of
subjects and confidentiality of data
Where appropriate, that there are additional safeguards in place to protect
vulnerable populations
8. Conflict of Interest
The conduct of clinical research often goes hand-in-hand with commercialization
ventures and involvement with companies with financial interests in the outcomes of the
research. As per the Memorial Healthcare System policy on Conflict of Interest,
“… the institution has the responsibility for maintaining objectivity in research by
ensuring that the design, conduct, or reporting of research will not be biased by any
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conflicting financial interest of investigators responsible for the research in accordance
with PHS 42 CFR part 50”
The conduct of clinical research must always be insulated from potential conflicts of
interest that might be perceived to influence its conduct or outcome. Conflict of interest
issues applies to anyone responsible for the design, conduct or reporting of research.
At MHS, the Office of Human Research (OHR) is responsible for research integrity,
which includes the management of conflict of interest in research. The OHR offers a
comprehensive collection of MHS policies and guidelines, federal policies and
guidelines, and other resources. This office, in accordance with federal regulations, also
administers the Conflict of Interest Committee (CIC), requires financial disclosure by
investigators, and enforces conflict of interest management mechanisms and sanctions.
8.1 Types of Conflict
Several types of conflicts of interest exist:
Conflict of Research Integrity
Investigators should maintain the highest level of scientific integrity in the conduct of
research. The complete, objective, and timely dissemination of new findings through
publications and presentations is essential for research integrity.
Conflict of Financial Interest
In general, this concept refers to an investigator in a relationship with a commercial
entity with financial interests in the company. In the context of clinical trials, this policy
defines the triggers that constitute a Significant Financial Interest as well as the
mechanisms for disclosing and managing such interests.
Definition
The following triggers of a Significant Financial Interest apply to the researcher, his/her
spouse and dependent children, and any corporation, foundation, trust or other entity
controlled or directed by the investigator or his/her spouse.
Significant Equity Interest
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Owning a significant equity interest of any company or entity that sponsors or
supports the clinical trial during the time of study and for 1 year following
completion of the study. Significant equity interest includes:
o
Any ownership, stock options, or other financial interest which cannot be
readily determined through reference to public prices (generally, interests
in a non-publicly traded corporation)
o
Equity Interest in a publicly traded corporation that exceeds $10,000 (or
exceeds 5% ownership)
Excluded is interest in any publicly traded diversified mutual fund.
Proprietary Interest
•
Owning a proprietary interest in the tested product. Proprietary interest is
property or other financial interest in the product including, but not limited to, a
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patent, trademark, copyright or licensing agreement, or right to receive income in
connection with the development or sale of the tested product.
Significant Payments
•
Receiving significant payments from any company or entity that sponsors or
supports the clinical trial during the time of the study and for 1 year following
completion of the study.
•
These are payments (e.g., retainers, honoraria, gifts) made by or on behalf of the
sponsor of the study that are more than $10,000 per year, exclusive of the costs
of conducting the study.
•
Excluded are payments to a department or school from the sponsor.
Service on Board
•
Serving on the Board of Directors or as an officer with fiduciary responsibility of
any company or entity that sponsors or supports the clinical trial. An officer with
fiduciary responsibility is someone who is entrusted with the management of
property for, or with the power to act on behalf of and for the benefit of, another.
Disclosure
Whether or not a significant financial interest exists, all investigators conducting clinical
trials are required to submit a Financial Disclosure Form. This form is submitted either in
connection with a submission of a grant application, or with a submission of a protocol to
the Institutional Review Board (IRB) for approval, to the Sponsor, as well as the IRB.
The IRB or the Sponsor reviews all disclosures to determine if it appears that the
investigator has a Significant Financial Interest as defined above.
Following are some examples of conditions or restrictions that might be imposed to
manage, reduce, or eliminate actual or potential conflicts of interest:
•
Public disclosure of Significant Financial Interests
•
Monitoring of research by independent reviewers
•
Modification of the research plan
•
Disqualification from participation in the portion of the funded research that would
be affected by the Significant Financial Interests
•
Divestiture of Significant Financial Interests
•
Severance of relationships that create actual or potential conflicts
Reporting potential undisclosed conflicts of interest
Any staff member who is concerned about a potential conflict of interest that may be
impacting the study or the safety and welfare of the subjects should first attempt to
speak directly to the investigator, informing him/her of the Conflict of Interest policy. If
this option is uncomfortable or does not result in a satisfactory resolution, the OHR can
be contacted to assist.
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Chapter: 2 Study Preparation
This section of the manual covers those activities that are conducted during the process
of preparing a research study, from assessing the feasibility of the research project
through protocol and study document development, submission and approval, and
initiating the research site.
1. Project Feasibility Assessment
When developing a potential research study, there are several aspects that require
careful consideration to determine whether or not the project is feasible. This section
attempts to outline some of the initial questions that need to be answered early in the
study planning stage.
This section will expose the researcher to the various areas that need to be assessed:
1.1 Scientific Validity
Is there sufficient scientific validity to proceed with the project?
Conduct a thorough literature review to evaluate the merit of a proposal with these
questions in mind:
•
Will the project contribute to the field?
•
Will the project replicate or challenge existing findings in the literature?
What type of study will be conducted?
A critical step early in the feasibility phase is to determine and clearly define the type of
project being considered. The complexity of the project will impact the resources that will
be needed.
Potential project types include:
Least Complex – Case Reports, Retrospective Cohort Studies, Prospective Cohort
Study, Analysis of Secular Trends
More Complex – Using routine clinical procedures in collaboration among departments,
Involving non-standard clinical procedures, Innovative treatment for the purpose of policy
change (change in standard of care)
Most Complex – Submitting an IND and IDE
1.2 Resource Assessment
Is there department/institute/center support?
Discuss the project with key persons in the department, center, or institute with the
following questions in mind:
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•
Is there an experienced mentor, collaborator, or consultant that can be involved
in the project?
•
Is there institutional support from the department director?
•
Does the study reflect the values and principles of the department and
institution?
•
Is the institution willing to accept responsibility for the level of risk involved?
•
Are there departmental resources that can be used to support the project?
•
Who are the key persons and staff who will contribute to the effort?
•
Do the faculty & staff have the ability and qualifications to carry out the methods
and procedures of the project?
What is the length of time required to obtain approval of a study?
The length of time for approval depends upon several factors including the type of
project, the amount of time the investigator and study team can dedicate to preparing the
study for approval, whether or not contract negotiation is required, etc. Obtaining
approval to commence a study involves more than just the IRB submission. There are
multiple processes involved, each with their own time lag.
1.3 Recruitment Potential
Are there enough subjects available to complete the project?
It is important to ascertain whether or not there exist enough subjects eligible to be
enrolled into the research study to achieve the proposed aims. To do this, first identify
how many people will meet the study's eligibility criteria. Next, estimate what percentage
of the targeted population can be accessed and realistically be expected to participate
and use this information to decide whether there are enough subjects to meet the
enrollment objectives.
Memorial Healthcare System has an extensive network of physicians, hospitals, clinics,
treatment centers, and community practices. All of these sites can be viewed as
potential sources for research subjects with specific diagnoses. Regardless,
investigators must identify methods for recruiting from their targeted audience via
medical records review, advertisements, word of mouth, or referrals.
1.4 Financial Feasibility
Funding for a study can come from a variety of sources that include federal agencies,
pharmaceutical companies, public charities, or foundations. It is important to analyze the
financial feasibility to determine whether there is enough funding to support the project.
A thorough analysis of financial feasibility can be accomplished by preparing a study
cost budget.
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2. Research Personnel and Staffing
2.1 Recruitment and Selection
Sources for Research Staff Recruitment
Effective research personnel recruitment requires a clear understanding of the position
being filled and related qualifications. The job description must accurately reflect the
expectations of the position, required experience, and education. This will ensure that
the position is properly graded and that a competitive offer can be made to the final
candidate. Successful recruitment requires the manager to understand the area market
for the specific position and who else is competing for these same individuals (i.e.
pharmaceutical companies, contract research organizations, colleges and universities,
temporary agencies), and area salary information (if available).
There are many sources for research staff recruitment including national clinical
research associations, internet based career sites, area colleges and universities, area
newspapers, hospitals, employment agencies. The posting should reflect the essential
elements of the job description along with characteristics unique to the position (i.e. fulltime, part-time, temporary, permanent, prior experience in clinical trials, etc.).
National Clinical Research Associations:
1. Association of Clinical Research Professionals http://careers.acrpnet.org/
2. Society of Clinical Research Associates http://www.socra.org/
Key Characteristics & Skills
The roles in research are multi-faceted, with a wide range of responsibilities, from patient
care to administrative. The following skills are essential for success in research:
1. Organizational skills
2. Ability to multi-task
3. Detail-oriented
4. People-oriented
5. Self-confident
6. Flexible
7. Able to manage time well
8. High energy level
2.2 Retention Strategies
Turnover of Clinical Research Coordinators (CRC) presents a costly impact on study
operations. A recent Thomson CenterWatch survey of 256 hiring decision makers found
that only 56% of Clinical Research Coordinators (CRC) have been in their positions for
less than 3 years, and that many CRCs were switching to careers in industry as study
monitors (CenterWatch Monthly, July 2004). This trend affects the study site with a loss
of productivity, money and time spent training replacements, and an overall less
experienced staff.
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The most commonly encountered reasons for the high rate of turnover among CRCs
include:
•
Heavy Workload (>40 hours per week)
•
Compensation
•
Personal Life Changes
•
Competitive hiring by other sites as CRC
•
Transition from CRC to study monitor in search of higher compensation and
flexibility
•
Lack of recognition and professional respect
•
Loss of funding on the part of the site
Burnout is a commonly reported occurrence among CRCs. Burnout is associated with
perceived daily workload, job satisfaction and low endurance and nurturance personality
traits. Aside from turnover, burnout can also affect productivity, data quality and
subsequently may have a financial impact on the clinical trial.
Several strategies are recommended for improving CRC retention and preventing
burnout. It is anticipated that implementation of the career paths identified earlier in this
section will contribute to improvement of CRC retention by providing a clear path for the
CRC and CR Nurse to advance within their profession.
Preventing Burnout
Respecting a realistic and flexible schedule for CRCs is another critical step toward
preventing burnout. It is recommended that CRCs be expected to work no more than 40
hours per week, with the exception of emergency situations. The hours may vary to
accommodate patient recruitment and visit needs, but the CRC should not routinely be
expected to work beyond 40 hours. Investigators who set these expectations should
consider that while the extra hours may reward the investigator with benefits such as
professional recognition, tenure, and other opportunities, there are very few such career
benefits for the CRC. If the workload is such that extra hours are required for the CRC to
accomplish necessary duties, it may be prudent to hire another CRC, or at minimum a
Clinical Research Assistant to reduce to burden on the CRC.
Professional Recognition
The CRC has long been an underappreciated role. Promoting a perception of being
appreciated and recognized for their contributions can greatly improve CRC retention.
This can be accomplished in several ways:
•
Supporting membership in professional organizations such as ACRP or SoCRA
•
Providing continuing education opportunities such as attendance at professional
conferences
•
Supporting pursuit of professional certification
•
Team Building Strategies
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•
Attendance to seminars to build skills
•
Acknowledgement for good or exceptional work via email, certificates, gift cards
2.3 Education and Training
2.3.1 Required Research Training
Collaborative IRB Training Initiative (CITI) Training
All personnel engaging in human research must have documented discipline-appropriate
training in human research protections. The Collaborative Institutional Training Initiative
(CITI) web-based modules satisfy this requirement. The "CITI Protection for Human
Subjects Training" course is available in CITI Training Initiative. Create your login and
affiliate yourself with MHS/Jo-DiMaggio to take the MHS-prescribed courses.
Health Insurance Portability and Accountability Act (HIPAA) Training
All research staff having contact with patient information are required to complete HIPAA
training. HIPAA regulations include specific rules about how protected health information
is used and protected in research. Researchers must complete the HIPAA training
offered on the CITI training website. (HIPS)
Dangerous Goods Regulations Training
The Occupational Safety & Health Administration (OSHA) requires relevant training for
employees who work with or ship hazardous substances including:
•
•
Chemicals
Human blood, blood products, fluids, and human tissue specimens
Through its Dangerous Goods Regulations and a comprehensive and effective training
program, the International Air Transport Association (IATA) ensures that shippers,
forwarders, and carriers have the tools and resources to ship dangerous goods safely.
Before you are allowed to ship these specimens, online training and certification must be
obtained. This is done through an invitation from Medialab. Please contact OHR for
further details.
The Florida Department of Health (DOH) sponsors training for health professionals in
“Infectious Substances Packaging and Shipping Training”. Please refer to the Florida
DOH website for details and schedules
Professional Research Associations
The following organizations offer training and certification programs for clinical research.
•
•
•
Association of Clinical Research Professionals (ACRP) http://www.acrpnet.org/
Drug Information Association (DIA) http://www.diahome.org/diahome/
Society for Clinical Research Associates (SoCRA) http://www.socra.org/
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Chapter 3: Grant Writing
Grants are written to obtain research funding from federal agencies, private foundations,
pharmaceutical companies, etc. Each agency has its own requirements for grant writing.
This section will concentrate upon the requirements for the National Institute of Health
(NIH). NIH uses activity codes (e.g. R01, R43, etc.) to differentiate the wide variety of
research-related programs. A comprehensive listing of different programs and activity
codes can be found at Types of Grant Programs
Deadlines for new NIH grant applications vary depending on the type of grant.
Information on NIH grant deadlines can be found at: Standard Due Dates for Grant
Applications
New investigators should estimate that the writing process will take between 2-6 months.
Applications for NIH research support are made on Grant Application Form PHS 398.
NIH also provides Grant Writing information and tutorials, available at: NIH Grant
Tutorial. Information regarding about the process can be found at Grants - How to Apply
General writing tips include:
•
Write clearly and concisely
•
Proofread
•
Write for technically diverse reviewers
•
Avoid unnecessary complexity
•
Collect preliminary data
•
Follow instructions carefully
•
Obtain outside opinions
Grant Writing Services
The Office of Human Research (OHR) can provide assistance with writing and editing
large, multidisciplinary proposals, such as program project (P01) and specialized center
(P50) grants. The OHR will help ensure:
•
Integration of distinct projects to create a cohesive proposal
•
Consistency of style and tone throughout the proposal
•
Clarity in the presentation of ideas, goals, and strategies
•
Polished grammar for maximum readability
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1. Components of an NIH Grant
Abstract
An abstract is a summary of the grant written for the educated non-specialist. It is
a concise description of the background, specific aims, the research methods,
and significance. The abstract is used to assign a grant to a study section. Study
section members (who are not primary reviewers) will rely heavily on the
abstract. The researcher may choose to write the abstract last to ensure the
content of the entire proposal is well summarized.
Specific Aims
The specific aims section is generally a page explaining the long-term goals, the
hypothesis, and the specific aims or objectives (Specific Aim #1, Specific Aim #2,
Specific Aim #3, etc.). The hypothesis should be clear and focused. The aims
should be related. Explain how the specific aims will be used to support the
hypothesis.
Background/Significance
The background/significance section is generally 3 pages describing the
problem, current knowledge, remaining questions, and importance of the
research. The investigator should provide a balanced review of the literature.
Elaborate upon how the knowledge gained from the hypothesis and specific aims
will improve the field and/or other related areas.
Preliminary Results/Progress Report
The preliminary data section is generally 6-8 pages describing what current and
prior work has done to support the feasibility of the study. Identify how each of
the specific aims in the work has been addressed and interpret the results
critically. Demonstrate that the investigator has the experience and capabilities to
conduct the proposed project. The investigator may include unrelated studies if
they demonstrate his/her competence to perform the experimental techniques.
Experimental Design/Methods
The research design and methods section is no more than 25 pages (items "a"
through "d") providing a concrete explanation of how the study aims will be
accomplished. A detailed and technical description of the study procedures and
methods should be incorporated. Avoid "shot gun" approaches or fishing
expeditions. This section should address potential problems or limitations in the
experimental design and, if possible, provide alternatives or solutions.
Reference Section
The reference section should accurately reflect the citations used throughout the
grant.
Consortium and/or Consultant Arrangements
Describe collaborators at other institutions or other local experts who may be
providing support or advice. This should include documentation substantiating
their participation.
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The grant application may also include:
•
A biographical sketch
•
Budget and justification
•
A description of other research support
•
Conflict of interest disclosures
•
Assurances/regulatory (IRB) approval
•
A description of resources and environment and letters from the department
chair.
The grant will be assigned to an Institute or Center (IC) who then sends it to a scientific
review group or "study section." The study section will review the grant and assign it a
priority score for funding.
Please refer to the NIH website for further information regarding the grant application
process - Application Guide for NIH Grants
2. Grant Revisions
Approximately 40% of the grants reviewed by a study section are resubmissions. Do not
be discouraged if you receive a poor priority score and need to resubmit your grant.
Identify the problems:
•
The most common criticisms include:
o
Grant is poorly written- the plan is unclear, incorrect, or incomplete
o
Aims cannot be supported- the sample size is inadequate or uncertain
o
Plan is not well conceptualized- the methods are incomplete
o
Insufficient expertise- missing talent, usually statistical
o
Poorly chosen population of inference - poor subject selection, usually
controls
o
Not enough evidence to support the planned response rates- need
pilot data
o
Plan is unfocused- hypothesis is absent or unclear
•
Ask for advice from experienced researchers
•
Address the problems
o
If there are problems with the review (reviewers were not interested,
did not have suitable expertise, or were biased), revise, resubmit, and
request a new study section
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3. Research Methods and Statistical Design
It is beyond the scope of this manual to provide information on various statistical
approaches and models. The following is meant as a high-level overview of the basic
elements of study design and clinical research statistics.
The researcher's goals influence the size, scope, and direction of the investigation. The
intended purpose of biomedical research varies and usually falls along a continuum:
Basic research is research to advance scientific knowledge and understanding across a
wide variety of areas such as physiology, pathophysiology, chemistry, etc., but is not
focused on a specific practical application of that knowledge.
Translational research, often called "bench-to-bedside research," focuses on assessing
the feasibility of translating basic research findings and knowledge into clinical therapies.
The interface between basic research and clinical application includes elements of
bench research necessary to support application to human medical care (e.g. biologic
mechanism of action, pharmacokinetics, toxicology, etc.) and early stage research in
humans.
Clinical application/development produces and evaluates materials, devices, systems, or
methods as they apply to human healthcare. Clinical trials and certain translational
research activities are components of this category.
A clinical trial is any investigation involving human subjects intended to identify the
clinical, pharmacological or other effects of an investigational product (drug or device) to
measure its safety and/or efficacy. The overall objectives of a clinical trial vary with the
phase of investigation:
•
Phase I - first study of a drug in humans, most commonly healthy adults; safety
and dose ranging tolerability; basic metabolism or mechanism studies (generally
small studies of 20 or less subjects)
•
Phase II - first study of drug in target populations (patients); safety, dose ranging
in patients; preliminary efficacy assessment (generally >100 subjects)
•
Phase III - larger study to prove efficacy and increase experience with safety
(generally large studies ranging from >100 to >1000 subjects ---- Phase III
cardiovascular studies have enrolled higher than 40,000 subjects)
•
Phase IV - post-marketing studies; vary in size; often to provide ongoing safety
data.
If a researcher is conducting research in human subjects, a clear hypothesis is
necessary in order to choose the study design. The study design, in turn, will impact
which techniques will be used to minimize bias and how the statistical analysis will be
conducted. The involvement of a statistician in the preparation of the statistical plan and
analysis is an indispensable part of this. Please contact the OHR for more information.
3.1 Basic Elements of Study Design
Once the purpose of the investigation is understood and the hypothesis and objectives
have been formulated it is necessary to identify the study design to be used for the
project.
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To help determine the appropriate research design:
•
Identify the condition and outcome of interest.
o
•
Select the type, order and frequency of observations and measurements.
o
•
What methods will be used to obtain data? How, when, and in what order
will these observations and measurements occur?
Identify the nuisance variables.
o
•
Will manipulation of the variable(s) occur or will observational methods be
used?
Are there any identifiable sources of variation which can confound the
results? Can their impact be minimized or controlled?
Identify the population of interest.
o
What sample size will be needed? How will sampling occur? Is there only
one group or will multiple groups be used for comparison?
3.2 Basic Types of Study Design
Study designs can be classified into two broad categories: experimental studies and
observational studies.
Experimental Studies
In an experimental study, the selection and allocation or assignment of individuals for the
experiment is under the control of the investigator. The controlled conditions help
validate a cause-and-effect relationship between the treatment and the outcome within
the population enrolled in the study (internal validity). However, it is important to
remember that findings from experimental studies do not always accurately reflect
findings under real-world conditions (external validity) since there are many factors in the
real-world that cannot be fully captured in a carefully controlled experiment (e.g. natural
variations in physiology and concomitant diseases or medications, patient compliance
with the treatment, etc.).
General characteristics that differentiate experimental research designs from each other
include the use of a control group, random assignment, and blinding. When used
correctly, these characteristics can significantly strengthen the ability to infer cause and
effect from experimental research.
Control Groups
Controls are subjects who are included in an investigation for comparison to the
intervention/treatment group. Controls are not given the intervention, or are given
a different intervention, or, depending on the type of experiment, do not have the
condition, background, or risk factor under investigation. A control group may be
enrolled concurrently with the intervention group, may be the same population as
the intervention group, or may be studied independently (as an external or
historical control).
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Some common examples of control-group designs include:
1. A cross-over design is a type of experimental study where subjects act
both as a control and as an actively treated subject. Generally, subjects
are enrolled into one treatment group, then after a waiting or wash-out
period (i.e. time for the treatment effect to be eliminated or "washed-out"),
are enrolled into an alternate treatment group. In this type of design the
subjects act as both the comparator group and the active treatment
group. This approach reduces the variability in comparing active to
treated subjects, but it is susceptible to bias if carry-over effects from the
first treatment occur.
2. A parallel groups design is a type of study where different treatment
groups are running simultaneously. The parallel-groups approach is
susceptible to non-comparability between groups if the subjects are not
properly allocated or assigned (i.e. the baseline characteristics may not
be equal between the two groups to such a degree that the groups are
not truly comparable).
o
A matched pairs group is a type of parallel study design in which
subjects with similar, pre-determined traits are first paired and
then randomized into different study arms for comparison.
3. A series group design assesses exposure to the study treatment in
phases- one treatment group is completed before beginning the next
treatment group. This design is most commonly used in Phase I doseescalations studies as a safety measure, allowing full evaluation of the
results from the first treatment group before subjecting another treatment
group to the next higher dose.
Random Assignment
Non-randomized: In a non-randomized investigation, subjects are assigned to a
treatment group as they appear for the study or based upon certain
characteristics.
Randomized: In a randomized investigation, subjects are assigned to treatment
groups on the basis of chance. The process of assigning subjects to treatment or
intervention groups affects internal validity. The overall goal of randomization is
to produce comparable groups across the study. Randomization strengthens the
foundation for statistical procedures and, when properly executed in an
experimental study, provides the strongest empirical evidence of any study
design.
The following summarizes some typical methods of randomization.
1. Simple randomization - This type of randomization does not involve any
restrictions. Since the treatment assignment is totally random there is no
way to guarantee that there will be an even distribution between groups.
For example, one site of a randomized multi-center drug trial may receive
a majority of active drug rather than placebo simply by random chance.
This type of randomization scheme can result in an unequal numbers of
subjects receiving a specific treatment at a given site or over a given
period of time.
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2. Random permuted blocks - This type of randomization compensates for
potential of simple randomization to unbalance treatment assignment.
With this approach a randomization block size is chosen (e.g. 4, 8, or
more subjects) in which the BALANCE OF TREATMENT ASSIGNMENTS
is kept proportional according to study design. For example if a block size
of 4 is chosen and the protocol defines two study groups, 1 active vs. 1
placebo drug group, then the block will contain 2 active study drug kits
and 2 placebo study drug kits. Since the entire block of 4 kits is randomly
assigned a treatment number, the subjects will receive their treatment
assignment randomly over a given period of time.
3. Stratified randomization - This type of randomization assigns study
treatment on the bases of certain baseline characteristics such as gender,
age, weight, etc. (i.e. a specific 'stratum' of the population being studied).
The goal of this approach is to balance the number the subjects with the
characteristic of interest in each treatment group to ensure comparable
groups. This type of randomization is most commonly used in smaller
studies where fully random assignment of study treatment could result in
an imbalance of subjects with a given baseline characteristic (e.g. the
majority of obese subjects in one treatment group vs. non-obese in the
other, or the majority of females in one treatment vs. males in the other.).
Large-scale studies, due to their size, usually have balance of baseline
characteristics and therefore less often require stratified randomization.
There are a variety of programs available to generate random allocation
sequences. An example of an on-line program can be found at:
http://www.randomization.com/.
Blinding and Placebo Control
Blinded: Blinding is the act of keeping the identity of a study intervention secret
(in other words, it would not be known if a study treatment was active treatment
or placebo). Single-blind means only the research subject is blind to the actual
intervention. Double-blind means two parties (usually the subject and the
investigator/research team) are blind to the actual intervention. Occasionally the
less-frequently used term of triple-blind is used to emphasize that non-study
personnel are also blind to the study intervention (e.g. study monitors/auditors,
end-point assessment committees, etc.). Blinded studies involving investigational
products may use placebos and double-dummy treatments to disguise treatment
assignment. A placebo is a study intervention designed to look like the active
treatment but having no active properties. A double-dummy treatment is a
method of blinding two treatments whose appearances are dissimilar by
administering both treatment forms - one active and one placebo. For example,
in designing a study comparing heparin (intravenously delivered) vs. a low
molecular weight heparin (subcutaneously delivered) if the study were to be
double-blinded, it would be necessary to have two types of placebo (two
"dummy" treatments), an intravenous placebo and a subcutaneous placebo.
Un-blinded: In an un-blinded study, the subject, investigator and evaluator are
aware of the actual study treatment. Un-blinded studies involving investigational
products are referred to as open-label.
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Observational Studies
In an observational study, specific events or findings within the study-defined population
are collected without any intervention by the researcher. In other words, the researcher
observes and studies findings in a setting outside of a randomized, blinded or placebocontrolled design. This type of design is usually used in investigations where it would be
unnecessary, infeasible or unethical to assign factors (e.g. smoking in pregnant women).
Like experimental studies, observational studies often use control groups for
comparison, but because a treatment is not assigned, randomization is not possible.
Observational studies have the potential for introducing confounding biases due to the
risk of an unknown association between the factor under study and the outcome.
Analytical
Cohort study: A cohort study examines specific events or outcomes in a group
of subjects who are followed over time. This study design compares the
incidence of a given event/outcome in exposed and unexposed groups in an
effort to determine an association. The common association measurement for a
cohort study is relative risk (see definition below).
Cohort studies can be prospective or retrospective. Prospective cohort studies
are expensive and time-consuming, but because of their prospective nature,
cohort studies can provide stronger empirical evidence than case-control studies.
Retrospective cohort studies are often less expensive to conduct, but may be
subject to data collection obstacles (e.g. the investigator has no mechanism of
ensuring documentation of a specific type of event or outcome).
Case-control study: A case-control study is a type of retrospective
observational study comparing persons with a disease, condition, or exposure
(the cases) and persons without the disease, condition or exposure (the control),
assessing differences in events or outcomes between the groups. The two
groups are otherwise comparable across all the relevant baseline characteristics.
The common association measure for a case-control study is the odds ratio (see
definition below). Case-control studies are usually used for broad-based,
inexpensive evaluation of risk factors and are also useful for evaluating rare
conditions or risk factors with long induction periods.
Descriptive
Cross-sectional study: A cross-sectional study is a descriptive study of the
relationship between diseases and other factors at one point in time in a defined
population. Cross-sectional studies determine the prevalence (presence) of an
exposure and disease, but lack information on timing of exposure. Crosssectional studies generally cannot be used to draw causal inferences and are
usually used for hypothesis generation.
Case reports and Case series: A case report is a description of a single patient
and usually includes a discussion of medical conditions and treatments along
with adverse events and outcomes. A case series is a group of case reports
describing patients that have been exposed to a specific treatment or agent. Due
to the typically small numbers of cases in a case series and the lack of a control
group, the value of interpreting the reported findings is limited. These types of
presentations are best used for hypothesis generation.
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4. General Guide to Statistical Consultation
The importance of early involvement of a statistician in the design of a clinical study
cannot be overstated.
To consult a statistician after an experiment is finished is often merely to ask him to
conduct a post mortem examination. He can perhaps say what the experiment died of.
- R.A. Fisher (in his 1938 address to the First Indian Statistical Congress)
Most often the assistance of a statistician will be required for the selection of an
experimental design, the development of the corresponding analysis plan and the
subsequent interpretation of parameter estimates and test results. Meaningful
involvement of a statistician in study development can permit significant contributions to
the following study elements:
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Problem Formulation
Background and significance
Methods and materials
Experimental design
Study flowcharts
Study schema
Feasibility of design
Sample size or power estimates
Statistical analysis plan
Data management plan
Case Report Form design
Choice of statistical software
Choice of Database Software
Implications of probable/possible results
Responses to reviewer comments
Help with resubmission
References
Even when the analytic needs of the investigator seem obvious, review of the research
plan by the "new eyes" of the statistician may lead to alternative methods that should
improve efficiency or lead to new insights. Since statistics is evolving science, not static
technology, new advances may replace or change analysis recommendations over time.
Dialogue between investigator and statistician will almost always help to clarify research
objectives, prioritize study aims, and lead to more informed and appropriate selection of
tests of hypotheses. Ideally, such exchanges will lead researcher to view statistician as
collaborator, rather than consultant, which should lead to improved research designs,
more comprehensive analyses and better scientific insight.
4.1 The initial meeting with the biostatistician
Preparation for an initial meeting with a statistician should include a written description of
the proposed project stating the general objectives of the study and the questions that
the investigator hopes to answer. The following are the key elements of the researcher's
proposed study that the statistician will need in order to best assess study design and
statistical approach:
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•
Study Objectives
•
Population(s) targeted by the study (e.g. healthy volunteers, patients with a
specific disease or combination of diseases, etc.)
•
Response variables of interest
•
Relevant classification (e.g. gender, race, severity type, smoking status, etc.)
•
Important variables associated with the response variable of interest (i.e.
covariates)
•
Background information from a variety of sources:
o
pilot studies (i.e. a small version of the full study being proposed)
o
previous studies (i.e. similar study population or intervention)
o
scientific literature (i.e. theoretical basis for proposal, animal studies)
o
collegial exchanges (e.g. scientific meetings, workshops, e-mail)
o
anecdotal observation (e.g. poor sense of smell in schizophrenics)
Construction of a Study Flowchart, often called a Time and Events Chart, and/or study
schema diagrams can summarize and communicate the study design, most effectively.
From the above information, the statistical consultant can assist with development of a
list of specific aims, which the researcher will classify as primary, secondary or
exploratory aims. These aims will give rise to null and alternative hypotheses (see
definitions in Basic Statistical Terms below) which may be subjected to statistical tests of
significance.
The statistical consultant needs to understand the purpose and context of the proposal,
rather than viewing the research as an abstract statistical problem. In addition to general
and technical details of the proposed study, the researcher should be prepared to
provide answers to the most basic questions concerning the study and core discipline.
These questions might require explanation of fundamental elements of the disease,
disorder or biological process being studied. For example, the statistician may not know
whether the origins of a process to be studied are genetic, environmental or both and
such information is important to the analysis approach to be used. Attention to this
upfront planning for a study will lead to a solid development of clear and comprehensive
narratives that will comprise the background, methods and other sections of a
researcher's protocol.
4.2 Basic Statistical Terms
To facilitate interaction with the biostatistician, the investigator should be familiar with
some basic statistical terminology. The following defines some basic terms.
Alpha error: A statistical error in testing an hypothesis, often referred to as type I error
(the "first type of error"), which incorrectly concludes that a treatment or intervention is
proven effective when it is actually is not effective; sometimes referred to as a false
positive result.
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Beta error: A statistical error, often referred to as type II error (the "second type of
error"), which incorrectly concludes that a treatment or intervention is proven ineffective
when it is actually effective; often referred to as a false negative result.
Confidence Intervals (CI): Confidence intervals are a way of expressing a level of
confidence in a specific statistical finding. If a study were repeated, the results of the
repeated study would not be exactly the same as the first study. If a study were repeated
many times, one would eventually establish a particular range of results in which the
"real" result that would prove (or disprove) the study are likely to be found. This range is
called the confidence interval. Therefore a 95% confidence interval would mean there is
a 95% chance that the "real" result of the study analysis falls within the stated interval or
range. The wider the confidence interval the greater the variability of the result, and the
narrower the confidence interval, the lesser the variability of the result, though there are
other factors to consider in determining whether the result likely proves or disproves the
study hypothesis. For example, in a study of a treatment vs. placebo, if the study
outcome showed the treatment to have a 10% decrease in events, and the calculated
range of likely values in which this result lies is found to be -1.2% to 12%, it would
generally be expressed as: endpoint reduction in the treatment arm of 10% (95% CI 1.2% to 12%). In this case, since the lower range of the confidence interval crosses over
0% (i.e. a value showing no difference in the treatment arm from placebo) if the result
was being viewed as either proving or disproving a difference in the study treatment
arms, it could be argued that the trial was negative since a result of 0% lies within the
range of possible results given the confidence interval. However, adopting a "likelihood"
approach to the study finding, the majority of the range of the confidence interval
extends in the positive direction beyond 0% (i.e. most of the likely values are greater
than 0%), one could argue that it is more likely that the study does show a reduction in
events by the treatment. (Excerpted from: T. Greenhalgh, BMJ No 7105 Volume 315,
August 16, 1997)
Null hypothesis (H0): A mathematical statement of the converse of (one of) the specific
aims of the study. Following the example used in the definition for the alternative
hypothesis, the corresponding null hypothesis would be that the proportion of children
who play video games and exhibit at least one violent incident is equal to or less than
(i.e. no worse than) the proportion of children who do not play video games. The null
hypothesis is the converse of the alternative hypothesis.
Odds ratio: An odds ratio compares the odds of an event in one group with the odds of
an event in a comparator group. Odds ratios are a common way to express outcomes in
observational studies. For example, a case-control study of two cohorts, one with an
exposure to a presumed noxious element and one without, included 100 subjects in
each group and looked at death rates after 5 years. In this example there were 20
subjects that died in the exposed group (case group) vs. 5 who died in the unexposed
group (control group). The odds of dying in the case group is the ratio of subjects who
died to subjects who did not die, i.e. 20/80, or 1/4, which can be expressed as 0.25. The
odds of dying in the control group would then be 5/90, or 0.05. Therefore the odds ratio
of the event rate comparing the case group to the control group would be displayed as:
0.25/0.05, or 5. Thus the odds of death in exposed group are 5 times the odds of death
in the unexposed group.
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Outlier: An extreme deviation from the mean (i.e. a data point that lies an abnormal
distance away from other values).
P value: A way of expressing statistical significance. Standard practice (which was
arbitrarily decided) is that a 5% likelihood that the study outcome is due to chance (i.e. a
95% likelihood the study outcome is not due to chance) is statistically significant. This
5% likelihood is expressed as P=0.05. A 1% likelihood that a study outcome is due to
chance (i.e. 99% likelihood that study outcome is not due to chance), is expressed as
P=0.01 and considered highly statistically significant. A criticism of the use of a P value
test of significance is that it relies on an arbitrary cut-off in answering a yes-no question
on a finding. An alternative approach is to look at a range of likelihood that a statistical
finding expresses reality (see Confidence Intervals).
Power: Power is defined to be equal to 1- ß; that is the probability of not committing a
Beta (Type II) error. Power is an index of sensitivity, since it is the probability of rejecting
a false null hypothesis. An analogous index of specificity is 1- ?, the probability of not
rejecting a true null hypothesis; although there is no common statistical name for this
probability.
Risk, relative risk, and risk reduction
Risk is a simple calculation of the number of subjects in a group that experience an
event divided by the total number of subjects in that group. The equation is: (number of
subjects with event/total number of subjects assessed for the event).
Relative risk compares the risk of an event in one group to the risk in a comparator
group. To show the relative risk of an event in a control group vs. a treatment group, the
equation is: (risk of event in control group/risk of event in the treatment group).
Absolute risk reduction shows the absolute amount of reduction in the risk of an event in
one group vs. a comparator group. To show the absolute risk reduction in a treatment
group vs. a control (non-treatment) group the equation is: (control group risk - treatment
group risk).
Relative risk reduction expresses the reduction in risk as the difference in the risk of an
event in one group vs. a comparator group divided by the overall risk of the event in the
first group (i.e. the amount of risk reduction relative to the overall risk). To show the
relative risk reduction in a treatment group vs. a control (non-treatment) group the
equation is: ([Control group risk - treatment group risk]/control group risk).
To illustrate the above definitions of risk, relative risk and risk reduction, consider the
following example:
A study of a target disease compares usual care to a new treatment by measuring the
number of deaths in each group. Two hundred subjects are enrolled in each study arm
and results are measured over the five-year duration of the study. The table below
shows the number of deaths in each group at 5 years.
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Treatment
intervention
Total number of
patients
Number of
Deaths
Control Group
200
40
Treatment Group
200
10
Risk: (subjects with events/total number subjects studied)
In the placebo group, the risk of death is 40/200, which is 0.20 or 20%. For the treatment
group, the risk of death is 10/200, which is 0.05 or 5%. In other words, at five years,
there is a 20% risk of dying in patients with the target disease if not treated compared to
a 5% risk of dying if treated.
Relative Risk: (risk in control group/risk in treatment group)
Relative risk compares the risk in one group relative to the risk in the other group. The
relative risk between the control group and the treatment group is .020/0.05, which is 4,
meaning patients who do not receive treatment are at 4 times the risk of death than
similar patients who receive the active treatment.
Absolute risk reduction: (risk in control group - risk in treatment group)
The control group risk of death is 20%, the treatment group risk of death is 5%, therefore
the absolute amount of risk that was reduced by treatment is 20% - 5%, which is 15%. In
other words, out of 200 patients treated 15% (or 30 patients) avoided death at five years.
Relative Risk reduction: [(risk in control group - risk in treatment group)/risk in control
group]
In the example noted above the relative risk reduction would be [(20% - 5%)/20%], or
15/20, or 0.75, most often expressed as a percent: 75%. Relative risk reduction is
usually more clinically useful than absolute risk reduction when trying to conceptualize
the benefit of a treatment. In other words, while the control grouped showed 40 patient
deaths and the treatment group showed 10, the relative risk reduction illustrates that this
reduction of 30 deaths represents 75% of the overall risk of death; i.e. the treatment
reduced the overall risk of death by 75%.
Statistical significance: The likelihood that a particular study outcome has arisen by
chance. This is commonly expressed as a P value. Note: Statistical significance does
not necessarily mean a finding is clinically significant.
Study arm: The different groups in a study. Each group represents an arm of the study.
A single-arm study would have only one group; a double-arm study would have two
groups, and so on.
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Chapter 4: Protocol Design/Review
The protocol is a document that describes the objectives, design, methodology,
statistical considerations, and organization of a research study. The protocol explains
the specific procedures of the study and outlines the scientific, organizational,
administrative, and financial aspects of the research study.
The protocol is distinct from the research grant. While the grant provides a broad
overview of the study procedures, the protocol clearly defines and operationalizes the
details of study implementation.
The required elements of a study protocol are dictated in the Good Clinical Practice
(GCP) guidelines.
Part I: Elements of a Study Protocol
The following sections describe the elements of a GCP standard protocol and are
contained in a template attached as an appendix to this chapter. Please contact the
Office of Human Research (OHR) for an electronic version of the template that uses
functionalities in Microsoft Word to create automated formatting and generation of a
table of contents. Various sections also contain suggested language that is compliant
with federal regulations (e.g. safety section, adverse event reporting requirements, etc.).
Note: This template was developed for drug studies, but can be adapted for other types
of studies. The National Cancer Institute (NCI) also has protocol templates available for
cancer studies at Protocol Development Guidelines and Templates.
Title Page
The protocol title page is the "front cover" of the study protocol and displays the
title prominently. Other information to include on the title page:
•
Principal Investigator name
•
Sponsor name
•
Protocol version/version date
Table of Contents
Very short protocols of only a few pages may not require a table of contents.
Larger protocols should have a table of contents to aid study personnel in easily
finding a specific protocol section or item.
Executive Summary
It is useful to develop a brief protocol summary and include it as part of the
protocol, typically located after the protocol table of contents. Generally only 1-3
pages in length, the protocol summary provides a way to quickly grasp the key
elements of the protocol. This is a useful tool when trying to communicate with
various parties about the study. The Executive Summary can be written with
headings and associated text, or summarized succinctly in table form. The key
elements of a protocol summary follow:
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Title
Full title of protocol
Short title
Shortened title, if one is typically used by you or your
Center/Dept.
Protocol
number
The standard protocol number used to identify this study.
Phase
Clinical study phase (e.g. Phase 1, 2, 2a, 2b, 3, 3a, 3b or 4)
Methodology
Design attributes such as single blind, double blind or open
label; Randomized, placebo or active placebo control; crossover design, etc.
Study
duration
Estimated duration for the main protocol (e.g. from start of
screening to last patient processed and finishing the study)
Study centers
Single-center or multi-center. If multi-center, note number of
projected centers to be involved.
Objectives
Brief statement of primary study objectives
Number of
subjects
Number of subjects projected for the entire study (e.g. not for
simply one site, rather for entire study, all sites combined)
Diagnosis and Note the main clinical disease state under study and the key
main inclusion inclusion criteria (i.e. not the entire list that will appear later in
criteria
the protocol -rather only the key inclusion criteria)
Study
Study drug name (generic name, though can also state
product, dose, marketed name if name-brand used in the study). Also dose,
route, regimen dose route and dose regimen
Duration and
Total duration of drug product administration (including any
administration open-label lead-in, if applicable).
Reference
therapy
Note if there is a standard reference therapy against which the
study product is being compared, or if the reference is a
placebo
Statistical
Methodology
A very brief description of the main elements of the statistical
methodology to be used in the study. (As few lines as
possible).
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1.
Introduction
The introduction should open with remarks that state that this document is a clinical
research protocol and the described study will be conducted in compliance with the
protocol, Good Clinical Practices standards and associated Federal regulations, and all
applicable MHS research requirements. The rest of the introduction should include the
following subsections.
1.1 Background
This section should contain a background discussion of the target disease state to which
the investigational product(s) hold promise and any pathophysiology relevant to potential
study treatment action.
1.2 Investigational Agent
This section should contain a description of the investigational product, its make-up,
chemical properties and any relevant physical properties, including any available
pharmacologic data. (A good example for this section is the "Description" and
"Pharmacology" sections for drugs listed in the Physicians' Desk Reference)
1.3 Preclinical Data
Summarize the available non-clinical data (published or available unpublished data) that
could have clinical significance.
1.4 Clinical Data to Date
Summarize the available clinical study data (published or available unpublished data)
with relevance to the protocol under construction - if none is available, include a
statement that there is no available clinical research data to date on the investigational
product.
1.5 Dose Rationale and Risk/Benefits
Describe the rationale used for selection of the dose for the protocol under construction.
This should be based on non-clinical and clinical data available to date. It should include
justification for route of administration, dosage, dosage regimen, and dosage period.
Discuss why the risks to subjects are reasonable in relation to the anticipated benefits
and/or knowledge that might reasonably be expected from the results.
2.
Study Objectives
Describe the overall objectives and purpose of the study. This should include both
primary and any secondary objectives, e.g.:
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2.1 Primary Objective
To assess the efficacy of XXXX on decreasing infarct size as measured by Sestamibi
scanning.
2.2 Secondary Objective
To assess the safety and tolerability of two doses of XXXX in subjects with acute
myocardial infarction.
3.
Study Design
3.1 General Design Include:
•
The type/design of the study (e.g. Phase, randomized, double-blind, parallel
group, etc.)
•
A schematic diagram of the trial design, procedures and stages is advisable
•
Expected duration of subject participation
•
A description of the sequence and duration of all trial periods including followup, if any
3.2 Primary Study Endpoints
Describe the primary endpoint to be analyzed in the study (e.g. could be safety or
efficacy, depending on the main objective of the study).
3.3 Secondary Study Endpoints
Describe any secondary endpoints to be analyzed in the study
3.4 Primary Safety Endpoints
All studies should include the primary safety endpoints to be measured. If the primary
objective of the study is a safety study and therefore the Primary Endpoint(s) of the
study are safety endpoints, then it should be noted in section 3.1 above and this
subsection 3.3 can be deleted.
4.
Subject Selection and Withdrawal
4.1 Inclusion Criteria
Create a numbered list of criteria subjects must meet to be eligible for study enrollment
(e.g. age, gender, target disease, concomitant disease if required, etc.) Generally should
include items such as: "subjects are capable of giving informed consent", or if
appropriate, "have an acceptable surrogate capable of giving consent on the subject's
behalf."
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4.2 Exclusion Criteria
Create a numbered list of criteria that would exclude a subject from study enrollment. If
appropriate, this list should generally include that subjects cannot be homeless persons,
or have active drug/alcohol dependence or abuse history. If exposure to certain
medications or treatments at screening is prohibited, that must be noted in the exclusion
criteria; if there are prohibited concomitant medications during the study period, that
should be noted here as well.
4.3 Subject Recruitment and Screening
Describe how subjects will be recruited for the study, e.g. from investigator or subinvestigator clinical practices, referring physicians, advertisement, etc. Note in this
section that information to be disseminated to subjects (handouts, brochures, etc.) and
any advertisements must be approved by the IRB for the site; include a sample of such
information in the attachment section of the protocol. Also in this section, list any
screening requirements such as laboratory or diagnostic testing necessary to meet any
noted inclusion or exclusion criteria (greater detail of timing, etc. can be included later in
section 6 "Study Procedures" section of the protocol).
4.4 Early Withdrawal of Subjects
When and How to Withdraw Subjects:
Describe the scenarios under which a subject may be withdrawn from the study prior the
expected completion of that subject (e.g. safety reasons, failure of subject to adhere to
protocol requirements, subject consent withdrawal, disease progression, etc.) Also, if
abrupt termination of study treatment could affect subject safety (e.g. in an
antihypertensive study, abrupt withdrawal without other intervention might cause
hypertensive rebound), describe procedure to transition subject off the study drug or to
alternate therapy.
Data Collection and Follow-up for Withdrawn Subjects
Even though subjects may be withdrawn prematurely from the study, it is imperative to
collect at least survival data on such subjects throughout the protocol defined follow-up
period for that subject (though careful thought should be give to the full data set that
should to be collected on such subjects to fully support the analysis). Such data is
important to the integrity of the final study analysis since early withdrawal could be
related to the safety profile of the study drug. If a subject withdraws consent to
participate in the study, attempts should be made to obtain permission to record at least
survival data up to the protocol-described end of subject follow-up period. IT MUST BE A
HIGH PRIORITY TO TRY TO OBTAIN AT LEAST SURVIVAL DATA ON ALL
SUBJECTS LOST TO FOLLOW-UP AND TO NOTE WHAT METHODS SHOULD BE
USED BEFORE ONE CAN STATE THE SUBJECT IS TRULY LOST TO FOLLOW-UP
(e.g. number of phone calls to subject, phone calls to next-of-kin if possible, certified
letters, etc.).
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5.
Study Drug
5.1 Description
This section should be a very brief synopsis of section 1.2 "Investigational agent", along
with how the how the drug product will appear (e.g. as tablets or capsules of "X" mg, as
a liquid with "X" mg dissolved in 10ml 5% dextrose and water, etc.)
5.2 Treatment Regimen
Describe dose, route of administration, and treatment duration.
5.3 Method for Assigning Subjects to Treatment Groups
Describe how a randomization number and associated treatment assignment will be
made. This could be selection of a sequentially numbered drug kit/box, or
communication with a randomization center that assigns a number associated with a
specific treatment kit/box, etc.
5.4 Preparation and Administration of Study Drug
Describe in detail all the steps necessary to properly prepare study treatment. Include
whether the drug preparation will be done in a pharmacy or by a study team member.
Fully describe how the study treatment is to be administered. If study drug is stored,
mixed/prepared or dispensed from the Investigational Drug Service, that should be noted
here, including the contact number to that service office.
5.5 Subject Compliance Monitoring
Describe how the study team will assess and track subject compliance with the study
treatment regimen, and what procedures must be followed for any subject who is
significantly non-compliant with the study treatment regimen.
5.6 Prior and Concomitant Therapy
In this section, describe:
•
What prior and/or concomitant medical therapy will be collected (if applicable).
•
Which concomitant medicines/therapies (including rescue therapies) are
permitted during the study
•
Which concomitant medicines/therapies are not permitted during the study (if
applicable)
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5.7 Packaging
•
Describe how the study drug and any comparator agent will be packaged along
with the amounts (e.g. "20 ml vials containing 30 mg", or "bottles containing 30
tablets of .", etc.) along with any associated labeling
•
Describe if drug is to be shipped in bulk (e.g. Study drug will be shipped in
boxes of 30 vials each, etc.) or as separate subject-specific kits/boxes
•
When subject drug kits are constructed, describe all the contents of the kit/box
and associated labeling.
5.8 Blinding of Study Drug
Describe how the drug is blinded (refer back to Section 8.4 "Unblinding Procedures").
5.9 Receiving, Storage, Dispensing and Return
Receipt of Drug Supplies
Describe how drug will be obtained i.e. what entity will ship the drug to the investigative
site, and to what location at the site, (e.g. investigational pharmacy, etc.)
Storage
Describe storage temperature requirements, whether supplies must be protected from
light, and the location of the supplies (e.g. study pharmacy). Describe any special
handling requirements during storage
Dispensing of Study Drug
Describe how the drug will be assigned to each subject and dispensed. This section
should include regular drug reconciliation checks (i.e. how much drug was assigned and
whether subjects actually received assigned dose or received dose properly, how much
remains, how much drug was inadvertently damaged, etc. For e.g. "Regular study drug
reconciliation will be performed to document drug assigned, drug consumed, and drug
remaining. This reconciliation will be logged on the drug reconciliation form, and signed
and dated by the study team.").
Return or Destruction of Study Drug
This section should note the procedures for final reconciliation of the site's drug supply at
the end of the study, and whether study drug is to be shipped back to a source or
destroyed on site. If drug is to be shipped back to a source, note the address and
contact information here.
6.
Study Procedures
In this section, describe all the procedures and treatments required at each visit, broken
out by visit. Create a study procedures flowchart/table that describes the activities and
procedures to be followed at each visit. Include this flowchart/table in the Attachment
section and refer to that attachment in this section.
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7. Statistical Plan
7.1 Sample Size Determination
Describe the statistical methods for determining the sample size for the study.
7.2 Statistical Methods
Summarize the overall statistical approach to the analysis of the study. The section
should contain the key elements of the analysis plan, but should not be a reiteration of a
detailed study analysis plan. The full Statistical Analysis Plan can then be a "standalone" document that can undergo edits and versioning outside of the protocol and
therefore not trigger an IRB re-review with every version or edit, as long as the elements
of the study plan do not change. Be clear on primary as well as any applicable
secondary analyses
7.3 Subject Population(s) for Analysis
This section should be very specific in defining the subject populations whose data will
be subjected to the study analysis - both for the primary analysis and any applicable
secondary analyses. Examples of such populations include:
•
All-randomized population: Any subject randomized into the study, regardless of
whether they received study drug
•
All-treated population: Any subject randomized into the study that received at least
one dose of study drug
•
Protocol-compliant population: Any subject who was randomized and received the
protocol required study drug exposure and required protocol processing
8.
Safety and Adverse Events
Procedures for eliciting reports of, recording, and reporting adverse events should be
specified. Note: See the protocol template from the OHR for GCP-compliant standard
language examples for subsections 8.1 though 8.3. The subsections include:
8.1 Definitions
8.2 Recording of Adverse Events
8.3 Reporting of Serious Adverse Events
Include the following:
•
Sponsor Reporting by Investigator
•
IRB Notification by Investigator
•
FDA Notification by Sponsor
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8.4 Unblinding Procedures
While the safety of the subject always comes first, it is still important to seriously
consider if unblinding the study therapy is necessary to ensure a subject's safety. This
section should clearly describe the procedures for unblinding study therapy on a subject,
including documentation of this in the subject's source document. For investigators, state
that the investigator must inform the sponsor of all subjects whose treatment was
unblinded - and describes the timelines for such reporting. In most cases, the unblinding
will be part of managing an SAE, and will be reported with the SAE, however, in cases
where unblinding was not associated with an SAE, such actions should be reported in a
timely manner. While there is no regulation governing this timeline, it is suggested to use
the same timeline requirements for investigator reporting of SAEs, (i.e. notification of
sponsor within 24 hours by phone or fax, followed by a written narrative of the event
within 48 hours.)
8.5 Stopping Rules
In studies with a primary safety endpoint or studies with high risk to study subjects, rules
should be developed that clarify the circumstances and procedures for interrupting or
stopping the study. If a central Data and Safety Monitoring Board (DSMB) or Committee
(DSMC) is set up for the study, the stopping rules should be incorporated into their
safety analysis plan as well.
8.6 Medical Monitoring
Refer to Monitoring Plan Development (Chapter 6 of this manual) for more information
about Medical Monitoring.
9. Data Handling and Record Keeping
Specifics should be provided for the handling of data to ensure the proper handling of
data and records. Note: See the protocol template for GCP-compliant standard
language examples for subsections 9.1 though 9.4. The subsections should include:
•
Confidentiality
•
Source Documents
•
Case Report Forms
•
Records Retention
10. Study Monitoring, Auditing, and Inspecting
It is recommended that the monitoring plan be referred to as a separate attachment.
Include a statement that direct access to source data/documents will be provided for
monitoring, audits, IRB review, and regulatory inspections. Monitoring plan development
is covered in more detail in Monitoring Plan Development. Include specific provisions for
the following:
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11.
•
Auditing and Inspecting
•
Study Monitoring Plan
Ethical Considerations
Include a statement that the study will be conducted in accordance with the protocol,
GCP, and applicable regulatory requirements. Provide specific reference as to how
consent will be obtained, and that IRB approval will be obtained before the study is
initiated. Standard language for this section is provided in the protocol template.
12. Study Finances
12.1 Funding Source
This section should describe how the study will be financed, but should not contain
specific dollar amounts (e.g. "This study is financed through a grant from the US
National Institute of Health", or "a grant from the American Heart Association", etc.)
12.2 Conflict of Interest
Reference SOP 105 (Prohibition of Financial Conflict).
12.3 Subject Stipends or Payments
Describe any subject stipend or payment here.
13.
Publication Plan
This section should include the requirements any publication policies of the Memorial
Healthcare System. If, in addition to the investigator, other investigators are involved
with the study, identify who holds the primary responsibility for publication of any results
of the study. Also define the need to first obtain approval from the primary responsible
party before any information can be used or passed on to a third party.
14.
References
This is the bibliography section for any information cited in the protocol. It should be
organized as any standard bibliography.
15.
Attachments
This section should contain all pertinent documents associated with the management of
the study. The following list examples of potential attachments:
•
Investigator Agreement (for any investigator, other than sponsor-investigator, who
participates in the study)
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•
Sample Consent Form
•
Study Procedures Flowchart/Table
•
Core Lab Instructions To Investigators
•
Specimen Preparation And Handling (e.g. for any specialized procedures that study
team must follow to process a study specimen, and/or prepare it for shipment)
•
Drug Conversion Plan (e.g. if there is a special regimen for transitioning a subject
from their baseline medication over to study medication)
•
Antidote Preparation And Delivery (e.g. special instructions for preparing and
delivering any therapy designed to reverse the effects of the study drug, if applicable)
Part II: Protocol Review
16.
Review of Protocol from Sponsor
For industry-sponsored studies, the protocol is written by the sponsor and provided to
the on-site investigator. It is the responsibility of the investigator to be thoroughly familiar
with the protocol, and to conduct the study in strict accordance with the protocol.
If the investigator meets the prescribed qualifications, the sponsor will forward a
confidentiality agreement. The confidentiality agreement is a legally binding document
that prohibits the investigator from disclosing the proprietary and confidential information
found within the protocol. The confidentiality agreement must submitted to the Office of
Human Research to be routed for internal approvals. Once finalized by the Legal
department, it can be returned to the sponsor. Once the agreement is received, the
sponsor will forward a study protocol (and Investigator's Brochure, if applicable), the
contract, and budget to the investigator for review.
The investigator and his or her study team will read and review the proposed protocol.
An overall evaluation of the study will include clinical interest and feasibility. The process
of evaluating the feasibility of conducting a research trial is complex and multi-factorial.
Some considerations that determine the difficulty of a protocol are summarized below:
17.
•
Study duration – short, moderate, or prolonged
•
Paperwork – can existing records be used, or are there additional requirements
•
Follow-up – will office visits be necessary, or will telephone calls suffice
•
Procedures – are they “standard of care” or would they require specialized
expertise
IRB Protocol Summary
The IRB requires a protocol summary as part of the IRB submission. This document
includes much of the information from the Executive Summary. The IRB provides
detailed guidance on constructing the IRB protocol summary.
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18.
Study Flowchart
The Study Flowchart (also known as the Time and Events Chart or Schedule of Events)
is a table that is created to display the schedule of study procedures. It outlines the
planned chronological occurrence of events that research subjects will undergo during
their study participation. The unified, visual format of a Study Flowchart helps promote
organization and communication.
A Study Flowchart facilitates several study processes including:
•
Project feasibility assessment
•
Statistical design
•
Case Report Form and Informed Consent Form development
•
Institutional Review Board (IRB) review
•
Site orientation and in-service presentation
•
Database construction
•
Subject enrollment and follow-up
The Study Flowchart can be included as an element of the protocol or presented as an
appendix to the study protocol.
19.
Study Schematic
The Study Schematic is a diagram illustrating key concepts of the study design, such as
sampling, randomization, and/or blinding. The unified, visual format of a Study
Schematic helps promote organization and communication.
A Study Schematic facilitates several study processes including:
•
Protocol design and implementation
•
Statistical design and analysis
•
IRB review
•
Site orientation and in-service presentation
The Study Schematic can be included as an element of the protocol or presented as an
appendix to the study protocol. See example below.
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APPENDIX – PROTOCOL TEMPLATE
INSERT TITLE OF THE PROTOCOL
[Include phase (e.g. phase I, phase II, etc.), design (e.g. randomized, double
blind, placebo controlled, etc), if the study is multi-centered, the investigational
drug, and target disease(s)]
Example title:
A phase II, randomized, double-blind, placebo-controlled, multi-center study of
the effects of XXXX on infarct size in subjects with diabetes mellitus presenting
with acute myocardial infarction.
Regulatory Sponsor:
Insert the Name of the Sponsor-Investigator
Insert Department Name
Insert Address
Insert Phone Number
Funding Sponsor:
Insert the Name of Primary Funding Institution
Insert Address
Insert Phone Number
Study Product:
Insert Study Drug Name – Generic, followed by
marketed name if applicable
Protocol Number:
Insert Protocol Number Used by Sponsor
IND Number:
Insert IND Number if applicable
Date:
Amended:
Administrative
Change:
CONFIDENTIAL
This document is confidential and the property of Memorial Healthcare
System. No part of it may be transmitted, reproduced, published, or used
by other persons without prior written authorization from the study
sponsor.
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Table of Contents
STUDY SUMMARY .................................................................................................................................... 17
1
INTRODUCTION ............................................................................................................................... 18
1.1
1.2
1.3
1.4
1.5
BACKGROUND ............................................................................................................................. 18
INVESTIGATIONAL AGENT ............................................................................................................. 18
PRECLINICAL DATA ...................................................................................................................... 18
CLINICAL DATA TO DATE .............................................................................................................. 18
DOSE RATIONALE AND RISK/BENEFITS ......................................................................................... 18
2
STUDY OBJECTIVES ....................................................................................................................... 19
3
STUDY DESIGN ................................................................................................................................ 19
3.1
3.2
3.3
3.4
4
GENERAL DESIGN........................................................................................................................ 19
PRIMARY STUDY ENDPOINTS........................................................................................................ 19
SECONDARY STUDY ENDPOINTS .................................................................................................. 19
PRIMARY SAFETY ENDPOINTS ...................................................................................................... 19
SUBJECT SELECTION AND WITHDRAWAL ................................................................................. 20
4.1
INCLUSION CRITERIA .................................................................................................................... 20
4.2
EXCLUSION CRITERIA .................................................................................................................. 20
4.3
SUBJECT RECRUITMENT AND SCREENING ..................................................................................... 20
4.4
EARLY W ITHDRAWAL OF SUBJECTS .............................................................................................. 20
4.4.1 When and How to Withdraw Subjects .................................................................................. 20
4.4.2 Data Collection and Follow-up for Withdrawn Subjects ........................................................ 21
5
STUDY DRUG ................................................................................................................................... 21
5.1
DESCRIPTION .............................................................................................................................. 21
5.2
TREATMENT REGIMEN.................................................................................................................. 21
5.3
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................... 21
5.4
PREPARATION AND ADMINISTRATION OF STUDY DRUG .................................................................. 21
5.5
SUBJECT COMPLIANCE MONITORING ............................................................................................ 22
5.6
PRIOR AND CONCOMITANT THERAPY ............................................................................................ 22
5.7
PACKAGING ................................................................................................................................. 22
5.8
BLINDING OF STUDY DRUG........................................................................................................... 22
5.9
RECEIVING, STORAGE, DISPENSING AND RETURN ......................................................................... 22
5.9.1 Receipt of Drug Supplies ...................................................................................................... 22
5.9.2 Storage ................................................................................................................................. 23
5.9.3 Dispensing of Study Drug ..................................................................................................... 23
5.9.4 Return or Destruction of Study Drug..................................................................................... 23
6
STUDY PROCEDURES .................................................................................................................... 23
6.1
6.2
6.3
7
STATISTICAL PLAN ......................................................................................................................... 24
7.1
7.2
7.3
8
VISIT 1 ........................................................................................................................................ 24
VISIT 2 ........................................................................................................................................ 24
ETC. ............................................................................................................................................ 24
SAMPLE SIZE DETERMINATION ..................................................................................................... 24
STATISTICAL METHODS ................................................................................................................ 24
SUBJECT POPULATION(S) FOR ANALYSIS ...................................................................................... 24
SAFETY AND ADVERSE EVENTS .................................................................................................. 24
8.1
DEFINITIONS................................................................................................................................ 24
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RECORDING OF ADVERSE EVENTS ............................................................................................... 27
8.2
8.3
REPORTING OF SERIOUS ADVERSE EVENTS.................................................................................. 27
8.3.1 Study Sponsor Notification by Investigator ........................................................................... 27
8.3.2 IRB Notification by Investigator ............................................................................................. 28
8.3.3 FDA Notification by Sponsor ................................................................................................. 28
8.4
UNBLINDING PROCEDURES .......................................................................................................... 28
8.5
STOPPING RULES ........................................................................................................................ 29
8.6
MEDICAL MONITORING ................................................................................................................. 29
8.6.1 Internal Data and Safety Monitoring Board........................................................................... 29
8.6.2 Independent Data and Safety Monitoring Board .................................................................. 30
9
DATA HANDLING AND RECORD KEEPING .................................................................................. 31
9.1
9.2
9.3
9.4
10
CONFIDENTIALITY ........................................................................................................................ 31
SOURCE DOCUMENTS.................................................................................................................. 31
CASE REPORT FORMS ................................................................................................................. 31
RECORDS RETENTION ................................................................................................................. 32
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 32
10.1
10.2
STUDY MONITORING PLAN ........................................................................................................... 32
AUDITING AND INSPECTING........................................................................................................... 32
11
ETHICAL CONSIDERATIONS .......................................................................................................... 33
12
STUDY FINANCES ........................................................................................................................... 33
12.1
12.2
12.3
FUNDING SOURCE ....................................................................................................................... 33
CONFLICT OF INTEREST ............................................................................................................... 33
SUBJECT STIPENDS OR PAYMENTS............................................................................................... 34
13
PUBLICATION PLAN ........................................................................................................................ 34
14
REFERENCES .................................................................................................................................. 34
15
ATTACHMENTS................................................................................................................................ 34
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Study Summary
Title
Short Title
Protocol Number
Full title of protocol
Shortened title, if one is typically used by you or your
Center/Dept.
The standard protocol number used to identify this study.
Diagnosis and
Main Inclusion
Criteria
Clinical study phase (e.g. Phase 1, 2, 3 or 4)
Design attributes such as single blind, double blind or open
label; Randomized, placebo or active placebo control; crossover design, etc.
Estimated duration for the main protocol (e.g. from start of
screening to last subject processed and finishing the study)
Single-center or multi-center. If multi-center, note number of
projected centers to be involved.
Brief statement of primary study objectives
Number of subjects projected for the entire study (e.g. not
for simply one site, rather for entire study, all sites
combined)
Note the main clinical disease state under study and the key
inclusion criteria (i.e. not the entire list that will appear later
in the protocol –rather only the key inclusion criteria)
Study Product,
Dose, Route,
Regimen
Study drug name (generic name, though can also state
marketed name if name-brand used in the study). Also
dose, dose route and dose regimen
Phase
Methodology
Study Duration
Study Center(s)
Objectives
Number of
Subjects
Total duration of drug product administration (including any
open-label lead-in, if applicable).
Note if there is a standard reference therapy against which
Reference therapy the study product is being compared, or if the reference is a
placebo
A very brief description of the main elements of the
Statistical
statistical methodology to be used in the study. (As few lines
Methodology
as possible).
Duration of
administration
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Introduction
The introduction should open with remarks that state that this document is a
clinical research protocol and the described study will be conducted in
compliance with the protocol, Good Clinical Practices standards and associated
Federal regulations, and all applicable MHS research requirements. The rest of
the introduction is broken out into subsections. Example language for the first
paragraph under “Introduction” and before the section “1.1 Background”:
This document is a protocol for a human research study. This study is to be
conducted according to US and international standards of Good Clinical Practice
(FDA Title 21 part 312 and International Conference on Harmonization
guidelines), applicable government regulations and Memorial Healthcare System
research policies and procedures.
Background
This section should contain a background discussion of the target disease state
to which the investigational product(s) hold promise, and any pathophysiology
relevant to potential study treatment action.
Investigational Agent
This section should contain a description of the investigational product, its makeup, chemical properties and any relevant physical properties, including any
available pharmacologic data. (A good example for this section is the
“Description” and “Pharmacology” sections for drugs listed in the Physicians’
Desk Reference)
Preclinical Data
Summarize the available non-clinical data (published or available unpublished
data) that could have clinical significance.
Clinical Data to Date
Summarize the available clinical study data (published or available unpublished
data) with relevance to the protocol under construction -- if none is available,
include a statement that there is no available clinical research data to date on the
investigational product.
Dose Rationale and Risk/Benefits
Describe the rationale used for selection of the dose for the protocol under
construction. This should be based on non-clinical and clinical data available to
date. It should include justification for route of administration, dosage, dosage
regimen, and dosage period. Discuss why the risks to subjects are reasonable in
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relation to the anticipated benefits and/or knowledge that might reasonably be
expected from the results.
Study Objectives
Describe the overall objectives and purpose of the study. This should include
both primary and any secondary objectives, e.g.:
Primary Objective
To assess the efficacy of XXXX on decreasing infarct size as measured by
Sestamibi scanning.
Secondary Objective
To assess the safety and tolerability of two doses of XXXX in subjects with acute
myocardial infarction.
Study Design
General Design
Include:
• The type/design of the study (e.g. Phase, randomized, double-blind,
parallel group, etc.)
• A schematic diagram of the trial design, procedures and stages is
advisable
• Expected duration of subject participation
• A description of the sequence and duration of all trial periods including
follow-up, if any
Primary Study Endpoints
Describe the primary endpoint to be analyzed in the study (e.g. could be safety or
efficacy, depending on the main objective of the study).
Secondary Study Endpoints
Describe any secondary endpoints to be analyzed in the study
Primary Safety Endpoints
All studies should include the primary safety endpoints to be measured. If the
primary objective of the study is a safety study and therefore the Primary
Endpoint(s) of the study are safety endpoints, then it should be noted in section
3.1 above and this subsection 3.3 can be deleted.
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Subject Selection and Withdrawal
Inclusion Criteria
Create a numbered list of criteria subjects must meet to be eligible for study
enrollment (e.g. age, gender, target disease, concomitant disease if required,
etc.) Generally should include items such as: “subjects are capable of giving
informed consent”, or if appropriate, “have an acceptable surrogate capable of
giving consent on the subject’s behalf.”
Exclusion Criteria
Create a numbered list of criteria that would exclude a subject from study
enrollment. If appropriate, should generally include that subjects cannot be
homeless persons, or have active drug/alcohol dependence or abuse history. If
exposure to certain medications or treatments at screening is prohibited, that
must be noted in the exclusion criteria—if these are also prohibited concomitant
medications during the study period that should be noted here as well.
Subject Recruitment and Screening
Describe how subjects will be recruited for the study, e.g. from investigator or
sub-investigator clinical practices, referring physicians, advertisement, etc. Note
in this section that information to be disseminated to subjects (handouts,
brochures, etc.) and any advertisements must be approved by the IRB for the
site; include a sample of such information in the attachment section of the
protocol. Also in this section, list any screening requirements such as laboratory
or diagnostic testing necessary to meet any noted inclusion or exclusion criteria
(greater detail of timing, etc. can be included later in section 6 “Study
Procedures” section of the protocol).
Early Withdrawal of Subjects
When and How to Withdraw Subjects
Describe the scenarios under which a subject may be withdraw from the study
prior the expected completion of that subject (e.g. safety reasons, failure of
subject to adhere to protocol requirements, subject consent withdrawal, disease
progression, etc.) Also, if abrupt termination of study treatment could affect
subject safety (e.g. in an antihypertensive study, abrupt withdrawal without other
intervention might cause hypertensive rebound), describe procedure to transition
subject off the study drug or to alternate therapy.
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Data Collection and Follow-up for Withdrawn Subjects
Even though subjects may be withdrawn prematurely from the study, it is
imperative to collect at least survival data on such subjects throughout the
protocol defined follow-up period for that subject (though careful thought should
be give to the full data set that should to be collected on such subjects to fully
support the analysis). Such data is important to the integrity of the final study
analysis since early withdrawal could be related to the safety profile of the study
drug. If a subject withdraws consent to participate in the study, attempts should
be made to obtain permission to record at least survival data up to the protocoldescribed end of subject follow-up period. IT MUST BE A HIGH PRIORITY TO
TRY TO OBTAIN AT LEAST SURVIVAL DATA ON ALL SUBJECTS LOST TO
FOLLOW-UP AND TO NOTE WHAT METHODS SHOULD BE USED BEFORE
ONE CAN STATE THE SUBJECT IS TRULY LOST TO FOLLOW-UP (e.g.
number of phone calls to subject, phone calls to next-of-kin if possible, certified
letters, etc.).
Study Drug
Description
This section should be a very brief synopsis of section 1.2 “Investigational agent”,
along with how the how the drug product will appear (e.g. as tablets or capsules
of “X”mg, as a liquid with “X”mg dissolved in 10ml 5% dextrose and water, etc.)
Treatment Regimen
Describe dose, route of administration, and treatment duration.
Method for Assigning Subjects to Treatment
Groups
Describe how a randomization number and associated treatment assignment will
be made. This could be selection of a sequentially numbered drug kit/box, or
communication with a randomization center that assigns a number associated
with a specific treatment kit/box, etc.
Preparation and Administration of Study Drug
Describe in detail all the steps necessary to properly prepare study treatment.
Include whether the drug preparation will be done in a pharmacy or by a study
team member. Fully describe how the study treatment is to be administered. If
study drug is stored, mixed/prepared or dispensed from the Investigational
Pharmacy Service, that should be noted here, including the contact number to
that office.
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Subject Compliance Monitoring
Describe how the study team will assess and track subject compliance with the
study treatment regimen, and what procedures must be followed for any subject
who is significantly non-compliant with the study treatment regimen.
Prior and Concomitant Therapy
In this section, describe:
• What prior and/or concomitant medical therapy will be collected (if
applicable).
• Which concomitant medicines/therapies (including rescue therapies) are
permitted during the study
• Which concomitant medicines/therapies are not permitted during the study
(if applicable)
Packaging
•
•
•
Describe how the study drug and any comparator agent will be packaged
along with the amounts (e.g. “20 ml vials containing 30 mg”, or “bottles
containing 30 tablets of …”, etc.) along with any associated labeling
Describe if drug is to be shipped in bulk (e.g. Study drug will be shipped in
boxes of 30 vials each, etc.) or as separate subject-specific kits/boxes
When subject drug kits are constructed describe all the contents of the
kit/box and associated labeling
Blinding of Study Drug
Describe how the drug is blinded (refer back to Section 8.4 “Unblinding
Procedures”).
Receiving, Storage, Dispensing and Return
Receipt of Drug Supplies
Describe how drug will be obtained i.e. what entity will ship the drug to the
investigative site, and to what location at the site, (e.g. investigational
pharmacy, etc.)
Upon receipt of the of the study treatment supplies, an inventory must be
performed and a drug receipt log filled out and signed by the person
accepting the shipment. It is important that the designated study staff
counts and verifies that the shipment contains all the items noted in the
shipment inventory. Any damaged or unusable study drug in a given
shipment (active drug or comparator) will be documented in the study files.
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The investigator must notify study sponsor of any damaged or unusable
study treatments that were supplied to the investigator’s site.
Storage
Describe storage temperature requirements, whether supplies must be
protected from light, and the location of the supplies (e.g. study pharmacy).
Describe any special handling requirements during storage
Dispensing of Study Drug
Describe how the drug will be assigned to each subject and dispensed.
This section should include regular drug reconciliation checks (i.e. how
much drug was assigned and whether subjects actually received assigned
dose or received dose properly, how much remains, how much drug was
inadvertently damaged, etc. --- eg. “Regular study drug reconciliation will be
performed to document drug assigned, drug consumed, and drug
remaining. This reconciliation will be logged on the drug reconciliation form,
and signed and dated by the study team.”)
Return or Destruction of Study Drug
This section should note the procedures for final reconciliation of the site’s
drug supply at the end of the study, and whether study drug is to be shipped
back to a source or destroyed on site. If drug is to be shipped back to a
source, note the address and contact information here.
At the completion of the study, there will be a final reconciliation of drug
shipped, drug consumed, and drug remaining. This reconciliation will be
logged on the drug reconciliation form, signed and dated.
Any
discrepancies noted will be investigated, resolved, and documented prior to
return or destruction of unused study drug. Drug destroyed on site will be
documented in the study files.
Study Procedures
In this section, describe all the procedures and treatments required at each visit,
broken out by visit. Create a study procedures flowchart/table that describes the
activities and procedures to be followed at each visit. Include this flowchart/table
in the Attachment section and refer to that attachment in this section.
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Visit 1
Visit 2
etc.
Statistical Plan
Sample Size Determination
Describe the statistical methods for determining the sample size for the study
Statistical Methods
Summarize the overall statistical approach to the analysis of the study. The
section should contain the key elements of the analysis plan, but should not be a
reiteration of a detailed study analysis plan. The full Statistical Analysis Plan can
then be a “stand-alone” document that can undergo edits and versioning outside
of the protocol and therefore not trigger an IRB re-review with every version or
edit –AS LONG AS THE KEY ELEMENTS OF THE ANALYSIS PLAN DO NOT
CHANGE.
Be clear on primary as well as any applicable secondary analyses
Subject Population(s) for Analysis
This section should be very specific in defining the subject populations whose
data will be subjected to the study analysis – both for the primary analysis and
any applicable secondary analyses. Examples of such populations include:
• All-randomized population: Any subject randomized into the study,
regardless of whether they received study drug
• All-treated population: Any subject randomized into the study that
received at least one dose of study drug
• Protocol-compliant population: Any subject who was randomized and
received the protocol required study drug exposure and required protocol
processing
Safety and Adverse Events
Definitions
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Adverse Event
An adverse event (AE) is any symptom, sign, illness or experience that
develops or worsens in severity during the course of the study. Intercurrent
illnesses or injuries should be regarded as adverse events. Abnormal
results of diagnostic procedures are considered to be adverse events if the
abnormality:
• results in study withdrawal
• is associated with a serious adverse event
• is associated with clinical signs or symptoms
• leads to additional treatment or to further diagnostic tests
• is considered by the investigator to be of clinical significance
Serious Adverse Event
Adverse events are classified as serious or non-serious.
adverse event is any AE that is:
• fatal
• life-threatening
• requires or prolongs hospital stay
• results in persistent or significant disability or incapacity
• a congenital anomaly or birth defect
• an important medical event
A serious
Important medical events are those that may not be immediately life
threatening, but are clearly of major clinical significance.
They may
jeopardize the subject, and may require intervention to prevent one of the
other serious outcomes noted above. For example, drug overdose or
abuse, a seizure that did not result in in-patient hospitalization, or intensive
treatment of bronchospasm in an emergency department would typically be
considered serious.
All adverse events that do not meet any of the criteria for serious should be
regarded as non-serious adverse events.
Adverse Event Reporting Period
The study period during which adverse events must be reported is normally
defined as the period from the initiation of any study procedures to the end
of the study treatment follow-up. For this study, the study treatment followup is defined as 30 days following the last administration of study treatment.
Preexisting Condition
A preexisting condition is one that is present at the start of the study. A
preexisting condition should be recorded as an adverse event if the
frequency, intensity, or the character of the condition worsens during the
study period.
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General Physical Examination Findings
At screening, any clinically significant abnormality should be recorded as a
preexisting condition. At the end of the study, any new clinically significant
findings/abnormalities that meet the definition of an adverse event must also
be recorded and documented as an adverse event.
Post-study Adverse Event
All unresolved adverse events should be followed by the investigator until
the events are resolved, the subject is lost to follow-up, or the adverse event
is otherwise explained. At the last scheduled visit, the investigator should
instruct each subject to report any subsequent event(s) that the subject, or
the subject’s personal physician, believes might reasonably be related to
participation in this study. The investigator should notify the study sponsor
of any death or adverse event occurring at any time after a subject has
discontinued or terminated study participation that may reasonably be
related to this study. The sponsor should also be notified if the investigator
should become aware of the development of cancer or of a congenital
anomaly in a subsequently conceived offspring of a subject that has
participated in this study.
Abnormal Laboratory Values
A clinical laboratory abnormality should be documented as an adverse
event if any one of the following conditions is met:
• The laboratory abnormality is not otherwise refuted by a repeat test
to confirm the abnormality
• The abnormality suggests a disease and/or organ toxicity
• The abnormality is of a degree that requires active management; e.g.
change of dose, discontinuation of the drug, more frequent follow-up
assessments, further diagnostic investigation, etc.
Hospitalization, Prolonged Hospitalization or Surgery
Any adverse event that results in hospitalization or prolonged hospitalization
should be documented and reported as a serious adverse event unless
specifically instructed otherwise in this protocol. Any condition responsible
for surgery should be documented as an adverse event if the condition
meets the criteria for and adverse event.
Neither the condition, hospitalization, prolonged hospitalization, nor surgery
are reported as an adverse event in the following circumstances:
• Hospitalization or prolonged hospitalization for diagnostic or elective
surgical procedures for a preexisting condition. Surgery should not
be reported as an outcome of an adverse event if the purpose of the
surgery was elective or diagnostic and the outcome was uneventful.
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•
•
Hospitalization or prolonged hospitalization required to allow efficacy
measurement for the study.
Hospitalization or prolonged hospitalization for therapy of the target
disease of the study, unless it is a worsening or increase in
frequency of hospital admissions as judged by the clinical
investigator.
Recording of Adverse Events
At each contact with the subject, the investigator must seek information on
adverse events by specific questioning and, as appropriate, by examination.
Information on all adverse events should be recorded immediately in the source
document, and also in the appropriate adverse event module of the case report
form (CRF). All clearly related signs, symptoms, and abnormal diagnostic
procedures results should recorded in the source document, though should be
grouped under one diagnosis.
All adverse events occurring during the study period must be recorded. The
clinical course of each event should be followed until resolution, stabilization, or
until it has been determined that the study treatment or participation is not the
cause. Serious adverse events that are still ongoing at the end of the study
period must be followed up to determine the final outcome. Any serious adverse
event that occurs after the study period and is considered to be possibly related
to the study treatment or study participation should be recorded and reported
immediately.
Reporting of Serious Adverse Events
Study Sponsor Notification by Investigator
A serious adverse event must be reported to the study sponsor by
telephone within 24 hours of the event. A Serious Adverse Event (SAE)
form must be completed by the investigator and faxed to the study
sponsor within 24 hours. The investigator will keep a copy of this SAE
form on file at the study site. Report serious adverse events by phone and
facsimile to:
[Name of Sponsor contact
phone
fax]
At the time of the initial report, the following information should be
provided:
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•
•
•
•
•
•
Study identifier
Study Center
Subject number
A description of the event
Date of onset
Current status
•
•
•
Whether study treatment was
discontinued
The reason why the event is
classified as serious
Investigator assessment of
the association between the
event and study treatment
Within the following 48 hours, the investigator must provide further
information on the serious adverse event in the form of a written narrative.
This should include a copy of the completed Serious Adverse Event form,
and any other diagnostic information that will assist the understanding of
the event. Significant new information on ongoing serious adverse events
should be provided promptly to the study sponsor
IRB Notification by Investigator
Reports of all serious adverse events (including follow-up information)
must be submitted to the IRB within 10 working days. Copies of each
report and documentation of IRB notification and receipt will be kept in the
Clinical Investigator’s binder.
FDA Notification by Sponsor
The study sponsor shall notify the FDA by telephone or by facsimile
transmission of any unexpected fatal or life-threatening experience
associated with the use of the drug as soon as possible but no later than 7
calendar days from the sponsor’s original receipt of the information.
If a previous adverse event that was not initially deemed reportable is later
found to fit the criteria for reporting, the study sponsor will submit the
adverse event in a written report to the FDA as soon as possible, but no
later than 15 calendar days from the time the determination is made.
Unblinding Procedures
While the safety of the subject always comes first, it is still important to seriously
consider if unblinding the study therapy is necessary to ensure a subject’s safety.
This section should clearly describe the procedures for unblinding study therapy
on a subject, including documentation of this in the subject’s source document.
For investigators, other than the sponsor-investigator, state that the investigator
must inform the sponsor of all subjects whose treatment was unblinded – and
describe the timelines for such reporting. In most cases, the unblinding will be
part of managing an SAE, and will be reported with the SAE, however, in cases
where unblinding was not associated with an SAE, such actions should be
reported in a timely manner. While there is no regulation governing this timeline,
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it is suggested to use the same timeline requirements for investigator reporting of
SAEs, (i.e. notification of sponsor within 24 hours by phone or fax, followed by a
written narrative of the event within 48 hours.)
Stopping Rules
In studies with a primary safety endpoint or studies with high risk to study
subjects, rules should be developed that clarify the circumstances and
procedures for interrupting or stopping the study. If a central Data and Safety
Monitoring Board (DSMB) or Committee (DSMC) is set up for the study, the
stopping rules should be incorporated into their safety analysis plan as well.
Medical Monitoring
It is the responsibility of the Principal Investigator to oversee the safety of the
study at his/her site. This safety monitoring will include careful assessment and
appropriate reporting of adverse events as noted above, as well as the
construction and implementation of a site data and safety-monitoring plan (see
section 9 Auditing, Monitoring and Inspecting). Medical monitoring will include a
regular assessment of the number and type of serious adverse events.
Internal Data and Safety Monitoring Board
The description and requirements of this Board are an MHS local
convention (i.e. is not a description from federal regulations or ICH
guidelines). An Internal Data and Safety Monitoring Board (DSMB) is a
group of professionals, experienced in clinical care and/or clinical
research, assembled to provide additional safety and oversight to a clinical
study. This type of oversight committee can include the sponsor and
selected investigators, though must include other members who are
independent of the study (can include members from within or external to
the sponsor or investigator’s institution). The DSMB will look only at
blinded data. This section should describe the above noted DSMB
attributes. Also include:
• Number of members and roles (e.g. clinicians, biostatisticians,
bioethicists, etc.). It is not necessary to list the names or contact
information of DSMB members in the protocol. However, the names
and contact information of DSMB members should be reported to the
EC/IRB and also maintained in the sponsor study file.
• How often the DSMB will meet (and if by phone, face-to-face, or webassisted conferencing)
• Type of safety information that will be assessed
• How the safety data will be supplied to the DSMB
• Summary of number and type of safety assessments the DSMB will
conduct
• How the DSMB will record the summary of its various meetings
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•
•
How the DSMB will report it’s findings and/or recommendations, and
to whom
Reference the DSMB charter in the Attachments section of the
protocol
If there is no internal DSMB, delete this section.
Independent Data and Safety Monitoring Board
The description and requirements of this Board are an MHS local
convention (i.e. is not a description from federal regulations or ICH
guidelines). A Data and Safety Monitoring Board (DSMB) is a group of
professionals, experienced in clinical care and/or clinical research,
assembled to provide additional safety oversight to a clinical study (and at
least one biostatistician). This type of oversight differs from a Internal
DSMB in that the Independent DSMB is independent of the investigator
and sponsor, and is therefore generally also independent of the sponsor’s
and investigator’s institution. Another important difference is that the
DSMB can, and most typically does, conduct unblinded analyses. The
DSMB should have a charter describing its function as well as an analysis
plan for a pre-planned safety analysis(es). This section should describe
the above noted DSMB attributes. Also include:
• Number of members and roles (e.g. clinicians, biostatisticians,
bioethicists, etc.) Since DSMBs typically review unblinded analyses,
in that case, they must be independent of the study. Therefore
names and/ or contact information of DSMB members should not be
noted in the protocol. However, the names and contact information
of DSMB members should be reported to the IRB and also
maintained in the sponsor study file.
• How often the DSMB will meet (and if by phone, face-to-face, or webassisted conferencing)
• Type of safety information that will be analyzed
• How the safety data will be supplied to the DSMB
• Summary of number and type of interim analyses the DSMB will
conduct, and who will conduct the actual analyses (including
plans/safeguards to keep any unblinded data or DSMB analyses
confidential
• How the DSMB will record the summary of its various meetings
• How the DSMB will report it’s findings and/or recommendations, and
to whom
• Reference the DSMB charter in the Attachments section of the
protocol
If there is no Independent DSMB, delete this section.
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Data Handling and Record Keeping
Confidentiality
Information about study subjects will be kept confidential and managed according
to the requirements of the Health Insurance Portability and Accountability Act of
1996 (HIPAA). Those regulations require a signed subject authorization
informing the subject of the following:
• What protected health information (PHI) will be collected from subjects in
this study
• Who will have access to that information and why
• Who will use or disclose that information
• The rights of a research subject to revoke their authorization for use of
their PHI.
In the event that a subject revokes authorization to collect or use PHI, the
investigator, by regulation, retains the ability to use all information collected prior
to the revocation of subject authorization. For subjects that have revoked
authorization to collect or use PHI, attempts should be made to obtain permission
to collect at least vital status (i.e. that the subject is alive) at the end of their
scheduled study period.
Source Documents
Source data is all information, original records of clinical findings, observations,
or other activities in a clinical trial necessary for the reconstruction and evaluation
of the trial. Source data are contained in source documents Examples of these
original documents, and data records include: hospital records, clinical and office
charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists,
pharmacy dispensing records, recorded data from automated instruments, copies
or transcriptions certified after verification as being accurate and complete,
microfiches, photographic negatives, microfilm or magnetic media, x-rays,
subject files, and records kept at the pharmacy, at the laboratories, and at
medico-technical departments involved in the clinical trial.
Case Report Forms
The study case report form (CRF) is the primary data collection instrument for the
study. All data requested on the CRF must be recorded. All missing data must
be explained. If a space on the CRF is left blank because the procedure was not
done or the question was not asked, write “N/D”. If the item is not applicable to
the individual case, write “N/A”. All entries should be printed legibly in black ink.
If any entry error has been made, to correct such an error, draw a single straight
line through the incorrect entry and enter the correct data above it. All such
changes must be initialed and dated. DO NOT ERASE OR WHITE OUT
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ERRORS. For clarification of illegible or uncertain entries, print the clarification
above the item, then initial and date it.
Records Retention
For non-FDA regulated studies, summarize the record retention plan applicable
to the study (taking into account any applicable Department, Division or
Research Center requirements)
For FDA-regulated studies the following sample language is appropriate:
It is the investigator’s responsibility to retain study essential documents for at
least 2 years after the last approval of a marketing application in their country
and until there are no pending or contemplated marketing applications in their
country or at least 2 years have elapsed since the formal discontinuation of
clinical development of the investigational product. These documents should be
retained for a longer period if required by an agreement with the sponsor. In
such an instance, it is the responsibility of the sponsor to inform the
investigator/institution as to when these documents no longer need to be
retained.
Study Monitoring, Auditing, and
Inspecting
Study Monitoring Plan
This study will be monitored according to the monitoring plan in Attachment ___.
The investigator will allocate adequate time for such monitoring activities. The
Investigator will also ensure that the monitor or other compliance or quality
assurance reviewer is given access to all the above noted study-related
documents and study related facilities (e.g. pharmacy, diagnostic laboratory,
etc.), and has adequate space to conduct the monitoring visit.
Auditing and Inspecting
The investigator will permit study-related monitoring, audits, and inspections by
the IRB, the sponsor, government regulatory bodies, and Memorial Healthcare
System compliance and quality assurance groups of all study related documents
(e.g. source documents, regulatory documents, data collection instruments, study
data etc.). The investigator will ensure the capability for inspections of applicable
study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.).
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Participation as an investigator in this study implies acceptance of potential
inspection by government regulatory authorities and applicable MHS compliance
and quality assurance offices.
Ethical Considerations
This study is to be conducted according to US and international standards of
Good Clinical Practice (FDA Title 21 part 312 and International Conference on
Harmonization guidelines), applicable government regulations and Institutional
research policies and procedures.
This protocol and any amendments will be submitted to a properly constituted
Institutional Review Board (IRB), in agreement with local legal prescriptions, for
formal approval of the study conduct. The decision of the IRB concerning the
conduct of the study will be made in writing to the investigator and a copy of this
decision will be provided to the sponsor before commencement of this study.
The investigator should provide a list of IRB members and their affiliate to the
sponsor.
All subjects for this study will be provided a consent form describing this study
and providing sufficient information for subjects to make an informed decision
about their participation in this study. See Attachment ___ for a copy of the
Subject Informed Consent Form. This consent form will be submitted with the
protocol for review and approval by the IRB for the study. The formal consent of
a subject, using the IRB-approved consent form, must be obtained before that
subject is submitted to any study procedure. This consent form must be signed
by the subject or legally acceptable surrogate, and the investigator-designated
research professional obtaining the consent.
Study Finances
Funding Source
This section should describe how the study will be financed, but should not
contain specific dollar amounts (e.g. “This study is financed through a grant from
the US National Institute of Health”, or “… a grant from the American Heart
Association”, etc.)
Conflict of Interest
Any investigator who has a conflict of interest with this study (patent ownership,
royalties, or financial gain greater than the minimum allowable by their institution,
etc.) must have the conflict reviewed by a properly constituted Conflict of Interest
Committee with a Committee-sanctioned conflict management plan that has
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been reviewed and approved by the study sponsor prior to participation in this
study. All Memorial Healthcare System (MHS) investigators will follow the MHS
conflict of interest policy.
Subject Stipends or Payments
Describe any subject stipend or payment here. If there is no subject
stipend/payment, delete this section.
Publication Plan
This section should include the requirements any publication policies of MHS. If,
in addition to the sponsor-investigator, other investigators are involved with the
study, identify who holds the primary responsibility for publication of the any
results of the study. Also define the need to first obtain approval from the
primary responsible party before any information can be used or passed on to a
third party.
Delete or modify the following sample language:
Neither the complete nor any part of the results of the study carried out under this
protocol, nor any of the information provided by the sponsor for the purposes of
performing the study, will be published or passed on to any third party without the
consent of the study sponsor. Any investigator involved with this study is
obligated to provide the sponsor with complete test results and all data derived
from the study.
References
This is the bibliography section for any information cited in the protocol. It should
be organized as any standard bibliography.
1. Author, Title of work, periodical and associated information.
2. Author, Title of work, periodical and associated information.
Attachments
This section should contain all pertinent documents associated with the
management of the study. The following list examples of potential attachments:
• Investigator Agreement (for any investigator, other than sponsorinvestigator, who participates in the study)
• Sample Consent Form
• Study Procedures Flowchart/Table
• Core Lab Instructions To Investigators
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•
•
•
Specimen Preparation And Handling (e.g. for any specialized procedures
that study team must follow to process a study specimen, and/or prepare it
for shipment)
Drug Conversion Plan (e.g. if there is a special regimen for transitioning a
subject from their baseline medication over to study medication)
Antidote Preparation And Delivery (e.g. special instructions for preparing
and delivering any therapy designed to reverse the effects of the study
drug, if applicable)
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Chapter 5: Research Involving Drugs and Devices
Part I: Investigational Drug Studies
One of the Food and Drug Administration's (FDA) primary mechanisms for ensuring the
safety of research subjects is through an Investigational New Drug Application (IND).
An IND Application is a request for authorization from the FDA to administer an
investigational drug or biological product to humans. The IND provides assurance that
the investigational product has sufficient preclinical safety data before it is used.
The IND holder is the person or company who has filed the IND with the FDA. The IND
Holder, often referred to as the Regulatory Sponsor, holds an additional set of
responsibilities. Essentially, the IND holder is responsible for keeping the FDA informed
of safety data from the study. This is critical for monitoring the safety of a drug. The FDA
may be receiving multiple safety reports of a drug from several IND studies being
conducted across the country and this allows them to identify safety trends more quickly.
1.
Clarifying the "New" in IND
The term IND can be misinterpreted, leading researchers to conclude that if the drug
they are studying is already approved by the FDA, it is not a "new" drug and, therefore,
does not need an IND Application. THIS IS INCORRECT!
There are many other considerations for whether a drug being investigated is "new". The
FDA approves a drug as safe with any or all of the following specifications. Altering
these specifications could result in the FDA determining the drug to be "new".
•
"New" route of administration
•
"New" dose or duration of exposure
•
"New" form of the drug (e.g. capsule vs. tablet)
•
"New" treatment indications (e.g. target disease, age, gender)
•
"New" use with concomitant meds
The FDA-approved labeling includes chemical structure, preclinical and human safety
information, as well as dosing information.
A study that uses a "new" aspect of the drug's use (i.e. different indication, dose,
population, etc.) usually requires the filing of an IND. Therefore, an IND can be required
for studies of a drug that is already approved for marketing.
In most situations where the study is sponsored by a pharmaceutical company, the
sponsor holds the IND with the FDA for the investigational product. In this case, the PI
holds responsibility for communicating with the sponsor in a timely manner so the
sponsor can communicate in turn with the FDA.
When there is not an IND in place for a drug study sponsored by a pharmaceutical
company, the researcher should consult with the Office of Human Research.
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Any investigator-initiated research study involving a drug or device should consult with
the Office of Human Research (OHR) to determine whether or not an IND application
needs to be filed. If it is possible that an IND exemption is appropriate for a study, the
researcher should complete the IND Determination Assessment Form and submit it to
the Office of Human Research for final determination.
For investigator-initiated clinical research involving drugs, the IRB requires either an IND
or Documentation of Exemption through a written communication from the FDA.
For more information regarding the IND process, please refer to the FDA website:
Investigational New Drug Application
2.
IND Facts
Did you know?
•
A single IND can have multiple projects/studies running under it.
•
For investigator-initiated research in which an IND is required, the investigator
may be able to reference an existing IND to support the preclinical requirements
of their application.
•
The FDA grants INDs, but does not "approve" specific studies. Therefore, an IND
study should never be referred to as "FDA-approved."
•
"Acknowledgement" (rather than approval) of IND research comes in the form of
non-objection to a study.
•
Unless otherwise noted, a study may proceed 30 days after the receipt date on
the FDA's IND acknowledgement letter. The letter acknowledges receipt of an
IND application.
3.
IND Submission
The IND application is prepared using FDA Forms 1571 and 1572. The required
information includes:
•
Sufficient preclinical data, including toxicity data
•
Details of the chemistry, manufacturing and controls to provide adequate quality
control information for the production of the agent and to describe the
mechanism of action of the agent
•
Background and rationale for intended clinical use
•
Proposed protocol for Phase I human use
The instructions and FDA Forms 1571 and 1572 can be found online at FDA Forms.
The Office of Human Research can assist in providing essential elements, guidance and
formatted documents in which to prepare an IND submission to the FDA.
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4.
IND Holder Responsibilities
The IND holder is responsible for:
•
Selecting qualified investigators
•
Ongoing monitoring of all studies under the IND
•
The validity of the data from all sites conducting research under the IND
•
Maintaining adequate records of receipt, shipment, and disposition of the
investigational drug
•
For multi-site studies, ensuring that all sites are kept informed of adverse events
and safety updates
•
Communication with the FDA of any protocol changes, drug changes, and safety
data.
The Office of Human Research provides a detailed outline of IND Holder Responsibilities
in the form of a checklist.
Part II: Investigational Device Studies
An Investigational Device Exemption (IDE) is the medical device equivalent of an IND
Application for drug studies. The IDE application is a request to the FDA for
authorization to use an unapproved medical device in humans. An Investigational Device
Exemption is required when the study poses a Significant Risk to participants. This
categorization is determined by the IRB, although the FDA makes the ultimate decision
in determining whether a device study poses a Significant or Non-Significant Risk.
The risk determination should be based on the proposed use of a device in a study, NOT
on the device alone.
5.
Significant Risk (SR) Device Study
An SR Device presents a potential risk to the health, safety, or welfare of a subject AND
is
•
An implant, or
•
Used in supporting or sustaining human life, or
•
Of substantial importance in diagnosing, curing, mitigating, or treating disease, or
otherwise prevents impairment of human health, or
•
Otherwise presents a potential serious risk to the health, safety, or welfare of a
subject.
•
An IDE Submission to the FDA AND IRB approval is required prior to initiation of
an SR device study.
An IDE Submission to the FDA AND IRB approval is required prior to initiation of an SR
device study.
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6.
Non-Significant Risk (NSR) Device Study
For device studies that do not meet the criteria of Significant Risk, the IRB can approve
the study without an IDE. The study may begin immediately after IRB approval
Please refer to SOP 201 Attachment H to determine if an IDE would be required.
Additional IDE Resource from FDA:
•
7.
Instructions for IDE Application: IDE Application
Investigator's Brochure
The Investigator's Brochure is a compilation of all preclinical, clinical and non-clinical
data on the investigational product that are relevant to human subjects. Its function is to
assist investigators in understanding the rationale behind the protocol, particularly dose,
dose frequency/interval, methods of administration, overdosing information, and safety
reporting/monitoring.
The type and extent of information available will vary with the stage of development of
the investigational product.
While there is no federal regulatory requirement that the Investigator's Brochure be
submitted to the Institutional Review Board (IRB), there are regulatory requirements for
submission of specific product information that can normally be found in the
Investigator's Brochure. If, for instance, a study involves an approved drug that does not
require an IND , the FDA-approved labeling found in the Physician's Desk Reference
(PDR) or package insert can be used to provide the required regulatory information to
the IRB.
8.
Special Provisions for Drug/Device Research
In certain research and clinical practice scenarios, investigational products may be used
to try to treat serious or life-threatening conditions either for a single subject or for a
group of subjects. Individuals may accept greater risks from investigational products that
offer the possibility of treating life-threatening, rare, or debilitating illnesses when they
have no viable alternatives. Under these circumstances, federal regulations provide
mechanisms to expand access to promising investigational products without
compromising subject protection measures.
These mechanisms include:
•
Humanitarian Device Exemption (HDE)
•
Treatment IND
o
Group C Treatment IND
•
Compassionate Use / Single Patient Use
•
Emergency Use
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Comparison of Special Research Provisions
Humanitarian
Treatment
Device Exemption
IND
(HDE)
IND/IDE Number
Emergency
Use
Yes from sponsor, manufacturer, or FDA;
Prospective IRB
approval required
Retrospective IRB
notification
Compassionate
Use
Yes
N/A
No
Yes
Informed Consent
Yes**
** exception found under emergency use
# of Patients
multiple
single subject
(in rare instances may be
multiple subjects)
8.1 Humanitarian Device Exemption (HDE)
A Humanitarian Device Exemption (HDE) is a mechanism used by the FDA to provide
access to devices that are developed to treat rare diseases and conditions. These
devices are listed on the FDA website (Designating Humanitarian Use Devices) and are
termed Humanitarian Use Device (HUD). By definition a HUD is intended to treat or
diagnose a disease or condition that affects less than 4,000 individuals in the United
States per year.
HUDs are exempt from the effectiveness requirements normally required by the FDA for
approval. Investigations involving HUDs usually occur through standard research
protocols, which must be IRB approved. If an investigator wishes to use a HUD for
treating a single individual, the investigator must follow the procedures outlined below for
compassionate use or emergency use.
8.2 Treatment INDs
A Treatment IND is a mechanism for providing eligible subjects with investigational
drugs for the treatment of serious and life-threatening illnesses for which there are no
satisfactory alternative treatments.
A Treatment IND may be granted by the FDA after sufficient data have been collected to
show that the drug "may be effective" and does not have unreasonable risks. A sponsor
applies a Treatment IND to an existing IND. Treatment protocols are planned and cover
an unspecified number of patients.
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There are four requirements:
i.
The drug is intended to treat a serious or immediately life-threatening disease
ii. There is no satisfactory alternative
iii. The drug is already under investigation
iv. The sponsor is actively pursuing marketing approval
Treatment IND protocols require full IRB review. The process for obtaining IRB approval
is the same as that for standard research protocols.
Please refer to the FDA website for more information: Treatment INDs
8.3 “Group C” Treatment IND
The "Group C" treatment IND was established through an agreement between the FDA
and the National Cancer Institute (NCI). The Group C program is a means for the
National Institute of Health to distribute investigational agents to oncologists for the
treatment of cancer under NCI protocols outside a controlled clinical trial. Most Group C
drugs have undergone Phase III testing and have some preliminary evidence of efficacy
in a specific tumor type.
8.4 Compassionate Use / Single Patient Use
In specific situations, a physician may be granted special permission to use an
investigational product for treatment purposes. Compassionate use involves a single
patient who is unresponsive to standard therapy or for whom no standard therapy is
available and there is reasonable scientific evidence to support the use of the
investigational product. (If the situation is a life-threatening emergency, emergency use
guidelines apply.)
Compassionate Use is not defined by the FDA; it falls under Treatment IND or
Humanitarian Device Exemption (HDE) regulations. However, an investigator must
follow additional Penn procedures in order to obtain approval to use an investigational
product for a single patient use (see procedures that follow).
8.5 Emergency Use
Emergency Use is defined as the use of an investigational product in a human subject
with a life-threatening condition in which no standard acceptable treatment is available
and in which there is insufficient time to obtain IRB approval.
All of the following conditions must be met to justify emergency use:
i.
There is a high likelihood of death unless the course of the disease is interrupted
ii. No alternative method or recognized therapy is available that provides an equal
or greater likelihood of saving the subject's life
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iii. The subject is in a life-threatening situation requiring intervention before review at
a convened meeting.
Data from emergency-use situations may not be utilized for investigational purposes.
FDA regulations require that any subsequent use of the investigational product have
prospective IRB approval.
Please refer to the FDA website for more information: Single Use IND for
Compassionate or Emergency Use
To obtain approval for Compassionate or Emergency Use
•
Contact the manufacturer of the investigational product and request permission
to use the drug/device under the manufacturer's IND, IDE, or HDE.
•
If the sponsor requests acknowledgement that the IRB is aware and recognizes
such emergency use, an acknowledgement letter can be obtained from the IRB
•
If an IND/IDE/HDE does not exist OR if sponsor is unwilling to sponsor a
physician under an existing IND, the FDA may issue an IND/IDE/HDE directly to
the physician. Contact the OHR for assistance in reaching the appropriate FDA
department.
A licensed physician must take responsibility for the study. This includes a commitment
to the manufacturer to complete data collection forms, if applicable. For a project
involving an investigational drug, the investigator must submit an FDA-1572 and
Curriculum Vitae.
•
A consent form must be prepared. Most manufacturers should be able to provide
a template; however, the consent must conform to MHS IRB standards.
•
Submit the protocol/treatment plan to the IRB for approval. Or, in an emergency
situation in which insufficient time is available, notify the IRB of the planned use
and obtain an independent assessment by a physician uninvolved with the
patient's care confirming the emergency status.
•
Investigational devices may be sent to the investigator's office or clinic.
•
Investigational drugs should be shipped to the appropriate Investigational Drug
Services Pharmacist
•
Obtain written informed consent from the subject prior to administering the
investigational product.
Exception: subjects who are in need of emergency medical intervention but
cannot give informed consent because of their life-threatening medical condition
and who do not have a proxy to represent them. In such circumstances, the
investigator and a second physician who is not otherwise participating in the
investigation or care of the patient must document:
o
the criteria that the patient met for emergency use of investigative product
o
AND the lack of alternatives
o
AND the inability to obtain consent from the subject
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o
AND the methods used to reach a legal representative and/or relatives
o
AND the lack sufficient time to obtain the aforementioned consent
•
Place a copy of the protocol/treatment plan in the location where the subject is
being treated.
•
A written report must be sent to the IRB within 5 working days of the start of
treatment. This letter must include 1-2 paragraphs about the situation that
required treatment, the protocol, and a copy of the signed consent form.
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Chapter 6: Monitoring Plan Development
The monitoring of a clinical trial is an essential element of study processes designed to
ensure the protection of the subject's rights, the safety of subjects enrolled in the trial
and the integrity and quality of the resulting data. It is important to note that monitoring
encompasses both data and safety oversight. Both activities complement one another to
ensure that the study is safe and ethical. The degree of oversight will vary based upon
the risk level, the size and complexity of the study, the nature of the investigation, the
regulatory requirements, and the study sponsor.
A monitoring plan specifies a course of action to oversee the integrity of the study data.
This plan typically details who will be responsible for monitoring (roles), what will be
monitored (scope), and when monitoring will occur (timing).
1.
Roles
The Principal Investigator is always responsible for ensuring that the protocol is followed,
the data is accurate, and the research subjects at his or her site are safe. The Principal
Investigator may designate some responsibilities to other study team members, but
ultimately he or she will be held accountable for their activities.
Depending on the risk level of the study, the following individuals or groups may review
the adverse events, safety data, and research activities and recommend a course of
action to ensure the safety of research participants.
1.1 Study Monitor or Clinical Research Associate (CRA)
The primary role of a study monitor is to verify data integrity and compliance to the
protocol. A study monitor reviews source data/medical records, Case Report Forms, and
regulatory documents for accuracy, completeness, and legibility in accordance with the
study protocol. A monitor need not be a person qualified to diagnose and treat the
disease or other condition under investigation.
1.2 Medical Monitor
The medical monitor is a licensed physician with clinical expertise in the area under
investigation. Typically, the PI is the medical monitor, however when the PI is not an MD,
a physician must be involved as the medical monitor. The medical monitor reviews and
interprets adverse events, relevant animal and toxicology studies, and other safety data
throughout the conduct of a research study and issues recommendations to maintain
subject safety. The medical monitor's role and responsibilities within the research project
should be clearly outlined prior to initiation.
NOTE: In cancer studies, the medical monitor must be independent from the study.
1.3 Safety Monitoring Committee
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A Safety Monitoring Committee is a group of individuals responsible for the oversight of
the study. The terms Safety Monitoring Committee may be used to refer to a less formal
group than a Data and Safety Monitoring Board, though the terms are sometimes used
interchangeably.
1.4 Data and Safety Monitoring Board (DSMB)
A Data and Safety Monitoring Board is an independent group of experts convened to
protect the safety of research subjects and to ensure that the scientific goals of the
project are being met. DSMBs are generally used in large multi-center studies, but may
also be used in early-phase investigations of high risk medical interventions or studies
with vulnerable populations.
Factors that suggest a DSMB is needed:
•
A large study population
•
Multiple study sites
•
Highly toxic therapies or dangerous procedures
•
High expected rates of morbidity or mortality in the study population
•
High chance of early termination of the study.
DSMBs should have a charter that outlines the structure and operation of the Board. A
charter typically includes: the board's composition, operating procedures, frequency of
ongoing monitoring, the data submitted to the DSMB, plans for statistical analysis and
review, and the content of reports issued by the DSMB. The DSMB should have a broad
multi-disciplinary representation including a biostatistician and a physician with relevant
clinical expertise.
The DSMB's analysis plan describing what data will be reviewed, how the data set will
be prepared for analysis, and the specific type of analysis used to assess safety.
Generally, these analyses are performed on un-blinded data. After conducting the
planned analysis (or analyses), the DSMB should issue a report either permitting the
study to continue or recommending halting the study. Typically, the DSMB disseminates
an 'open' report that contains aggregate data and administrative recommendations while
also maintaining a 'closed' report that contains confidential data, un-blinded statistical
reviews, and individual discussions.
2.
Scope
Items typically monitored include study regulatory files, Case Report Forms, tracking
logs (e.g. for enrollment, drug storage and dispensing, etc.), subject Informed Consent
Forms, and study source documents. The monitoring plan should include a plan for
collecting study data (Case Report Form). The plan should outline the procedures used
to verify that the data collected on the CRF is correct and that the protocol has been
followed.
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The protocol defines procedures for reporting, reviewing, and analyzing safety data and
plans for intervening (e.g. stopping rules or un-blinding procedures). The monitoring plan
ensures that these procedures have been followed.
3.
Timing
The occurrence of monitoring activities depends primarily upon the risk of the study. The
higher the risk to subjects, the more frequently monitoring should be conducted.
Monitoring frequency will also depend upon the size of the research study, the accrual
rate, and the complexity of the Case Report Form. In general, there is a need for on-site
monitoring before, during, and after the study.
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Chapter 7: Informed Consent Form Development
The consent form is a document used to inform potential subjects about research
participation. It is important to recognize that Informed Consent is an ongoing process
that includes disclosure of information, comprehension, and voluntary choice. The
consent form is used as a tool to help researchers fully disclose information.
The elements of the consent form are specifically regulated in 45 CFR 46 and 21 CFR
50, as well as outlined in the Good Clinical Practice (ICH) Guidelines. The IRB
scrutinizes the consent form during its review to ensure that the proper elements are
present, the form is written in lay language, and no coercive or misleading statements
are included. The investigator cannot employ the informed consent form until it has
received final IRB approval. The MHS IRB (or any IRB of record) indicates this approval
by stamping the consent form with valid dates.
An informed consent template to assist researchers in developing an Informed Consent
Form that is understandable, written in lay language, and includes all of the required
elements of the consent form can be found in this Chapter, or by referring to SOP 601
Attachment A. Please contact the OHR for an electronic version of the template.
For non-investigator-initiated studies, the research sponsor may provide investigators
with a consent form template. This template should be integrated with the Memorial
Healthcare System IRB’s informed consent requirements and approved language. The
revised consent should be forwarded to the sponsor for comments and approved prior to
submitting to the IRB. At the IRB Subcommittee, further consent form changes may be
recommended and should be incorporated before submission to the sponsor and IRB
final submission.
1.
General ICF Writing Tips
Do's and Don'ts
•
DO view the consent form as an instructional tool rather than a legal tool
•
DO, if using published data that is not part of the FDA-approved label to discuss
safety and/or efficacy, clarify that this is "research data" and not FDA-endorsed
or FDA-approved as evidence of safety or efficacy of the study agent
•
DON'T make claims that a study is FDA-approved. The FDA does not "approve"
non-significant risk device studies; it only approves medical treatments and
devices for marketing.
•
DON"T make statements that would suggest a subject is waiving his/her rights in
any way (refer to Exculpatory Language below).
•
DON'T make statements that would suggest a subject, the PI or study sponsor is
relieved from liability for negligence (refer to Exculpatory Language below).
•
DON'T make claims about safety/efficacy of the study agent that haven't been
demonstrated (i.e. approved by the FDA), or are not applicable to the study
population.
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2.
Content
•
•
•
•
2.1
Be brief, but include complete information
o
sentences should be short, simple, and direct
o
paragraphs should convey one idea at a time
Be comprehensible
o
written towards a reading age commensurate with the proposed subjects.
It is recommended that consent forms not exceed the 8th grade reading
level in most cases.
o
use lay language and avoid technical words or jargon
o
where use of technical terms are unavoidable, provide clear definitions
o
use the same words consistently when referring to a condition or
treatment
o
use words that are concrete rather than abstract
o
use verbs that are active rather than passive
Help people remember information
o
state ideas explicitly rather than implicitly
o
restate important points throughout and/or summarize critical study issues
at the beginning or end
o
highlight important points by underlining, bolding, or boxing information
Facilitate discussion
o
organize the form logically
o
use numbering or lists when presenting facts
o
use charts and visual aids
Lay Term Glossaries
A number of institutions have developed lay term glossaries, which may be helpful in
defining and describing procedures and risks in informed consent forms. Please note
that the IRB has not reviewed or approved any of these definitions, and so use of these
does not guarantee IRB acceptance of the definitions.
•
PRISM: http://www.nhlbi.nih.gov/crg/pdf-docs/ghchs_readability_toolkit.pdf
•
Stanford: Stanford Glossary of Terms for Lay Terms for Informed Consent
•
Partners Human Research Committee: Alternative Terms
•
National Cancer Institute: NCI Dictionary
•
University of Kentucky: Glossary of Lay Terms
•
Lawrence Berkley National Laboratory: Glossary of Lay Terminology
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3.
Exculpatory Language
The consent form is not a legally binding contract. The researcher should view the
consent form as an instructional tool rather than a legal document. Exculpatory language
is not allowed, which means the consent form cannot waive or appear to waive legal
rights or release the investigator, sponsor, or institution from liability for negligence.
3.1 Examples of Exculpatory Language:
In the following examples, subjects are being asked to agree with and accept these
unfavorable conditions.
•
I waive any possibility of compensation, including any right to sue, for injuries
that I may receive as a result of participation in this research.
•
If you suffer a research-related injury, neither the institution nor the
investigator can assume financial responsibilities for the expenses of
treatment for such injury.
•
In the event that you suffer a research-related injury, your medical expenses
will be your responsibility or that of your third party payer.
3.2 Examples of Acceptable Language
In the following examples, the intent and policies are set forth in a factual manner, but
subjects are not being asked to agree with or accept the conditions as part of their
participation in the research.
• Although future research that uses your samples may lead to the
development of new products, you will not receive payments for these new
products.
• By agreeing to this use, you are giving up all claims to any money obtained
by the researchers from commercial or other use of these specimens.
• By consenting to participate in this research, I give up any property rights I
may have in bodily fluids or tissue samples collected during this research.
• In the event that you suffer a research-related injury, your medical expenses
will be your responsibility or that of your third-party payer. You are not giving
up any legal rights to sue for injury related to malpractice, fault, or blame on
the part of those involved in research.
Examples adapted from Office for Human Research Protections (OHRP) Cooperative
Oncology Group Chairpersons Meeting guidance document "'Exculpatory Language’ in
Informed Consent." OHRP Exculpatory Language in Informed Consents
4.
Format
•
The second person pronoun (you and your) should be used consistently
throughout the document.
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•
Type should be easy to read.
o
•
•
Use standard margins.
o
White space increases readability.
o
Do not sacrifice font size or margin space for fewer numbers of pages.
Leave paragraphs unjustified. Double-space between paragraphs.
o
•
5.
This reduces the speed of comprehension and reading.
Place the Study Title, Principal Investigator, and Institution in the header of each
page.
o
•
This increases the speed and ease of reading.
Avoid using sentences in all capital letters or italics.
o
•
Use sans serif fonts, legible size (e.g. Arial 12 pt, Times Roman 12 pt,
Verdana 12 pt).
Consider adding the IRB Protocol Number as an additional identifier.
Place the Page # of # and the Consent Form Version in the footer of each page.
Elements of Informed Consent
The elements of the Informed Consent Form required by Federal regulations and GCP
guidelines are listed below. The Common Rule, FDA regulations and ICH guidelines
have been harmonized to contain the same requirements (45 CFR 46.116, 21 CFR
50.25, ICH E6 4.8.10).
•
A statement that the study involves research.
•
An explanation of the purpose of the research.
•
An explanation of the expected duration of the subject's participation.
•
A description of the procedures to be followed.
•
*If applicable, include:
o
Aspects considered experimental
o
Procedures to be followed, including all invasive procedures and
treatments
o
Probability for random assignment to each treatment.
o
Subject's responsibilities.
•
A description of any reasonably foreseeable risks or discomforts.
•
A description of any benefit to the subject or to others which may reasonably be
expected from the research. When there is no intended clinical benefit to the
subject, the subject should be made aware of this.
•
A disclosure of appropriate alternative procedures or courses of treatment, if any,
that may be advantageous.
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•
•
If applicable for a clinical trials regulated by the FDA, include verbatim wording,
“A description of this clinical trial will be available on http://www.ClinicalTrials.gov,
as required by U.S. Law. This Web site will not include information that
can identify you. At most, the Web site will include a summary of the
results. You can search this Web site at any time.”
•
If applicable, include:
o
Important risks and benefits of alternatives.
o
The option of choosing "no treatment" or doing nothing.
•
A statement describing the extent, if any, to which confidentiality of records will
be maintained.
•
If applicable, include:
o
The possibility that the government agencies (e.g. FDA, NIH, etc.) may
inspect records.
o
Records will be kept confidential, and to the extent permitted by law
and/or regulations, will not be made publicly available.
o
Published results will not identify the subject.
•
For studies involving more than minimal risk, an explanation as to whether any
treatment or compensation is available if injury occurs.
•
An explanation of whom to contact for answers to pertinent questions about the
research, the research subject's rights, and in the event of a research-related
injury.
•
A statement that participation is voluntary.
•
Statement that refusal to participate will involve no penalty/loss of benefits. A
statement that the subject may discontinue at any time without penalty/loss of
benefits.
5.1 When relevant, the informed consent must also include the following
elements:
•
Unforeseeable risks to embryo, fetus, or nursing subject.
•
Anticipated circumstances under which a subject's participation may be
terminated without regard to the subject's consent.
•
Any additional expenses that may result from participation in research.
•
*If applicable, include:
o
The anticipated prorated payment, if any, to the subject.
•
The consequences of a subject's decision to withdraw. A description of the
procedures for termination.
•
A statement that the subject will be told of significant new findings or information
that may be relevant to the subject's continued willingness to participate.
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•
Approximate number of subjects involved in the study.
•
That the monitor(s), the auditor(s), the IRB, and the regulatory authorities will be
granted direct access to the subject’s original medical records for verification of
clinical trial procedures and/or data, without violating the confidentiality of the
subject, to the extent permitted by applicable laws and regulations.
•
It is recommended that the investigator inform the subject’s primary physician
about the subject’s participation in the study if the subject has a primary
physician and if the subject agrees to the primary physician being informed.
•
These elements are specific to ICH E6 Guidelines
6.
Informed Consent Template
The MHS IRB has created a template to aid in the construction of a research subject
informed consent form. This standard form flows logically from a research subject
perspective, and is designed to ensure all required elements of informed consent are
captured as well as to improve the ease of IRB review. Please contact the OHR or MHS
IRB for an electronic version of the Informed Consent template.
The elements of the Informed Consent Form include the following:
WHAT IS THIS STUDY ABOUT?
•
The subject is being invited to participate in a research study and why they are
being asked to volunteer.
•
Participation is voluntary
•
The subject will get a copy of the consent form and should ask questions
•
The subject will be asked to sign this form if consent is given to participate
•
OPTIONAL: Can include some information about the study such as "a study of
"X" (drug or device, etc.) in patients with "Y" disease
We are asking you to take part in a research study. This form gives you information that
will help you decide. If you do decide to take part, you will be given a copy of this form
to keep.
A research study tests treatments. The treatments could be study drugs or devices.
They could be new ways to combine treatments to find out if the treatments are safe and
if they work well for a particular disease.
WHY IS THIS STUDY BEING DONE?
•
A concise explanation of the purpose of the research, incorporating any intent to
assess safety +/- efficacy
•
A Clarification that the drug/device is investigational. Can note that the
drug/device is approved for another indication if applicable, but must clarify that
the use of the drug/device in this study is experimental
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HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
•
Total number of subjects in study
•
Number of subjects expected at MHS
WHAT WILL HAPPEN TO ME ON THIS STUDY?
•
A high level overview of the major elements of the study and what is expected of
the subject (i.e. note here only the major procedures and milestones)
•
Following the overview, provide a full list of procedures/tests by lay-term names;
Consider including number of times each test will occur, amount, exposure if
appropriate, etc. in easy lay terms
•
Describe each test/procedure in lay terms
•
Clearly identify which procedures are experimental
•
OPTIONAL: May be complimented by a simple table or chart and/or other
additional materials may be inserted here or given as a handout; any such
materials require IRB approval
HOW LONG WILL I BE ON THIS STUDY?
•
Expected duration of a subject's involvement with the study
•
Expected total duration of study
WHAT ARE THE RISKS OF THE STUDY?
•
Known risks from the study agent. May also be detailed in chart format and
additional material inserted here or given as a handout. Any such materials
require IRB approval.
•
Risks, discomforts/inconveniences of study-related procedures noted in the
section “What am I being asked to do?”. If standard of care is testing is being
changed, describe any resultant risk, if applicable. May also be detailed in chart
format and additional material inserted here or given as a hand out. Any such
materials require IRB approval.
•
Clarify that if the subject is injured, they should inform treating physician that they
are in a research study.
•
Include information on reproductive issues, if appropriate. NOTE: If male
contraception methods or warnings are warranted, the appropriate information
must be provided in this section as well.
•
Do not make statements of proven safety unless that safety data is part of FDAapproved labeling. If the labeling safety data does not include data in the
proposed study population for this study, make clear that there is no safety data
in the population under study.
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•
Include a statement that the research may involve risks that are currently
unforeseeable.
Childbearing risks:
It is not known how this treatment might affect an unborn child. It is not known how this
treatment will affect male sperm. This treatment will not be offered to females who are
pregnant. Females able to have children must be tested to prove they are not pregnant
before starting the study. If you sign, this means you agree you will not have sex unless
you use a study doctor approved method of birth control during the study.
(APPROPRIATE ONCOLOGY- If it applies to you, your study doctor will tell you about
ways to keep eggs or sperm outside the body, so that you might still have a chance of
having children if this treatment makes you unable to naturally have children.
ONCOLOGY ENDS) Females taking part in the study promise not to breast feed during
this study. You agree to notify the study doctor if you become pregnant during this study.
WILL I BENEFIT FROM THIS STUDY?
•
If direct subject benefits can reasonably be anticipated as a result of participating
in the protocol then describe these possible benefits. Conclude with the following
standard clause:
“You may not get any benefit from being in this research study.”
•
If direct subject benefits are NOT anticipated, then use the following standard
clause
“You are not expected to get any benefit from being in this research study.”
•
Anticipated benefits to society
ARE THERE OTHER OPTIONS?
•
Information on other treatments available.
•
Alternatives to entering the study including, when appropriate, supportive care
with no additional disease-directed therapy
•
A statement that they may discuss alternatives with their personal physician
WILL MY MEDICAL INFORMATION BE KEPT PRIVATE?
AUTHORIZATION (PERMISSION) TO USE OR DISCLOSE (RELEASE)
IDENTIFIABLE HEALTH INFORMATION FOR RESEARCH
This research study will use records of current and/or future identifiable health
information. This information will come from the records of your hospital, doctors’
offices, clinics, or other places you get healthcare. This information also comes from
your healthcare billing records or insurance records. It includes information about the
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cost of your treatments and care. The information you allow to be disclosed and used is
described in the “What will happen to me on this study?” section of the consent for this
study. It is also the information described in the consent under the section about
coverage of research-related injuries (if applicable). This information will be used for the
purpose of meeting the goals of this study. You allow the use and disclosure of this
information to:
•
__________________________________(SPONSOR OF RESEARCH);
•
_______________________(maker of the study drug or device), if applicable;
•
any other research company or person who has a contract with the sponsor;
•
agents of the sponsor;
•
the researchers, doctors taking part in the study and their assistants;
•
Memorial Healthcare System Institutional Review Board;
•
the Food and Drug Administration;
•
the National Cancer Institute (if NCI study);
•
the U.S. Department of Health and Human Services (if NIH)
•
People and organizations acting for any of the above.
Other people or organizations who help with this research may also get your medical
information. They may get your blood, or body tissue samples, or slides. These other
people and organizations include central laboratories, central review centers, and
central reviewers.
If it applies to your case, you give permission to use or disclose information about:
•
Acquired Immunodeficiency Syndrome (AIDS)
•
Human Immunodeficiency Virus (HIV) infection
•
mental or behavioral health or psychiatric care
•
or treatment for drug or alcohol abuse.
You are letting Memorial Healthcare System and your healthcare facilities and providers
give this information to the people, organizations, and parties listed above. You are
also allowing blood or body tissue samples to be sent to a central laboratory to help with
this study.
The term “Protected Health Information” means the information about your health that is
protected under the law. It includes new and existing medical records and test results
that contain information that could be used to identify you. It means medical records
that include ways to identify you, such as your name; address; telephone number; date
of birth; and/or medical record number. This may include information in your medical
record and information created or collected during this study. It includes long-term
information about your general health status and the status of your disease.
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Federal and state laws require your records to be kept private. However, no one can
promise complete confidentiality. Your Protected Health Information will sometimes be
used or disclosed in the ways described in this form. In addition, after the researcher
discloses your records to others then the law may no longer protect the privacy of your
records listed above.
The results of this study may be published, but those publications will not identify you.
Scientific data from this study may be presented at meetings. It may be published so
that the information may be used to help others. Your participation in the study will not
be made known and will be kept strictly confidential.
This authorization is voluntary. You do not have to give it. But, if you will not allow the
use and disclosure of your identifiable health information, you will not be allowed to be
part of this study. You can cancel this authorization at any time. But if you cancel
after you have started the study, you will be removed from the study. Your canceling
this authorization will not affect any use or disclosure made before the cancellation.
That information will continue to be used in the study. Blood and body fluids you gave
to the study may continue to be used. It will not change any action that anyone had
made because he or she relied on your authorization. It means that no new Protected
Health Information about you will be used or disclosed. You may cancel this
authorization by giving a written notice to:
Dr. Name
Address
City, State zip.
“BLINDED STUDIES: Until this study is over, you will not be given study information
about yourself. You will not be told which study treatment you are getting. That has
been kept secret from you during the study so that your beliefs about the drug will not
change the results. You will be able to get this information at the end of the study. END
OF BLINDED STUDY”
NON-BLINDED: You have the right to see and copy your records related to the study for
as long as the study doctor has this information. You do not have the right to review or
copy records kept by ___________(sponsoring agency) or other researchers associated
with this study. You will not get the results from the special research tests done on your
donated specimens.
This authorization does not have a fixed ending date. It stays in effect until it is
cancelled.
WHAT ARE THE COSTS (PAYMENTS) ASSOCIATED WITH THIS STUDY?
•
Procedures or tests that will be covered by the study
•
Procedures or tests that are not covered by the study, stating how they will be
paid for (i.e., third party payer (payor), etc.)
•
Description of any monetary compensation (*payments/stipend), if subjects are
being compensated for their time and travel. If there is no compensation for
participation in this study, state that here
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•
You and/or your health insurance may be billed for the costs of medical care
during this study if these expenses would have happened even if you were not in
the study, or if your insurance agrees in advance to pay.
The study drug(s) are free. So are the tests and other procedures that are needed
because of the study. All of your other medical care will be charged and paid for in the
same way it would be if you were not part of the study. You will not be charged extra for
taking part in the study.
No one will pay you to take part in this study. The study sponsor will (or will not) pay
your healthcare provider for his or her services to you as part of the study. These
payments (may be more than his or her costs of taking part in the study or These
payments will not be more than his or her costs of taking part in the study. If this is a
concern to you, please feel free to discuss this with the study doctor or study
coordinator.
WHAT IF I AM INJURED FROM TAKING PART IN THIS STUDY?
•
Provide contact information for research-related injury (i.e. can refer to the
contact information noted in Consent header, if appropriate)
•
Describe what treatment will be provided for research related injuries
•
Explain how treatment for research related injuries would be paid
•
Describe procedure for emergency care
•
OPTIONAL: Subject's responsibilities relating to research related injuries
There is a risk you may be hurt by this study. If you are hurt, medical care will be
provided to you. All of that medical care will be charged and paid for in the same way it
would be if you were not part of the study. Neither the study sponsor, nor the
investigating doctors, nor the Hospital will pay for that care. Signing this form does not
take away any of your legal rights. It does not release anyone from liability for
negligence. (Insert sponsor statements here or if no sponsor statement for coverage
then include) Funds to pay for pain, expenses, lost wages, and other damages caused
by the injury are not routinely available. If you need help paying for losses or care
caused by such an injury, ask the study doctor or a social worker about how you might
get help.
WHAT ARE MY RIGHTS AS A STUDY PARTICIPANT?
•
Note that the subject can elect to leave the study at any time
•
If early withdrawal could expose the subject to medical risks, describe and how
those risks will be minimized or prevented (e.g. in a hypertensive study, it may be
necessary to wean a subject off of the study medication or to transition them to
alternate therapy)
•
A statement that if information about the safety of the study drug/device/study is
discovered during the study, which may affect one's willingness to participate, the
subject will be notified
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You do not have to be in this research study. You can agree to be in the study now and
change your mind later. Your decision will not affect your regular care. Your doctor’s
attitude toward you will not change. There will be no penalty or loss of benefits. You
are free to seek care from a doctor of your choice at any time. You will continue to
receive medical care.
You may be taken out of the study if:
1. Staying in the study would be harmful to you.
2. You need treatment not allowed in the study.
3. You fail to follow instructions.
4. You become pregnant (females).
5. The study is cancelled.
We may learn about new things that might make you want to stop being in the study. If
this happens, you will be informed. You can then decide if you want to continue to be in
the study.
(If appropriate, “Even if you stop taking part in the study your medical information will
still be collected and shared as part of the study. This is to try to find out the long term
results of the care you got while you were part of the study. However, none of your
future medical information will be used or shared as part of the study, if you request
that.”)
WHAT IF I HAVE QUESTIONS OR PROBLEMS?
The Principal Investigator, _________, can be contacted at (address) or (telephone
number) (e-mail address). Ask the Principal Investigator any questions you have about
the research. Let the Principal Investigator know if you have a research-related problem
or injuries at any time during the study.
If you have any questions about your rights in this study, you may contact in writing or by
telephone:
The Chairman of the Institutional Review Board
Memorial Healthcare System
3501 Johnson Street, Hollywood, Florida 33021
Telephone number (954) 265-1857.
WHERE CAN I GET MORE INFORMATION?
(Cancer studies)
You may call the National Cancer Institute’s Cancer Information Service at:
1-800-4-CANCER (1-800-422-6237)
You may also visit the NCI Web site at http://cancer.gov/.
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Or
(Non-Cancer studies)
You may also visit the following Web site at http://clinicaltrials.gov/ to learn more
information about participating in research studies.
If you want more information about this study, ask your study doctor.
7.
Special ICF Language Requirements
7.1 Assent Forms
Generally, minors and adults with limited decision-making capacity do not have the legal
authority to provide consent for their own participation in a research study. However, an
investigator should still seek affirmative agreement (assent) from such research
subjects. An assent form is a simplified version of the consent form and should be
written to the subject's level of understanding. A typical assent form explains a study's
purpose, procedures, risks, benefits, confidentiality, and voluntary nature in simple
terms.
7.2 Human Immunodeficiency Virus (HIV) Testing
Florida state law requires HIV testing to be reported to the Florida Department of Health.
If HIV testing is completed as part of the research procedures, prospective subjects must
be informed of the reporting requirements.
Sample consent form language for HIV testing:
“Florida state law, like laws in most states, requires health care workers to report the
names of people who test positive for HIV to the Florida Department of Health. The
reason for this is to keep track of how many people in the U.S. have HIV infection, and to
make sure that the U.S. government provides enough money to each state to support
the medical care of people living with HIV. The Florida Department of Health does not
share the names of HIV infected individuals with any other governmental or
nongovernmental agency. This maintains the privacy of HIV infected individuals whose
names are reported.”
7.4 Radiation
If participants will be subjected to Radiation beyond that of common diagnostic
procedures, and/or biological effects are anticipated from the radiation, then a statement
about the biological effect must be included in the radiation risk statement.
7.5 Tissue or Blood Banking
If a secondary aim of the research study is to bank tissue or blood for future genetic
analyses, subjects should have the ability to refuse without jeopardizing overall study
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participation. To do this, the consent form can include an opt-in/opt-out section or a
separate consent form can be used for blood and tissue banking.
8.
Variations in Informed Consent
8.1 Deception in Research
Certain research studies are designed to test responses when the research subjects are
intentionally misinformed or have had certain information withheld from them. This type
of research is categorized as deception.
To request approval from the IRB for the use of deception, the investigator should
demonstrate that:
•
the use of deceptive techniques is unavoidable (alternatives are not feasible)
•
deception does not involve significant risk
•
subjects are not deceived about aspects of the study that would affect their
willingness to participate
•
data collection will be followed by a sensitive debriefing session (explanation of
the deception) that protects the rights and dignity of research subjects
8.2 Writing an informed consent form for a study that involves deception
•
the consent form cannot include anything that is untrue
•
the consent form should reveal as much information as possible without
compromising the study aims
•
this may include a statement that the subject may not be told complete
information due to the study design, but will be informed at the completion of the
study
•
a separate post-debriefing consent form is recommended to give subjects the
opportunity to opt-out of having their data included in the research
8.3 Waiver of the informed consent process
In specific circumstances, the IRB may waive part or all of the informed consent process.
For example, an investigator may want to conduct a retrospective study of existing,
anonymous laboratory specimens without obtaining informed consent.
To request a waiver of informed consent, the investigator must demonstrate in a letter to
the IRB that all of the following conditions are met:
•
The research involves no more than minimal risk
•
The waiver will not adversely affect the rights or welfare of subject
•
The research could not practicably be carried out without a waiver
•
When appropriate, the subjects will be provided with additional, pertinent
information after participation
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Note: The investigator will also be responsible for requesting an exemption or waiver of
the HIPAA authorization.
8.4 Translated Consent Forms
The consent form must be written in a language understandable to the subject or the
subject's representative. If non-English speaking subjects are anticipated to be enrolled
into the study, or if it is found that more than a few subjects are enrolled who speak the
same non-English language, the consent form must be translated. The IRB must
approve the translated form before it can be used to consent subjects.
Translated consent forms must be certified as correct. The translation service will be
asked to provide a letter certifying that the translation is a true and accurate translation
of the original English version. Please contact the OHR for MHS approved translation
services.
9.
HIPAA Authorization
The Health Insurance Portability and Accountability Act (HIPAA) are privacy regulations
that limit the collection and disclosure (defined below) of protected health information.
Protected health information (PHI) is individually identifiable health information. PHI
includes any of the following individually identifiable elements:
•
Names
•
Street address
•
Postal or street address information (some exclusions apply here)
•
All elements of dates (except year) related to an individual (including hospital
admission and discharge dates)
•
Ages of individuals over 89
•
Telephone and fax numbers
•
Email addresses
•
Social security numbers
•
Medical record, health plan, or other account numbers
•
Certificate/license numbers
•
Vehicle identifiers
•
Device identifiers
•
Web (URLs) and Internet (IP) addresses
•
Biometric identifiers
•
Full face photos
•
And any other unique identifying number
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Investigators must obtain a signed HIPAA Authorization form or IRB Waiver of HIPAA
Authorization from the subject to collect, use, or disclose protected health information for
research.
Disclosure refers to the release of PHI outside of the "covered entity." Each Informed
Consent will list the entities that will have access to the participants’ PHI.
9.1 HIPAA Authorization Form
The content of the HIPAA form is regulated in the Code of Federal Regulations in 45
CFR 160 and 164.
A HIPAA authorization must include the following core elements:
•
Description of the protected health information (PHI) in a specific and meaningful
way
•
Who may use or disclose the information
•
Who may receive the information
•
Purpose of the use or disclosure
•
An expiration date or event
•
Individual signature and date
•
Right to revoke the authorization including exceptions
•
Reference to the Notice of Policy Practices
•
Right to inspect or copy PHI disclosed
•
Right to signed copy of HIPAA
•
Covered entity may continue to use PHI pursuant to authorization
•
Covered entity may continue to use data to protect the integrity of the research
•
Re-disclosure of health information are no longer protected by HIPAA
The HIPAA authorization may be incorporated into the research consent form or it may
be kept as a separate document. The MHS IRB template has incorporated the HIPAA
authorization into the informed consent template, but it may be a separate document in
cases where other IRBs are utilized.
A sponsor-supplied HIPAA Authorization form cannot be used in place of the MHS IRB
HIPAA Authorization form. HIPAA regulations apply to the healthcare institution, not the
industry sponsor.
9.2 IRB Exemption/Waiver of HIPAA Authorization
Research Using De-identified Information
De-identified information is health information that has been stripped of all identifiers and
is no longer protected under HIPAA. A research study may use or disclose de-identified
data for research purposes if it is an IRB-approved protocol that received an exemption
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from IRB review. For exempt studies, the IRB Waiver of HIPAA Authorization form
should be completed and submitted with the Request for Exemption form sent to the
IRB.
IRB Waiver of HIPAA authorization
In certain instances, an investigator may access protected health information for
research without obtaining a HIPAA authorization from subjects. In these situations, the
IRB may waive part or all of the HIPAA authorization. For example, an investigator may
request a HIPAA waiver to conduct a retrospective chart review.
To request an IRB waiver, the investigator must contact the MHS IRB.
To be granted a waiver of HIPAA authorization, the investigator must demonstrate that:
•
The disclosure involves no more than minimal risk and has in place the following:
o
Protection Plan: plan to protect identifiers from disclosure
o
Destruction Plan: plan to destroy identifiers at earliest opportunity
o
Assurances against Re-disclosure: information will not be reused or
disclosed except as required by law
•
The research could not practicably be carried out without a waiver
•
The research could not be carried out without access to protected health
information
9.3 Exception from HIPAA Requirements
Research Using a Limited Data Set
Investigators can use a “limited data set” without obtaining a HIPAA authorization,
provided that the following identifiers have been removed:
•
names
•
street addresses (other than town, city, state and zip code)
•
telephone numbers
•
fax numbers
•
e-mail addresses
•
Social Security numbers
•
medical records numbers
•
health plan beneficiary numbers
•
account numbers
•
certificate license numbers
•
vehicle identifiers and serial numbers, including license plates
•
device identifiers and serial numbers
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•
URLs
•
IP address numbers
•
biometric identifiers (including finger and voice prints)
•
full face photos (or comparable images)
A limited data set may include the following indirect identifiers:
•
dates such as admission, discharge, service, date of birth, date of death;
•
city, state, five digit or more zip code; and
•
ages in years, months or days or hours
Please contact the MHS IRB when conducting research using a Limited Data Set.
9.4 Activities Preparatory for Research to Prepare a Protocol
An investigator can obtain PHI for data collected "preparatory for research" without a
HIPAA authorization provided that all of the following conditions are met:
•
The data is sought solely to review PHI as necessary for activities preparatory for
research.
•
No PHI will be removed from MHS by the researcher in the course of review.
•
The PHI is necessary for the research purposes.
"Preparatory for research" includes developing research questions, determining study
feasibility, and determining study eligibility. Please note, that although HIPAA regulations
consider determining study eligibility an activity preparatory to research, the actual
process used to recruit subjects remains a research activity that requires IRB approval.
9.5 Research Using Decedent Information
An investigator may use or disclose the protected health information of individuals who
have died without a HIPAA Authorization or a Waiver of Authorization provided that the
researcher can demonstrate in a letter to the IRB that:
•
The use is solely for research on the protected health information
•
The research could not be carried out without access to protected health
information
•
Individuals are deceased
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Chapter 8: Subject Recruitment Plan
Successfully recruiting the desired number of subjects for a study is critical to its
success. Subject recruitment can often be challenging. There are several methods that
can be developed in a comprehensive subject recruitment plan to help meet this
challenge.
1.
Recruitment Strategies
1.1 Clinical Care Settings and Resources
•
Screening incoming patients in healthcare setting
•
Medical record reviews
•
Departmental databases and registries
1.2 Physician Referral
•
Networking with other practices and clinics
•
Educational forums for physicians, nurses and hospital staff
•
Mailings, referral packets
1.3 Community Awareness
2.
•
Advertising through news, magazine, and journal ads
•
Advertising through direct mail, posters, flyers, and brochures
•
Advertising to the general public through media such as radio, TV and the
Internet
•
Participating in community health events and forums
•
Educational forums to patient advocacy groups and community
•
Press releases and media events
Considerations for Subject Payments
Subjects are sometimes offered monetary payments for their participation in research
studies. While many differing perceptions exist on the ethics and effectiveness of this
practice, the decision to provide payment to research subjects is generally made by the
PI in order to facilitate timely recruitment of subjects for the study. The justification for
payment to research subjects include the provision of an incentive to participate,
reimbursement for expenses that the subject may incur to participate, or payment for the
subject’s time and inconvenience. It is never acceptable to use payment as a benefit to
offset the risks of a study.
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Several important ethical considerations should be weighed when considering whether
or not to pay subjects, how much, and on what schedule. One important concern is that
the payment may cause undue influence on the subject’s decision to participate in the
study. That is, the financial incentive may render potential subjects less likely to fully
weigh the potential risks. While there is no concrete guidance on what size payment may
induce undue influence on a subject, it is essential to evaluate the nature of the study,
the contributions and sacrifices made on the part of the research subject, vulnerabilities
that may be inherent in the study population, and local and societal norms.
Subject payments typically are classified as either reimbursement or remuneration.
•
Reimbursement refers to payment, monetary or other form, paid to a subject for
out-of-pocket expenses such as study-related travel, lodging, meals or lost
wages.
•
Remuneration refers to monies paid to subjects as repayment for their personal
time and effort committed to study participation.
NOTE: The term “compensation” should be used only to refer to payment or medical
care provided to subjects injured in research.
All subject payments should be described in the study protocol and informed consent
form, which must be approved by the IRB prior to project initiation.
2.1 Determining the Amount of Payment
Payments vary based upon the complexity of the study, the type and number of
procedures, the time involved, and the anticipated inconveniences. Sponsors may offer
up to a given maximum amount, and Investigators may calculate payments by
estimating the number of biological samples collected, the amount of time spent on the
project, the subject's anticipated out-of-pocket expenses, or a variety of other factors.
Monetary inducements are not allowed solely for the purpose of attracting subjects for
studies involving significant risk or excessive pain or discomfort, such as a bone marrow
biopsy.
2.2 Payment Schedule
Payment should be accrued or prorated as the study progresses and not be contingent
upon the subject completing the entire study. Subjects who withdraw early from the
study may be paid at the time they would have completed the study had they not
withdrawn (unless it creates undue inconvenience or appears coercive). All information
concerning the payment, including the amount and schedule of payment(s), should be
described in the informed consent form.
The investigator may include a small extra payment at the end of the study (bonus) as
an incentive for completion, providing that it is not coercive. If a bonus is awarded it
should be provided to all completed subjects, not just "favorite" or compliant subjects.
The bonus should not be offered as an alternative to withdrawal if the subject wishes to
discontinue participation in the study.
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3.
Privacy Rules Regarding Subject Recruitment
3.1 Acceptable Methods of Contacting the Subject (in order of priority)
1. The preferred method is to have the physician or other health care provider who
has taken care of the patient in the past to contact the patient directly. Or the
research staff can be authorized by the physician to contact the patient on the
physician's behalf.
2. If this is impractical, the Investigator may develop a letter to be used to contact
the patient. The letter must be approved and signed by a physician or other
health care provider who has cared for the patient. Alternatively the physician
may authorize the research staff to send a letter on the physician's behalf and
signed by the research staff. The language of the letter must also be approved by
the IRB.
3. If the first two methods are impractical, the Investigator may contact the potential
subject directly. This method of recruitment will require specific IRB approval,
and approval will only be granted if the impracticality of the first two methods is
well-substantiated.
3.2 Advertisement Development
Direct advertisements (radio, television, print, internet, telephone, brochures, websites,
etc.) are used to recruit subjects for research in general and/or for specific studies.
Direct recruiting advertisements are considered a part of the informed consent and
subject selection process and, therefore, governable by federal regulations. Several
federal regulations govern the use of advertisements (21 CFR 50, 21 CFR 56 and 21
CFR 812). These regulations stipulate that advertisements must not present any
coercive or misleading information by implying a certainty of favorable outcome, claiming
the safety or efficacy of an investigational product, implying the study is a medical
treatment, promising free medical care, or overemphasizing payments.
The IRB provides guidance on recruitment materials and will need to approve any
materials intended to come in contact with potential participants.
Advertisements are not limited to the printed word, such as appears in newspapers or
brochures. Radio advertisement and videos (such as are used for television) also fall
within this purview and are subject to the same guidelines and submission requirements.
To recruit subjects, advertisements may include the following information:
•
Name and address of the investigator and/or research facility
•
Condition under study and/or the purpose of the research
o
Include the word research, investigational, or experimental
o
Specify if a placebo will be involved
•
Abbreviated description of criteria that will be used to determine eligibility
•
A brief list of participation benefits, if any
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•
Time and/or expected commitment required of the subject
•
The person to contact for further information
Well-designed advertisements are clear in phrasing and simply worded, using nonmedical terminology where possible. An appropriately worded advertisement may
include the expected payment as long as it is not overemphasized so that it can be
perceived as a benefit.
3.3 Recruitment Brochures
Brochures are a type of advertisement tool used to help with the recruitment of subjects.
Brochures are often created in the start-up phase of research. However, recruitment
brochures are usually not subject to the space limitations of other written advertisements
and, as such, their formatting may vary slightly.
Recruitment brochures generally incorporate the elements of an advertisement in
several distinct sections:
Call to action
This section notifies the potential subjects of the focus of the project. Typically
this call to action is worded in question format asking the reader if they have
experienced a given situation.
e.g. Have you ever..?, Are you planning..? Do you have..? Have you and your
provider discussed..?
Study Significance
This section explains the importance of the research project and the significance
of the intended research. Typically this section is worded as a question drawing
attention to the study importance.
e.g. Why is this study important?
Inclusion/Exclusion Criteria
This section outlines the protocol-defined parameters for study eligibility. This
section helps the targeted audience understand the likelihood of participation.
Typically inclusion/exclusion criteria are worded as a directive guiding
participation eligibility.
e.g. You may participate if you: .. You may not participate if you.
Study Procedures
This section explains the study-related procedures and clearly discusses the
activities as part of research participation. Typically this section outlines the
activities in chronological order and directly correlates with the study protocol and
informed consent form.
Principal Investigator
This section includes the name, title and affiliation of the Principal Investigator.
Typically this section is located on the back of the brochure.
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e.g. Name of Principal Investigator
Title of Principal Investigator
Affiliation
4.
Institutional Review Board (IRB) Submission
Research advertisements must be approved by the IRB prior to implementation. The IRB
must ensure that advertisements do not contain information that is misleading to
potential research subjects. Most advertisements are reviewed in an expedited fashion.
The IRB prefers that radio and video advertisements be submitted as transcripts rather
than audio or video presentations. If an advertisement is translated, the translation must
be submitted with a copy of the original English version for review and approval. Copies
of recruitment letters to subjects and intermediaries ("Dear Doctor" letters) must also be
submitted to the IRB.
5.
Clinical Trials Web Posting
All U.S. drug or device clinical trials must be registered on the ClinicalTrials.gov website
in accordance with requirements published by the International Committee of Medical
Journal Editors (ICMJE) and the FDA Amendment Act of 2007. The following clarifies
who is responsible for registering your clinical trial:
1. Investigator holding IND or IDE applications with the FDA: the Investigator
IND/IDE holder is required to register the clinical trials conducted under the
IND/IDE application
2. Investigator-initiated, government-sponsored clinical trials: Generally the
sponsoring federal or state agency is required to register the clinical trial
3. Industry-sponsored clinical trials: the industry sponsor is required to register the
clinical trial
In order to register your trials directly to ClinicalTrials.gov, you will need to designate a
person who will be responsible for posting your clinical trials. The OHR and IRB are
responsible for all clinical trial information that is released to ClinicalTrials.gov from the
Memorial Healthcare System. Prior to releasing the trial information for public access,
the OHR must ensure the following for each submission:
1. There are no system-generated red error warnings in the submission;
2. The study is IRB approved; and
3. If the listed collaborator is an industry sponsor, that written authorization for
posting has been provided by the industry sponsor
When entering your registration information into the ClinicalTrials.gov web form, please
ensure that all red error warnings have been resolved prior to clicking the "Complete"
button. The red error warnings indicate missing or discrepant information.
For more information, visit ClinicalTrials.gov at http://www.clinicaltrials.gov/.
If your study is already registered please visit Clinical Trials Login at
https://register.clinicaltrials.gov/.
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Chapter 9: IRB Submission
The Institutional Review Board (IRB) is an independent committee that oversees the
protection of human subjects. This committee reviews research studies and the ongoing
activities of approved research.
In compliance with federal regulations, the IRB must include at least 5 people including
men and women and representing various professions and affiliations. At least one
member may not be affiliated with the institution. Minimal attendance at a meeting,
called a quorum, is defined as a convened meeting with a majority of members present
including one member whose primary concerns are nonscientific. The regulations
require that a quorum be present in order for the full board to review full board actions,
including new studies, amendments, continuing review of previously reviewed research,
reports of unanticipated problems posing risk to subjects or others, and reports of
serious or continuing noncompliance with the regulations.
1.
Memorial Healthcare System IRB Review
The Memorial Healthcare System IRB holds monthly meetings (typically convened the
second Monday of each month). For new studies, the IRB application, Informed
Consent, and Protocol will be reviewed at an IRB Subcommittee meeting (typically
convened every other Wednesday) prior to formal submission to the IRB.
The submission deadlines for IRB subcommittee meetings as well as IRB meetings are
roughly three weeks prior to the meeting dates. Amendments to protocols, however, are
to be submitted a week earlier than other full board submissions. Please contact the
IRB or OHR for schedules of submission and meeting dates for IRB Subcommittee and
IRB meetings. The IRB also offers guidance regarding required documents and number
of copies of each needed for each type of submission (see below).
2.
Determining IRB Review Type
These are general guidelines to determine the level of risk and corresponding IRB
review mechanism and submission requirements for research protocols involving human
subjects. Other factors that may impact review type include: the involvement of
vulnerable populations, the use of protected health information (PHI),
privacy/confidentiality issues, psychological effects, conflicts of interest, experience of
research team, etc. Assessing the review type for a study will determine the
requirements for submitting the study to the IRB for review. Please note that the IRB
makes the final determination of level of review.
The first question one should consider when assessing the requirement for IRB review is
whether the activity meets the regulatory definition of human research (see Chapter 1:
Introduction). Anyone unsure about IRB review requirements and whether their
proposed activity constitutes “human research” requiring IRB review should contact the
Office of Human Research (OHR). If an activity does not meet the regulatory definition of
human research, the IRB will, upon request, issue a letter stating that the project does
not require IRB review or approval. Communication with the IRB office should occur prior
to initiating the study.
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Once it is determined that the project meets the definition of human research, the level
of review must then be determined. The initial criteria used in determining the review
level is ascertaining if a study meets the criteria for minimal risk. Minimal risk research
may be eligible for either expedited or full board review.
Minimal risk means that “the risk of harm anticipated in the proposed research that is not
greater, considering the probability and magnitude, than those ordinarily encountered in
daily life of a healthy individual or during the performance of routine physical or
psychological examinations or tests.”
Below are general guidelines for determining the review level. All research-related
activities within a study must fall in their entirety within the exempt categories in order to
qualify for exempt status. This is also true for expedited review.
2.1 Exempt from Review
DHHS and FDA regulations allow specific categories of research to be exempt from
human subject review. Research that is considered exempt from Committee review must
still be filed with the IRB and screened for exempt status. Protocols qualifying for exempt
status do not require annual continuing review. Investigators are required to notify the
IRB if any changes are proposed that could alter the exempt status of the protocol.
Categories of Exempt Research
Following is a list of categories that are typically eligible for Exemption from IRB Review.
Additional conditions and limitations exist for each category as specified in the IRB’s
Claim of Exemption Instructions.
NOTE: The FDA only allows research to qualify for Exempt from Review that falls under
Category 6 below. All other categories of research that is subject to FDA regulations
require Expedited or Full Board Review.
Category 1
Research conducted in established or commonly accepted educational settings,
involving normal educational practices, such as research on regular and special
education instructional strategies, or research on the effectiveness of, or the comparison
among instructional techniques, curricula, or classroom management methods.
NOTE: This category may be applied to research involving children.
NOTE: This category may not be applied to FDA regulated research.
Category 2
Research involving the use of educational tests (cognitive, diagnostic, aptitude,
achievement), survey procedures, interview procedures or observation of public
behavior, unless:
a) Information obtained is recorded in such a manner that human subjects can be
identified, directly or through identifiers linked to the subjects and
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b) Any disclosure of the human subjects' responses outside the research could
reasonably place the subjects at risk of criminal or civil liability or be damaging to
the subjects' financial standing, employability, or reputation.
NOTE: The section of this category pertaining to standardized educational tests may be
applied to research involving children. This category may also apply to research with
children when the investigator observes public behavior but does not participate in that
behavior or activity. This section is not applicable to survey or interview research
involving children.
NOTE: This category may not be applied to FDA regulated research.
Category 3
Research involving the use of educational tests (cognitive, diagnostic, aptitude,
achievement), survey procedures, interview procedures, or observation of public
behavior that is not exempt under paragraph (b) above, if:
a) The human subjects are elected or appointed public officials or candidates for
public office or
b) Federal statute(s) require(s) without exception that the confidentiality of the
personally identifiable information will be maintained throughout the research and
thereafter.
NOTE: This category may not be applied to FDA regulated research.
Category 4
Research involving the collection or study of existing data documents, records,
pathological specimens, or diagnostic specimens, if these sources are publicly
available or if the information is recorded by the investigator in such a manner that
subjects cannot be identified, directly or through identifiers linked to the subjects.
a) To qualify for this exemption the data, documents, records, or specimens must
be in existence before the project begins. Investigator must describe where the
information exists.
b) Under this exemption, an investigator (with proper institutional authorization) may
inspect identifiable records, but may only record information in a nonidentifiable
manner. Investigator must describe how information will be obtained, what data
elements will be recorded, and whether any links to identifiers will be recorded.
NOTE: Inclusion of fetal tissue in the pathological specimens category of exempt
research is prohibited by regulation and requires additional IRB review.
NOTE: This category may not be applied to FDA regulated research.
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Category 5
Research and demonstration projects which are conducted by or subject to the approval
of federal Department or Agency heads, and which are designed to study, evaluate, or
otherwise examine:
a) Public benefit or service programs; this exemption is for federally supported
projects and is most appropriately invoked with authorization or concurrence by
the funding agency. The following criteria must be satisfied to invoke the
exemption for research and demonstration projects examining "public benefit or
service programs."
i.
The program under study must deliver a public benefit (e.g.,
financial or medical benefits as provided under the Social Security
Act) or service (e.g., social, supportive, or nutrition services as
provided under the Older Americans Act)
ii.
The research or demonstration project must be conducted
pursuant to specific federal statutory authority.
iii.
There must be no statutory requirement that an Institutional
Review Board review the project.
iv.
The project must not involve significant physical invasions or
intrusions upon the privacy of participants.
b) Procedures for obtaining benefits or services under those programs;
c) Possible changes in or alternatives to those programs or procedures;
d) Possible changes in methods or levels of payment for benefits or services under
those programs.
e) Before invoking this exemption, the IRB will obtain concurrence of the funding
agency that this exemption can be applied.
NOTE: This category may not be applied to FDA regulated research.
Category 6
Taste and food quality evaluation and consumer acceptance studies if:
a) Wholesome foods without additives are consumed or
b) if a food is consumed that contains a food ingredient at or below the level and for
a use found to be safe, or agricultural chemical or environmental contaminant at
or below the level found to be safe, by the Food and Drug Administration or
approved by the Environmental Protection Agency or the Food Safety and
Inspection Service of the U.S. Department of Agriculture.
NOTE: This category may be applied to children.
NOTE: This category may be applied to FDA regulated research.
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2.2 Expedited Review
To qualify for expedited review the following must apply:
1) Clinical studies of drugs and medical devices only when condition (a) or (b) are met.
a)
Research on drugs for which an investigational new drug application is not
required. (Research on marketed drugs that significantly increases risks or
decreases acceptability of risks is not eligible.)
b)
Research on medical devices for which (i) an investigational device
exemption application is not required; or (ii) the device is cleared/approved
for marketing and being used in accordance with its labeling.
2) Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture
a)
From healthy, non-pregnant adults who weigh at least 110 pounds. The
amounts drawn may not exceed 550 ml in an 8 week period and collection
may not occur more frequently than 2 times per week; or
b)
from other adults and children, considering the age, weight, and health of
subjects, collection procedure, amount of blood to be collected, and
frequency with which it will be collected. The amount drawn may not
exceed the lesser 50 ml or 3 ml/kg in an 8 week period and collection may
not occur more frequently than 2 times per week.
3) Prospective collection of biological specimens for research purposes by noninvasive
means:
a)
Hair and nail clippings in a non-disfiguring manner;
b)
Deciduous teeth at time of exfoliation or if patient care indicates a need for
extraction;
c)
Permanent teeth if patient care indicates a need for extraction;
d)
Excreta and external secretions (including sweat);
e)
Uncannulated saliva collected in an unstimulated fashion or stimulated by
chewing gumbase or wax or by applying dilute citric solution to the tongue;
f)
Placenta removed at delivery;
g)
Amniotic fluid obtained at the time of rupture of the membrane prior to or
during labor;
h)
Supra- and sub-gingival dental plaque and calculus, provided the collection
procedure is not more invasive than routine prophylactic scaling of the teeth
and the process is accomplished in accordance with accepted prophylactic
techniques;
i)
Mucosal and skin cells collected by buccal scraping or swab, skin swab, or
mouth washings;
j)
Sputum collected after saline mist nebulization
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4) Collection of data through noninvasive procedures (not involving general anesthesia
or sedation) routinely employed in clinical practice, excluding procedures involving xrays or microwaves. Where medical devices are employed, they must be
cleared/approved for marketing. (Studies intended to evaluate the safety and
effectiveness of the medical device are not generally eligible for expedited review,
including studies of cleared medical devices for new indications). Examples include:
a)
physical sensors that are applied either to the surface of the body or at a
distance and do not involve input of significant amounts of energy into the
subject or an invasion of the subject’s privacy;
b)
weighing or testing sensory acuity;
c)
magnetic resonance imaging;
d)
electro-cardiography, electroencephalography, thermography, detection of
naturally occurring radioactivity, electroretinography, ultrasound, diagnostic
infrared imaging, Doppler blood flow, and echocardiography
e)
moderate exercise, muscular strength testing, body composition
assessment, and flexibility testing where appropriate given the age, weight,
and health of the individual.
Examples of research eligible for expedited review:
•
Non-invasive medical procedures that do not involve x-rays or sedation (e.g.
MRI, EKG, EEG)
•
Minimal blood draw amounts in healthy non-pregnant subjects
•
Prospective collection of biological specimens by noninvasive means (e.g. buccal
scrapings, saliva, excreta, sputum)
•
Voice recordings; research on individual or group behavior such as interviews or
focus groups.
•
Moderate exercise by healthy volunteers
Note: HIPAA waiver applies to the extent that identifiable data sources are accessed &
used.
2.3 Full Board Review
Studies that do not qualify for expedited review require approval by an IRB panel
composed of members trained to review research in that field (full board review).
Examples of minimal risk research requiring full board review include:
•
DEXA scan for bone density
•
Any protocol involving X-Rays occurring for the purposes of the research
Examples of greater than minimal risk research requiring full board review include:
•
Any survey or interview that is likely to be stressful for the subjects
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•
Research that involves experimental drugs or devices, invasive procedures
•
Involve increased risk due to the nature of the research or the population being
evaluated.
•
Involve a washout period or placebo use in an otherwise treatable disease.
•
Involve “greater than minimal risk and no prospect of direct benefit to the
individual subjects but likely to yield generalized knowledge about the subject’s
disorder or condition” (CFR 45 Part 46.406}).
3.
IRB Submission Requirements
For a detailed listing of application procedures and required documents, please contact
the OHR or IRB.
3.1 Tips for IRB Submission
•
Contact the IRB and OHR to ensure that correct version of submission forms,
application forms etc. are used.
•
Include page numbers, version number & date on all study documents: protocol,
protocol summary, informed consent, HIPAA Authorization, etc.
3.2 Submission Process
Documents Needed for IRB Subcommittee Meeting
•
One (1) electronic version of the protocol (PDF)
•
MHS IRB application
•
Informed Consent Form using MHS Template (MS Word)
•
Recruitment or subject tools
•
Four (4) copies of the protocol
•
Two (2) copies of the investigator’s brochure (drugs) or Directions for Use
(device)
•
One (1) FDA 1572 signed form (if applicable)
•
One (1) letter noting regulatory status of study device from sponsor
The IRB will review all documents on a first come, first serve basis unless a patient is waiting
to be treated. If there is a high volume of submissions, there is a chance that protocols will be
reviewed at a later subcommittee date on the schedule, even if they are submitted on time.
The subcommittee can review approximately three protocols per meeting, and typically, two
subcommittee meetings are held per month. Additional subcommittee meetings may be
convened as determined on a case-by-case basis.
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Documents Needed for IRB Meeting:
New Protocols
•
Two (2) copies of submitted original application and ONE ORIGINAL
APPLICATION SIGNED AND DATED.
•
Two (2) copies of informed consents (and assents) AND ONE ORIGINAL
CONSENT(S) (and ASSENTS, if applicable) TO BE STAMPED.
•
Two (2) copies of recruitment tools, subject tools.
Re-Approval of Progress Reports and Informed Consent
•
One (1) signed original progress report including FORM A personnel and FORM
B (deviations)
•
Two (2) copies of the signed progress report
•
One (1) copy of the current ORIGINAL CONSENT(S) (and ASSENTS and
translations, if applicable) untracked without stamped IRB approval located on
front page,
•
One (1) original of the current consent(s)/assent(s)for stamping.
If you are making minor changes to the consent(s), assents, or consenting tools at this
time then:
•
One (1) copy tracked version of the current document and
•
One (1) copy untracked version of the revised document for stamping.
•
One (1) copy of sponsor’s report on the status of the study (include all that
apply such as data safety monitoring committee’s reports, Study Chair report, or
Annual Device progress report).
Revisions/Amendments
•
Submit one (1) electronic version (each) of the amendment, the amendment
summary, protocol that incorporates the amendment
•
If amendment requires changes to MHS consent, submit one (1) sponsor’s
consent sample and one (1) tracked version of current MHS consent with the
changes required only by this amendment. The IRB office will review the
consent changes requested for understandability, and completeness against the
sponsor’s sample. Identified issues may need to be further discussed with the
sponsor or MHS legal prior to final submission.
At the IRB deadline, submit:
•
one (1) signed revision form,
•
two (2) hard copies of amendment summaries and ONE COMPLETE ORIGINAL
AMENDMENT which includes the summary where applicable,
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•
ADDITIONALLY, one (1) copy of the protocol incorporating the amendment. If
the amendment is not sufficient to describe the detailed changes then the IRB
office reserves the right to request copies of the entire amendment.
Revised Consent
•
One (1) signed revision form,
•
Two (2) copies of revised informed consents (red lined with changes with new
revision date)
•
ONE (1) INFORMED CONSENT TO BE STAMPED (WITHOUT THE REDLINE).
Unanticipated Problems that are Adverse Events or Unanticipated Problems that are not
Adverse Events Report Forms (prompt reporting within 10 working day of becoming
aware of issue)
•
One (1) signed original and
•
One (1) copy of the unanticipated problem reporting form including sponsor
reports attached to each or supporting documentation (redact patient identifiers).
If the study is closed at site and sponsor requires submission acknowledgement, then
only submit one (1) original.
Other Documents
4.
•
One (1) signed revision form,
•
One (1) original document,
•
One (1) copy.
IRB Post-Review Actions
Following the IRB review of the study, one of the following outcomes will result. The
follow-up actions taken by the investigator depend upon the outcome of the IRB review.
4.1 Outcomes
Approval
No action is needed. The study can begin provided that approval has been
received from all other applicable reviewing entities (Sponsor etc.).
Approved with conditions that need to be satisfied for full approval
The IRB will provide the investigator with specific modifications that are
necessary for approval. Revise the study documents and/or provide clarifications
as recommended. Return one copy with the revisions tracked or documentation
requested. Response is reviewed and may not need to return to the full board
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unless the conditions cannot be satisfied. The study cannot begin until the
revised submission has been approved.
Tabled
The IRB will provide the investigator with specific questions that need to be
addressed before approval will be considered. Revise the study documents as
recommended. Tabled studies are re-reviewed by the full IRB. Investigators are
encouraged to attend the IRB meeting following a tabled decision. Studies may
be tabled if the investigator is unavailable to present the study to the IRB
committee.
The study cannot begin until the revised submission has been approved.
Disapproval
The investigator may discuss the review with the IRB Chairperson. The protocol
must be resubmitted in its entirety as per the Submission Requirements.
The study cannot begin until the new submission has been approved.
Investigators whose studies are not approved can benefit from a consultation with the
Office of Human Research on issues such as protocol design, informed consent and
other human subject protection issues.
For more information on the IRB process, please refer to the FDA website:
Guidance Documents for IRBs, Sponsors & Investigators
Please refer to the chart below to assist with determining the appropriate IRB review
category for your study. Please note: The IRB makes the final determination of the
review category.
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Determining IRB Review Category – Exempt, Expedited, or Full Board Review
Does the research pose less than minimal
risk, i.e. no known physical, emotional,
psychological, or economic rist?
YES
Does your research involve a vulnerable
population?
Meets the EXEMPT Category for
IRB Review
NO
NO
YES
Does the research pose minimal risk
typically encountered in daily life such as
moderate exercise, minor stress from
testing or surveys?
YES
Does your research involve a vulnerable
population?
YES
NO
Does the research pose greater than
minimal risk typically encountered in daily
life, such as maximal exercise, stressful
psychological tests, questions about illegal
activities?
Chapter 9: IRB Submission
Meets the EXPEDITED Category
for IRB Review
NO
YES
Meets the FULL BOARD
Category for IRB Review
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Chapter 10: Contracts and Study Finances
Contracts and Study Finances
1.
Study Budget Development
When requesting funding for a study, all study-related costs should be noted in the budget
including personnel, consultants, equipment, supplies, travel, and other expenses. NIH
applications have special Budget and Justification forms that contain detailed instructions.
Investigators should develop a budget based upon the expected expenses at each site. Billing
rates for the same procedure will vary from place to place. When participating in a sponsored
study, it is the sponsor’s responsibility to provide a budget template.
When considering an industry sponsored-study, all study related expenses should be
determined and compared to the overall reimbursement offered by the sponsor to ensure the
study is financially feasible.
Depending on the funding source, items may or may not be included in the budget and
expenses may have different associated overhead charges.
The following is a list of potential expenses involved in the conduct of a study:
a. Personnel
Estimate the amount of time for the PI, the coordinator(s), Pharmacist(s), Data Managers,
and any other staff that would be paid out of the study budget (i.e. research assistants,
administrative staff, statisticians). This estimate should include not only salary, but also
fringe benefit costs.
b. Labs, Tests, and Procedures
Technical Fees - A technical fee is the cost incurred for use of the mechanical equipment
and processing. Tests/procedures that are study related and are not "standard of care" must
be charged to the research budget. Every effort should be made to provide documentation
to determine what tests/procedures would be considered “standard of care” (i.e. drug
labeling information, established guidelines for monitoring/treating the particular disease,
generally accepted practices by the medical community etc.).
Professional Fees - The professional fee is the physician's charge for interpretation of
diagnostic procedures/tests. It is important to note that if there is a professional fee
associated with a test/procedure, that charge must be included in the expenses. A limited
number of laboratory tests have professional fees associated with them. All radiology and
cardiology procedures have a professional fee, as do various other procedures.
c. Subject Reimbursement
These charges may be incurred per visit or per subject. Examples include monetary
compensation, meals and parking/transportation costs. Sponsors may not provide subject
reimbursement for all studies
d. Additional Study Expenses
Other potential study expenses to consider:
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•
Training/Seminars/Conferences (directly related to the research projects)
•
Institutional Review Board (IRB) fees
•
Investigational Drug Service (IDS) fees
•
Advertising/Recruitment
•
Monitoring
•
Non-refundable start-up costs
•
Screen failures
•
Supplies
o
E.g. blood collection tubes, chemicals, dry ice)
o
E.g. centrifuges, mass spectrometers, liquid simulation counters)
o
Technology (e.g. telephone, computer)
o
Shipping/Packaging Supplies (e.g. dry ice)
•
Service Contracts (e.g. instrument maintenance)
•
Archival fees
•
Site Visit & Site Initiation Costs
e. Facilities and Administrative Cost
Facilities and Administrative (F&A) cost is the indirect cost associated with the project or
study; e.g. space, research administration, facilities, maintenance, human resources, etc.
F&A can only be assessed on certain activities and items depending on whether or not the
study is federally-funded (see the specific grant guidelines). For industry-sponsored studies,
the contract may specify which items can include F&A, though typically F&A is applied to all
costs for industry-sponsored studies. If you cannot locate the F&A rule on the Chart of
Allowable Expenses, you can consult with the OHR.
2.
Contract Submissions
Contract Submission for Sponsored Research
Contracts should be submitted with an appropriately developed budget to the Office of Human
Research as soon as possible to ensure that negotiations with the sponsor are resolved and
project initiation is not delayed.
The following documents should be included in a contract submission packet, which is
submitted to the Department Business Office (Business Administrator):
•
Clinical Trial Agreement (CTA)
•
Draft Budget
•
Protocol
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•
Informed Consent
•
Any lab manuals, pharmacy manuals etc.
The contract submission packet, for either Investigator-Initiated or Sponsored Clinical Trials
follows the process below:
2.1 Clinical Trial Agreement (CTA)
The Clinical Trial Agreement is a contract between the South Broward Hospital District (SBHD)
and the industry research sponsor that includes provisions to define the scope of work,
performance period and enrollment of subjects, cost and payment, proprietary rights, and
publications.
The CTA represents the legal agreement between the Sponsor and the SBHD and an
acceptance of such by the Investigator. The elements of a research contract may include: (1)
Scope of work, (2) Responsible investigator (Principal Investigator), (3) Performance period, (4)
Record-keeping obligations, (5) Reimbursement, (6) Confidentiality of Information, (7) Patents
and Inventions, (8) Advertising (mutual agreement covering use of institution or sponsor's
name), (9) Indemnification (see below), (10) Termination of the Contract, (11) Publication
Rights/Intellectual Property.
2.2 Budget Agreement
The budget agreement is a part of the Clinical Trial Agreement and specifies the reimbursement
to be paid per enrolled subject, the miscellaneous and non-subject expenses, and the
reimbursement schedule. Refer to Study Budget Development for more details.
The budget should be evaluated and negotiated during the review of the protocol or
grant/proposal submission and should realistically capture all costs associated with conducting
the research, including faculty time commitment. Payment is usually received by the Finance
Manager at the OHR.
2.3 Indemnification Agreement
The indemnification language of the Clinical Trial Agreement protects the investigator and
institution from liability for damage incurred by a research subject as a result of study
participation. This protection is contingent upon the investigator practicing standard of care
medicine and complying with the protocol and regulatory requirements and GCP standards.
The sponsor is held accountable for medical expenses incurred by research subjects as a result
of study participation. It does not obligate the sponsor to reimburse for "standard medical care"
or care that would have occurred irrespective of study participation.
In certain types of research, the sponsor may not be accountable for all expenses incurred by a
subject's participation in a study. One example is cancer research where expenses for certain
procedures and drug regimens are often borne by the subject's insurance carrier.
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2.4 Letter of Understanding
When an investigator not employed by MHS wishes to conduct research within MHS facilities, a
Letter of Understanding needs to be executed in order to inform the Investigator and his team of
the responsibilities and obligations of MHS and Contractor pertinent to the project. Please
contact the OHR for more information regarding this process.
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Chapter 11 Site Implementation
Site Selection for Multi-Center Studies
For multi-center studies, it is the responsibility of the sponsor to choose sites to
participate in the research study. The sponsor may be an investigator collaborating with
other institutions or a pharmaceutical company conducting a multi-center trial.
Regardless, sponsors and sponsor-investigators should follow the criteria set forth in
Good Clinical Practice Guidelines 5.6.1. The selection process identifies investigators
who are qualified and have adequate resources to implement the protocol.
The following items are evaluated during the site selection process:
Suitability of the investigator
•
•
•
•
•
Does the investigator have expertise in the area being studied?
Does the investigator have experience with this type of research?
Is the investigator accessible?
Does the investigator have appropriate training and qualifications in clinical
research?
Has the investigator ever been sanctioned for research misconduct?
Presence and experience of staff
•
•
•
•
Are research-designated staff members involved and are they qualified?
Are the potential sub-investigators qualified for the protocol?
Is there an affiliated IRB to review the protocol?
Will there be a qualified pharmacist or research pharmacist?
Adequacy of facilities/resources
•
•
•
Is there a research office? A location for monitoring? An examination office?
Is there a secured location for storing study files and/or investigational products?
Does the investigator have access to the technology and equipment needed for
the study (e.g. centrifuge, freezers, computers, ultrasounds, etc.)?
Access to subjects
•
•
•
How many individuals with the appropriate diagnosis are accessible?
Are there any studies that may be competing for the same population?
What is the investigator's enrollment history in previous studies?
If the site fulfills the needed requirements for the study, the sponsor will notify the site of
acceptability as an investigative site. The sponsor will begin the site initiation process.
Sponsor-investigators often choose sites based upon their interactions with fellow
researchers at other institutions. Whether sites are evaluated through a telephone
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interview, documented correspondence, or on-site visits, the Sponsor-Investigator must
take the appropriate measures to select and evaluate investigative sites.
Generally, site selection is accomplished initially via questionnaires or surveys, and
further evaluated during the site qualification visit by the monitor (CRA). The site
qualification visit may include:
•
•
•
•
Tour of facilities including: patient care areas, screening areas, lab processing
area, research office, pharmacy (if applicable) and location for monitoring of
study data
Introduction to study personnel including: Principal Investigator, research
coordinator(s), sub-investigators, and pharmacists
Confirmation of secured location for storage of investigational materials: separate
area/office for Case Report Forms (CRF) and an area for study drugs and/or
devices (if the pharmacist is responsible for investigational drugs, there must be
a separate locked area for storage within the pharmacy)
Discussion of the investigator's responsibilities, monitoring plans, and review of
the protocol.
Site Orientation
Prior to study initiation, the research team should be versed in the proper techniques to
conduct the study in accordance with the protocol, federal regulations, and GCP. This is
true regardless of whether a study involves one department or institutions from around
the world. Study orientation may be accomplished through an investigator meeting,
onsite training, online training, conference calls, or a combination of these methods.
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Site orientation may include:
Site Initiation
During the site initiation visit, the study monitor (CRA) will have a list of criteria to
evaluate and review. The monitor will also provide one-on-one instruction and reinforce
protocol training/orientation with the research team.
Sponsor-Investigators are similarly responsible for evaluating and initiating sites. For the
monitor's Site Initiation Checklist, see the applicable forms in the Sponsor-Investigator
SOPs (refer to SOP 402).
A monitor's site initiation checklist may include:
•
•
•
•
•
•
•
Confirmation of regulatory documentation
Collection of outstanding regulatory documentation
Review of protocol procedures, amendments, case report form completion, etc.
Review study monitor expectations
Review consent form and consent process
Inspect and inventory study supplies
Inspect storage site and dispensation records of study drug and/or device
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Chapter 12: Research Project Management
Conducting a clinical research study requires a well-organized approach to project
management. Many aspects of study conduct can be discussed in relation to individual
subjects and are covered in detail in the Subject Management section of this manual.
This section discusses the aspects of project management that relate to the overall
project.
While this manual defines the requirements and offers standards for research project
management, general project management skills are critical to effective and efficient
study conduct. These skills include the ability to:
•
develop project management strategies
•
effectively prioritize
•
translate strategies into step-by-step plans for action
•
develop logical and practical approaches to implementing action plans
•
organize large amounts of information by creating and maintaining well organized
systems
•
monitor work progress to completion
•
pay close attention to detail
•
ensure timely documentation of study processes
1.
General Guidelines of Study Management
Effective project management involves careful planning, organization, and regular
assessments of the progress of the study. This section of the Manual details important
elements of project management. While it's important to tailor a project management
plan to the logistics of a specific study, there are basic elements of effective
management that are common to all clinical research studies:
•
•
Measurement and tracking of key study progress and safety parameters
o
Screening/Enrollment
o
Adverse events
o
Data collection
o
Study finances
Study management meetings between the Principal Investigator (PI) and Clinical
Research Coordinator (CRC)
1.1 Tracking Key Parameters
In patient care, it's important to ascertain basic parameters and to track them over time
to best manage the health of a patient. Similarly, to manage the "health" of a clinical
study there are certain basic parameters common to all research projects that should be
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measured and tracked regularly at regular intervals during the course of the study. The
following summarizes these key parameters:
1.1.1 Projections
In the planning stages of the study, it is important to create projections of expected rates
of the key study parameters of screening, enrollment, data collection activities, and
adverse events. This becomes the benchmark against which regular measurement and
tracking of actual rates of these parameters can be compared.
1.1.2 Screening and Enrollment
While individual studies will vary, it has become a common statistic in academic settings
for it to take two to three months for a site to enroll its first subject. Additional effort in
upfront planning can reduce this lag from study site activation to first subject enrolled
(see below: Subject Recruitment Plan). Screening and enrollment logs are essential in
measuring the study enrollment progress and are required as part of Good Clinical
Practice (GCP) guidelines. Assessing the number of individuals screened to the number
enrolled is critical to time and effort projections as well as enrollment timeline
projections. Once the study has actually started enrollment, it is important to frequently
compare actual to projected enrollment rates per month.
•
Symptom: High screening rates
Early in the course of a study, there may be a high ratio of screened-to-enrolled
subjects as the study team adjusts to the process of screening for participants.
However, if a high ratio of screened-to-enrolled subjects continues, it is an important
flag to reassess the recruitment plan.
•
Symptom: Lags in projected versus actual enrollment rates
Assuming screening to enrollment rates are acceptable, lags in projected enrollment
usually indicate problems in research staff workload, study recruitment plans, or may
be related to study staff vacations or seasonal variation in subject availability.
Seasonal variation in subject availability has been noted in national and international
studies and is thought to be related to study subject vacations. In creating the initial
enrollment projections for a study site, staff vacations and seasonal variability in
subject availability must be taken into account.
Potential treatments: Careful planning of study recruitment techniques and
research staff allocation, including seasonal variation in initial pre-study projections,
is the most effect preventative action. If there are screening problems or enrollment
lags despite this "preventative medicine," based on the above differential diagnoses,
consider:
o
re-assessing screening techniques and process, (i.e. re-education to
screening process may be required, or screening to enrollment rates may
be acceptable but the screening process may be too laborious or overly
involved)
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o
assessing Clinical Research Coordinator workload and impact on the
screening or enrollment process
o
reassessing inclusion/exclusion criteria
o
adding additional recruitment outreach actions
o
If all recruitment/screening remedies have been exhausted and it is not
possible to adjust the inclusion/exclusion criteria, re-project workload,
cost and enrollment rates, the study team and Investigator need to
determine if re-projections are acceptable and therefore whether the
study is still feasible.
1.1.3 Adverse Events
Collecting and reporting adverse events are important elements of GCP; however, it is
essential that rates of specific adverse events be followed to effectively assess safety
trends across the study. Adverse event rates can be hand-tallied from paper tracking
logs, or on electronic spreadsheets (e.g. MS EXCEL). Electronic tracking generally
allows easy sorting by event type so that rates of events can be easily assessed. If the
study intervention has an expected rate of certain adverse events based on previous
experience or clinical studies, it is important to track expected versus actual rates of
those events. Additionally, in assessing events it is important to see if there are research
subject factors that seem to be common to a specific type of adverse event such as
concomitant illness, concomitant medications, age, gender, etc. Looking for such
possible associations is essential in determining the best course of action when serious
adverse event types or rates of events are out of range from expected.
•
Symptom: Higher than expected rates of serious adverse events or reason to be
alarmed about an unexpected event (due to apparent severity or relationship to
study intervention)
It is possible that the SAEs are:
o
a sporadic event
o
related to interaction between intervention and research subject
characteristic
o
related to dose and dosing regimen for drug studies or interventional
techniques for non-drug studies
o
related to study intervention and risk ratio still acceptable
o
related to study intervention and risk ratio not acceptable
Potential treatment: When in doubt about the reasons for a rise over expected rates
of serious adverse events or if there is reason to be alarmed about an unexpected
event, it is essential to interrupt study enrollment and do a prompt but in-depth
evaluation of safety, or in certain cases involving investigational medications, stop all
administration of study article. Based on findings, follow-up actions may include
revising inclusion/exclusion criteria (if the issue appears to be related to research
subject characteristics), reassessing and adjusting dose and dosing regimen for drug
studies or interventional techniques for non-drug studies (if the issue appears related
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to how the study intervention is implemented), continuing the study with additional
safety monitoring techniques and efforts, or discontinuing the study. See Premature
Discontinuation of Study for issues to consider when discontinuing study subjects or
discontinuing a study prematurely. Remember to summarize findings and actions to
the IRB for any of the interventions noted above.
1.1.4 Data collection
It is important to transcribe data onto the study Case Report Forms (CRF) in an ongoing
fashion during the course of a study rather than wait until the end of the study to perform
this function. To avoid a back-up of work on data collection, tracking completed study
visits vs. completed visit-related CRFs is an effective way to keep on top of the
workload.
Once CRFs have been submitted for data entry, another important workload issue is the
number of data queries generated to resolve data discrepancies. Tracking the number of
data queries received vs. the number of answered queries helps manage this data task.
•
Symptom: Lag in CRF completion vs. study visits completed, or Lag in
responding to data queries vs. number of queries received
Time management problems, project work overload, overly complex CRFs
•
Symptom: Large number of data queries
Learning curve in completing CRFs, inadequate attention to detail in completing
CRFs, confusing or overly complex CRFs
Potential treatments: review of CRF completion process, team training on time
management, reassessment and redistribution of workload, slowing of study
enrollment until backlog caught-up, possible redesign of problematic CRFs
1.1.5 Financial tracking
Generally, study payments are triggered by certain milestones such as specific activities
(e.g. screening and enrollment), specific visits completed, or Case Report Forms
completed. Different departments and divisions have various methods of tracking studyrelated payments. The Office of Human Research offers the use of a Clinical Trials
Management System – CREDIT. Clinical Research Environmental Data Information
Tracking (CREDIT©) is a comprehensive web-based software program for all aspects of
clinical trials administration and patient scheduling. CREDIT simplifies the management
of clinical trials administrative tasks including tracking of patient schedules, simplification
of record-keeping and reporting, notification of patients regarding changing protocol
information, and IRB-related activities. At MHS, CREDIT is routinely utilized to track
study related milestones as well as invoicing and receivables.
At a minimum, it is important to regularly track study milestones and their dollar value
against payments received, and to compare total study budget versus expenditures. You
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can work with the Office of Human Research for the optimum method of financial
tracking for your studies.
1.2 Study Management Meetings
It is imperative to hold regularly recurring meetings between the Principal Investigator
and the Clinical Research Coordinator to review the key measures of study progress
noted above in Tracking Key Parameters. The standard interval for these regularly
occurring meetings will vary depending on type of study or portfolio of studies, however it
is critical to set aside adequate time on a regular basis for such meetings. The structure
of these meetings is decided in the study planning phase, so that when the study is up
and active, everyone is aware of his or her role, the expected tracking reports and
required update information for the meetings, and the date, time and interval of the
meetings. It is important that the key tracking reports are completed and current at the
time of the meeting, and that other issues for discussion are identified and ready for
action (e.g. outstanding laboratory review, new operational issues or problems, etc.).
2.
Study Documentation Management
The research records provide vital historical documentation of the research activity,
correspondence, and project management. Any clinical research study by nature both
requires and produces a sizable amount of documentation. A methodical and wellexecuted system for managing these documents is critical for efficient project
management and regulatory compliance, and is also a requirement of federal regulations
and Good Clinical Practice (GCP) guidelines.
The Principal Investigator (PI) is ultimately responsible for ensuring proper record
maintenance. The PI often delegates this responsibility to the Clinical Research
Coordinator (CRC).
This section groups the various types of study documentation into four file systems:
2.1 Study Administrative File/Regulatory File
Federal regulations require the existence and maintenance of documents relating to the
study. These documents, when properly maintained, provide clear evidence that the
study has been conducted according to federal regulations and GCP guidelines. The
Study Administrative File is the central file for all of these critical regulatory documents.
The structure and contents of the Study Administrative File are covered in this section.
2.1.1 Study Administrative File Contents
The following is a list of the documentation that should be kept in the Study
Administrative File, as well as guidelines for maintaining the binder. The order of the
different sections may vary according to need. In general, the most frequently used
sections should be closer to the beginning. Also consider dividing the contents of the
Study Administrative File across more than one binder. For example, a study may have
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3 binders - 1 binder with all Correspondence, a second binder with all Study Documents
and Research Personnel, and a third binder with all Study Tracking Logs.
Protocol
•
•
•
Protocol
o
The document that describes the objective(s), design, methodology,
statistical considerations, and organization of a research study.
o
Maintain all versions in file.
Protocol Signature Page
o
Contains a statement that the Principal Investigator (PI) will comply with
all protocol requirements and applicable research regulations and GCP
o
The PI must sign and date the protocol signature page
Protocol Amendments
o
A written description of a change(s) to or formal clarification of a protocol
o
Each amendment should indicate a date of revision and version number
o
Note : Protocol amendments must be IRB-approved before being
implemented
Case Report Form Sample
•
Clean Copy of the paper Case Report Form
o
•
All versions of the CRF should be maintained
Case Report Form Completion Guidelines
Curricula Vitae and Licenses
•
•
•
Curriculum Vitae (CV)
o
A summary of the educational and academic backgrounds, teaching and
research experience, publications, presentations, awards, honors,
affiliations of each research staff
o
CVs should be maintained for the PI, Sub-Investigators and Research
Coordinators
o
CVs should be signed and recent (within 2 years)
Medical Licenses
o
Current professional licensure should be present for physicians and other
licensed personnel
o
The CV and license documents the qualifications and eligibility of staff to
provide medical supervision and to conduct the study
Training Certificates
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o
May include copies of relevant training certificates (Protocol training, GCP
CITI training, HIPAA training, e-CRF, IATA, etc.)
Signature/Delegation of Responsibility Log
•
•
Signature Form
o
A document that contains examples of the signatures and initials of
research staff
o
Any provision of signature authorities approved by the PI should be
included
Delegation of Authority Log
o
A document that identifies the study-related tasks that the PI has
delegated to other research staff
o
The delegation log and signature form may be combined into a single
document
o
May include a clear description of activities conducted by key staff at
collaborating sites
Informed Consent
•
•
•
Informed Consent Form
o
A copy of the IRB-approved Informed Consent Form must be kept on file
o
A consent form is not valid for subject use without an affixed IRB approval
stamp on the first page
o
All versions of the approved consent are kept in the regulatory files: the
original version and all revisions
IRB Approved Educational Materials and Advertisements
o
Information describing the study that is to be presented to subjects in
verbal or written form, including recorded audiovisual media
o
These material help substantiate that subjects were given appropriate
information to support their ability to give fully informed consent
HIPAA Authorization Form/Waivers
o
A copy of the HIPAA Authorization that was submitted to the IRB must be
kept on file
o
All versions of the HIPAA Authorization forms are kept in the regulatory
files: the original version and all revisions
o
If there is no HIPAA Authorization Form for the study, include the IRB
Waiver of HIPAA Authorization letter or other documentation to support
the fact that HIPAA Authorization is not required.
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Laboratory Documents
•
•
Laboratory Certifications and Licenses
o
Required for studies utilizing laboratory data or results
o
Provides evidence of the competence of the facility to perform the
required test(s) and supports the reliability of the lab results
o
Certifications may include: the state laboratory license/permit (AHCA), an
accreditation by The College of American Pathologists (CAP), Clinical
Laboratory Improvement Amendment Accreditation (CLIA), and the Joint
Commission on the Accreditation of Healthcare Organizations (JCAHO) ,
CV of laboratory license holder, medical license of laboratory director
Normal Reference Ranges
o
•
Laboratory reference ranges may vary from laboratory to laboratory;
therefore, it is necessary to include documentation of the laboratory's
normal range values. All updates to the laboratory ranges must also be
maintained.
Lab Manual(s), if appropriate
Correspondence with Institutional Review Board (IRB) & Other Reviewing Entities
•
•
IRB Correspondence
o
Correspondence between the research site and the IRB regarding the
conduct of the study and the research subjects
o
IRB correspondence may include: approval letters, protocol amendments,
changes to the consent form, study updates, protocol violations, adverse
event reporting, continuing review reports, and notification of study
termination
IRB Membership/Assurance
o
MHS IRB issues a Federal Wide Assurance number (FWA00003898) that
documents the IRB is in conformance to federal regulations. Please
contact the IRB or OHR if further information regarding the FWA number
is required.
•
Sponsors
•
Federal Agencies
Subject Logs
•
Screening Log
o
Identifies who was evaluated for the study and documents the criteria that
excluded them from study participation
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o
•
Generally, subjects who were reviewed or consented for study
participation, but were then found to be ineligible are considered screen
failures
Enrollment Log
o
Confidential list with identifiable information (e.g. name, date of birth, date
of hospital admission)
o
Identifies subject enrollment in chronological order
o
Subjects who enrolled in the study and who withdrew or have been
withdrawn
General Correspondence
o
Includes relevant communication between investigative sites, clinical
personnel, pharmacy, sponsor, etc. regarding study administration, study
conduct, subject management, protocol violations, and adverse events
o
Correspondence may take the form of letters, facsimiles, telephone
discussions, and emails

Document correspondence in such a manner that the date,
persons involved, and relevance to the study is apparent
o
Facsimile confirmations and shipping receipts should be saved and filed
with the corresponding documents as proof (receipt) of communication
o
Telephone calls may be documented on a Telephone Contact Log
Adverse Events
o
Adverse Events (AE) and Serious Adverse Events (SAEs) Tracking Log
o
Investigational New Drug (IND) Safety Reports (including MedWatch
forms)
o
Data and Safety Monitoring Board or interim analyses reports
o
Documents tracking AE Reporting (e.g. IRB, sponsor, federal agencies,
etc.)
Protocol Deviations
o
All deviations from the protocol should be tracked on a Protocol Deviation
Log
Monitoring
•
Monitor Signature Log and Visit Record
o
•
Tracking document that records the visits made by the monitor throughout
the course of the study
Study Initiation Reports
o
Letter documenting that the procedures were reviewed prior to study
initiation and the site was determined to be suitable for enrollment
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•
Interim Monitoring Reports
o
•
Close-Out Report
o
•
Letter documenting the findings after each monitoring visit
A report or letter documenting that the study had a final monitoring visit
after the conclusion of the study to ensure any outstanding issues have
been resolved
Monitor Curriculum Vitae (CV)
o
If monitor is hired by the PI, a copy of the monitor's CV
For studies involving drugs and devices, additional sections are required to be included
the regulatory binder.
2.1.2 Regulatory Binder - Additional Elements for Drug and Device Research
For studies involving an Investigational New Drug (IND) or Investigational New Device
(IDE), these documents must be maintained in addition to the regulatory documentation
required by GCP standards and federal regulations.
FDA Form 1571 (if applicable)
o
FDA form cover sheet for Sponsor-Investigators filing an IND application
o
Prior to study initiation, an investigator submits a 1571 to propose
studying an unapproved drug, or an approved product for a new
indication or in a new patient population
FDA Form 1572
o
FDA form that declares the Principal Investigator's commitments and
identifies the participating personnel, institution, and facilities in the study
o
The original, signed 1572 is be filed with the sponsor prior to study
initiation and a copy will be placed in the regulatory files
o
If changes or additions are made, a new 1572 must be completed,
resubmitted to the sponsor, and a copy is stored in the Regulatory Binder
with previous versions
o
FDA regulations do not require a 1572 to be filed for device trials
Investigator's Brochure and Product Labeling
•
Investigator's Brochure
o
Provides relevant and current scientific information about the
investigational product
o
If an Investigator's Brochure will not be utilized, an equivalent packet of
information (such as package insert) with safety information should be
kept on file
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o
•
Maintain most current brochure including updates and revisions
Product Labeling and Handling Instructions
o
Maintain a sample of the label(s) attached to the containers
o
Include instructions for handling the investigational product
o
If applicable, include procedures for un-blinding
Drug/Device Accountability
•
Accountability Forms
o
Drugs and devices must be inventoried via a tracking or accountability
form
o
Documentation may include shipments, receipt, dispensation, return and
destruction of the investigational product
o
Include shipment receipts and supply correspondence
o
For drug studies utilizing MHS Investigational Drug Services (IDS), these
can be kept in the pharmacy during the study, but should be placed in the
regulatory binder at study closeout
o
The National Cancer Institute (NCI) mandates use of the Agent Drug
Accountability Record Form (DARF) for investigational medications. This
template is available at Form, Templates & Documents.
2.2 Financial Documents File
The financial documents include any agreements, contracts, disclosures, salaries or
grant funding documents. Financial Records are not considered regulatory documents
and should be kept in a separate confidential file. The structure and contents of the
financial documents are covered in this section. Typically, this file will be maintained at
the OHR.
2.2.1 Financial Documents
DO NOT include financial documentation in the Regulatory Binder. Financial
documents should be stored in a separate secure location in the OHR.
•
Contract
o
Financial Agreement
o
Insurance Statement
o
Indemnification
•
Salaries & Grant funding documents
•
Financial Disclosures
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o
For all MHS investigators, include copy of Confidential Financial
Disclosure Form
o
For studies sponsored by other organizations (such as pharmaceutical
companies), the Sponsor may provide a Financial Disclosure Template
that would need to be maintained in the Regulatory File.
o
For FDA studies, study personnel must complete a Form FDA 3454
Financial Interests or 3455 Arrangements of Clinical Investigators which
reveals all significant financial arrangements with the sponsor, proprietary
interest in the investigational product, or significant equity interest while
conducting the study and for a period of 2-3 years thereafter. These forms
are available from the FDA Electronic Forms page FDA Forms
2.3 Informed Consent File
While copies of the signed Informed Consent Forms are included in several places, it is
recommended that the original signed Informed Consent Forms be kept together in one
binder. Alternatively, original signed Informed Consent Forms may be maintained in the
Regulatory File. Most regulatory auditors are interested in reviewing every consent form.
Keeping the original informed consent forms in one file facilitates this review, removes
the burden of collecting all subject files and reduces the likelihood of expanding the audit
scope.
2.4 Subject Files/Case Report Files
Each study subject should have an individual file, where copies of forms, data, and
records of correspondence are maintained. The Subject File is described in more detail
in Study Procedures.
3.
Data Management
At the heart of all research projects are the data to be collected and analyzed. Careful
data management procedures are critical to maintaining data integrity. Proper
procedures ensure that data are identifiable, verified, validated, retrievable and
protected.
The various components of data management include: data collection, data entry, data
verification, and data validation. When properly executed these steps prepare data for
statistical analysis.
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Chapter 13: Investigational Product Inventory
The Principal Investigator is responsible for securing, dispensing, and accounting for all
study drugs or devices that are received. The sponsor is responsible for assuring that
the investigator is meeting these requirements.
Throughout the study, Drug/Device Accountability includes:
•
Documenting drug/device shipment and receipt
•
Dispensing/utilizing the investigational product according to protocol
•
Maintaining an accountability log
•
Maintaining randomization (if applicable)
•
Ensuring blinding (if applicable)
•
Ensuring proper and secure storage conditions
•
Documenting any drug/device that is returned to sponsor or destroyed
Through investigational product inventory records, any member of the research team or
an outside auditor should be able to track every unit of the investigational product from
the time it leaves the manufacturer until the time it is used by a subject, destroyed or
returned back to the manufacturer.
The Investigational Drug Services (IDS) Pharmacists at MHS can be contracted to
manage study drugs and non-significant risk devices, as well as maintain accountability
for outpatient clinical studies.
1.
Storage of Drugs/Devices
1.1 Storing Medications
Generally, medications need to be:
•
kept in a locked room, drawer or cabinet with restricted access
•
secure and accessible only to authorized pharmacy staff or delegated members
of the study team
•
stored separate from samples, food, blood products, and commercial drugs
•
adequately labeled
•
inventoried via a tracking or accountability form
1.2 Temperature Requirements
"Room Temperature" is defined by the United States Pharmacopeial Convention
(USPC) as 59º to 77ºF (15º to 25ºC).
This is the recommended storage temperature for most medications. Some
drugs, such as capsules or powders, may start to degrade when exposed to
warmer temperatures or to moisture.
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Medications requiring room temperature storage should be kept in a dry place,
free from moisture. Storage near radiators, windows or sinks should be avoided
to prevent exposing the medication to moisture.
"Refrigeration" is defined by the USPC as 38º to 46ºF (2º to 8ºC).
Note: Do not store refrigerated medications with food. A medication refrigerator
must be used ONLY for medications; this is a Joint Commission on Accreditation
of Healthcare Organizations (JCAHO) requirement.
A thermometer should be kept in the refrigerator and checked regularly to assure
that the refrigerator stays within the proper temperature range. The staff should
maintain a temperature log, recording periodic temperature readings. Excursions
outside of the approved temperature ranges must be reported to the sponsor
expeditiously to assess the validity of the drug product.
"Frozen" is defined by the USPC as -4º to 14ºF (-20º to -10ºC).
If using a common household refrigerator with a freezer compartment, a lowtemperature thermometer should be obtained to check it regularly, as these
freezers fluctuate in temperature throughout the day. The staff should maintain a
temperature log, recording periodic temperature readings. Excursions outside of
the approved temperature ranges must be reported to the sponsor expeditiously
to assess the validity of the drug product.
1.3 Storing Devices
Devices will generally be stored within the department it will be used in. The devices
need to be:
•
kept in a locked drawer or cabinet with restricted access
•
secure and accessible only to authorized pharmacy staff or delegated members
of the study team
•
adequately labeled
•
inventoried via a tracking or accountability form
2.
Product Labeling
Proper labeling of an investigational product is an essential part of Good Clinical
Practice (GCP) guidelines and is important in reducing medication errors. Labeling of
ANY prescription drug, whether marketed or investigational, is required by federal and
state law. This is especially important if the subject is having an adverse reaction or if
the subject is admitted to an outside healthcare institution.
For investigational drugs, Florida Code outlines the following items to be included on a
label:
•
Name of study drug (if blinded, see below for suggested wording)
•
Serial number of the prescription (optional for clinics, mandatory for pharmacies)
•
Name of the subject & unique identifier or randomization number
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•
Complete directions for use, including precautions
•
Name of the prescriber
•
Phone number that subject can call for assistance, typically a 24-hour contact
number is used
•
The date dispensed
•
The following statement: "CAUTION: New Drug - Limited by Federal Law to
Investigational Use"
Note: To best document drug assignment, a copy of the label may also be included in
the subject's file, typically affixed to the subject's CRF. The label can be designed with a
perforation so that a removable copy can be detached at the time of dispensation.
2.1 Blinded Studies
When conducting a blinded study, include the names of both study drugs and/or placebo
on the label. A method for unblinding in the event of an emergency should be detailed in
the protocol, and a member of the study team should have a means for breaking the
blind.
•
Example: "Study Drug Name: Drug X / placebo 40 mg"
•
Example: "Study Drug Name: Drug X 40 mg / Drug Y 80 mg"
2.2 Supplemental Labels
For industry-sponsored studies, the sponsor may provide investigational agents in prepackaged containers. However, the investigator is still required to supplement the
sponsor's label with any missing information (discussed above) in a supplemental label.
3.
Dispensing Drugs/Devices
3.1 Dispensing Medication
If dispensing study drugs, the investigator or a member of the research team must
properly store, secure, track, and inventory the study drug.
The JCAHO requires that anyone administering an investigational product have a
working knowledge of the drug including its purpose, side effects, and precautions.
Therefore, the investigator should take care to in-service the clinical staff as well as
provide access to written materials describing the investigational product.
3.2 Investigational Drug Service
If utilizing MHS Investigational Drug Services (IDS), the research pharmacy will store
and dispense the study drug, retain detachable labels, maintain shipping records and
complete accountability/dispensation forms.
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Study drugs ordered from the IDS should indicate the dose, frequency, and time of
delivery in addition to the subject, the study and, when applicable, the subject weight. In
randomized studies, the pharmacist may need to be informed of the randomization
assignment or randomization numbers.
Unused study drugs or returned empty containers should be returned to IDS for
inventory and tracking. At the conclusion of the study, discrepancies are resolved
through the coordinated efforts of the pharmacist, the research team, and the sponsor (if
applicable).
3.3 Dispensing Devices
Devices will be stored in a locked cabinet or drawer within the department it will be used
in. Dispensing devices requires the same documentation mentioned with regards to
drugs (i.e. shipping records, accountability/dispensing records etc.)
3.4 Drug/Device Accountability Records
Accountability records may include the following documentation:
•
Certificates of analysis
•
Sample of labels
•
Handling instructions
•
Master randomization list
•
Un-blinding procedures
•
Shipping receipts
•
Accountability Log
Accountability records should be incorporated into the regulatory binder. Depending
upon the type of study and the delegated responsibilities, accountability records may be
handled by the clinical research staff, pharmacist, or sponsor.
3.5 Accountability Log
The accountability log is a standardized tool for documenting exactly what happens to a
medication or device during the course of a study. The log documents the receipt, the
dispensation, the transfer to other sites, and the return or destruction of the
investigational product. Drugs and devices are inventoried by the lot and/or serial
numbers.
Note: All unused, expired or damaged products must be returned to the IND/IDE holder
or manufacturer who supplied the products. If the investigator is the IND or IDE holder,
he or she must carefully document destruction of the investigational.
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Templates are available from the OHR.
The National Cancer Institute (NCI) mandates use of the NCI Investigational Drug
Accountability Record Form for investigational medications. This template is available at
ctep.cancer.gov/forms/index.html.
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Chapter 14: Adverse Events and Unanticipated Problems
During the course of conducting clinical research, events occasionally occur that were
not anticipated and involve risk to the subjects or others. Typically in drug and device
trials, researchers think of abnormal reactions to a study medication and intercurrent
medical problems as an event that needs to be documented and reported. However, in
addition there exists a much broader set of “events” that require attention and reporting,
generally classified as “Unanticipated Problems Involving Risk to Subjects or Others.”
It’s important to consider this broader definition when assessing an event.
1.
Definitions (Adverse Events/Unanticipated Problems)
Unanticipated Problems Involving Risk to Participants or Others
This is an event that:
•
Was unanticipated --and--
•
Suggests that participants or others are at greater risk of harm than was
previously known or recognized.
This definition specifically includes the following:
•
Information that indicates a change to the risks or potential benefits of the
research, in terms of severity or frequency. For example:
o
An interim analysis indicates that participants have a lower rate of
response to treatment than initially expected
o
Safety monitoring indicates that a particular side effect is more
severe, or more frequent than initially expected
o
A paper is published from another study that shows that an arm of
your research study is of no therapeutic value
•
Change in FDA labeling or withdrawal from marketing of a drug, device,
or biologic used in a research protocol.
•
Breach of confidentiality.
•
Incarceration of a participant when the research was not previously
approved under Subpart C and the investigator believes it is in the best
interest of the subject to remain on the study.
•
Event that requires prompt reporting to the sponsor
•
Complaint of a participant when the complaint indicates unexpected risks
or the complaint cannot be resolved by the research team.
•
Protocol violation (meaning an accidental or unintentional change to the
IRB approved protocol) that placed one or more participants at increased
risk, or has the potential to occur again.
•
Sponsor imposed suspension
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Unexpected/Unanticipated
An event is classified as “unanticipated” when the specificity or severity is not
reflected in the study documents including the protocol, informed consent
document, or the investigator brochure. In most cases, an unexpected or
unanticipated event heightens the urgency for reporting.
Related to Study Procedures
The determination of how likely the event is related to the study procedures is
made by the principal investigator, the classification of which may vary. The IRB
asks if the event is "more likely than not" related to the study procedures. FDA
regulations consider an adverse event associated if is "reasonably" or "probably"
caused by the drug.
Involved Risk to Participants or Others
"Participants or others" may involve anyone, including research subjects,
research staff, or others not directly involved in the research. The unanticipated
problem can occur in either clinical or non-clinical research. "Risks" include
physical, psychological, economic, legal or social consequences.
2.
Drug and Device Research Definitions
When involved in drug and device research, researchers must also be familiar with
terminology used to define and classify unanticipated problems.
Adverse Event (drug and biologics research)
An Adverse Event (AE) is a subcategory of the broader category of
"Unanticipated Problems Posing Risk to Participants or Others", most commonly
used in drug and device studies. An adverse event is defined as:
•
any unfavorable or unintended sign (including an abnormal laboratory
finding), symptom, or disease occurring at any stage of the study
•
may include an exacerbation of a pre-existing condition, intercurrent
illness, drug interaction, drug overdose, failure of expected action or
significant worsening of the disease under study
•
an event that may compromise the rights, safety, or welfare of research
subjects
Any event that could be characterized by the definitions above is an AE whether
or not considered related to the study or product.
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Serious Adverse Event (drug and biologics research)
An AE becomes a Serious Adverse Event (SAE) when any of the following
outcomes occurs:

Death

Life-threatening experience

Inpatient hospitalization or prolongation of hospitalization

Persistent or significant disability/incapacity

Congenital anomaly/birth defect in the subject's offspring

An important medical event that, based upon appropriate medical
judgment, may jeopardize the subject and may require medical or surgical
intervention to prevent one of the outcomes listed above.
Unanticipated Adverse Device Effect (device research)
Any serious adverse effect caused by or associated with a device that was not
previously identified in nature, severity, or degree of incidence in the
investigational plan or application; or any other unanticipated serious problem
associated with a device that relates to the rights, safety, or welfare of subjects.
Investigators who hold an IDE for a device study must conduct an immediate
investigation of any unanticipated adverse device effects. If the sponsor
determines that the effect poses an unreasonable risk to subjects, the sponsor
must terminate all investigations that present that risk as soon as possible, but
within 5 working days after the determination. A terminated study may not be
resumed without IRB approval (for Non-Significant Risk Device studies) or FDA
and IRB approval (for Significant Risk Device studies).
3.
Documentation (Adverse Events/Unanticipated Problems)
3.1 Documenting Non-serious Adverse Events
Non-serious AE's are typically documented in the appropriate source documents where
applicable (i.e. medical chart or subject record), the Case Report Form, and the Adverse
Event log of the Regulatory Binder for the study.
Documentation should include the following information:
•
Protocol name and numbers
•
Subject identifiers
•
Date and time of onset and outcome
•
Course
•
Intensity
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•
Action taken
•
Relationship (causality) to the study
•
Outcome
3.2 Documenting Serious Adverse Events
An SAE Form should be used to document all SAEs for the study. The form should
capture the following information:
•
Protocol name and number
•
Subject identifiers
•
Demographic data
•
Nature of the event
•
Severity of the event
•
Probable relationship (causality) of SAE to study or investigational product
•
Date and time of SAE onset
•
Date and time of SAE resolution, if available
•
Clinical assessment of subject conducted at time of SAE
•
Results of any laboratory tests and/or diagnostic procedures
•
Autopsy findings (if appropriate)
•
Outcome
•
Follow-up plan
•
Studies involving an investigational article
•
Lot number and expiration date
•
Possible test articles involved (investigational product, comparator, or placebo)
with administration start/stop date
•
Dose, frequency, and route of administration
•
Concomitant medications and therapies: the Sponsor-Investigator and/or the
reporter should separately list the concomitant medications that the subject was
taking for the treatment of his/her underlying medical conditions and also the
concomitant medications plan
The SAE Form is often provided by the sponsor as part of the CRF for industrysponsored studies, but needs to be developed on-site for investigator-initiated and grantfunded studies. A suggested SAE form template is available for download to customize
for a specific study.
4.
Reporting Serious Adverse Events
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Depending on the nature of the event and the study, Unanticipated Problems Posing
Risk to Subjects or Others and Serious Adverse Events (see previous section for
definitions) are required to be reported to one or more of the following:
•
The IRB
•
The Sponsor (for industry-sponsored studies)
•
The FDA (for sponsor-investigators)
•
Participating sites (for sponsor-iInvestigator of multi-center studies)
•
Federal funding agencies
If more time is needed to prepare a complete report than the reporting time requirement
allows, then the immediate report can be incomplete, and then supplemented as soon as
possible with a more detailed, written report. When reporting adverse events, the subject
should not be identified by name. Study identifiers should be used to protect subject
confidentiality.
5.
IRB Reporting
The IRB should be notified of Adverse Events only when they are both:
•
Unexpected AND
•
More likely than not related to the study
Adverse Events and other "Unanticipated Problems Posing Risk to Subjects or Others"
that meet the criteria above should be reported to the IRB promptly, defined as within 10
days.
Several MHS studies are currently under the review of the Western IRB (WIRB); the
WIRB website provides access to forms and instructions for submitting Unanticipated
Problems that ARE and ARE NOT adverse events
(http://www.wirb.com/Pages/DownloadForms1c.aspx)
5.1 Expedited IRB and Sponsor Reporting
•
When a death of a research subject indicates that subjects or others are at
increased harm, that event must be reported to the IRB within 24 hours.
•
When death of a research subject occurs in an investigator-sponsored research
project the death must be reported to the IRB within 72 hours, regardless of
relationship to the study or study investigational agents.
5.1.1 Reporting Mechanisms
The IRB is should be notified promptly when an SAE becomes known to the study team.
The MHS IRB Principal Investigator’s Adverse Event Reporting Form must be completed
and submitted according to the reporting requirements.
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5.1.2 Sponsor Reporting
As a general rule, Serious Adverse Events should be reported promptly to the sponsor
when applicable (the protocol may identify events that do not need to be reported to the
sponsor). Although “promptly” is not defined in FDA regulations in terms of reporting to
the sponsor, an industry standard for reporting to the sponsor is within 24 hours of
discovery of the event.
5.5.3 Expedited Sponsor Reporting
•
Any event that is life-threatening or fatal is required to be reported immediately to
the sponsor in industry-sponsored research.
5.5.4 Reporting Mechanisms
•
6.
Sponsor reports of Serious Adverse Events are typically submitted through a
form provided by the sponsor. When not provided, the SAE form discussed in the
previous section is recommended
FDA Reporting (Drug, Biologic and Device Studies)
Serious Adverse Events that are not “unexpected” - whether or not they are associated
with the use of the drug or device - are reported to the FDA in the Annual Safety Report.
6.1 Expedited FDA Reporting
•
An SAE that is drug-related and unexpected must be reported to the FDA within
15 calendar days of discovery of the event
•
An SAE that is drug-related, unexpected and life-threatening or fatal must be
reported to the FDA within 7 calendar days of discovery of the event
•
An unanticipated adverse effect involving a Significant Risk device that is devicerelated and unanticipated must be reported to the FDA within 10 working days of
discovery of the event.
o
If such an event is found to pose an unreasonable risk to subjects, the
study must be terminated within 5 days after the sponsor makes this
determination and no later than 15 days after discovery of the event
6.2 FDA Reporting for Studies that are IND Exempt
Good Clinical Practice standards apply for all drug and device research at MHS
regardless of IND or IDE status. Although the regulations do not define specific timelines
for spontaneous reporting, it is recommended in the case of such a need for an INDexempt study, that the IND standards of 15 days for non-life threatening, and 7 days for
life-threatening serious, unexpected, drug-related adverse events are followed.
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However, there is no requirement for providing the FDA with an annual safety report (I.e.
the annual IND report).
6.3 Reporting Mechanism
The FDA is notified using the MedWatch form. The MedWatch form can be downloaded
from the FDA web site (www.fda.gov/opacom/morechoices/fdaforms).
21 CFR 312.32(c)
6.4 Reporting to Federal Funding Agencies
NIH and other federal agencies that provide funding for clinical studies often have
additional reporting requirements.
Examples of some federal funding agency reporting requirements are:
•
National Cancer Institute ( NCI )
o
•
National Heart, Lung, and Blood Institute (NHLBI)
o
7.
NCI utilizes ADEERS (Adverse Event Expedited Reporting System), a
web-based system for submitting serious and/or unexpected events. All
trials using a NCI -sponsored investigational agent are required to use
this system, which can be accessed at:
ctep.cancer.gov/reporting/adeers.html
NHLBI requires additional reporting to its agency, according to guidelines
which can be found at:
http://www.nhlbi.nih.gov/funding/policies/adverse.htm
Reporting for Participating Sites
Sponsor-Investigators (holding an IND or IDE) of studies that are being conducted at
multiple sites are also required to report SAEs to the investigators at those participating
sites. For both drug and device studies, this notification should be done concurrently with
notification to the FDA. 21 CFR 312.32(c) (1), 21 CFR 812.150(b) (1)
Resources: Western Institutional Review Board forms and instructions for submitting
Unanticipated Problems that ARE and ARE NOT adverse events
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Chapter 15: Data and Safety Monitoring
1.
Data Monitoring
Data monitoring is necessary to verify the study data and assess compliance with the
protocol.
A study monitor (which can be a Clinical Research Associate, or CRA) reviews study
documentation to assess the initiation, progress, and conduct of the research study in
order to ensure the scientific integrity of the data and the protection of study subjects.
The industry standard is that the monitor is independent of the conduct of the study.
In drug or device studies conducted under an Investigational New Drug (IND) application
or an Investigational Device Exemption (IDE), it is the responsibility of the IND/IDE
holder to conduct periodic data monitoring visits. The industry sponsor will send a
monitor to the study site.
All federally-funded studies must have a data and safety monitoring plan. Refer to the
funding agency for data and safety monitoring plan guidelines.
In investigator-initiated studies where the MHS investigator holds the IND or IDE,
monitoring services are often contracted with an external agency or contractor. The
Office of Human Research will also conduct periodic monitoring visits. The investigator
should ensure that monitoring visits are conducted at intervals specified in the Data and
Safety Monitoring Plan.
The frequency of monitoring activities depends primarily upon the risk of the study. The
higher the risk to subjects, the more frequently monitoring should be conducted.
Monitoring frequency can also depend upon the size of the study, the accrual rate, and
the complexity of the Case Report Form (CRF). In general, there is a need for on-site
monitoring before, during and after the study. The monitor may also conduct
unscheduled visits as needed based upon reports or evidence of potential noncompliance with the protocol or other concerns about the proper conduct of the study or
research subject safety. Significant increases in enrollment rates and changes in the
protocol or key study personnel may also trigger an unscheduled monitoring visit.
The monitor will confirm the date and logistics of the monitoring visit in writing and
provide the investigator with a list of records and source documents (e.g. hospital charts,
laboratory records, etc.) that will be reviewed during the monitoring visit. At each visit,
the monitor must sign the site visit log in the regulatory documents. Monitoring should
take place in a private area with access limited to the project and subject record(s) under
review.
The goals of the study monitor are to assess compliance with the research protocol,
federal regulations and Good Clinical Practice (GCP).
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The review activities will vary from visit to visit and may include any or all of the
following:
•
Informed Consent
o
•
Drug and/or Device Accountability
o
•
Confirm that all enrolled subjects met inclusion/exclusion criteria for study
participation and documentation exists to verify the fulfillment of eligibility
criteria
Adverse Events/Serious Adverse Events (AEs/SAEs)
o
2.
Confirm contents of the Regulatory Binder fulfill regulatory and GCP
guidelines
Eligibility Criteria
o
•
Confirm that the data recorded on the CRF is consistent with the
corresponding data in the source documents.
Regulatory Documents
o
•
Confirm proper documentation of receipt, storage, dispensation, and
return or destruction of the study drug/and or devices
Source Data
o
•
Confirm appropriate documentation of the informed consent process
Confirm that AEs/SAEs are captured, accurately documented, and
reported in a timely manner.
Communicating Findings
At the conclusion of each monitoring visit, the monitor should meet with the Principal
Investigator and/or Research Coordinator to review any monitoring findings and discuss
management to determine appropriate action and resolution. It is the PI's responsibility
to ensure that the recommended actions are implemented.
3.
Safety Analysis
Safety analyses are an essential element of study oversight that involves periodic
assessments of the study population. A safety analysis protects the well-being of the
study population by ensuring a comprehensive review of the overall data and safety
information, compliance to the protocol, and other factors that can affect subject safety.
A safety analysis should also incorporate factors external to the study, including
scientific or therapeutic developments in the disease under study. This process
facilitates an ongoing evaluation of the risk-to-benefit ratio.
Safety monitoring involves reviewing the available data, preferably through a safety
analysis, and making recommendations to continue, modify, or terminate the research
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study. Safety monitoring is always managed by the Principal Investigator for his or her
subjects. In addition, safety monitoring can also be conducted by an independent
medical monitor, committee, or Data & Safety Monitoring Board.
The timing of a safety analysis will be dependent upon several factors including the
likelihood of risk, the actual occurrence of adverse events, the natural history of the
disease, the effect of the intervention, and the power of the study design. The number of
events that occurs in a group determines the power of the study. A multi-center, high-risk
study involving a patient population with a large number of adverse events will require
more frequent oversight than a small, minimal risk study involving healthy volunteers.
The data reviewed during a safety analysis will vary based upon the study design, but
usually includes reports on the subject population, enrollment, adverse events,
laboratory findings, protocol compliance, and study endpoints. It is important to monitor
for imbalances between the expected and actual rates of adverse events. A safety
analysis will not only look for clear evidence of benefits or harms, but will also monitor
concerning data trends. Good clinical judgment and a working knowledge of the
population are crucial to the decision-making process. In certain patient populations,
there may be no other way other than by statistical analysis, to know whether the
adverse events are related to the study or the underlying disease and a formal interim
analysis may be necessary.
Note: If new risks or benefits are discovered during the course of a safety analysis, the
investigator is responsible for notifying the appropriate regulatory/oversight groups,
revising the Informed Consent Form, and re-consenting previously enrolled subjects.
4.
Interim Analysis
An interim analysis is a preplanned analysis conducted at some point during the study to
assess safety and in some studies, efficacy. There can be more than one interim
analysis depending on the safety plan. The interim analysis provides an opportunity to
invoke 'stopping rules' to prevent research subjects from being exposed to unnecessary
risk. For example, the study may be stopped early because the new intervention is
better, a substantial number of subjects experience serious side effects, or there is clear
evidence that the study is going to be negative. Generally, stopping rules are
asymmetrical- a more conservative boundary is reserved for adverse effects than for
beneficial effects.
Since the interim analysis is conducted on a data set smaller than planned for the final
study analysis, it is important that the statistical plan employ accepted methods designed
for interim analyses. These methods require a more extreme result than the
conventional p< 0.05 to account for the decreased statistical power. Each time an interim
analysis is performed, it has an effect on the power of the final analysis of the study.
Therefore the overall statistical analysis plan for a study must be designed to account for
effects on power from planned interim analysis.
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Chapter 16: Protocol Modifications
1.
Protocol Amendments
An amendment is any change to the research protocol that is approved by the Principal
Investigator (PI) of the study. Amendments to the protocol may be initiated by the study
sponsor, the PI, or may be recommended by an Institutional Review Board (IRB) or
other regulatory entity. Protocol amendments include administrative changes,
clarifications, study modifications and changes to the study design.
The investigator will notify the IRB, Food and Drug Administration (FDA), and other
investigative sites of the protocol amendment (as described below). The investigator is
also responsible for notifying the appropriate individuals, groups, or departments that
may be affected by a change in the study plan. This may include other individuals
providing care, fellow research team members, and the departments responsible for
implementing study procedures.
2.
Submission to IRB
Amended protocols must be forwarded to the IRB for review and approval. Protocol
amendments may not be initiated until the IRB has granted its approval. If the changes
are minor or present no more than minimal risk, the amended protocol can be submitted
for Expedited Review and approval by the IRB chair. Major protocol revisions will require
a Full Board Review. If the amendment necessitates changes to the consent form, a
revised consent form should also be submitted to the IRB for review and approval.
It may be necessary to have previously consented subjects sign the revised consent
form. Previously enrolled subjects must be re-consented if there are changes made to
the procedures they will undergo, the consent includes pertinent new information, or the
revisions may affect their willingness to participate. Consult the IRB if you are uncertain
whether this is necessary.
Protocol changes may require modification of other IRB-approved study documents,
such as advertisements, HIPAA Authorization, or subject data collection forms given to
the subject. These revisions must also be submitted to the IRB for approval.
The most current version of the IRB-approved documents should always be used with
study subjects.
2.1 Updates/Minor Changes
Occasionally, there may be new information or changes that do not necessarily require a
formal protocol amendment. Examples include location or staff changes, updated
information on investigational products (such as its approval in another therapeutic
area), or interim analysis of study data. Pertinent information should be communicated to
the IRB in a timely manner.
If a new Principal Investigator or sub-investigator is added to the protocol, the following
documents must be submitted to the IRB: investigator's Curriculum Vitae (CV), CITI
GCP training certificate, financial disclosure form or Conflict of Interest disclosure, and a
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memo from the PI with a signature indicating acceptance of the sub-investigator’s role
on the project.
3.
Submission to FDA (Sponsor-Investigators)
Protocol amendments made by the Sponsor must also be submitted to the FDA when
the revisions significantly affect the safety of participants and/or significantly affects the
scope of investigation or scientific quality of the study.
Significant protocol changes cannot be implemented without a submission to the FDA
and an approval from the IRB (and other applicable regulatory authorities, if applicable).
Protocol amendment submissions should include:
•
Summary page describing the changes made
•
Copy of the amended protocol clearly showing the revisions
•
Clean copy of the new protocol amendment
•
Copy of the IRB approval letter
3.1 Minor Changes
Minor changes, which include editorial changes, correcting typographical errors and
appropriate scientific or technical clarifications can be made to the protocol and related
documents. These changes should be documented in a Table of Modifications, and
submitted to the FDA at the time of the next protocol amendment submission.
The FDA also permits modifications to the experimental design of Phase I protocols that
do not affect critical safety assessments to be reported to the FDA only in annual
reports.
4.
Submission to other investigative sites (Sponsor-Investigators)
Sponsor-Investigators conducting a multi-center study are responsible for submitting
protocol amendments and updates to all participating centers. The investigator at each
center, in turn, is responsible for submitting the amendments to their institution's IRB.
5.
Protocol Deviations and Violations
Protocol deviations and violations refer to both purposeful and accidental variances from
the approved study protocol.
There is no regulatory definition of a protocol violation that differentiates itself from a
protocol deviation - both indicate a variance from the approved study protocol. For the
purpose of this manual, a protocol violation is considered to have a greater potential
effect on the study than a deviation, i.e. could affect a subject (rights, safety, or
wellbeing) or the data integrity (safety and efficacy endpoints).
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5.1 Protocol Deviations
Non-Serious Variances
Non-serious variances to the protocol will not jeopardize the safety or integrity of the
research project. Examples of protocol deviations include: failing to perform minor study
related tasks, performing follow-up visits or testing just outside the window, and
minimally exceeding the number of IRB-approved enrollment numbers. These types of
deviations usually do not require IRB reporting. However, if a pattern of non-serious
deviations becomes apparent, this should be reported to the IRB and an amendment to
the protocol should be considered.
Prospective Approval
Some variances in the protocol that have the potential to change the risk/benefit ratio
can be prospectively approved by the IRB, the sponsor (if applicable) and other
appropriate reviewing entities. In these situations, when prospective approval is granted,
the variance is considered a Protocol Deviation, even though the variation is more
serious in nature.
For example, an investigator may want to enroll a subject into a research study who
does not meet the eligibility requirements. An exception can be granted on a one-time
only basis, if the subject’s enrollment will not compromise his or her safety. This will
require pre-approval by the IRB and the study sponsor, if applicable. The request should
include information on the project, the criteria causing exclusion, and the justification for
enrollment. If an investigator finds that eligibility exceptions are required more than once,
he or she should consider submitting an amendment to the IRB that revises the eligibility
criteria.
5.2 Protocol Violations
Serious variances to the protocol have the potential to change the risk/benefit ratio, the
validity of the study results, or a subject’s rights or well-being. When such a variance
occurs and prospective approval was not obtained (see "Prospective Approval" above),
this is then considered a Protocol Violation.
Examples of protocol violations include: subjects enrolled who did not fulfill eligibility
criteria, failing to obtain informed consent, confidential information disclosed, enrolling
subjects during a lapse in IRB approval, conducting unapproved research tests or
procedures, and administering investigational medications in a manner not specified in
the study protocol.
The IRB should be notified of any protocol violations promptly after the violation is
discovered. The investigator should include a detailed plan of how to prevent serious
protocol violations from occurring in the future. If necessary, the IRB has the authority to
intervene by terminating approval for the project or suspending an investigator for
extremely serious or repeated non-compliance issues.
5.3 Reporting Requirements
Non-serious protocol deviation – Reporting to IRB not required
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Prospective protocol deviation - Reporting to Sponsor and IRB required prior to event
Protocol Violations - Promptly the deviations/violations may be required to be reported to
the sponsor. Sponsor reporting should be defined in the protocol.
5.4 Food & Drug Administration (FDA): In studies being conducted under an
Investigational New Drug (IND) application or an Investigational Device Exemption
(IDE), a protocol violation can have the impact of a protocol amendment or a change in
the investigational plan. Serious protocol variances must be reported to the FDA. This
can be done in the form of a letter outlining the nature of the variance.
5.5 Documentation
Any deviation or violation as defined above must be documented regardless of outcome.
Documentation should be placed:
•
In the Case Report Form
•
In the appropriate source documents where applicable (i.e. medical chart)
•
In correspondence with Investigator or Sponsor, Pharmacy, IRB, or other
regulatory entities
6.
Premature Discontinuation of a Study
Studies can be discontinued prematurely for a variety of reasons, such as subject safety
(discovered through regular safety assessments or a pre-planned interim safety
analysis), study finances, poor enrollment, a business decision (in the case of industrysponsored research), or even early proof of efficacy or lack of efficacy noted in a preplanned interim analysis. Regardless of the reason for discontinuing a study before its
planned end, there are a number of issues to consider and manage.
•
Research subject safety - The first consideration when prematurely
discontinuing a study should be for the welfare of the study subjects. For
interventional studies, the research team must think about the effect the
withdrawal of the study treatment will have on research subjects. It may be
necessary to wean a study drug rather than discontinue abruptly, or to transition
from study treatment to another appropriate therapy. Additionally, if the study
was discontinued due to safety concerns about the study treatment, it may be
necessary to evaluate subjects for residual effects and to work out the best
follow-up plan to evaluate possible lasting effects from the study intervention.
•
Communication - The study sponsor initiates the communication about the
study discontinuation. It is the investigator's responsibility to inform the IRB, other
reviewing entities and research offices, and the team involved in the study.
Careful thought and planning should go into the communication of the decision
and any follow-up plans to the study subjects.
•
Study Finances - Study contracts and grants address the costs and method of
payment for work done on research studies. In industry-sponsored research, it is
important to have the study agreement clarify the sponsor's responsibility to
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cover any unforeseen costs incurred due to a premature discontinuation of a
study not related to investigator or site performance problems.
•
Data management - Any changes to the protocol-defined data management
plans depend upon the reason for study discontinuation. When a study has been
stopped earlier than planned for safety or efficacy reasons, finalization of the
data and data analysis is essential for the full characterization of the safety or
efficacy issue. The investigator and sponsor should work together to clarify the
data management plan in light of the early study discontinuation.
•
Record retention - Regardless of the reasons for early study termination, the
sponsor and investigator must still retain study records according to Good
Clinical Practice (GCP) standards and the contract stipulations.
7.
Continuing Review/Renewal
7.1 Institutional Review Board (IRB) Continuing Reviews
Research must be reviewed by the IRB at least once every twelve months, but may be
reviewed more frequently depending upon the level of risk. The MHS IRB will notify
investigators by email 2-3 months prior to the expiration of IRB approval with a
continuing review form. It is the responsibility of the Principal Investigator (PI) to submit
regardless of having received notification.
Continuing review forms should be completed and submitted to the IRB within 60 days of
expiration to assure uninterrupted activity.
If an investigator has failed to provide continuing review information to the IRB or the
IRB has not reviewed and approved a research study by the continuing review date
specified by the IRB, the research must stop, unless the IRB finds that it is in the best
interests of individual subjects to continue participating in the research interventions or
interactions. Enrollment of new subjects cannot occur after the expiration of IRB
approval.
Copies of IRB Continuing Review documents and correspondence should be retained in
the regulatory binder even when the study is being terminated or enrollment is closed.
7.2 National Institutes of Health (NIH) Renewals
The National Institutes of Health (NIH) requires an annual renewal update for NIHfunded studies. Progress reports must be submitted two months before the beginning
date of the next budget period. The NIH uses a renewal form, PHS 2590, also known as
the Streamlined Non-Competing Grant Progress Report (SNAP form), which
requests the following information:
Progress Report Summary
•
The title of the project, grant number, funding agency, and Principal Investigator
name
•
Information concerning any changes to:
o
Support of key personnel since last reporting period
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o
Level of effort for key personnel from what was approved for the project
o
Estimates of un-obligated balance that will be greater than 25% of the
current year's total budget
•
Outcomes to date
•
Projected plans for the future years of the project
•
Significance of findings and publications
Personnel Report
•
List of the key personnel and a renewal of the percent effort
Enrollment
•
List of enrolled subjects distributed by ethnic category, racial category and
sex/gender
Budget
•
Updated budget for the renewal year
It is recommended that the investigator work directly with the grants department
that handles the funding distribution of the grant in order to correctly revise the
budget each renewal year.
•
Year-to-year Carryover Justification
At year's end, if the study budget has an unobligated carryover (i.e. unspent
funds) greater than 25%, a justification will need to be provided in the NIH
renewal to the funding agency. More information about this can be found at
http://grants2.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm
7.3 No-Cost Extension
The forms and instructions for completing PHS 2590 can be downloaded from
http://grants1.nih.gov/grants/funding/2590/2590.htm.
If it becomes necessary to extend the project beyond the original grant expiration date, a
No-Cost Extension can be granted. NIH can approve a No-Cost Extension for up to 12
months provided that no additional funds are required, there will be no change in the
project's original objectives, and adequate justification is provided. More information
about submitting a No-Cost Extension can be found at http://era.nih.gov/index.cfm
8.
Food and Drug Administrations (FDA) Annual Reports
8.1 Document Submission for Investigator-Initiated Research
Sponsors are required to submit an annual report to the FDA of any studies being
conducted under an Investigational New Drug (IND) application or Investigational Device
Exemption (IDE). The elements of this report are described under the IND regulations.
•
Summary of each study in progress including, for each study:
o
The title, protocol number, purpose, subject population, statement of
whether or not completed;
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•
o
Information about the number of subjects anticipated, entered, completed,
and dropped out; tabulate by age group, gender, and race;
o
Any available study results
Summary from the year, including:
o
Summary of most frequent and most serious adverse experiences by
body system
o
Summary of all IND Safety Reports
o
List of subjects who died during participation, with cause of death
o
List of subjects who dropped out in association with any adverse
experience
o
Description of what was obtained pertinent to an understanding of the
drug's actions
o
List of preclinical studies completed or in progress during the past year;
summary of findings
o
Summary of any significant manufacturing or microbiological changes
made
•
Plan for coming year, in the format of the IND submission
•
Description of any significant Phase I protocol modifications made
•
Summary of significant foreign marketing developments with the drug
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Office of Human Research
Chapter 17: Financial Accounting
Pre-Award Process
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PRE AWARD PROCESS
a. PURPOSE: To define the pre-award procedures necessary to determine
financial feasibility for each sponsored research project.
b. POLICY: Sponsored Research projects are administered in accordance with
the terms and conditions specified in the grant or contract and applicable
regulatory requirements.
During the Pre Award process OHR will perform:
1) Medicare Coverage Analysis
1.1 Research Manager reviews protocol schema and clinical trial agreements for
study details
1.2 Performs analyses using the most current policies and guidelines of the
Centers for Medicare & Medicaid Services;
1.3 Submits completed coverage analyses/reviews to a query able database
where other relevant members of the clinical research team can access
information about a study
1.4 If applicable, seek advice from the PI or outside staff to determine whether
a procedure meets the standard of care in research.
2) Labor Worksheet
2.1 OHR Finance provides a custom labor worksheet specific for the protocol for
the Nurse Manager to complete
2.2 Nurse Manager provides an estimate of the time required for each event in
the protocol
2.3 Estimates include effort for Principal Investigator, Research Nurse,
Pharmacy, and Regulatory staff
2.4 Research time is inclusive of
o Lab and procedure: processing, scheduling, shipping, authorization
o Data collection, interpretation and analysis
3) Budget Development
3.1 OHR’s budget matrix is inclusive of three sections: Non Billable, Billable, and
Labor
3.2 Non-Billable Items : These are events in the protocol which the study team
has identified as Standard of Care (SOC) or Routine Care that will be billed
to the patient’s insurance
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3.3 Billable Items: These events are procedures which can be identified by CPT
codes. We use our pre-negotiated rates from our hospitals and/or physician
group partners
3.4 Labor: Nursing Labor Worksheet used to determine applicable study hours.
4) Feasibility Analysis & Negotiations w/ Sponsor
4.1 Upon completion of our per patient budget, OHR Finance will negotiate the
budget and terms & conditions with the sponsor
4.2 MHS institution’s overhead is 28% and OHR’s non-refundable start-up
includes (but not limited to) the following activities: administrative review,
regulatory set-up, pharmacy, storage and archive, study close out, and
marketing/advertising
4.3 Once OHR & Sponsor agree to terms, document are routed for signatures
POST AWARD PROCESS
5) Billing and Collection
a. PURPOSE: To define the billing and collection procedures necessary to
maintain an appropriate level of internal controls over Research revenue
collection operations.
b. POLICY: Sponsored Research projects are administered in accordance
with the terms and conditions specified in the grant or contract and
applicable regulatory requirements.
OHR Finance is responsible for:
• determining sponsor financial terms and conditions;
• maintaining all Accounts Receivable records, including open
bills awaiting payment;
• ensuring that Sponsors are accurately and promptly billed;
• ensuring that all invoices are properly paid, or otherwise
adjusted; and
• allocating payments appropriately to projects and cost centers.
5.1 Billing/Invoicing
An invoice should be issued each time a project reaches payment milestones,
direct costs or other costs as defined by the grant, trial or agreement with the
Sponsor. When a project reaches a milestone, an invoice generated by OHR
Finance staff enters the receivable into CREDIT, OHR’s Clinical Trials
accounting system. The accounting system assigns sequential invoice numbers,
which:
• appear on each invoice; and
• enable OHR staff to track payment
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The invoice directs the Sponsor to send all payments directly to OHR Payment
Address, and provides the name and telephone number of the appropriate
contact person(s) in OHR Finance. Statement or other notices or reports may
accompany the invoice, but should not be substituted for the invoice.
5.2 Collection
OHR Finance is responsible for collecting the amounts billed, recording the
collections, and following up on outstanding invoices.
When an invoice is not paid within a reasonable time, normally thirty to sixty
days, OHR Finance will investigate the reason for the payment delay and take
appropriate follow-up action.
OHR Finance will record and apply payments received to the corresponding
invoices, and investigate and reconcile any variance between an invoice and its
payment.
5.3 Document Aging
Each month OHR Finance will review the list of accounts receivable to verify
balances are correct. Invoices 60-90 days past due are investigated i.e.
sponsors are contacted for payment status and documented in the OHR monthly
Financial report – Aging Report.
6) OHR Monthly Financial Reporting
a. PURPOSE: To define the reconciliation procedures required to account
for financial activity/transactions on each active Sponsored Research
project.
b. POLICY: A verification of all income and expenses against each active
Sponsored Research project, as well as necessary corrections is required
each month to ensure the OHR monthly financial reports are correct.
6.1 Clinical Trial Reconciliation
Each month OHR Finance will perform a financial review of all income/expense
transactions posted to each Sponsored Research project to ensure that account
assignments and activity allocations are correct for OHR Monthly Financial
Reports. Financial review consists of cash receipts reconciliation, payment
allocation, invoicing and billing, direct payables, direct cost and other
miscellaneous reimbursements. Any errors found are corrected and documented
before the close of the accounting period following the period the charges were
processed.
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6.2 Monthly Reports
By the 10th of each month OHR will prepare and distribute the following financial
reports to its stakeholders:
• Clinical Trial Summary (profit and loss summary by Trial)
• Invoicing & Payment Summary
• Payment & Invoicing Details
• Payment Summary
• Invoice Aging
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Chapter 18: Audits
Any clinical research study being conducted at Memorial Healthcare System is subject to
audits by a number of sources. Although there are many types of audits, generally
speaking, an audit of a clinical research study seeks to validate the quality of the clinical
study and assures that the rights and welfare of the human subjects in the study have
been protected.
An on-site audit may be conducted by federal government agencies, by internal MHS
offices, or by the industry sponsor of the study. Depending on what agency/office is
conducting the audit, there may be specific methods for preparing for and conducting the
audit.
1.
External Auditing Sources
1.1 Food & Drug Administration (FDA)
•
Applicable to any research study using an FDA-regulated product
•
May be Routine (determined by subject accrual rate or amount of data being
obtained) or For Cause (potentially based upon a complaint of non-compliance)
1.2 National Institutes of Health (NIH) and any of its Centers or Institutes (e.g. NCI)
•
Applicable to any study being funded by an NIH Center or Institute or where the
cooperative group holds the IND
1.3 Study Sponsor
•
Applicable to industry funded studies, investigator-sponsor initiated studies
1.4 Cooperative Groups, Data Collection Agencies
•
2.
Applicable to studies conducted through Cooperative groups such as eg.
National Cancer Institute - NCCTG, COG, etc.
Internal Auditing Sources
2.1 Office of Human Research (OHR)
3.
•
Applicable to any research conducted within MHS
•
May be Prospective (such as a Pre-FDA Audit) or in response to a complaint of
potential non-compliance or routine
Audit Procedures
The investigator must notify the Office of Human as soon as possible if an audit has
been scheduled:
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3.1 FDA Audits
The Office of Human Research (OHR) has extensive knowledge and experience
in research regulations and will assist investigators and their study teams in the
preparation and conduction of an FDA inspection. OHR will provide a Pre-Audit
Review, facilitate the inspection, and provide assistance in responding to the
FDA's inspection observation. For more information, please contact the OHR.
3.2 NCI Audits
The OHR will coordinate and facilitate all NCI audits.
3.3 Site Responsibilities
In anticipation of an audit, the Principal Investigator (PI) needs to ensure the following:
•
Time and flexibility in his/her schedule to meet with the inspector
•
A controlled environment in which the investigation will be conducted
•
The inspector has access to all necessary source documentation (medical and
clinical records), study records (case report forms or electronic data capture
systems), and regulatory documentation.
•
FDA AUDITS:
4.
o
Always ask for the inspector's identification. They are required to present
their identification and you are required to ask for it prior to handing over
any confidential documentation for review.
o
The inspector will present the investigator with an FDA Form 482 Notice
of Inspection. The Principal Investigator will sign the 482 and receive a
copy.
Audit Areas
4.1 Protocol
The inspector will review all versions of the protocol to document that all versions
received proper IRB approval and that NO CHANGES to the protocol were implemented
prior to IRB approval.
4.2 Authority and Administration
The inspector will review the regulatory documentation, including monitoring log,
delegation of responsibility log, CV's, IRB and sponsor communications and lab
information to determine:
•
How the investigator is informed of his/her requirements regarding the study
protocol and, if applicable, accountability of the test article
•
Proper delegation of various study related tasks
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•
List of individuals performing study tasks and their positions
•
Name and address of the laboratory facility and its ability to perform studyspecific tasks
4.3 Subject Records
The inspection of subject records is an effort to confirm:
•
The existence of all subjects
•
Validity of data (case report form data versus source documentation)
•
Proper documentation of AEs/SAEs
•
Accurate documentation of concomitant medications and medical history
•
Subject eligibility (inclusion criteria met, no subjects meeting exclusion criteria
were enrolled)
•
The handling of subjects who come to meet exclusion criteria during the course
of the study
•
Complete and accurate records kept on the subject throughout exposure to the
investigational product and during the course of the study
•
Proper documentation of adverse events
•
The proper follow-up and management of all study dropouts
For paper case report forms and/or source documentation, the inspector will need to
assure that records are secure from tampering, and that they can be maintained for the
required period of time after the conclusion of the study.
4.4 Consent of Human Subjects
The inspector is required to verify that informed consent was obtained from all subjects
prior to study entry and in accordance with the regulations. The inspector may review all
consent forms on subjects enrolled and screened. Therefore it is considered best
management practices to maintain all original consent forms in one study file for ease of
verification and to avoid the need to pull all subject records (copies of the original signed
consent form can be kept with the subject records).
4.5 IRB Communications
The audit may typically include a review of the investigator's reports and
communications with the IRB. This includes submission of reports, protocol
deviations/violations, protocol amendments, informed consent amendments,
advertisements, and adverse events.
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4.6 Sponsor Communications
The investigator's communication with the study sponsor will also be inspected to ensure
that both sponsor and investigator have met all regulatory obligations. The inspection will
include review of:
•
The IRB-approved consent form
•
Periodic reports from the investigator
•
Adverse events (within the required timeframes)
•
On-study illness and concomitant medication information
•
Timely Case Report Form (CRF) submissions
In addition, the inspector may be verifying that the sponsor conducted adequate
monitoring of the study's progress.
4.7 Investigational Product Accountability
Maintenance of investigational product inventory and records is critical in verifying
accountability. Proper documentation of investigational product accountability includes:
•
Receipt dates and quantity
•
Dates and quantity dispensed with subject ID
•
Distribution of investigational product only to subjects enrolled in the study
•
Quantity, frequency, duration, and route of administration
•
Investigational product disposition (what was received from, used, and sent back
to the sponsor)
•
Comparison of receipt and usage against shipping records
Investigational product accountability also includes proper storage of the investigational
product with adequate security in a controlled environment. Inspectors will also want to
confirm the investigational product was dispensed and administered by qualified and
authorized personnel.
4.8 Electronic Records/Record Retention
21 CFR Part 11 provides specific regulations governing the management of electronic
records and electronic signatures. 21 CFR 11 regulations apply to any records required
to be maintained according to Food and Drug Administration (FDA) Good Clinical
Practice (GCP), Good Manufacturing Practice (GMP) and Good Laboratory Practice
(GLP) regulations if such records are maintained primarily in electronic form. Since these
regulations were created to support GCP, GMP and GLP, they apply to all studies using
FDA-regulated products, regardless of whether data will be submitted to the FDA.
If there is any doubt whether a given electronic system is subject to 21 CFR 11
regulations, please contact the OHR for assistance.
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5.
Common Audit Findings
A report published by the FDA's Office of Inspector General in June of 2000, reviewed
184 official actions taken by the FDA since 1994. These actions were then categorized
into different types of violations. (The full report can be viewed at
http://oig.hhs.gov/oei/reports/oei-05-99-00350.pdf). In summary, the report found of
those violations reviewed:
•
85% were based on documentation problems, including missing data, data
discrepancies, falsification of data, and poor data collection.
•
82% were protocol violations, including enrollment violations, failure to follow
the protocol, problems with investigator agreements, and violations related to
drug use
•
74% were reporting violations, including failure to submit to the IRB or sponsor
reports, consent forms, protocols, advertisements, and adverse events.
•
67% were human subject protections violations, most often surrounding the
use of a deficient informed consent form, not obtaining signed informed consent
prior to performing a study procedure, or missing signatures or dates on the
informed consent form.
•
44% were drug/device/biologic control violations, citing poor control of the
receipt, use and disposition of investigational drugs, devices, or biologics.
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Chapter 19: Subject Management
This section focuses on the management and conduct of research activities that are
specific to the research subject.
1.
Screening
The screening process identifies individuals who fulfill the inclusion and exclusion criteria
in the protocol and are therefore eligible to participate. Screening methods will vary
depending upon the type of study, the population, and the setting.
Screening should not be confused with recruiting. Recruitment refers to the systematic
gathering of a population that meets prescribed characteristics. Recruitment almost
always takes longer than originally anticipated and new recruitment strategies may be
needed to identify appropriate candidates for screening.
1.2 Gathering Screening Information
Appropriate screening questions specifically address eligibility and adherence to the
protocol (such as an individual's ability to complete research procedures). It is not
appropriate during the screening process to collect information that does not directly
address inclusion/exclusion criteria or suitability for the study. It is also inappropriate to
use the collected data for purposes other than screening for the particular study.
Screening may require:
1. Obtaining data from existing records (e.g. medical records, databases)
2. Obtaining data directly from potential subjects:
o
through interviews (e.g. discussions, questionnaires)
o
through assessments, tests, or procedures (e.g. physical exams, lab
results)
It may be helpful for investigators to develop a checklist for study staff to use during the
screening process. A checklist contains a list of the inclusion and exclusion criteria and
may also contain a signature line for the person completing the screening.
Reviewing records
A researcher may need to access charts and existing records to determine eligibility
and/or to contact someone about a study.
If it has been approved by the Institutional Review Board (IRB), the researcher does not
need to obtain a written consent or HIPAA authorization to review records. HIPAA
regulations (preparatory to research) allow researchers under the covered entity to
review existing records provided that the information is not removed from the covered
entity. However, researchers should not “cold-call” prospective subjects identified during
a record review without first obtaining permission from them. This permission can be
obtained through their health care provider or through a letter of introduction.
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Interviewing
During a screening interview, the researcher will ask the prospective subject questions
to help determine eligibility, suitability, and interest in the study. The screening interview
may precede or be a part of the consenting process.
Before the screening interview begins, potential subjects should be informed who they
are speaking to, why they are being approached, who referred them, and the purpose
and nature of the inquiry.
To screen MHS patients, the following contact methods in descending order of
preference are:
1. By the Health Care Professional who has taken care of the patient.
2. By another health care professional from within the covered entity using a cover
letter agreed upon by the health care provider who has taken care of the patient
and containing script approved by the IRB.
3. By the researcher. When both of the other two alternatives are impractical, direct
recruitment by a researcher who has not taken care of the patient will require
specific IRB approval.
Phone Screening
If a prospective subject is being approached for the first time by telephone, they should
be informed who they are speaking to, how long the discussion will take, the purpose
and nature of the questions, the purpose and voluntary nature of the research, and how
confidentiality will be protected. If the person is interested, the interviewer should obtain
verbal permission to proceed with the questions. Often, the IRB will request a script of a
planned telephone dialogue.
Minimally, the researcher should provide the IRB with the following information regarding
procedures for telephone scripts:
1. How is the personal information conveyed to the appropriate person for further
eligibility determination?
2. What happens to the personal information if the caller ends the interview or
simply hangs up?
3. Are the data gathered by a marketing company? If so, are names, etc. released
to others?
4. Are names of non-eligible subjects maintained in case they would qualify for
another study? If so, how are they maintained? What is the procedure for
ensuring confidentiality and security of this information?
5. Are paper copies of telephone screening records shredded or are readable
copies put out as trash?
Questionnaires
As with any written instrument that is administered to a subject during a study, screening
questionnaires must be submitted to the IRB for review prior to their use.
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2.
Performing Assessments, Tests and Procedures
The investigator must obtain informed consent prior to conducting any clinical
assessments, tests, or procedures solely for the purpose of determining eligibility for
research. This may include complete medical histories, physical exams, blood work, and
withdrawal from medication (wash-out). This does not include procedures that are
performed as part of the standard practice of medicine for clinical purposes.
Only a physician can make a medical diagnosis that determines eligibility. PhysicianInvestigators should take extra care with their patients to differentiate between
examinations and procedures for research purposes and those for medical (nonresearch) purposes.
3.
Screening Documentation
As part of the research records, investigators should have documentation to verify that a
subject has met the eligibility criteria for a study. This may include existing medical
records, a physician referral letter, a written account of screening interviews,
questionnaires, and/or results from research tests.
To protect confidentiality, investigators should minimize the amount of identifying
information that is collected during the screening process. For example, the investigator
may record non-identifiers during the pre-screening process (e.g. first name, initials),
contact information during the screening process (e.g. full name, telephone number),
and additional identifiers after enrollment (e.g. birth date, medical record number).
Identifiable information may be retained until it is clear that an individual will not be
enrolled. After that point, the investigator must either obtain a HIPAA authorization or
destroy the identifiers.
3.1 Screening Logs
A screening log includes information on all the individuals that were screened for a
research study, regardless of whether they were enrolled. Screening logs can provide
useful information about the population and may help identify barriers to enrolling eligible
candidates.
3.2 Screen Failures
Screen failures are individuals who are evaluated for participation in a study, but not
enrolled. Screen failures either do not meet the eligibility criteria or decline participation.
An investigator may only retain identifiable health information about a screen failure if a
HIPAA authorization has been obtained. If a HIPAA authorization is not obtained, the
segments of the screening records that contain identifiers should be blacked out or
removed as soon as it becomes obvious that the individual is not eligible for
participation.
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4.
Consenting
Informed consent is a process by which a subject acts autonomously to make an
informed and voluntary decision to participate in a research project. Informed consent
involves an ongoing exchange between the researcher and/or research staff and the
subject. This process starts before any documents are signed and continues through the
completion of the entire study. Subjects tend to recall more about the practical aspects
of a study than the theoretical aspects and tend to forget risks more quickly than
benefits. Because of this, researchers will need to re-discuss information throughout
study participation to promote ongoing understanding.
4.1 Underlying Principles of Consent
A valid informed consent requires:
•
Voluntary Choice
•
Disclosure
•
Understanding
4.1.1 Voluntary Choice
A voluntary choice involves the exercise of free will and is free of undue duress. Undue
duress can be introduced to the consent process by means of coercion, manipulation or
force. Subjects may be coerced by the promise of excessive inducements (e.g. large
payments or access to expensive treatments) or the threat of retribution (e.g. fear of
receiving poor medical care or a failing grade). Subjects may be manipulated if they are
improperly informed about the research, their role, or their rights. Subjects may feel
forced if they are not given an opportunity to decline.
Researchers must be aware of the subtle factors that influence the decision-making
process. Relationships that have a high level of trust and dependency, such as the
doctor/patient or professor/student relationship, can introduce feelings of indebtedness
and obligation. When researchers are involved in a dual relationship with the subject, for
example as the treating physician and the study investigator, the scope of the
relationship in each situation must be clearly defined and delineated. Likewise, certain
populations, such as those that are restricted, dependent, or compulsorily detained, may
feel unduly pressured by figures of authority. This may include not only prisoners, but
also members of the armed services and residents of chronic care institutions. During
the consent process, researchers should remain cognizant of these factors and keep the
consent process as neutral as possible. This can be done by involving research team
members in the consent process who do not evoke feelings of authority or dependency.
This can also be done by clearly communicating to subjects that they can refuse
participation without fear of negative repercussions.
4.1.2 Disclosure
The elements of disclosure can be scrutinized by reviewing the content of the informed
consent form; however, long, detailed consents may be confusing and overwhelming for
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subjects. Disclosure, in and of itself, does not constitute informed consent. Obtaining a
signature on a consent form without having discussed its contents violates the principles
of informed consent.
Researchers must carefully balance full disclosure with comprehension and
understanding. Legal criteria state that researchers should disclose any risks to which a
reasonable person would attach significance in that particular situation. Researchers
must develop the skills necessary to identify how much information each subject needs
to make an informed decision.
4.1.3 Understanding
A well-written consent form and a carefully planned dialogue alone cannot guarantee
understanding on the part of the subject. Information must be presented in a manner that
is both meaningful and culturally sensitive to promote comprehension.
It is often difficult to identify whether a subject has adequate understanding.
Researchers should try to assess a subject's level of understanding by asking them to
describe the research in their own words. Through this interchange, the investigator can
identify any lost information and rearticulate the information until it is understood.
Therapeutic misconception occurs when a person believes that a research study will
provide personalized medical care that imparts direct benefits. The purpose of research,
its risks and benefits may often be disclosed, but presented in a manner so that it is
misunderstood as treatment. Presentation factors that influence understanding include
descriptors (innovative, cutting-edge), quantitative vs. qualitative presentations
(uncommon versus 5%), and framing ("lives saved" versus "lives lost"). Investigators
conducting therapeutic research should explain the difference between research and
standard medical care. Therapeutic research should always be presented as choice
between participating and receiving standard care. Research should also be framed in
neutral terms that do not over-emphasize potential benefits nor under-emphasize
potential risks. An effective method of communicating magnitude and probability of risk
is to use visual aids.
4.2 Obtaining Informed Consent
It is the responsibility of the Principal Investigator (PI) to ensure that informed consent
has been properly obtained. This activity may be delegated to a research coordinator or
other research staff who are knowledgeable about the study, the research subject, the
subject's alternative choices, as well as informed consent regulations. The PI remains
accountable for the actions of any research staff to whom the responsibility of obtaining
informed consent has been delegated.
During the consent process, the investigator should:
1. Approach the prospective subject to introduce the research team and the project.
o
The discussions should take place in an area where privacy and
confidentiality can be respected.
o
Subjects must be given sufficient time to comprehend the research.
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2. Review the research study and the informed consent form with the subject.
o
The researcher should clearly explain the background/purpose, voluntary
nature, commitment, risks, benefits, alternatives, and other elements
making sure to include all the necessary elements of informed consent.
3. Answer any preliminary questions.
4. Allow the subject time to review the informed consent form independently.
o
In non-emergency situations, subjects should be given at least 30
minutes for reflection and 24 hours whenever possible.
o
Provide the subject with a sample consent form to review prior to the
consenting process and study appointment.
o
If possible, subjects should be given time to discuss participation with
family or friends.
5. Evaluate the subject's understanding by asking open-ended questions about the
study and address any misperceptions or unanswered questions. Possible
questions include:

Can you describe the study in your own words?

What more would you like to know?

Would you please explain to me what we are asking you to do?

What are your concerns?
6. If willing, ask the subject to sign and date the consent document.
o
Subjects must personally sign and date the most recent IRB-approved
version of the informed consent form
o
The consent form must contain an approval stamp from the IRB.
o
The person obtaining consent and, if necessary, the witness should also
sign and date the informed consent form.
7. Give the subject a copy of the signed and dated informed consent form.
8. Document the informed consent process (see below).
A signed informed consent form must be obtained prior to initiating any research
procedures. This includes procedures conducted solely for the purpose of determining
eligibility for research and drug washout periods.
If the subject consents to participation, the original consent form is kept with the
research records, a copy is given to the subject, and a copy may be placed in his or her
medical records (if applicable).
4.3 Documenting the Informed Consent Process
A note in the chart and/or research records should include:
•
Name of study and subject
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•
Date and time of consent
•
Statement that the benefits, risks, commitment and alternatives were discussed
•
Presence of any family members, friends, or witnesses
•
Specific, relevant criteria not otherwise captured (e.g. time frames of screening
tests that are not apparent in records)
Outside auditors may prefer a narrative, handwritten note over a checklist or printed
template language, however there is no regulatory requirement to that effect. A sample
informed consent note may look like the following:
“On 11/21/11, I reviewed the research protocol [study title] with [patient's name]. She
was given an opportunity to read the consent form and was given ample time to ask
questions and have them answered. The study's purpose, procedures involved,
voluntary nature, risks and benefits were discussed with her. She indicated her decision
to participate and signed the consent form. I provided her with a copy of the signed
informed consent and HIPAA authorization form. The informed consent form was signed
prior to any study related procedures outside of standard of care were performed.”
5.
Consenting Special Populations
In certain circumstances the informed consent process must be tailored to meet the
needs of special populations including minors, adults with a limited decision-making
capacity, and individuals who are blind, illiterate, or do not speak English.
5.1 Assent
Generally, children and adults with limited decision-making capacity do not have the
legal authority to provide consent for their own participation in a research study.
However, an investigator should still seek affirmative agreement (assent) from such
research subjects. An assent form is a simplified version of the consent form and should
be written to the subject's level of understanding. A typical assent form explains a
study's purpose, procedures, risks, benefits, confidentiality, and voluntary nature in
simple terms.
5.1.1 Children/Minors
Definitions
Federal regulations define "children" as persons who have not attained the legal age for
consent to treatments or procedures involved in the research, under the applicable law
of the jurisdiction in which the research will be conducted.
Under Florida law, persons under the age of 18 will generally meet the definition of
"children" with the exceptions noted below.
•
In Florida, minors who are independent and living on their own may be declared
emancipated minors by the court and may consent for themselves
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•
Florida law permits a person under the age of 18 may consent to medical care or
treatment if the person:
o
has graduated from high school;
o
is married; or,
o
is or has been pregnant
Individuals who are defined as "children" will be afforded the protections under the
regulations that protect children involved as subjects in research (Subpart D, 45 CFR
46.401 - 409 and 21 CFR 50.50 - 54). Additionally, the IRB may determine that minors
who are not children (such as a person meeting one of the exceptions noted above) are
potentially vulnerable, at which point the IRB might apply additional protections.
5.1.2 Parental Permission
A parent or guardian must grant permission for the child to participate in research. If the
research involves greater than minimal risk and offers no prospect of direct benefit,
permission must be obtained from both parents (granted they have custody and are
reasonably available).
Parental permission is typically documented through having the parent(s) sign and date
a Parental Permission Form. The Parental Permission Form looks like and contains all
the same elements as an adult consent form, except that "You" is replaced with "Your
child" throughout the document.
5.1.3 Child’s Assent
Generally, children 7 to 18 years of age may be capable of providing assent. However,
individual subjects may not have the cognitive and emotional maturity to understand the
research project and decide whether or not to participate. So, even when the IRB
requires that assent, an investigator must use discretion in determining whether the
subject is capable of providing assent. Investigators need to document the rationale
when assent is not obtained.
It is important to note that assent must be affirmative, meaning that if a child says
nothing or simply doesn't disagree, then assent has NOT been obtained. Additionally,
parental permission does not override a child's assent, unless the child's health is at
stake. The assent process must be tailored to the individual child's age, maturity and
psychological state.
5.2 Documenting Assent
In most situations, the IRB will allow the child to sign the parental permission/ consent
form to indicate his or her willingness to participate. Parental consent/ permission forms
should also include a separate section where investigators are required to document the
reason(s) why it is not feasible or appropriate to obtain assent from a particular subject.
In some situations, determined by the on a case-by-case basis, the IRB may require a
separate assent form. This may apply in non-therapeutic studies that involve older
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children and adolescents. These assent forms must be simple and easy to understand.
Investigators may
Assent of the minor is not required when the IRB determines:
1. that the capability of a minor is so limited that he or she cannot reasonably be
consulted, or
2. that the intervention or procedure involved in the research holds out a prospect of
direct benefit that is important to the health or well-being of the child/adolescent
and is available only in the context of the research
6.
Pregnancy Testing in Minors
Under FL state law, minors have the right to confidential pregnancy testing. If pregnancy
testing is required as part of the study, it is required that both the assent form and the
parental permission form include language that makes clear that the results will may be
shared with parents.
6.1 Pregnant Minors
Pregnant minors and minors with children are entitled to make decisions about their own
health care and may make decisions on behalf of their fetus/child (except for decisions
about abortion), this includes the ability to provide informed consent for their
participation, or the participation of their children, in clinical research. However, the
intent to enroll subjects from this special category of minor, or to permit this category of
minor to consent to the enrollment of their children into research, must be stated in the
protocol and have received IRB review and approval before it can be implemented. This
is in order to conform to regulatory requirements for the protection of vulnerable
populations (i.e. 45CFR46 subpart B, concerning pregnant women and fetuses), and to
engage the IRB concerning any additional protections for this specialized group of
minors.
Minors that reach the age of majority (18 years) during the conduct of a research study
will need to be re-consented as an adult in order to continue participation. Minors who
become pregnant during their participation in a study should be re-consented in order to
continue participation, presuming such subjects are permitted to continue participation
according to the protocol and IRB approval.
7.
Limited Decision-Making Capacity
Decisionally impaired adults are individuals who have a diminished capacity for
judgment and reasoning due to a psychiatric, organic, developmental, or other disorder
that affects cognitive or emotional functions. Other individuals may be considered
decisionally impaired or have limited decision-making ability because they are under the
influence of or dependent on drugs or alcohol, suffering from degenerative diseases
affecting the brain, are terminally ill, or have severely disabling physical handicaps.
If an individual does not have the capacity to make an informed decision about
participation in a research study and is not likely to acquire or regain that capacity, proxy
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consent may be obtained. Ideally, the proxy is a legally authorized representative who
has firsthand knowledge of that individual's needs and wishes. Researchers should ask
surrogates who are making decisions if they think that the subject would have decided in
the same manner if they were competent. Even if a subject has been judged
incompetent, the person should be considered competent to refuse participation and
should be included in the informed consent process as much as possible.
8.
Legally Authorized Representatives
The following individuals may be considered legally authorized representatives of the
subject and capable of providing surrogate consent:
1. A court-appointed guardian authorized to consent to the subject's participation in
the protocol in a current court order issued within the subject's jurisdiction.
2. A health care proxy appointed by the subject in a power of attorney.
3. If neither of the above are designated, the investigator may obtain informed
consent from one of the following individuals in the order listed:
1. Spouse
2. Natural or adoptive parent
3. Adult child
4. Adult brother or sister
5. Any other available adult relative related through blood or marriage
known and documented to have made decisions for the subject in prior
health care settings
6. An adult individual with significant personal relationship with the subject to
warrant their authority outside the currently accepted legal spousal
relationship.
If it is appropriate to have a surrogate sign the informed consent form, indicate the
surrogate's relationship to the research subject and, if available, attach a copy of the
legal document which gives that individual the right to sign for the research participant. If
a legal document is not available, the PI must document a statement that the individual
is acting as the legally effective representative under the above conditions.
9.
Non-English Speaking
Subjects who do not speak English must be consented in a language understandable to
them. This may require the use of a certified interpreter. The MHS intranet provides a list
of certified interpreters by facility and language; the individuals listed are employed by
the health care system, and must agree to provide the required services to interpret
informed consents etc.
A witness is required to confirm that the subject was reasonably informed about the
clinical research study and consented freely to take part. If the interpreter is independent
from the research team, the interpreter may serve as witness.
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Subjects who do not speak English should also be provided with a consent document
written in a language understandable to them (or their authorized representative).
10.
Re-Consenting
A formal re-consenting process is required if new information becomes available that
may impact a subject's willingness to continue participation in the study (e.g. newlyidentified risks or changes in the research procedures). Re-consenting requires a
revised consent form. Revisions to the consent can take the form of a fully revised
consent form or an additional addendum. The IRB must approve any revisions or
addenda to the informed consent form prior to implementing them. Subjects who have
been informed about substantive new information must sign and receive a copy of the
revised IRB-approved consent form or addenda.
10.1 The following procedures should be used for re-consenting subjects with a
revised consent form:
1. If the study is actively enrolling, previously enrolled subjects must be told about
the new information at their next scheduled meeting. The subjects should sign
the revised consent form as documentation of their willingness to continue in the
research.
2. If the study is closed to accrual, but subjects are being followed, the subjects
must sign either the revised consent form or an addendum to the original consent
that presents the new findings.
3. If the study is closed to accrual, and subjects are being followed only through
phone contact, the investigators may send the subjects a consent form
addendum using certified or registered mail. Documentation of their receipt of
this addendum may be noted in the research records at the time of their next
phone contact.
4. If the study is closed to follow-up and the significant new findings may affect the
long term health of the subject, the investigator shall attempt to send a letter to all
prior subjects' last known address using certified mail. This letter should contain
a name and phone number for the subject to contact should they require
additional information.
10.2 Non-substantive changes to the study
Subjects may be informed of non-substantive changes to the study (changes that would
not impact their willingness to continue participation) verbally or through the use of a
letter. Examples include a change in study team members or contact information. The
date of the conversation or the date of the distribution of the letter informing the subject
of the non-substantive study change should be documented in the subject's research
file.
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11.
Enrollment
11.1 Enrollment Implementation
The protocol should clearly delineate at what point a person is considered 'enrolled' to
differentiate enrolled subjects from screen failures. The IRB has acknowledged that an
enrolled subject is one who has
•
Signed informed consent and HIPAA authorization
•
Completed all research related screening tests
•
Has met all inclusion criteria - and
•
Has been appointed a study number
If inclusion criteria have not been met, this can be considered a screen failure. If a
subject has been enrolled and randomized to a treatment arm, if applicable, but never
received study drug, this can be considered an early withdrawal.
11.2 Randomization
Randomization is a process that assigns research subjects by chance to a study arm.
Randomization prevents undue bias from affecting study results.
The randomization process should be outlined in the study protocol. For blinded studies,
an un-blinded person or group should hold responsibility for un-blinding and maintaining
a master randomization list of all participants.
Examples of randomization assignment methods include:
•
Interactive Voice Randomization System (IVRS)
•
Web-based randomization system
•
Randomization envelopes
•
Randomization schedules
11.3 Prioritizing
At times, a research candidate may be eligible for more than one study. In such
instances, the investigator and coordinator must examine the "best fit" for the subject
(his or her interest in the study or willingness to complete the follow-up procedures), the
priority of the research study, and the enrollment history.
11.4 Enrollment Documentation
For many studies it is helpful to develop enrollment packets. An enrollment packet
contains research tools and documents to complete screening, enrollment, and protocol
procedures. Enrollment packets can be stored individually in folders or large envelopes
in an easy access location where subjects will be screened.
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Possible documents/tools to include in an enrollment packet:
Study-specific
•
Eligibility checklist (inclusion/exclusion criteria)
•
Source documents
•
Timeline/checklist of study procedures
•
Randomization tools
Subject-specific
•
Screening forms
•
Forms requiring signatures
o
Informed Consent Form, HIPAA authorization, Medical Release, W9 tax
form
•
Educational Materials/Instructions
•
Registration forms
•
Prescriptions
•
Wallet 'alert' cards
•
Vouchers
Procedure-specific
•
Laboratory requisitions
•
Specimen labels
•
Questionnaires
•
Evaluation forms
Once a subject is actively enrolled in the study, completed documents from the
enrollment packet are transferred into the subject's study file (e.g. eligibility checklist,
source documents, screening forms, consents, questionnaires, etc.).
11.5 Enrollment Tracking
The investigator should establish enrollment goals to ensure successful and timely
completion of the project. Enrollment goals specify how many subjects should be
enrolled at each site over a certain period of time. By comparing expected to actual
enrollment, problems can be identified and eliminated early.
If enrollment is poor, the investigator should identify the problem:
•
Was the prevalence of the population overestimated?
•
Are advertisements reaching the appropriate audience?
•
Has there been any negative publicity associated with the research, investigator,
or institution?
•
Are subjects being referred appropriately or in sufficient numbers?
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•
Are enough resources devoted to screening? Are the resources distributed
appropriately?
•
Are the eligibility requirements overly-rigorous?
•
Is there sufficient reimbursement for subjects?
•
Are the protocol requirements too demanding on subjects?
•
Are competing studies interfering with enrollment?
Once the problems have been identified, the investigator can try to remove the barriers
to enrollment. This may involve changing the design of the study, revising recruitment
strategies, increasing payment, redistributing resources, or amending the protocol.
12.
Study Procedures
12.1 Subject File
It is recommended that the researcher develop a file specific to each subject. This
enables the Clinical Research Nurse (CRN)/Clinical Research Coordinator (CRC),
Principal Investigator (PI), Clinical Research Associate (CRA)/monitor, or other reviewer
to quickly ascertain information about a particular subject's participation in the study. The
Subject File should be filed according to an identifier rather than by name and access
should be restricted and secured to protect confidentiality. Standard Operating
Procedures (SOPs) should be created to dictate office standards and to assure
uniformity.
A Subject's File may include any and all records necessary to delineate the progression
of the subject throughout the research project. The contents of the subject files will vary
from study to study as well as from research office to research office.
The Subject File should contain the following:
•
A copy of the Informed Consent form (the original should be filed in a separate
Informed Consent Forms file)
•
Completed Case Report Form(s)
•
Source documents (see below)
•
Copies of pertinent medical records that may not be easily retrievable on site
(e.g. lab work done by the subject's primary care physician between study visits)
•
Correspondence with or about the subject (e.g. a phone log)
•
Explanations (i.e. Notes to File) by the study staff explaining variances from
protocol, discrepancies, missing data, etc.
•
Queries from the data coordinating center and the responses
•
Dosing or randomization documents
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12.2 Source Documents
Source documents prove the existence of a subject and substantiate the integrity of
research data. They are the first documentation of any study observations or data.
Source documents are the original hospital records/charts, laboratory data, x-rays,
pharmacy records, study records, etc. Source documents may even include scraps of
paper where information is first recorded. Together they comprise a subject's research
records and delineate the details of his or her progress throughout the research project.
To create a customized source document template:
•
Compare the protocol, the case report form (CRF), and current practice in
existing records.
•
List data not routinely charted in the existing records. Focus upon capturing a
comprehensive summation of information relevant to the subject's research
status including, but not limited to, the information necessary to complete the
CRF.
•
Create source documents that are as close to standard charting procedures as
possible.
•
Create a line for the person gathering information to sign and date the source
document.
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Chapter 20: Withdrawing a Subject
1.
Withdrawing a Subject
A subject may be withdrawn from a study for several reasons, including failure to follow
the protocol after being enrolled or having an adverse reaction to the investigational
article. It is also a subject's right to voluntarily withdraw at any time during study
participation.
2.
Follow-Up
In the event that a subject is withdrawn, a final visit should be scheduled. Many study
protocols require that follow-up be continued for a specified period of time after a subject
is withdrawn, regardless of the reason, to maintain safety. Every effort should be made
to monitor the subject's health; however, ultimately, a mentally competent individual has
the right to refuse all follow-up even if it compromises his or her safety. If this is the case,
it is important to document the subject's refusal of follow-up.
3.
Notifications
When a subject is withdrawn from a study for any reason, the study sponsor (if
applicable) should be notified as soon as possible. The withdrawal must also be reported
to the IRB at the time of continuing review.
If the withdrawal is the result of an adverse event, this should be documented and
reported following the AE reporting guidelines.
4.
Data Management
In the case of subject withdrawal, it is imperative to collect at least survival data on the
subject throughout the follow-up period. This data is important to the integrity of the final
study analysis since early withdrawal could be related to the safety profile of the study
intervention. The protocol should clearly define what types of data should be collected
and the follow-up period for withdrawn subjects.
5.
Subject withdrawal of authorization to use protected health information
In addition to withdrawing participation in a study, the subject also has the right to
withdraw the authorization to use his or her protected health information. This
authorization was provided when they signed the HIPAA Authorization Form as part of
the Informed Consent Form and process. If a subject decides to withdraw from a study,
the researcher should remind the subject of this right to withdraw HIPAA Authorization.
The subject must withdraw their HIPAA authorization in writing as explained in the
Informed Consent Form. If a subject verbally indicates that he/she would like to withdraw
HIPAA authorization the investigator should re-inform the subject of the written
withdrawal procedure.
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If the subject withdraws HIPAA authorization, the investigator should
•
Inform the subject that no further information will be accessed for the research
purposes as outlined in the HIPAA authorization;
•
Remind the subject that even though he/she has withdrawn authorization, the
information already obtained may remain a part of the research as necessary to
preserve the integrity of the research study; and
•
Withdraw the subject from the research study.
6.
Lost to Follow-up (LTF)
A subject is considered lost to follow-up (LTF) when they fail to return for a scheduled
visit, cannot be contacted, and do not complete any final evaluations.
Occasionally, subjects may become difficult to contact or may miss scheduled visits.
The following sequence should be followed for contacting "lost" subjects:
1. Subjects should be contacted 2-3 times via telephone at varying times and dates.
Document dates of contact and outcome in the subject's study file (e.g. left
voicemail message, phone disconnected, etc.).
2. A telephone call should be placed to his or her contact person to determine the
subject status. A contact person (that does not live with the subject) should be
obtained at the onset of study participation.
3. A certified letter should be sent to the subject's mailing address.
4. The local Vital Records department may be contacted to determine if the subject
has expired.
Several methods should be used to try to contact subjects. After several unsuccessful
attempts, the subject is considered lost to follow-up and must be withdrawn from the
study. If this is the case, the coordinator should document the dates of attempted contact
and the contact methods used in the Subject file.
7.
Managing Adverse Events
7.1 Assessing Adverse Events
The investigator and study coordinator should assess each participant for adverse
events (AE) throughout study participation and during the follow-up period. This includes
conducting a thorough investigation of any suspected AE that may come from a variety
of sources:
•
Spontaneous reports by subjects
•
Observations by key study personnel
•
Reports to study staff by the subject's family or medical care providers
•
Possible AE documented in medical records, progress notes, etc.
•
Death of a subject
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In addition to receiving reports of potential AE, the investigator and study coordinator
should develop and implement a plan to consistently and routinely monitor for AE
through proactive measures such as:
•
Interview subjects at every visit
•
Review lab reports
•
Review subject's medical records for additional information
•
Review subject's diaries (if applicable)
•
Communicate with subject's medical providers
7.2 Clinical Management of Adverse Events
All appropriate resources should be directed toward subject safety and well-being by
instituting therapeutic intervention/support measures for subjects experiencing an AE.
This may include a discontinuation, reduced dosage or interruption of the therapeutic
agent, the procedures for which would be defined in the protocol. The subject
experiencing the AE should be followed and assessed until the AE is stabilized and
resolved.
The study team must fully document the occurrence and management of the AE in the
appropriate source document.
7.3 Breaking the Study Blind
If necessary for the immediate medical care of an AE in one of the subjects, the
investigational product blind may be broken. The protocol should clearly describe the
procedures for un-blinding study therapy on a subject. When the blind is broken, the
data collected for that study subject must be excluded from the study.
While the safety of the subject always comes first, it is still important to seriously
consider if un-blinding the study therapy is necessary to ensure a subject's safety. It is a
common misconception that the blind needs to be broken for every Serious AE, but this
is only true if the breaking of the blind is necessary for the medical care of the subject or
if the protocol requires it. In cases where the blind is broken and is not necessary for the
care of the subject, valuable study data will be lost unnecessarily.
If available, the investigator should consult with the study pharmacist to assist in
breaking the blind.
All incidences of un-blinding should be documented in the CRF and in the participant's
file. If the unblinding is associated with the management of an AE, the event should be
reported to the IRB.
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Chapter 21: Study Closeout
1.
Study Closeout
Once the study has been closed to enrollment and all follow-up data have been
collected, the study is considered to be in the Closeout Phase. It is during this phase that
data are prepared for final analysis, regulatory and reviewing bodies are notified, the
investigational product inventory is reconciled, and final reports are completed.
1.1 Study sites may be closed when:
Externally or internally funded protocols
When follow-up data are no longer being collected on subjects enrolled in a
protocol AND database finalization has taken place.
Industry-sponsored studies
As above, AND after the site has been notified by the Industry sponsor that the
site may be closed.
The ultimate goal of a clinical research study is to further the knowledge and
understanding of human behavior, physiology or pathophysiology, often in the context of
testing a treatment intervention. Important to this goal is making such knowledge
available to the research community and the public. Study findings can be
communicated in a number of ways including publishing results, generally in peerreviewed journals, or presenting research results at regional, national or international
conferences. The research may also result in important new discoveries which may lead
to the need for intellectual property rights protection in the form of patents and
copyrights.
This section of the manual outlines the required steps necessary to close out a study
and highlights issues and resources for communicating study findings and protecting
intellectual property.
2.
Final Reconciliations
For industry-sponsored studies, the sponsor will determine the disposition of the
remaining inventory of the study drug or devices. The sponsor may request that the
unused product be returned or destroyed. In either case, it is important for the research
staff to document the following information:
•
Identifying information (lot, batch, or serial numbers)
•
Quantity of drug or device used and unused
•
Shipping information (for returned drugs or devices)
•
Means of drug or device destruction and person responsible for destruction
•
Date of drug or device destruction (see below)
The Investigational Product Accountability Log should also reflect the disposition of
unused product(s). The Investigational Drug Services Pharmacist can assist with the
necessary reconciliation of investigational drugs.
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For investigator-initiated studies, the Investigator has the same responsibility for
investigational product inventory as an industry sponsor. In addition to documenting the
above information for his/her site, the Sponsor-Investigator must also ensure the same
reconciliation/disposition information for investigational product at each participating site.
3.
Destruction of Investigational Drugs and Devices
The destruction of investigational drugs and devices must be tightly controlled with
detailed record-keeping to capture study-specific information which will not be retrievable
once the once the products are destroyed, as well as to assure that there is no loss or
theft of the product.
In addition to the Accountability log, the following forms should be completed when
destroying investigational products:
IF sponsor-specific forms are available
Destruction should be documented on the sponsor-provided forms. However, any
pertinent data which is not collected on those forms should be documented on a
separate sheet and attached to the sponsor form.
IF a sponsor-specific form is not available
Destruction may be documented in a typed letter, other record, or on a
destruction log provided by the Investigational Drug Services Pharmacist (IDS).
IF the product is a Schedule II Narcotic
Destruction should be documented on a DEA-41 form and signed by two
licensed individuals
http://www.deadiversion.usdoj.gov/21cfr_reports/surrend/41_form.pdf
When investigational products are destroyed, the destruction forms should include
detailed information about the items destroyed. This includes inventory numbers, lot
numbers, serial numbers, subject identifiers, expiration dates, etc. The destroyer and a
witness must sign and date the destruction forms (two witnesses are preferred). A copy
of destruction documentation must be kept in the regulatory files. The IDS Pharmacist
will provide you a copy of the SOPs used in drug destruction at MHS
Please note: When destroying medications or devices, the date (of removal) in the
accountability log should match the date (of destruction) recorded on the destruction
form/log.
4.
Database Finalization
In order to conduct the statistical analysis, study data must be subjected to a series of
processes to resolve data discrepancies (data management processes termed data edit
check and query resolution, or simply "database cleaning") and to standardize certain
aspects of the data. It is important to submit study data for database entry as soon as
possible after processing a research subject visit in order to facilitate efficient and timely
data management, and ultimately the final study analysis.
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4.1 Data Discrepancies and Coding
Data discrepancies are generally assessed through a combination of:
•
direct monitoring of data collected against the original source of such data during
data monitoring, and
•
the use of automated database edit checks.
Any discrepancies or missing data are addressed by generating written queries to the
research site requesting resolution of the discrepancy.
Additionally, certain data must be converted to standard terminology in a process termed
"data coding". The coding process can be manual, although it is typically facilitated with
sophisticated automated coding programs.
4.2 Database Freeze and Standardization
Before the database is considered truly finalized and ready for data analysis, it is often
subjected to a final standardization process. This process occurs after data entry has
been completed, all data queries have been resolved as best as possible, and data
coding has been completed. Closing the database in such a manner is often referred to
as "freezing the database."
The subsequent data standards process defines, in a blinded fashion, the standards for
managing outlier data (out of range values) or incomplete data elements. For example
for a measured study event, if month/day/year information is required to define the timing
of the event, and only month and year information is available, a data standards meeting
would define the standard approach to assigning a "day" for events missing that data
point. This standard would be used consistently every time that "day" information was
missing.
4.3 Database Lock
Once such data standards have been defined and applied, the database is considered
finalized and can be formally closed to further data editing, a process often termed
"locking the database." The statistical data analysis can be conducted once the
database has been locked.
It is important to have a well-defined and documented process for finalizing a database.
The following overviews the steps to finalizing the clinical database:
•
Data entry
•
Data monitoring and edit checks for discrepancies and missing data
•
Data queries generated and sent to research sites to resolve data discrepancies
•
Database changes according to query results
•
Data coding
•
Database freeze
•
Data standards definitions and application
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•
Database lock
•
Statistical analysis
These steps are typically performed by data management and biostatistical personnel,
but generally require the cooperation and assistance of the research study staff. Once all
the steps are complete, all relevant parties should be notified, edit access should be
removed and the date documented. If errors are found after the database is locked and it
needs to be re-opened, the same steps as above should be followed to re-lock it after
the errors are corrected.
5.
Post-Study Communication
5.1 Institutional Post-Study Notifications
At the conclusion of a study, the investigator is required to notify the Institutional Review
Board (IRB) by submitting a Study Closure Report.
Study sites may be closed when:
Externally or internally funded protocols
When follow-up data are no longer being collected on subjects enrolled in a
protocol AND database finalization has taken place.
Industry-sponsored studies
As above, AND after the site has been notified by the Industry sponsor that the
site may be closed.
5.2 Final Reports
For investigator-initiated studies, the Principal Investigator (PI) is responsible for
preparing a Final Report of the study. This report is prepared using the guidelines of the
recipient, and submitted to the following regulatory and funding entities as applicable:
•
Institutional Review Board
•
National Institutes of Health (NIH) funding agency - for NIH-funded studies
•
Food and Drug Administration (FDA) - for investigator-initiated studies conducted
under an Investigational New Drug (IND) application or an Investigational Device
Exemption (IDE)
•
Funding agency / Sponsor
Institutional Review Board
The PI should forward a copy of the Final Report to the IRB regarding the overall
conduct of the study and any publications.
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NIH
NIH Grantees must submit the following reports within 90 days of the end of grant
support:
•
Final Financial Summary Report (OMB269)
•
Final Progress Report - The final progress report should include a summary of
progress toward the achievement of the research project's aims, a list of
significant results (positive or negative), and a list of publications. The report
should address the inclusion of gender, minorities and children, and include any
data, research materials protocols, software, or other information resulting from
the research that is available to be shared with other researchers with
information on how it can be accessed.
•
Final Invention Statement and Certification (HHS 568) - The grantee must submit
a Final Invention Statement and Certification regardless of whether or not the
funded project results in any subject inventions. The HHS 568 must list all
inventions that were conceived or first actually reduced to practice during the
course of work under the project. If there were no inventions, the form should
indicate “None.” http://grants.nih.gov/grants/hhs568.pdf
All forms can also be found at http://grants.nih.gov/grants/forms.htm. Failure to submit
timely final reports may affect future funding to the organization.
FDA
For FDA reporting, the final report should follow the format of the FDA annual report.
This format can also be used to prepare the report for the IRB and the sponsor. This
format includes the following information:
•
A statement that the study is completed
•
The title, protocol number, purpose, population
•
Information about the number of subjects anticipated, entered, completed and
dropped out; tabulate by age group, gender, and race
•
Summary of study results
•
Summary of most frequent and most serious adverse experiences by body
system
•
Summary of all IND Safety Reports
•
List of subjects who died during participation, with cause of death
•
List of subjects who dropped out in association with any adverse experience
•
Description of what was obtained pertinent to an understanding of the drug's
actions
•
List of preclinical studies completed or in progress during the study; summary of
findings
•
Summary of any significant manufacturing or microbiological changes made
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•
Description of any significant Phase I protocol modifications made
•
Summary of significant foreign marketing developments with the drug
Funding Agency
For studies conducted using funds from a foundation grant or other source, the funding
agency often requires submission of a final report. If not required, it is a generally
accepted courtesy to do so. The format of the report should be specified by the funding
agency.
6.
Subject Unblinding and Follow-Up
6.1 Unblinding
In blinded studies, subjects often request information regarding their treatment group.
This information may not be made available for many months or even years after followup has been completed. Although it is not required to divulge the treatment assignment,
test results or research findings to research subjects, doing so is an important way to
recognize the contribution the research subject has made and can enrich the research
experience for completed subjects. In certain situations it may be necessary to supply
such information when it could affect the quality of follow-up care to research subjects.
Research subject notification usually involves composing a letter identifying the subject's
group assignment, acknowledging their contributions, and, if possible, disclosing the
research findings. In industry-sponsored studies, the investigative site may need to
actively request this information from the sponsor following study termination.
6.2 Follow-Up
It may also be necessary to follow-up with subjects who have completed participation in
a research study if significant new findings are discovered that may affect the long-term
health of the subject. Examples include a product recall on an implanted investigational
device or carcinogenicity associated with an investigational drug. In these instances, the
investigator should attempt to send all prior subjects an IRB-approved informational
addendum (letter) to their last known address. This addendum should contain a name
and phone number for the subject to contact should they require additional information.
The investigator should retain evidence of the communication or attempts at
communication through a delivery tracking method such as certified mail.
7.
Storage and Archiving
7.1 Study Record Retention
The Principal Investigator (PI) is responsible for storing regulatory documents, subject
files and financial records for the period of time specified by law and the study sponsor.
The time period for maintaining research records is defined in various regulations. If
multiple regulations apply to a particular study, the longest retention period applies.
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•
HIPAA regulations require that any HIPAA-regulated information, authorizations,
waivers, etc. must be maintained for at least 6 years subsequent to the
Institutional Review Board (IRB) acknowledgement of the termination of the
research project.
•
DHHS regulation (45 CFR 46.115) and FDA regulation (21 CFR 56.115) state
that IRB records relating to research shall be retained for at least 3 years after
completion of the research.
•
For research funded by the National Institutes of Health (NIH), research records
must be retained for at least 3 years from the date the Final Financial Status
Report is submitted.
•
Research involving an FDA Investigational New Drug application (IND) must
additionally comply with 21 CFR 312.57 and 21 CFR 312.62 by retaining records
for:
o
A period of 2 years following the date a marketing application is approved
for the drug for the indication for which it is being investigated - or -
o
If no application is to be filed or if the application is not approved for such
indication, until 2 years after the investigation is discontinued and FDA is
notified
The sponsor or funding agency may require that records be retained for a longer period
of time, so it is important to determine the sponsor's or funding agency's requirement as
per their contract.
7.1.1 General Tips for Record Retention
•
Maintain lists for tracking archived research records.
•
Check with department for policies on storage and destruction.
•
Keep research records secure and confidential.
•
Check with sponsor or funding agency for record retention requirements.
•
Obtain authorization prior to record destruction.
o
Maintain an accurate list of records destroyed.
7.1.2 Storage Location
Study documents should be retained in a secured, limited access area. It is
recommended that the Recall Miami (Brambles) be utilized for the purposes of archiving
study records.
The address for this facility is:
RECALL MIAMI (BRAMBLES)
11800 NW 100 Rd., Medley, FL 33178
Phone: (305) 884 1733.
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7.2 Human Tissue Retention
The plans and procedures for retaining research subject tissue samples (includes blood,
serum, urine, other bodily fluids, hair, soft tissue, bone, etc.) should be fully addressed in
the study protocol. The research consent form and HIPAA authorization form must also
refer to any plans for tissue retention. The study protocol should describe how the
tissues will be prepared for storage and who is responsible for such preparation, how
samples will be stored, the procedures to track samples and associated information as
well as the security procedures to prevent unauthorized access to samples and
associated information.
Ownership and sponsor retention requirements for human tissue samples are generally
also addressed in the Clinical Trial Agreement (CTA). It is important to be aware of the
contractual requirements for tissue retention in an industry-sponsored study.
7.2.1 When tissue retention constitutes general tissue banking
When tissue samples are retained for reasons beyond use of the specific research study
for which they were obtained (i.e. future possible research), it is considered general
tissue banking. The IRB requires written procedures describing how samples are
obtained, how consent to procure samples is obtained, how samples are prepared and
stored, and a security plan preventing unauthorized access to the samples and their
associated information. The Informed Consent must inform the patient about the
purpose their tissue/blood
8.
Publications and Presentations
In order to fulfill the goal of contributing to generalizable knowledge, it is generally
accepted and expected that research results should be shared with the research
community and the public. There are a number of venues for communicating study
findings, including:
•
Lecture or poster presentations at seminars and conferences
•
Professional peer-reviewed journals and books for the discipline of study
•
Press releases, newspaper articles
8.1 Clinical Trials Listing Requirement
Researchers intending to publish research results should be aware of the recent
requirements published by the International Committee of Medical Journal Editors
(ICMJE), requiring that information about clinical trials be registered on a website
supported by a non-profit organization and easily accessible. For more information about
this requirement, as well as other information regarding publishing, refer to the ICMJE
website at http://www.icmje.org/
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8.2 Publication Rights
8.2.1 National Institutes of Health (NIH)
In the case of research funded or supported by the NIH, investigators are encouraged
and expected to submit publications based upon their work.
The NIH requires acknowledgement of NIH grant support with a citation on the
publication such as:
"This publication was made possible by Grant Number ### from xxx. Its contents are
solely the responsibility of the authors and do not necessarily represent the official views
of (awarding office)."
8.2.2 Industry-sponsored
In the case of industry-sponsored research, or any research project conducted under a
contract, a publication clause is usually included in the study contract. This clause
specifies whether or not the Principal Investigator and the Institution has the right to
publish study results, and if so, the specific requirements for that publication. It is
therefore important to refer to the contract or Clinical Trial Agreement to determine
publication rights. It is also expected that the industry sponsor/source of funding is
acknowledged in the publication.
9.
Responsible Authorship
Whatever the venue, publications and authorship should present the study findings in an
honest, unbiased manner. The Responsible Conduct of Research standards assert
several principles that should be followed to ensure the practice of "responsible
authorship." (Steneck, Nicholas H. 2004, Introduction to the Responsible Conduct of
Research. Office of Research Integrity - http://ori.hhs.gov/documents/rcrintro.pdf).
One of the more taxing decisions in publishing study findings is the names that will
appear as authors and the order in which those names will appear. To fairly and
accurately represent the person(s) responsible for the work, authorship should include
only those individuals who make significant contributions to the work, including any or all
of the following phases:
•
Study design
•
Data collection and interpretation
•
Drafting of the publication
•
Final approval of the publication
In general, the first author listed is the person who contributed most to the work and is
typically responsible for writing the first draft of the publication manuscript. The
sequence of the other authors may be dependent upon relative contributions, but in
some departments, are listed in order of importance.
The practice of "honorary authorship" is strongly discouraged. In this practice, authors
are listed solely on the basis that they are chair of the department, a mentor to the
primary author, or have provided funding for the research. Those individuals that
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contributed to the research project but do not qualify as authors should be credited in the
Acknowledgement section.
10.1
Journal Submission
There are often multiple journals in any given field of study. The publication author
should consider the implications of the research, the most appropriate audience, and the
intended message when selecting the potential journal to which the manuscript should
be submitted. Editors require authors to submit manuscripts in a style and format
specific to the given journal. Instructions to authors are published at least yearly in each
journal and some may have instructions available online.
10.1.1 Elements of a Publication
The following are widely-expected elements of any publication:
Abstract
Summary of the content of the publications; provides the reader with sufficient
information to determine relevance of the publication
Methods
Detailed description of the scientific methods used in to conduct the research;
establishes credibility of the results
Results
Presentation of the data analysis, but no interpretations in this section - just the
facts; include all results, even those that are contradictory to the researcher's
conclusions
Discussion/Conclusion/Summary
Presentations of the significance of the findings, identification of unresolved
problems, future research needs; avoid bias and one-sided reporting
Notes/Bibliography/Acknowledgements
The editor will evaluate whether the paper is appropriate for their journal by evaluating:
•
Importance of the research question
•
Knowledge of the current literature
•
Appropriateness of research methods
•
Clearly stated and interesting conclusions
Journals usually acknowledge receipt of submissions. Typically, journals will take 3-6
months to notify investigators of acceptance, rejection or requested revisions for
publication.
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10.2 Poster Presentation
Many researchers choose to present study findings in the form of a scientific poster at a
regional or national professional conference. Unlike an abstract or journal submission,
the researcher must pay special attention to the layout and design of a scientific poster.
The visual appeal of a poster will greatly impact how effectively the information will be
received by audience at the conference - poorly designed, cluttered posters will least
likely be read over those that have a professional, creative, and well-organized "look and
feel" to them.
10.2.1 Poster Presentation Content
Posters/presentations generally should include the following sections:
Title Page
The title page lists the intended title of the poster/presentation and eventual
paper, the authors and schools or centers affiliated with the project, and the grant
number (if applicable).
Background
The background describes the basis for the research and refers to the indications
and previous research results in this area of research.
Abstract
The abstract summarizes the research by providing a basic description of the
sampling methodology and major findings.
Demographic Table
This table should include more specific information about the sample population,
for example, age, race, gender, and study variables intended in the specified
research.
Measurement
This section contains information pertaining to the measurements used for the
results of the presented research. For example, interviews, standardized
measurements, data abstraction, etc.
Methods
A description of the study design and sample detail for the indicated results.
Results
Detailed results are specified in the results section of a poster or presentation.
Use tables in this section and be sure to state major findings.
Tables
Suggested tables should include basic demographic results, statistical results,
and findings specific to the research presented. The tables presented should
include the results from the statistical analysis.
Discussion
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The discussion explains the findings of the research, detailing the specific
differences, causes, effects, likelihood, and/or predictions of the research.
10.2.2 Poster Preparation
Design Advice
The author of a poster can choose to design and develop his/her own poster or have a
staff member design and develop it. There are several sites on the web which can assist
with design. Some of them are listed below:
•
University of Medicine and Dentistry of New Jersey:
http://cte.umdnj.edu/career_development/career_posters.cfm
•
Ph.D. Posters: http://phdposters.com/howto.php
•
Do’s and Don’t’s of Poster Presentation:
http://www.stanford.edu/group/blocklab/dos%20and%20donts%20of%20poster%
20presentation.pdf
•
Scientific Posters Made Easy:
http://www.postergenius.com/cms/?q=articles/readability
Depending on the technical experience of the researcher/author, posters can be
designed using standard office software (such as Microsoft PowerPoint or Microsoft
Publisher) or professional design software (such as Adobe Illustrator, Quark Express, or
Adobe InDesign).
In designing the poster, plan ahead for the method of printing and desired format of the
finished poster. One option is to print several smaller pages on an available color printer,
and then arrange and affix those pages to a larger poster board. Alternatively, it may be
more desirable to print a full-size poster, in which case professional print services
(Kinko’s, for e.g.) should be sought.
As an alternative to designing a poster in typical software programs, a number of
commercial services dedicated to producing scientific posters have emerged that
simplify the design process. These providers may offer templates, design, and printing
services. Using these services, the author typically chooses a template, uploads the
content for each section, and a final printed version is produced and mailed back to the
author. Two such providers are:
•
PosterSession.com (http://www.postersession.com/)
•
SciencePresentations.com (http://www.sciencepresentations.com/)
10.3 Intellectual Property
By the nature of research activities, it is often the case that a new discovery is made or
important unique knowledge has been gained as the result of research. This discovery
or knowledge may be considered Intellectual Property. While there are a number of
definitions, generally speaking, Intellectual Property is any product of the human intellect
that is unique, novel, not obvious and possesses commercial value.
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Several legal mechanisms are available to protect Intellectual Property, granting the
owners the right to decide who can use their property. The mechanisms usually used to
protect Intellectual Property that is derived from clinical research are patents,
trademarks, and copyrights.
At times, more than one type of protection may apply to a particular discovery, with each
type providing protection to different aspects of the discovery. The patent protects the
test itself, while the trademark protects the name of the test.
10.3.1 Categories of Intellectual Property
The type of legal protection that is sought depends on the type of Intellectual Property.
Data
In the context of human subjects, research data refers to the information collected and/or
recorded in the course of conducting the research activities. Study data can take the
form of laboratory notebooks, case report forms, subject records, and the study
database itself.
The National Institutes of Health (NIH) defines Research Data as the "recorded factual
material commonly accepted in the scientific community as necessary to validate
research findings, but not any of the following: preliminary analysis, drafts of scientific
papers, plans for future research, peer reviews, or communications with colleagues."
This 'recorded' material excludes physical objects (e.g. laboratory samples). Research
data also do not include:
1. Trade secrets, commercial information, materials necessary to be held
confidential by a researcher until publication of their results in a peer-reviewed
journal, or information which may be copyrighted or patented; - and 2. Personnel and medical files and similar files the disclosure of which would
constitute a clearly unwarranted invasion of personal privacy, such as information
that could be used to identify a particular person in a research study.
Invention
An invention includes "technical information, trade secrets, developments, discoveries,
know-how, methods, techniques, formulae, data, processes and other proprietary ideas
or matter".
Tangible Research Property
Tangible Research Property includes unique research products such as biological
materials or chemical moieties or engineered products. Examples including organisms,
cells, viruses, cell products, cloned DNA, sample compounds, sensors, devices, or
diagrams.
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Copyrightable Works
Copyrightable works includes creations such as books, journals, articles, text,
administrative reports, studies or models, glossaries, bibliographies, study guides,
instructional materials, laboratory manuals, syllabi, tests, proposals, lectures, musical or
dramatic compositions, films, film strips, charts, transparencies, video or audio
recordings or broadcast, computer software, CD ROMS, circuitry, microprocessor
designs and other works that may be copyrightable under laws of the United States and
other jurisdictions.
11.
Intellectual Property Ownership at MHS
11.1
Intellectual Property
All Intellectual Property made, discovered, or created by MHS employees while acting
within the course and scope of their employment or while performing their job duties is
deemed to be “Work for Hire” which means the work is the property of MHS.
All Intellectual Property made, discovered, or created by MHS employees while acting
within the course and scope of employment or while performing their job duties must be
disclosed to MHS.
MHS may, at its discretion, enter into agreements with its employees to develop
Intellectual Property as part of their job duties, which agreements may contain provisions
for the sharing of ownership of the Intellectual Property, and division of royalties or other
payments associated with such Intellectual Property. Such agreements must be in
writing and entered into in advance of the performance of any job duties associated with
said development.
For additional information, please refer to the MHS Standard Practice titled Intellectual
Property.
11.2
Research Data
All data and research records generated in MHS remain the property of MHS. It is
important to note that the data does not belong to the investigator, meaning that if the
investigator should leave the institution, the data continues to be the property of the
MHS.
Research Data that is collected under a National Institutes of Health (NIH) grant is
subject to the Freedom of Information Act (FOIA)
(http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm). This policy
ensures that all data will be made available to the public that is:
1. supported with federal funds - and -2. cited publicly and officially by a federal agency in support of an action that has
the force and effect of law
Also relevant to research data resulting from an NIH-funded study, NIH's Data Sharing
Policy supports the sharing of final research data for use by other researchers in an
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effort to expedite translation of research results into knowledge, products, and
procedures to improve human health. All NIH grant applications requesting $500,000 or
more must include a plan for data sharing. The NIH provides more information
concerning the NIH Data Sharing Policy at
http://grants.nih.gov/grants/policy/data_sharing/
12.
Intellectual Property Protection Mechanisms
The following descriptions are taken directly from the US Patent and Trademark Office
(http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm)
12.1 Patent
A patent for an invention is the grant of a property right to the inventor, issued by the
Patent and Trademark Office. The term of a new patent is 20 years from the date on
which the application for the patent was filed in the United States (U.S) or, in special
cases, from the date an earlier related application was filed, subject to the payment of
maintenance fees. US patent grants are effective only within the U.S., U.S. territories,
and U.S. possessions.
The right conferred by the patent grant is, in the language of the statute and of the grant
itself, "the right to exclude others from making, using, offering for sale, or selling" the
invention in the United States or "importing" the invention into the United States . What is
granted is not the right to make, use, offer for sale, sell or import, but the right to exclude
others from making, using, offering for sale, selling or importing the invention.
12.2 Copyright
Copyright is a form of protection provided to the authors of "original works of authorship"
including literary, dramatic, musical, artistic, and certain other intellectual works, both
published and unpublished. The 1976 Copyright Act generally gives the owner of
copyright the exclusive right to reproduce the copyrighted work, to prepare derivative
works, to distribute copies or phone records of the copyrighted work, to perform the
copyrighted work publicly, or to display the copyrighted work publicly.
The copyright protects the form of expression rather than the subject matter of the
writing. For example, a description of a machine could be copyrighted, but this would
only prevent others from copying the description; it would not prevent others from writing
a description of their own or from making and using the machine. Copyrights are
registered by the Copyright Office of the Library of Congress.
12.3 Trademark
A trademark is a word, name, symbol or device which is used in trade with goods to
indicate the source of the goods and to distinguish them from the goods of others. A
servicemark is the same as a trademark except that it identifies and distinguishes the
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source of a service rather than a product. The terms "trademark" and "mark" are
commonly used to refer to both trademarks and servicemarks.
Trademark rights may be used to prevent others from using a confusingly similar mark,
but not to prevent others from making the same goods or from selling the same goods or
services under a clearly different mark.
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