Pediatric Template
HIC# if known
YALE UNIVERSITY
HUMAN INVESTIGATION COMMITTEE
Application to Involve Pediatric Human Subjects in Biomedical Research
100 FR17 (2011-5)
Please refer to the HIC website for application
instructions and information required to
complete this application. The Instructions are
available at http://www.yale.edu/hrpp/formstemplates/biomedical.html
HIC OFFICE USE ONLY
DATE STAMPED-RECEIVED
PROTOCOL NUMBER
Submit the original application and two (2)
copies of all materials including relevant
sections of the grant which funds this project
(if applicable) to the HIC.
This template is meant to be used for pediatric protocols conducted by
researchers from the Yale School of Medicine, Yale School of Public Health
and Yale School of Nursing.
Please note: The instructions in this pediatric annotated template
supplement the Application Instructions located at:
http://www.yale.edu/hrpp/forms-templates/biomedical.html . This template
does not replace those instructions, but gives further information for those
researchers enrolling minors.
Note: Delete the template instructions and any template language that
is not applicable to your protocol, before submission of your
application to the PPRC and then the HIC.
SECTION I: ADMINISTRATIVE INFORMATION
Title of Research Project:
Principal Investigator:
Yale Academic Appointment:
Campus Address:
Campus Phone:
Fax:
Pager:
Protocol Correspondent Name & Address (if different than PI):
Campus Phone:
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Fax:
E-mail:
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E-mail:
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Faculty Advisor:(required if PI is a student,
resident, fellow or other trainee)
NA
Yale Academic Appointment:
Campus Address:
Campus Phone:
Fax:
Pager:
E-mail:
Does the principal investigator, co-investigator, or any other responsible research team member, or any of
their family members (spouse, child, domestic partner) have an incentive or interest, financial or otherwise,
that may be viewed as affecting the protection of the human subjects involved in this project, the scientific
objectivity of the research or its integrity? See Disclosures and Management of Personal Interests in Human
Research http://www.yale.edu/hrpp/policies/index.html#COI
Yes
No
If yes, list names of the investigator or responsible person:
The Yale University Principal Investigator and all Yale University and Yale New Haven Hospital
individuals who are listed as co-investigators on a protocol with a Yale University Principal
Investigator must have a current financial disclosure form on file with the University’s Conflict
of Interest Office. Conflict of Interest Office. If this has not been done, the individual(s) should
follow this link to the COI Office Website to complete the form: http://www.yale.edu/coi/
NOTE: The requirement for maintaining a current disclosure form on file with the University’s
Conflict of Interest Office extends primarily to Yale University and Yale-New Haven Hospital
personnel. Whether or not they are required to maintain a disclosure form with the
University’s Conflict of Interest Office, all investigators and individuals deemed otherwise
responsible by the PI who are listed on the protocol are required to disclose to the PI any
interests that are specific to this protocol.
SECTION II: GENERAL INFORMATION
1. Performing Organizations: Identify the hospital, in-patient or outpatient facility, school or
other agency that will serve as the location of the research. Choose all that apply:
a. Internal Location[s] of the Study:
Magnetic Resonance Research Center
(MR-TAC)
Yale Cancer Center/Smilow
Yale Cancer Center/Clinical Trials Office
Yale-New Haven Hospital
Specify Other Yale Location:
Yale University PET Center
YCCI/Church Street Research Unit (CSRU)
YCCI/Hospital Research Unit (HRU)
YCCI/Keck Laboratories
Cancer Data Repository/Tumor Registry
b. External Location[s]:
APT Foundation, Inc.
Connecticut Mental Health Center
Clinical Neuroscience Research Unit (CNRU)
Other Locations, Specify:
location(s)):
Haskins Laboratories
John B. Pierce Laboratory, Inc.
Veterans Affairs Hospital, West Haven
International Research Site (Specify
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c. Additional Required Documents (check all that apply):
N/A
*YCCI-Scientific and Safety Committee (YCCI-SSC)
Approval Date:
*Pediatric Protocol Review Committee (PPRC)
Approval Date:
*YCC Protocol Review Committee (YRC-PRC)
Approval Date:
*Dept. of Veterans Affairs, West Haven VA HSS
Approval Date:
*Radioactive Drug Research Committee (RDRC)
Approval Date:
YNHH-Radiation Safety Committee (YNHH-RSC)
Approval Date:
Magnetic Resonance Research Center PRC (MRRC-PRC) Approval Date:
YSM/YNHH Cancer Data Repository (CaDR)
Approval Date:
Dept. of Lab Medicine request for services or specimens form
*Approval from these committees is required before final HIC approval is granted. See instructions
for documents required for initial submission and approval of the protocol. Allow sufficient time for
these requests. Check with the oversight body for their time requirements.
2. Probable Duration of Project: State the expected duration of the project, including all
follow-up and data analysis activities.
The numbers of subjects need to match in all documents (e.g. parental permission and
consent form if you have participants > 18 years of age) as well as within this HIC
application, especially if you have different groups participating in the study. It is important for
PPRC to know how many minors are being exposed to the observation or intervention. The
number of subjects should be minimized consistent with good study design. Also, this is the
place to indicate if you think that you need to enroll more subjects or have more subjects sign
the consent form because there will be a certain drop-out or non-completion rate.
3. Research Type/Phase: (Check all that apply)
a. Study Type
Single Center Study
Multi-Center Study
Does the Yale PI serve as the PI of the multi-site study? Yes
Coordinating Center/Data Management
Other:
b. Study Phase
Pilot
Other (Specify)
N/A
Phase I
Phase II
Phase III
4.
No
Phase IV
Area of Research: (Check all that apply) Note that these are overlapping definitions and
more
than one category may apply to your research protocol. Definitions for the following can be found
in the instructions section 4c:
Clinical Research: Patient-Oriented
Clinical Research: Outcomes and
Clinical Research: Epidemiologic and Behavioral
Health Services
Translational Research #1 (“Bench-to-Bedside”)
Interdisciplinary Research
Translational Research #2 (“Bedside-to-Community”)
Community-Based Research
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5. Is this study a clinical trial? Yes
No
NOTE the current ICMJE (International Committee of Medical Journal Editors) definition of a
clinical trial: “any research study that prospectively assigns human participants or groups of
humans to one or more health-related interventions to evaluate the effects on health outcomes.”
Health-related interventions include any intervention used to modify a biomedical or healthrelated outcome (for example, drugs, surgical procedures, devices, behavioral treatments,
dietary interventions, and process-of-care changes). Health outcomes include any biomedical or
health-related measures obtained in patients or participants, including pharmacokinetic
measures and adverse events”
If yes, where is it registered?
Clinical Trials.gov registry
Other (Specify)
Registration of clinical trials at their initiation is required by the FDA, NIH and by the ICMJE.
If this study is registered on clinicaltrials.gov, there is new language in the consent form and
compound authorization that should be used.
For more information on registering clinical trials, including whether your trial must be
registered, see the YCCI webpage, http://ycci.yale.edu/researchers/ors/registerstudy.aspx or
contact YCCI at 203.785.3482)
6. Will this study have a billable service as defined by the Billable Service Definition?
Yes
No
If you answered "yes", this study will need to be set up in Patient Protocol Manager (PPM)
http://medicine.yale.edu/ymg/systems/ppm/index.aspx
7. Are there any procedures involved in this protocol that will be performed at YNHH or one of
its affiliated entities? Yes ___ No ___ If Yes, please answer questions a through c and note
instructions below. If No, proceed to Section III.
a. Does your YNHH privilege delineation currently include the specific procedure that you will
perform?
b. Will you be using any new equipment or equipment that you have not used in the past for
this procedure?
c. Will a novel approach using existing equipment be applied?
If you answered “no” to question 7a, or "yes" to question 7b or c, please contact the YNHH
Department of Physician Services (688-2615) for prior approval before commencing with your
research protocol.
SECTION III: FUNDING, RESEARCH TEAM AND TRAINING
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1. Funding Source: Indicate all of the funding source(s) for this study. Check all boxes that
apply.
Provide information regarding the external funding source. This information should include
identification of the agency/sponsor, the funding mechanism (grant or contract), and whether
the award is pending or has been awarded. Provide the M/C# and Agency name (if grantfunded). If the funding source associated with a protocol is “pending” at the time of the
protocol submission to the HIC (as is the case for most NIH submissions), the PI should note
“Pending” in the appropriate section of the protocol application, provide the M/C# and
Agency name (if grant-funded) and further note that University (departmental) funds support
the research (until such time that an award is made).
PI
Title of Grant
Name of Funding Source
Funding
Federal
State
Non Profit
Industry
Other For
Profit
Other
Federal
State
Non Profit
Industry
Other For
Profit
Other
Federal
State
Non Profit
Industry
Other For
Profit
Other
Funding Mechanism
Grant-M#
Contract#
Contract Pending
Investigator/Department
Initiated
Sponsor Initiated
Other, Specify:
Grant-M#
Contract#
Contract Pending
Investigator/Department
Initiated
Sponsor Initiated
Other, Specify:
Grant-M#
Contract#
Contract Pending
Investigator/Department
Initiated
Sponsor Initiated
Other, Specify:
IRB Review fees are charged for projects funded by Industry or Other For-Profit Sponsors.
Provide the Name and Address of the Sponsor Representative to whom the invoice should be
sent. Note: the PI’s home department will be billed if this information is not provided.
Send IRB Review Fee Invoice To:
Name:
Company:
Address:
2. Research Team: List all members of the research team. Indicate under the affiliation
column whether the investigators or study personnel are part of the Yale faculty or staff, or
part of the faculty or staff from a collaborating institution, or are not formally affiliated with
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any institution. ALL members of the research team MUST complete Human Subject
Protection Training (HSPT) and Health Insurance Portability and Accountability Act
(HIPAA) Training before they may be listed on the protocol. See NOTE below.
Name
Affiliation: Yale/Other
Institution (Identify)
NetID
Principal Investigator
Role:
Role:
Role:
Role:
Role:
Role:
NOTE: The HIC will remove from the protocol any personnel who have not completed required training.
A personnel protocol amendment will need to be submitted when training is completed.
SECTION IV:
PRINCIPAL INVESTIGATOR/FACULTY ADVISOR/ DEPARTMENT CHAIR
AGREEMENT
As the principal investigator of this research project, I certify that:
 The information provided in this application is complete and accurate.
 I assume full responsibility for the protection of human subjects and the proper conduct of the
research.
 Subject safety will be of paramount concern, and every effort will be made to protect subjects’
rights and welfare.
 The research will be performed according to ethical principles and in compliance with all federal,
state and local laws, as well as institutional regulations and policies regarding the protection of
human subjects.
 All members of the research team will be kept apprised of research goals.
 I will obtain approval for this research study and any subsequent revisions prior to my initiating the
study or any change and I will obtain continuing approval of this study prior to the expiration date
of any approval period.
 I will report to the HIC any serious injuries and/or other unanticipated problems involving risk to
participants.
 I am in compliance with the requirements set by the University and qualify to serve as the
principal investigator of this project or have acquired the appropriate approval from the
Dean’s Office or Office of the Provost, or the Human Subject Protection Administrator at
Yale-New Haven Hospital, or have a faculty advisor.
 I will identify a qualified successor should I cease my role as principal investigator and facilitate a
smooth transfer of investigator responsibilities.
_____
PI Name (PRINT) and Signature
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Date
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As the faculty advisor of this research project, I certify that:
 The information provided in this application is complete and accurate.
 This project has scientific value and merit and that the student or trainee investigator has the
necessary resources to complete the project and achieve the aims.
 I will train the student investigator in matters of appropriate research compliance, protection of
human subjects and proper conduct of research.
 The research will be performed according to ethical principles and in compliance with all federal,
state and local laws, as well as institutional regulations and policies regarding the protection of
human subjects.
 The student investigator will obtain approval for this research study and any subsequent revisions
Prior to initiating the study or revision and will obtain continuing approval prior to the expiration
of any approval period.
 The student investigator will report to the HIC any serious injuries and/or other unanticipated
problems involving risk to participants.
 I am in compliance with the requirements set forth by the University and qualify to serve as
the faculty advisor of this project.
___________
______
_____
Advisor Name (PRINT) and Signature
Date
______
Department Chair’s___________
Assurance Statement
_____
Advisor Name (PRINT) and Signature
Date
Do you know of any real or apparent institutional conflict of interest (e.g., Yale ownership of a
sponsoring company, patents, licensure) associated with this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC.)
No
As Chair, do you have any real or apparent protocol-specific conflict of interest between yourself and
Signature of PI
Date
the sponsor of the research project, or its competitor or any interest in any intervention and/or method
tested in the project that might compromise this research project?
Yes (provide a description of that interest in a separate letter addressed to the HIC.)
No
I assure the HIC that the principal investigator and all members of the research team are qualified by
education, training, licensure and/or experience to assume participation in the conduct of this research
trial. I also assure that the principal investigator has departmental support and sufficient resources to
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conduct this trial appropriately.
____________________________
Chair Name (PRINT) and Signature
Date
_________________________________
Department
YNHH Human Subjects Protection Administrator Assurance Statement
Required when the study is conducted solely at YNHH by YNHH health care providers.
As Human Subject Protection Administrator (HSPA) for YNHH, I certify that:
 I have read a copy of the protocol and approve it being conducted at YNHH.
 I agree to notify the IRB if I am aware of any real or apparent institutional conflict of interest.
 The principal investigator of this study is qualified to serve as P.I. and had the support of the hospital
for this research project.
______________________________________
YNHH HSPA Name (PRINT) and Signature
Date
For HIC Use Only
Date Approved
Human Investigation Committee Signature
SECTION V: RESEARCH PLAN
1. Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested.
Explain the purpose or aim(s) of the study clearly so that the reviewer(s) are able to justify
the inclusion of a pediatric population. The reviewer needs to understand the PI’s justification
for the inclusion of children; therefore, the rationale should be clear and fully explained. The
reviewer(s) should also be able to ascertain if the question(s) or the study/aim(s) or purpose
is clinically meaningful, scientifically sound, significant, and with value to children in general,
and in most cases, to the individual child subject.
2. Background: Describe the background information that led to the plan for this project. Provide
references to support the expectation of obtaining useful scientific data.
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Provide all relevant studies to your research (adult and pediatric), especially any
pediatric studies that are relevant. If no pediatric studies have been performed, state
so.
If no pediatric studies have been performed, include the literature from as many adult
studies as possible, preferably studies in which research of the test article has reached
Phase III and beyond. Depending upon the severity of the disease and the availability of
an analogous disease or test article being used in adults, include a justification for the
study of this test article in this pediatric population at this point in its development.
The research problem needs to be one of true scientific uncertainty; that is, the
investigator should explain his/her level of true uncertainty and that of the literature
about which of the treatments or drugs, etc. being compared (in a comparative study) is
superior.
3. Research Plan: Summarize the study design and research procedures using non-technical language
that can be readily understood by someone outside the discipline. Be sure to distinguish between standard
of care vs. research procedures when applicable, and include any flowcharts of visits specifying their
individual times and lengths.
In addition to providing an orderly description of each research procedure or observation that
the minor will undergo, state if the procedure/test/assessment is standard of care or
research-related. Include all visits and procedures and not just a summary of the
procedures. The extent to which children are exposed to an intervention is important for a
pediatric review. This helps reviewers to assess the risk to the child/adolescent.
If there are different groups, provide this description for all groups, especially noting which
procedures will NOT be performed on/with the control group.
If blood is to be drawn, include the amount and the route, e.g. drawing off an IV,
venipuncture, finger stick. Also include the circumstances around the blood draw, e.g. where
possible drawn with necessary clinical specimens, only drawn with clinical specimens, etc.
Also include the amount of blood to be drawn at each visit and cumulatively, where indicated.
(This may also be included in the risks section.) Note (per NIH Guidelines; revised June 5,
2009): Maximum blood volumes for the pediatric patient are as follows: No more than 5ml/kg
in a single day (24 hour period) and no more than 9.5 ml/kg to be drawn over any 8 week
period. For adolescents the amount drawn may not exceed the maximum amount of blood to
be drawn in adults (550 ml over any 8 week period.) For infants (less than one year of
age), the weight, medical condition, and the physiological status of the infant or
neonate needs to be considered when proposing the amount of blood to be drawn per
24 hour and/or 8 week period. (The Committee will review these blood draw amounts
on a case by case basis.)
Include the approximate time for each visit or test/procedure. Also disclose this to the
parent/child in the permission/assent documents.
Include a mechanism for follow-up of research subjects, as applicable, especially with regard
to studies of test articles without predicted side/adverse effects.
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4. Genetic Testing
N/A
A. Describe
i. the types of future research to be conducted using the materials, specifying if
immortalization of cell lines, whole exome or genome sequencing, genome wide
association studies, or animal studies are planned
ii. the plan for the collection of material or the conditions under which material will
be received
iii. the types of information about the donor/individual contributors that will be
entered into a database
iv. the methods to uphold confidentiality
B. What are the conditions or procedures for sharing of materials and/or distributing for
future research projects?
C. Is widespread sharing of materials planned?
D. When and under what conditions will materials be stripped of all identifiers?
E. Can donor-subjects withdraw their materials at any time, and/or withdraw the
identifiers that connect them to their materials?
i. How will requests to withdraw materials be handled (e.g., material no longer
identified: that is, anonymized) or material destroyed)?
F. Describe the provisions for protection of participant privacy
G. Describe the methods for the security of storage and sharing of materials
5. Subject Population: Provide a detailed description of the types of human subjects who
will be recruited into this study.
Children--Definition
Specific conditions are cited in the federal regulations regarding the inclusion of children
into research. Children include all persons who have not attained the legal age to
consent for themselves to treatments or procedures under the applicable law of the
jurisdiction in which the research will be conducted. In Connecticut, this legal age is 18
years, except for children seeking treatment for substance abuse, mental health, and
reproductive health, or when the child is emancipated. Investigators should note that in
the State of Connecticut, pregnancy does not qualify a child as being emancipated.
Emancipated minor: According to CT State Statute, Sec. 46b-150 at
http://www.cga.ct.gov/2009/pub/Chap815t.htm#Sec46b-150.htm. “Any minor who has
reached such minor’s sixteenth birthday and is residing in this state, or parent or
guardian of such minor may petition the superior court for juvenile matters or the
probate court for the district…for a determination that the minor named in the petition be
emancipated.” The order of emancipation (Sec. 46b-150b.) may be granted by the
Superior Court or Probate Court, after a hearing if the court finds that: (1) The minor has
entered into a valid marriage, whether or not the marriage has been terminated by
dissolution; or (2) the minor is on active duty with any of the armed forces of the United
States of America; or (3) the minor willingly lives separate and apart from his parents or
guardian, with or without the consent of the parents or guardian, and that the minor is
managing his own financial affairs, regardless of the source of any lawful income; or (4)
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for good cause shown, it is in the best interest of the minor, any child of the minor or the
parents or guardian of the minor, the court may enter an order declaring that the minor
is emancipated.” The statute continues with regard to the effect of emancipation (Sec.
46b-150d.) which states that, “(1) The minor may consent to medical, dental, or
psychiatric care, without parental consent, knowledge, or liability; (2) the minor may
enter into a binding contract…” Investigators should take care to check for the court
order of emancipation before treating the minor as emancipated for consenting or other
research purposes. See the statute for further information.
Institutionalized children: These children should be rarely considered for inclusion in
research studies, because institutionalization may deprive them of some of the
safeguards necessary for the conduct of ethical investigations. These children may be
involved in studies of special conditions unique to them or to the type of institution in
which they reside. They should also have access to experimental drug therapy when
the research therapy is the only treatment available for the illness that affects them. The
IRB may require that the PI consult and document the consultation with an advocacy
group that will assist with the overall design of the study as it relates to the rights,
clinical condition, and needs of such a targeted population. Explain these conditions in
the HIC application.
Provide a description of the minors to be included, items like age and, in cases where
drugs are being given or large amounts of blood drawn, average weight or range of
weight for inclusion are important.
6. Subject classification: Check off all classifications of subjects that will be targeted for
enrollment in the research project. Will subjects who may require additional safeguards
or other considerations be enrolled in the study? If so, identify the population of subjects
requiring special safeguards and provide a justification for their involvement.
Children
Non-English Speaking
Decisionally Impaired
Yale Students
Healthy
Fetal material, placenta, or dead fetus
Prisoners
Economically disadvantaged persons
Employees
Pregnant women and/or fetuses
Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as
potential subjects?
Yes
No (If yes, see HIC Application Instructions section VII #2 for
further requirements)
Check off all appropriate populations.
7. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion
or exclusion?
The inclusion/exclusion criteria should take into account the unique physiology,
anatomy, psychology, pharmacology, social situation and special needs of children and
their families (as indicated by the study.)
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List, in sufficient detail, in this section, inclusion/exclusion, criteria so that the reviewer
can assess if the minors are being protected by appropriate selection. For example,
screening for pregnancy for females of childbearing potential for interventional drug
studies, appropriate frequency and pertinent parameters for baseline and follow-up
laboratory values for certain tests or procedures, (based upon the clinical condition of
the patient and the purpose of the research), and the subject’s weight for certain
amounts of blood to be drawn. If you are drawing the maximum amount of blood within
an 8 week period, the child/parent should be advised not to participate in other studies
where blood is drawn and young adults (over 17 years of age) should be advised not to
donate blood for a period of 8 weeks after study participation (American Red Cross
Blood Donation Guidelines). (See Research Plan section for maximum amounts of
blood to be drawn.)
8. How will eligibility be determined, and by whom?
9. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy,
discomforts, or inconveniences associated with subjects participating in the research.
List all foreseeable risks and inconveniences to the minor and to his/her parents. Since
all research has some risk, it can be stated that the research has “minimal” risks or “no
physical risks” depending upon the situation. These risks should include the known and
predictable risks of the drug/test article being studied as determined from previous
human (adult and pediatric) and animal studies in addition to the inherent risks of the
procedures themselves. These risks should match internally within this document and
with the consent/permission/assent documents.
List risks of all procedures performed, where applicable.
Blood drawing: list the risks of the blood draw, depending upon the method, (e.g. IV or
venipuncture), such as pain, bleeding at site, redness, inflammation, ecchymosis; rarely
phlebitis, infection and fainting.
As per the research plan, list the risks of all procedures, noting those that are for
research purposes only. For example, if it would be standard of care to obtain a chest xray once per year in the population you are studying, but you want to obtain an x-ray
every 6 months, this should be clearly noted as a risk with the amount of radiation cited
for that risk. If the radiation utilized in the protocol is for research purposes, complete
the Radiation Safety Committee application located at http://rsc.med.yale.edu.
10. Minimizing Risks: Describe the manner in which the above-mentioned risks will be
minimized.
Overall, the plan to minimize risks and monitor safety needs to be robust. The type and
number of invasive tests should be minimized and scientifically sound, and creative
methods to obtain needed information non-invasively should be sought.
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Denote how each risk listed above will be minimized.
For example, for blood drawing, it is preferable to include whether a topical anesthetic
will be utilized prior to the blood draw or intravenous placement. Include the types of
topical anesthetic in the HIC application and the consent documents. The methods of
administration of these anesthetics include intradermal and topical, e.g. creams and/or
patches.
Include the pediatric protections and opt out clause for pregnancy, as applicable.
Investigators may refer to http://www.ct.gov/dph/lib/dph/Sec19a-216.pdf, which is
generally used as a guideline for dealing with the issue of confidentiality of pregnancy
testing in minors. If the minor is less than 13 years of age, the facility or physician is
advised to report the name, age, and address of the pregnant minor to the
Commissioner of Children and Families or his designee.
Also, in an opinion written by the Attorney General (September 30, 2002), Attorney
General Blumenthal stated, “The Department has taken the position that a mandated
reporter is obliged to report any sexual relations involving a minor less than the age
of 13 [years]…” See this opinion for further information with regard to mandatory
reporting of abuse or neglect.
The pregnancy language to be included in each document is as follows: (Modify
for your protocol procedures for the patient population of interest, as applicable.)
Protocol: Female subjects of childbearing potential will require urine/serum pregnancy
testing prior to enrollment in the protocol. Because full confidentiality regarding
pregnancy cannot be entirely guaranteed, these testing requirements and the limited
scope of confidentiality will be made known to all subjects during the consent
procedure. In this manner, young women who would not be comfortable with pregnancy
testing or sharing the results of such testing can “opt out” of the study at the time of the
initial consent, without having to declare specific reasons. According to CT state
statutes for mandatory reporting, pregnancy in females less than age of 13 years, will
be reported to parent(s) and to the State of Connecticut Department of Children and
Family Services (DCF). Confidentiality with regard to pregnancy test results will be
maintained for females > 13 years.
Parental Permission: Female subjects of childbearing potential will require urine/serum
pregnancy testing prior to proceeding with the protocol. Only your daughter, if she is at
least 13 years of age, will be told the results. We will, of course, counsel your daughter
to seek appropriate healthcare and the support of an adult if she were found to be
pregnant. A positive pregnancy test means that your daughter cannot participate in this
study. Because she will be asked to leave the study, you may find out that she is
pregnant. If you and/or your daughter are uncomfortable with pregnancy testing, then
we would recommend that your daughter does not participate. If a positive pregnancy
test is found in a minor less than 13 years of age, we will need to report this to you and
to the State of Connecticut, Department of Children and Family Services (DCF).
Assents may be structured as per developmental age of the patient population
versus chronological age. If the patient population of interest is of childbearing
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age, then it is advisable that the assent include pregnancy language, if indicated
by the study procedures. For the assent form(s), the information about females
less than 13 years of age does NOT need to be included, unless it is warranted by
the developmental characteristics of patient population under study (in bold type
below).
Adolescent Assent: We will ask you to have a pregnancy test before you start this
study. Only you will be told the results, if you are at least 13 years old. If you are
pregnant, we will advise you to get care for your pregnancy and also to get the support
of an adult. You will be asked not to participate or you will be removed from the study if
your pregnancy test is positive. You need to know that your parents may ask you why
you cannot participate or why you were asked to leave the study. So if there is any
chance that you are pregnant or you might become pregnant during the time of this
study, we would recommend that you think carefully about whether you should
participate. It is okay if you decide that you do not want to participate or to stay in this
study. You do not need to give a reason for not participating. If you are less than 13
years old, we will need to report a positive pregnancy test to your parents and to
the proper authorities, called DCF. We will explain all of this to you and help you
to get the care that you need.
Precautions with regard to confidentiality of questioning about drugs or drug
testing: (Should also be added to confidentiality section of consent form or section
where drug testing is discussed in research plan.)
Investigators may refer to
http://www.ct.gov/dph/lib/dph/practitioner_licensing_and_investigations/plis/psychology/psych_s
tatelawstudyguide.pdf for general guidance regarding the confidentiality of questioning about
“illicit” drugs or drug testing/treatment in research protocols. In general, the
confidentiality of drug testing, questioning about substance abuse history, and mental
health treatment is considered confidential between the researcher and the minor,
unless the researcher believes that the minor is in imminent risk of serious harm or that
maintaining this confidentiality would be associated with serious detriment to the minor’s
well-being. Investigators are encouraged to assess adolescents as per their
developmental level and their psychiatric or psychological condition. In general, the
guidelines of breeching confidentiality and disclosing to parents positive drug testing in
a younger adolescent (less than 13 years of age) is accepted practice. For those minors
(of any age) who are considered to be exhibiting behavior that the investigator believes
may be of harm to the subject or others, the investigator is encouraged to refer these
subjects to a licensed psychologist or psychiatrist, who will provide evaluation and
treatment, as needed.
Note: Judgment with regard to the confidentiality of drug screening may be made by the
investigator and the PPRC on a case by case basis, depending upon the nature of the
research and the clinical condition/developmental age of the subject. General guidelines
and examples of pertinent language are presented throughout this section.
Suggested language with regard to confidentiality of drug testing/treatment to be
included in each document is as follows: (Modify for your protocol procedures,
as applicable.)
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For the HIC protocol: In order to participate in this protocol, the pediatric subject will
need to be asked questions about his/her prior and/or current illicit drug use or undergo
drug testing (urine or blood). Because drug use will exclude the minor from participating,
the parent may ask why the child was asked not to participate or to leave the study.
Therefore, parents and/or minors who are uncomfortable with questions about drug use
can "opt out" of the study at the time of initial consent, without having to declare specific
reasons.
Drug use information (in the adolescent > 13 years of age) will not be shared with
parents unless the study team feels that the minor is exhibiting behaviors that would
pose an immediate threat to the minor or to others. The PI or co-investigator will ask the
minor if the study team can share the drug testing results with parents. If the minor
declines, the study team will refer the minor for evaluation based upon the clinical
judgment of the Principal Investigator. In all cases, the safety and well-being of the
minor will be protected. We will explicitly inform parents and minors, in the permission
and assent documents, and orally with regard to these guidelines.
Parental permission form language for confidentiality of drug use: We will need to
ask your child/adolescent about current or past use of illicit "street" drugs (or this could
be testing if you were going to do urine testing). If he/she is using drugs now or has a
history of using drugs, he/she may not be able to participate in this study (or you can
make this stronger--he/she will not be able to participate.) If your child is 13 years of age
or older, we will keep this information confidential. If your child is 12 years of age or
younger, we will notify you and refer your child for an evaluation for substance abuse. If
your child is of any age, and in immediate danger of hurting him/herself or someone
else, then we will notify you and refer your child for an evaluation. If you or your child is
uncomfortable with drug testing or discussing drug use, then we would recommend that
your son/daughter does not participate in this study.
Adolescent Assent (for > 13 years of age): We will ask you about/or test you for (any
past or) current use of “street” drugs. If you are using drugs now or have a history of
using drugs, you may not be able to participate in this study. You need to know that
your parents may ask you why you cannot participate or why you were asked to leave
the study. So if there is any chance that you are using drugs or have used drugs, we
would recommend that you think carefully about whether you should participate. It is
okay if you decide that you do not want to participate or to stay in this study. You do not
need to give a reason for not participating.
If your urine is positive for drugs, then you cannot participate in this study. We will ask
you if we can discuss your positive drug screening results with your parents. If you
decline, we will keep the results of your drug test confidential and we will give you a
referral for an evaluation. However, if we feel that you are in danger of hurting yourself
or someone else, then we will need to tell your parents and also refer you for help.
Adolescent Assent (for 12 years of age and younger), if necessary, for the
population of your study:
We will ask you for a urine/blood sample or we will ask you about your use of “street
drugs.” We will give you a container that you can use in a private bathroom or need to
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explain the blood draw. We will check your urine/blood for drugs. These drugs will
include “street drugs.” If you are positive for drugs, then you cannot participate in this
study. We will discuss these results with you first, and then we will need to discuss
these results with your parent(s). This is so we can get you some help.
This age group may also be offered the “opt out” of testing or questioning as noted in
the adolescent assent section above. .
Blood amounts: include the calculation of blood amounts so as to prove that they do
not exceed the maximum allowable/approvable limits, e.g. Maximum blood volumes for
pediatric patients are as follows: No more than 5ml/kg in any single day (24 hour period)
and no more than 9.5 ml/kg to be drawn over any 8 week period. For adolescents, the
amount drawn may not exceed the maximum amount of blood to be drawn in adults
(550 ml over any 8 week period.) For infants (less than one year of age), the weight,
medical condition, and the physiological status of the infant or neonate needs to
be considered when proposing the amount of blood to be drawn per 24 hour
and/or 8 week period. (The PPRC will review these blood draw amounts on a case
by case basis.)
As noted in the inclusion/exclusion criteria section, the baseline Hematocrit or
hemoglobin of the child should be based upon the clinical condition of the patient and
the purpose of the research. The child/parent should also be advised not to participate
in other studies where blood is drawn and young adults (over 17 years of age in CT)
should be advised not to donate blood for a period of 8 weeks after study participation.
(The American Red Cross Blood Donation Guidelines are that minors must be 17 years
of age in CT, weigh 110 lbs, and not have given whole blood, i.e. 550 ml of blood, within
an eight week period.)
For children who are ill and/or hospitalized, investigators should be especially
cognizant of the hematocrit and hemoglobin values at which drawing blood for research
purposes should be terminated. Investigators should also be noting the number of
studies in which children are enrolled, in order to minimize blood drawing anemia states.
Another method to minimize blood loss in children with a closed intravenous catheter
system, in which blood is to be removed, is to re-infuse the “waste” from the indwelling
catheter, provided that the “waste” is kept sterile and the practitioner has followed the
institutional policy for re-infusion of such “waste” blood from an indwelling intravenous
(peripheral and/or central) catheter. For policies regarding peripheral intravenous
therapy in the pediatric subject, the YNHH Policy for Peripheral Intravenous Therapy
may be consulted at http://intranet/ynhh/policies/CPM/homepage.html.
Blood amounts may be further minimized by combining the need for pharmacokinetic
and safety data with pharmacodynamic data (drug studies), the use of sensitive assays,
use of pediatric specific laboratories, and population pharmacokinetic approaches.
With this in mind, if it would be detrimental for the child to be enrolled in more than one
study for blood drawing reasons, other safety reasons, or due to confounding scientific
validity, this should be explicitly stated in the protocol and monitored for by the
investigator and study staff.
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If you will monitor the patient for certain side/adverse effects, explain how this will be
done and any stopping rules for either the intervention or the research procedure. For
example, it should always be noted that if children need a break from testing one will be
provided; if children want to stop a procedure at any time, it will be stopped; if children
want to be removed from a scanner/MRI, they will be removed. With regard to MRI
scanning or any procedure in which minors need to be still, the method for keeping
children quiet and/or still should be noted, as necessary. If this involves sedation, the
method for the sedation should be clearly explained, with how the child will be
monitored and any other necessary precautions. Utilize the “YNHH Policy for
Sedation/Analgesia for Diagnostic and Surgical Procedures Multi-Disciplinary Protocol”
when explaining the monitoring and precautions. A copy of the policy may be obtained
from the Yale-New Haven Hospital, Clinical Administrative Policy and Procedure
Manual” located on the YNHH clinical work station.
Clinical problems not previously known to the parent/subject and communication
with other care providers (pediatricians, etc):
If there are tests or procedures that are completed as part of the research that are
appropriate for clinical care (diagnostic or treatment use), the plan to communicate
these results to the caregiver (parents) and health care providers should be noted in the
HIC application and in the parental permission form. If these tests or procedures are
purely for research purposes, but could indicate a clinical problem, then the plan to
notify the family/care givers should be noted with the provisions for re-testing or referral
to the appropriate provider noted. An example of this wording may be found in the
MRRC templates:
This MR study is for research purposes only and is not in any way a clinical examination.
The scans performed in this study are not designed to find abnormalities. The primary
investigator, the lab, the MR technologist, and the Magnetic Resonance Research Center
are not qualified to interpret the MR scans and are not responsible for providing a
diagnostic evaluation of the images. If a worrisome finding is seen on your child’s scan, a
radiologist or another physician will be asked to review the relevant images. Based on his
or her recommendation (if any), the primary investigator or consulting physician will
contact you, inform you of the finding, and recommend that you seek medical advice as a
precautionary measure. The decision for additional examination or treatment would lie
solely with you and your child’s physician. The investigators, the consulting physician, the
Magnetic Resonance Research Center, and Yale University are not responsible for any
examination or treatment that your child receives based on these findings. The images
collected in this study are not a clinical MR exam and for that reason, they will not be
made available for diagnostic purposes.
11. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan
(DSMP) based on the investigator’s risk assessment stated below. (Note: the HIC will make the final
determination of the risk to subjects.) For more information, see the Instructions, page 24.
a.
What is the investigator’s assessment of the overall risk level for subjects
participating in this study?
b.
If children are involved, what is the investigator’s assessment of the overall risk
level for the children participating in this study?
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c.
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Copy and paste, and then tailor an appropriate Data and Safety Monitoring Plan
from http://www.yale.edu/hrpp/forms-templates/biomedical.html for
i. Minimal risk
ii. Greater than minimal/moderate risk
iii. High risk
There are 4 possible risk assessments for children participating in pediatric
studies, according to The Code of Federal Regulations, Title 45, Volume I,
Subpart D-Additional Protections for Children Involved as Subjects in
Research:
(1) 45 CFR 46.404: Research not involving greater than minimal risk
(2) 45 CFR 46.405: Research involving greater than minimal risk, but presenting
the prospect of direct benefit to individual subjects
(3) 45 CFR 46.406: Research involving greater than minimal risk and no prospect
of direct benefit to individual subjects, but likely to yield generalizable
knowledge about the subject’s disorder or condition.
45 CFR 46.407: Research not otherwise approvable which presents an
opportunity to understand, prevent, or alleviate a serious problem affecting
the health or welfare of children. HHS will conduct or fund research that
the IRB does not believe meets the requirements of Sec. 46.404, Sec.
46.405, or Sec. 46.406 only if:
A. The IRB finds that the research presents a reasonable
opportunity to further the understanding, prevention, or
alleviation of a serious problem affecting the health or welfare
of children; and
B. The Secretary of DHHS (Department of Health and Human
Services) after consultation with a panel of experts in pertinent
disciplines (for e.g., science, medicine, education, ethics, law)
and following opportunity for public review and comment, has
determined that certain conditions have been met and the
research may be approvable. (See 45 CFR 46.407 for further
information.)
There are analogous risk determinations in the Federal Drug Administration Regulations
for children participating in pediatric studies (that involve test articles such as
investigational drugs, devices, and any other articles regulated by the FDA), according
to Subpart D Additional Safeguards for Children in Clinical Investigations of Title 21Food and Drugs, Chapter I-Food and Drug Administration, Department of Health and
Human Services, Part 50 Protection of Human Subjects. These may be found at
http://www.accessdata.fda.gov/SCRIPTs/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=5
0&showFR=1&subpartNode=21:1.0.1.1.19.4
The Data and Safety Monitoring Plan should include a plan to terminate the study
should an unexpected hazard be identified.
Data and Safety Monitoring Boards: It is recommended (AAPGuidelines, 2010) that an
independent data and safety monitoring committee or board be created for all Phase III
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drug/test article trials conducted in children. A data and safety monitoring committee or
board may be necessary as well for some Phase I and II trials, especially those that
include blinding. In Phase I and II trials with a DSMB/C, a robust data monitoring plan
must be in place.
Utilize the DSMP template examples at
http://www.yale.edu/hrpp/resources/docs/420FR1DSMPTemplate.pdf as per the risk
assessment. The moderate risk template may be used for those protocols that are
deemed greater than minimal risk.
Especially note the language with regard to the reporting of serious adverse events to
the HIC: (This is only one part of the DSMP. Utilize the entire template (as appropriate
to the level of risk of your protocol) located on the HRPP website at:
http://www.yale.edu/hrpp/resources/docs/HICProtocol_Application_Instructions02-1210.doc)
Plan for reporting serious AND unanticipated AND related adverse events, anticipated
adverse events occurring at a greater frequency than expected, and other unanticipated
problems involving risks to subjects and others to HIC:
The investigator will report the following types of adverse events to HIC: a) serious AND
unanticipated AND possibly, probably, or definitely related events; b) anticipated
adverse events occurring with greater frequency than expected; and c) other
unanticipated problems involving risks to subjects or others.
d. For multi-site studies for which the Yale PI serves as the lead investigator:
ii. How will adverse events and unanticipated problems involving risks to subjects or
others be reported, reviewed and managed?
iii. What provisions are in place for management of interim results?
iv. What will the multi-site process be for protocol modifications?
12. Statistical Considerations: Describe the statistical analyses that support the study
design.
In particular, sample size justification, proposed analyses for your primary and
secondary outcomes (including adverse events, if possible), and considerations for
missing values should be included.
Outcomes should be meaningful and measurable, with adequate control or normative
data for comparison and there should be appropriate power analysis to ensure
enrollment of an adequate number of subjects to answer the research question.
For complex statistical elements of study design and/or assistance with pilot study
design in which preliminary data may be limited, you may find it useful to contact the Yale
Center for Analytical Sciences (YCAS) at ycas@yale.edu.
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SECTION VI: RESEARCH INVOLVING DRUGS, BIOLOGICS, PLACEBOS AND DEVICES
If a drug/substance is being used in a study and it is NOT approved by the FDA for minors
(children or adolescents), indicate the IND number(s) below and answer the questions 1.a
and 1.b. If the drug being studied is FDA approved, then indicate this and the indication for
the use of the drug/device in this section.
If you or the sponsor have not filed for an IND with the FDA and you are not planning to file
for an IND, complete the appropriate exemption information below.
If the study does not meet the criteria indicated in the exemption categories below, then an
IND may be indicated. The IRB (HIC) will determine whether application for an IND is
necessary.
A. DRUGS and BIOLOGICS
1. Identification of Drug or Biologic: What is (are) the name(s) of the drug(s) or
biologic(s) being used? Identify whether FDA approval has been granted and for what indication(s).
All protocols which utilize a drug or biologic not approved by, but regulated by, the FDA must
provide the following information:
What is the Investigational New Drug (IND) number assigned by the FDA?
Who holds the IND?
All protocols which utilize a radiotracer not approved by, but regulated by the FDA must provide
the IND number: _______________
Alternatively, use of the investigational radiotracer may be under RDRC/RSC oversight: (check
if appropriate)_____________
For all investigational radiotracers, attach a copy of the RDRC/RSC application ( for
radioisotopes used in the PET Center, PET Center personnel may complete this step)
Go to http://rsc.med.yale.edu/login.asp?url=myApps.asp. When you have logged in, complete
the application and attach a copy to this submission
Alternatively, an exemption from IND filing requirements may be sought for a clinical
investigation of a drug product that is lawfully marketed in the United States. If there is no IND and
an exemption is being sought, review the following categories and complete the category that applies
(and delete the inapplicable categories):
Exempt Category 1
The clinical investigation of a drug product that is lawfully marketed in the United States can be
exempt from IND regulations if all of the following are yes:
i. The intention of the investigation is NOT to report to the FDA as a well-controlled study in support
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of a new indication for use or to be used to support any other significant change in the labeling for
the drug.
Yes
No
ii. The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and
the intention of the investigation is NOT to support a significant change in the advertising for the
product.
Yes
No
iii. The investigation does NOT involve a route of administration or dosage level or use in populations
or other factor that significantly increases the risks (or decreases the acceptability of the risks)
associated with the use of the drug product.
Yes
No
iv. The investigation will be conducted in compliance with the requirements for institutional (HIC)
review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50
and 21 CFR Part 56).
Yes
No
v. The investigation will be conducted in compliance with the requirements regarding promotion and
charging for investigational drugs.
Yes
No
Exempt Category 2 (all items i, ii, and iii must be checked to grant a category 2 exemption)
i. The clinical investigation is for an in vitro diagnostic biological product that involves one or
more of the following (check all that apply):
Blood grouping serum
Reagent red blood cells
Anti-human globulin
ii. The diagnostic test is intended to be used in a diagnostic procedure that confirms the
diagnosis made by another, medically established, diagnostic product or procedure; and
iii. The diagnostic test is shipped in compliance with 21 CFR §312.160.
Exempt Category 3
The drug is intended solely for tests in vitro or in laboratory research animals if shipped in
accordance with 21 CFR 312.60
Exempt Category 4
A clinical investigation involving use of a placebo if the investigation does not otherwise
require submission of an IND.
2. Background Information: Provide a description of previous human use, known risks, and data
addressing dosage(s), interval(s), route(s) of administration, and any other factors that might
influence risks. If this is the first time this drug is being administered to humans, include relevant
data on animal models.
Include any previous studies in minors (children or adolescents), if they exist. If no studies
have been done with minors, indicate this. Be clear about how this substance will be used
in minors, e.g. “the first time the substance will be given by this route for this particular
indication,” or “the first time it will be given in minors altogether.”
Include the pediatric dose per unit of measure, e.g. dose per kg or dose per m 2. Justify
the dose if it is not computed via such a measure.
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3. Source: a) Identify the source of the drug or biologic to be used.
b) Is the drug provided free of charge?
If yes, by whom?
Yes
No
4. Storage, Preparation and Use: Describe the method of storage, preparation, stability information,
and for parenteral products, method of sterilization and method of testing sterility and
pyrogenicity.
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.
Check applicable Investigational Drug Service utilized:
YNHH IDS
Yale Cancer Center
CMHC Pharmacy
West Haven VA
PET Center
None
Other:
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in
detail how the PI will oversee these aspects of drug accountability, storage, and preparation.
5. Use of Placebo:
Not applicable to this research project
Provide a justification which addresses the following:
a. Describe the safety and efficacy of other available therapies (if any).
b. State the maximum total length of time a participant may receive placebo while on the study.
c. Address the greatest potential harm that may come to a participant as a result of not receiving
effective therapy (immediate or delayed onset.)
d. Describe the procedures that are in place to safeguard participants receiving placebo.
Fully describe the conditions of placebo use and provide the justification as noted above.
It is necessary to understand the use of placebo in minors to further assess risk in this
population. The risk to subjects from the placebo arm should be minimized.
The conditions under which placebos may be ethically used in children are as follows:
1. When there is no commonly accepted therapy for the condition and the agent/test
article under study is the first one that may modify the course of the disease process.
2. When the commonly used therapy is of questionable efficacy;
3. When the commonly used therapy for the condition carries with it a high frequency of
undesirable adverse effects and the risks may be significantly greater than the
benefits;
4. When the placebo is used to identify incidence and severity of adverse effects
produced by adding a new treatment to an established regimen; or
5. When the disease process is characterized by frequent, spontaneous exacerbations
and remissions and the efficacy of the therapy has not been demonstrated.
These conditions, as applicable to the plan of study, should be included in the HIC
application.
6. Use of Controlled Substances:
Will this research project involve the use of controlled substances in human subjects?
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Yes
HIC# if known
No See HIC Application Instructions to view controlled substance listings.
If yes, is the use of the controlled substance considered:
Therapeutic: The use of the controlled substance, within the context of the research, has the
potential to benefit the research participant.
Non Therapeutic: Note, the use of a controlled substance in a non therapeutic research study
involving human subjects may require that the investigator obtain a Laboratory Research License.
Examples include controlled substances used for basic imaging, observation or biochemical studies
or other non-therapeutic purposes. Note, the use of a controlled substance in a non-therapeutic
research study involving human subjects may require that the investigator obtain a Laboratory
Research License. Examples include controlled substances used for basic imaging, observation or
biochemical studies or other non-therapeutic purposes. See HIC Application Instructions for
further information.
7. Continuation of Drug Therapy After Study Closure
Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has
ended?
Yes If yes, describe the conditions under which continued access to study drug(s) may
apply as well as conditions for termination of such access.
No
If no, explain why this is acceptable.
Respond to this section. Especially for conditions for which there are no established FDAapproved therapies for children, it is important for the reviewer to know if a therapy that
works may be continued and if not, why not, or what other options may or may not be
available to the child/parents.
B. DEVICES
If the device being studied is FDA approved, then indicate this and the indication for the use
of the device in question 2.
If a device is being used in the study and it is NOT approved by the FDA for minors (children
or adolescents), indicate the IDE number(s) below and answer the question 3.
If you or the sponsor have not filed for an IDE with the FDA and you are not planning to file
for an IDE, complete the appropriate exemption information below in question 6.
If the study does not meet the criteria indicated in the exemption categories below, then an
IDE may be indicated. The IRB (HIC) will determine whether application for an IDE is
necessary.
1. Are there any investigational devices used or investigational procedures performed in a YNHH
Operating Room? Yes
No
If Yes, please be aware of the following requirements:
a. A YNHH OR New Product/Trial Request Form must be completed. Please contact the OR
Materials Manager, Chris Baillargeon, at 203-688-8912 for more information on this
requirement;
b. Your request must be reviewed and approved by the Operating Room New Technology
Committee before patients may be scheduled; and
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c. The notice of approval from the OR New Technology Committee must be submitted to the
HIC for the protocol file.
Please contact Gina D’Agostino, gina.d’agostino@ynhh.org or 688-5210, to initiate the
process.
2.
What is the name of the device to be studied in this protocol?
Has this device been FDA approved?
If yes, state for what indication.
Yes
No
3. Background Information: Provide a description of previous human use, known risks, and any other
factors that might influence risks. If this is the first time this device is being used in humans, include
relevant data on animal models.
Include any previous studies in minors (children or adolescents), if they exist. If no studies
have been done with minors, indicate this. Be clear about how this device will be used in
minors, e.g. “the first time the device will be used for this particular indication,” or “the first
time it will be used in minors altogether.”
If this is a device to be used in the pediatric population and the sponsor or PI has not filed
for an IDE because the sponsor states that the device is substantially equivalent or is
already approved in another country for an indication that may meet Class I (General
Controls, e.g. elastic bandages, surgical instruments) or Class II designation (e.g. infusion
pumps, specific types of imaging machines, etc.) provide enough information about the
device in the background section for the HIC to make a determination of significant vs.
non-significant risk. (In some instances, the risk determination may need to be referred to
the FDA, but this will give the HIC an initial understanding.) The HIC will determine
whether or not the device presents non-significant risk to subjects.
4. Source:
a) Identify the source of the device to be used .
b) Is the drug provided free of charge?
If yes, by whom?
Yes
No
5. What is the PI’s assessment of risk level (significant or non-significant) associated with the use of
the device?
Significant Risk (SR) Device Study: A study of a device that presents a potential for serious
risk to the health, safety, or welfare of a participant and 1) is intended as an implant; 2) is used in
supporting or sustaining human life; or otherwise prevents impairment of human health; 3) is of
substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise prevents
impairment of human health; or 4) otherwise presents a potential for serious risk to the health,
safety, or welfare of a participant.
Significant Risk Devices require an Investigational Device Exemption (IDE) issued by the FDA.
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a. What is the IDE number assigned by the FDA?
b. Did the FDA approve this IDE as Category A (experimental/investigational)
or as Category B (non-experimental/investigational)?
c. Who holds the IDE?
Non-Significant Risk (NSR) Device Study: A study of a device that does not meet the
definition for a significant risk device and does not present a potential for serious risk to the
health, safety, or welfare of participants. Note that if the HIC concurs with this determination,
an IDE is not required.
6. Abbreviated or Exempt IDE: There are abbreviated requirements for an IDE and there also are
exemptions to the requirement for an IDE. See the criteria in the HIC Application Instructions,
Section VI.B.4 at http://www.yale.edu/hrpp/forms-templates/biomedical.html to determine if these
pertain to this study.
Abbreviated IDE or Exempt IDE – If criteria set forth in the HIC Application Instructions are
met, copy and paste the completed relevant section from the Instructions into this application.
7.
Investigational device accountability
State how the PI, or named designee, ensures that an investigational device is used only in
accordance with the research protocol approved by the HIC, and maintains control of the
investigational device as follows:
a. Maintains appropriate records, including receipt of shipment, inventory at the site,
dispensation or use by each participant, and final disposition and/or the return of
the investigational device (or other disposal if applicable):
b. Documents pertinent information assigned to the investigational device (e.g., date,
quantity, batch or serial number, expiration date if applicable, and unique code
number):
c. Stores the investigational device according to the manufacturer's
recommendations with respect to temperature, humidity, lighting, and other
environmental considerations:
d. Ensures that the device is stored in a secure area with limited access in accordance
with applicable regulatory requirements:
e. Distributes the investigational device to subjects enrolled in the IRB-approved
protocol:
SECTION VII: RECRUITMENT/CONSENT/ ASSENT
1. Targeted Enrollment: Give the number of subjects:
a. targeted for enrollment at Yale for this protocol___
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b. If this is a multi-site study, give the total number of subjects targeted across all
sites___
2. Indicate recruitment methods below. Attach copies of any recruitment materials that will
be used.
Flyers
Posters
Letter
Medical Record Review
Departmental/Center Newsletters
YCCI Recruitment Database
Other (describe):
Internet/Web Postings
Radio
Mass E-mail Solicitation
Telephone
Departmental/Center Website
Television
Departmental/Center Research Boards
Newspaper
Web-Based Clinical Trial Registries
Clinicaltrials.gov Registry (do not send materials to HIC)
3. Recruitment Procedures:
a. Describe how potential subjects will be identified.
b. Describe how potential subjects are contacted.
c. Who is recruiting potential subjects?
Strategies should be included for dealing with potential problems of recruitment and
retention. There needs to be a sufficient number of subjects to answer the research
question.
4. Screening Procedures:
A. Will email or telephone correspondence be used to screen potential subjects for eligibility
prior to the potential subject coming to the research office?
Yes
No
B. If yes, identify any health information and check off any of the following HIPAA
identifiers to be collected and retained by the research team during this screening process.
If you have answered yes to this question, complete question 9, Request for HIPAA
waiver.
HEALTH INFORMATION TO BE COLLECTED:
HIPAA identifiers:
Names
All geographic subdivisions smaller than a State, including: street address, city, county, precinct, zip codes and their
equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly-available data from
the Bureau of the Census: (1) the geographic unit formed by combining all zip codes with the same three initial digits
contains more than 20,000 people, and (2) the initial three digits of a zip code for all such geographic units containing
20,000 or fewer people is changed to 000.
Telephone numbers
Fax numbers
E-mail addresses
Social Security numbers
Medical record numbers
Health plan beneficiary numbers
Account numbers
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All elements of dates (except year) for dates related to an individual, including: birth date, admission date, discharge
date, date of death, all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages
and elements may be aggregated into a single category of age 90 or older
Certificate/license numbers
Vehicle identifiers and serial numbers, including license plate numbers
Device identifiers and serial numbers
Web Universal Resource Locators (URLs)
Internet Protocol (IP) address numbers
Biometric identifiers, including finger and voice prints
Full face photographic images and any comparable images
Any other unique identifying numbers, characteristics, or codes
5.
Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical
relationship with any potential subject?
Yes, all subjects
Yes, some of the subjects
No
If yes, describe the nature of this relationship.
If you choose any other response, than “Yes, all subjects,” consider how recruitment will
take place. Consider how you will know/gain access to the Personal Health Information
(PHI) of the subjects, as needed, for recruitment. If subjects will refer themselves to the
study via posters or flyers, then this is not an issue. If a study team member is not the
treating clinician and will initiate contact with potential participant, then consider filling out
no. 9, entitled, “Request for waiver of HIPAA authorization.”
6.
Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA
Authorization for either the entire study, or for recruitment purposes only. Note: if you are collecting
PHI as part of a phone or email screen, you must request a HIPAA waiver for recruitment purposes.)
Choose one: For entire study: ______ For recruitment purposes only: ______
i. Describe why it would be impracticable to obtain the subject’s authorization for
use/disclosure of this data;
ii. If requesting a waiver of signed authorization, describe why it would be
impracticable to obtain the subject’s signed authorization for use/disclosure of this
data;
By signing this protocol application, the investigator assures that the protected
health information for which a Waiver of Authorization has been requested will not
be reused or disclosed to any person or entity other than those listed in this
application, except as required by law, for authorized oversight of this research
study, or as specifically approved for use in another study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale
HIPAA-Covered entity must be accounted for in the “accounting for disclosures log”, by subject
name, purpose, date, recipients, and a description of information provided. Logs are to be
forwarded to the Deputy HIPAA Privacy Officer.
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7. Required HIPAA Authorization: If the research involves the creation, use or disclosure
of protected health information (PHI), separate subject authorization is required under the
HIPAA Privacy Rule. Indicate which of the following forms are being provided:
Compound Consent and Authorization form
HIPAA Research Authorization Form
8. Consent Personnel: List the names of all members of the research team who will be
obtaining consent/assent.
9.
Process of Consent/Assent: Describe the setting and conditions under which
consent/assent will be obtained, including parental permission or surrogate permission and
the steps taken to ensure subjects’ independent decision-making.
Parents of children can only provide “permission” for their minor child. Only an individual
with full decision-making capacity can give consent for him/herself. According to the
American Academy of Pediatrics criteria, children > 7 years of age may provide written
assent. Children younger than 7 years of age should provide verbal assent for
participation, as developmentally appropriate.
See Section VII, no. 3 Inclusion/Exclusion Criteria: Children, for a full list of those
considerations for Children. A parent is defined as a child’s biological or adoptive
parent, and a guardian is defined as an individual who is authorized under applicable
state law to consent on behalf of a child to general medical care.
As appropriate to the protocol, the clarification of legal guardianship may need to be
elucidated. If the investigator or consenting personnel has reason to believe that the
legal guardianship of the person signing consent is at issue, possible methods of
verification include: (a) child’s birth certificate to establish biological parents; (b) divorce
decree to establish custody; (c) court order which may validate a transfer of legal
guardianship to a relative or transfer custody to another entity such as DCF; (d) calling
the court. If the legal guardianship cannot be established, then it may be advisable to
state that in these instances, the child will not be enrolled in the study. Foster parents
cannot provide consent for foster children to participate in research, because they are
not considered their legal guardians. However, foster parent(s) may need to be
consulted with as the research may require their commitment; for example, driving the
child to and from research appointments.
Refer to 45CFR46.406 at
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.406 with regard to
the adequate provisions for obtaining permission of parents when research is deemed
to be greater than minimal risk and no prospect of benefit to individual subjects, but
likely to yield generalizable knowledge about the subject’s disorder or condition. Where
the research is covered under Sec. 46.406 and permission is to be obtained from
parents, both parents must give their permission unless one parent is deceased,
unknown, incompetent, or not reasonably available, or when only one parent has legal
responsibility for the care and custody of the child.
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Finally, consider whether or not the child will remain in the study once he/she reaches
the age of majority (18 years). If yes, then describe the process of obtaining the consent
of the young adult to continue participation (or allow continued use of his/her study
information/sample(s), especially applicable to repository studies or those studies in
which samples are requested to be used for future research) in this study.
10. Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how
the personnel obtaining consent will assess the potential subject’s ability and capacity to
consent to the research being proposed.
Explain how you will assess the decision making capacity of parents and children.
Parents should be free of duress enough to be able to give permission for their minor
child to participate in the proposed study. If you will enroll children who are less than 7
years of age (the youngest “intellectual” age for which written assent is recommended by
the American Academy of Pediatrics), you do not need an assent form. Also explain any
special circumstances in which it might be justified for children (> 7 years) not to provide a
written assent. For example, if you will enroll children with severe autism and it is
assessed that even though they are above the chronological age of 7 years, they will be
developmentally incapable of providing assent, this should be explained in this section.
Another example might be children who are hospitalized in the Pediatric Intensive Care
Unit. They will not be able to assent for themselves, but parents should be able to give
permission (unless they are under too much emotional distress.) In addition to limited
intellectual capabilities, the IRB may also waive the provision of assent if the intervention
or procedure involved in the research holds out the prospect of direct benefit to the health
or well being of the child and is available only in the context of the research, e.g. some
chemotherapy protocols, or if the research meets the same conditions as those for waiver
or alteration of consent in research involving adults.
In the case of parents who may be under duress due to their child’s emergent hospital
admission or surgery, etc., the option of asking the parent to provide permission prior to
the “index” event is acceptable or at any other time that the parent is not considered to be
under stress. For example, children with sickle cell that may have frequent vaso-occlusive
crisis. Perhaps parents can provide permission at a routine clinic visit and then the
permission can be verified or confirmed with the parent when the hospitalization occurs.
The same may hold true for elective surgeries, etc. It is preferable for parents to give
permission when they have the time to review the permission form and to understand all
study procedures, risks, and benefits. For research in which the researcher cannot
anticipate the “index” or the “stressful” event, it is possible to do the research, if conditions
for seeking permission are justified.
It is important for the study team to acknowledge the parent’s emotional state, lack of
medical knowledge, and inexperience with clinical trials. During the consent process (and
throughout the trial), research staff need to educate parents about the child’s disease and
how clinical trials work. Potential risks should be enumerated and described without
overstating benefits.
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11. Documentation of Consent/Assent: Specify the documents that will be used during the
consent/assent process. Copies of all documents should be appended to the protocol, in the
same format that they will be given to subjects.
If you will enroll participants who are 18 years or older, include a Compound Authorization
and Consent Form or a Consent Form and a HIPAA Authorization Form.
For minors, include a Compound Authorization and Parental Permission Form or a
Parental Permission Form and a HIPAA Authorization Form.
If you will include all minors capable of providing assent, i.e. 7 years to 17 years of age,
include 2 assent forms:
One assent form should be developed for children ages 7 to 12 years of age and a
separate assent form developed for adolescents 13 to 17 years of age. The form for 13
year olds generally includes pregnancy/contraception precautions and drug use
precautions as necessary for your study. If you are enrolling a smaller span of ages, then
one assent form may be considered developmentally appropriate. All forms should be
written according to the grade level of the above age groups.
If only children younger than 7 years of age will participate or it is assessed that the
children who are participating will not be able to provide written assent, then only a
Compound Authorization and Parental Permission Form or a Parental Permission Form
and HIPAA Research Authorization Form may be provided. Include an explanation of this
fact in the section above entitled, “Evaluation of Subject(s) Capacity to Provide Informed
Consent/Assent.” For example, if you will enroll children with severe autism and it is
assessed that even though they are above the chronological age of 7 years, they will be
developmentally incapable of providing assent, this should be explained in this section.
See also the Application to Involve Human Subjects in Research Instructions in
Biomedical Research (http://www.yale.edu/hrpp/formstemplates/biomedical.html ) for further information about parental permission and
assent.
12. Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for
research involving non-English speaking subjects. Translated copies of all consent
materials must be submitted for approval prior to use.
If you will not include Non-English speaking families, i.e., usually families whose primary
language is Spanish, provide a justification for this decision here.
13. Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed
consent, or a full waiver of consent, depending on the study. If you will request either a
waiver of consent, or a waiver of signed consent for this study, complete the appropriate
section below.
Not Requesting a consent waiver
Requesting a waiver of signed consent
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Requesting a full waiver of consent
A. Waiver of signed consent: (Verbal consent from subjects will be obtained. If PHI is
collected, information in this section must match Section VII, Question 6)
Requesting a waiver of signed consent for Recruitment/Screening only
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research?
Yes
No
b. Does a breach of confidentiality constitute the principal risk to subjects?
Yes
No
OR
c. Does the research activity pose greater than minimal risk?
Yes If you answered yes, stop. A waiver cannot be granted. Please note:
Recruitment/screening is generally a minimal risk research activity.
No
AND
d. Does the research include any activities that would require signed consent in a nonresearch context?
Yes
No
Requesting a waiver of signed consent for the Entire Study (Note that an information
sheet may be required.)
If requesting a waiver of signed consent, please address the following:
a. Would the signed consent form be the only record linking the subject and the research?
Yes
No
b. Does a breach of confidentiality constitute the principal risk to subjects?
Yes
No
OR
c. Does the research pose greater than minimal risk?
Yes If you answered yes, stop. A
waiver cannot be granted.
No
AND
d. Does the research include any activities that would require signed consent in a nonresearch context?
Yes
No
B. Full waiver of consent: (No consent from subjects will be obtained.)
Requesting a waiver of consent for Recruitment/Screening only
a. Does the research activity pose greater than minimal risk to subjects?
Yes If you answered yes, stop. A waiver cannot be granted. Please note:
Recruitment/screening is generally a minimal risk research activity
No
b. Will the waiver adversely affect subjects’ rights and welfare?
Yes
No
c. Why would the research be impracticable to conduct without the waiver?
d. Where appropriate, how will pertinent information be returned to, or shared with
subjects at a later date?
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Requesting a full waiver of consent for the Entire Study (Note: If PHI is
collected, information here must match Section VII, question 6.)
If requesting a full waiver of consent, please address the following:
a. Does the research pose greater than minimal risk to subjects?
Yes If you answered
yes, stop. A waiver cannot be granted.
No
b. Will the waiver adversely affect subjects’ rights and welfare?
Yes
No
c. Why would the research be impracticable to conduct without the waiver?
d. Where appropriate, how will pertinent information be returned to, or shared with
subjects at a later date?
Note: parental permission may not be modified or waived, under federal
regulations, in protocols that involve an FDA-regulated product.
There are two situations in which parental permission may be modified or waived.
These include: (a) research that involves only minimal risk, does not negatively affect
the welfare of subjects, and cannot be practically performed without the waiver; (b)
research in which obtaining permission will not function to protect the child. The IRB
may determine and PPRC may agree that the protocol is designed for conditions or a
specific population for which parental permission or guardian permission is not a
reasonable requirement to protect the subjects, e.g. neglected or abused children. This
situation is conditional, provided that an appropriate mechanism for protecting the
children who are targeted for participation is substituted, and the waiver is not
inconsistent with federal, state, or local law.
If you are asking for a waiver of signed consent, note that “Information Sheets” as noted
above (in the documentation of consent section) for the parent/subject/minors are
needed. Include their provision in the section (above) and also include these forms with
your PPRC submission. [They basically follow the same format as consent/permission
or assent forms, but do not include a signature page.]
The only waiver of parental permission that the FDA considers is for research involving
emergent and life-threatening situations.
Waivers of permission for emergency research with minors may be granted when the
following conditions are met: (All applicable conditions need to be explained in this HIC
application.)
1. Patients must have specific life-threatening medical conditions and the
family/parents are not available to provide informed consent or permission.
2. The research must hold out the prospect of individual benefit to the subject.
3. The minor must have a life-threatening condition for which available treatments
are unproven or unsatisfactory.
4. For the treatment to be effective, it must be initiated before consent/permission
can be obtained by the subject’s parent, guardian, or legally authorized
representative.
5. An IND or an IDE is required.
6. The sponsor of the study must have received written authorization from the FDA.
7. The IRB needs to document that these specific conditions have been met.
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8. The development and implementation of a plan for community consultation and
public disclosure before the start of the study.
9. A mechanism for contacting and providing information to the subject’s legally
authorized representative or family member/parent within the therapeutic window
or at the earliest feasible opportunity.
10. Opportunity for family members/parents to object to a subject’s continued
participation in the study.
SECTION VIII: PROTECTION OF RESEARCH SUBJECTS
Confidentiality & Security of Data:
a. What protected health information (medical information along with the HIPAA identifiers)
about subjects will be collected and used for the research?
b. How will the research data be collected, recorded and stored?
c. How will the digital data be stored?
CD
DVD
Flash Drive
Portable Hard
Drive
Secured Server
Laptop Computer
Desktop Computer
Other
d. What methods and procedures will be used to safeguard the confidentiality and security of
the identifiable study data and the storage media indicated above during and after the
subject’s participation in the study?
Do all portable devices contain encryption software?
Yes
No
e. What will be done with the data when the research is completed? Are there plans to destroy
the identifiable data? If yes, describe how, by whom and when identifiers will be destroyed. If
no, describe how the data and/or identifiers will be secured.
f. Who will have access to the protected health information (such as the research sponsor, the
investigator, the research staff, all research monitors, FDA, Yale Cancer Center Data and
Safety Monitoring Committee (DSMC), SSC, etc.)? (please distinguish between PHI and deidentified data)
g. If appropriate, has a Certificate of Confidentiality been obtained?
h. Are any of the study procedures likely to yield information subject to mandatory reporting
requirements? (e.g. HIV testing – reporting of communicable diseases; parent interview incidents of child abuse, elderly abuse, etc.). Please verify to whom such instances will need to
be reported.
If by state statute you belong to a profession (e.g. physicians, nurses, social workers),
that is considered a mandatory reporter of abuse and/or neglect (child, domestic,
elderly) and/or a reporter of communicable diseases in the State of CT, then the answer
to this question is that you will report these incidences to the proper authorities, even
though in some studies this may be a rare occurrence or an incidental finding.
SECTION IX: POTENTIAL BENEFITS
Potential Benefits: Identify any benefits that may be reasonably expected to result from the
research, either to the subject(s) or to society at large. (Payment of subjects is not considered a
benefit in this context of the risk benefit assessment.)
Clearly state the benefit of the research and/or the research
procedures/assessments/tests to the individual subject or to the population at large
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either at present or in the future. The benefit statement should be consistent in all
documents, internally in the HIC application and match with the parental
permission/consent/assents. Especially for studies of greater than minimal risk, it is
important to be clear if the individual subject will benefit or if the population at large (that
the subject belongs to) will benefit.
SECTION X: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.
Alternatives: What other alternatives are available to the study subjects outside of the research?
If this is a study providing any type of treatment, list what alternatives are available to
parents/minors. Other alternatives, as appropriate to your study, may include: (1) other
research protocols if similar ones are offered at this site; (2) the intervention may be
provided as standard of care (outside of the protocol, e.g. an FDA approved drug, if
applicable). If not a treatment study or the other alternatives as noted above do not
apply, then the option may simply be not to participate.
2.
Payments for Participation (Economic Considerations): Describe any payments that will be
made to subjects, the amount and schedule of payments, and the conditions for receiving this
compensation.
If there are separate payments for parents and children, explain this here and in the
parental permission documents. If there is only one payment or gift, etc, indicate to
whom this payment will be given. For an example, consider the following: a gift
certificate to a music or book store for the adolescent and money for transportation
given to the parent/guardian.
The American Academy of Pediatrics (2010) advises that payments are to be
reasonable and minimal to either the child or the parent. The IRB must be certain and
the PPRC may advise as to whether the payment is fair and does not become an undue
inducement for participation of the child.
3.
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs
associated with participation in the research, and the interventions or procedures of the study that
will be provided at no cost to subjects.
Differentiate those procedures/tests/assessments that are standard of care and will be
billed to parent’s insurance versus those procedures that are research related and will
be paid for by the study. This should also be consistent and clear in the parental
permission and/or consent form (depending upon the ages to be enrolled.)
Any potential financial costs should also be outlined for parents.
4.
In Case of Injury: This section is required for any research involving more than minimal risk.
a. Will medical treatment be available if research-related injury occurs?
b. Where and from whom may treatment be obtained?
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c.
d.
e.
HIC# if known
Are there any limits to the treatment being provided?
Who will pay for this treatment?
How will the medical treatment be accessed by subjects?
References:
Blumenthal, R. (2002). Attorney General’s Opinion written to the Honorable Kristine
Ragaglia, Commissioner of Children and Families. September 30, 2002, accessed from
http:///www.ct.gov/ag/cwp/view.asp on April 14, 2007.
Code of Federal Regulations. Subpart D Additional Safeguards for Children in Clinical
Investigations of Chapter 1 Food and Drug Administration, DHHS; 21 CFR 50.51 to 21
CFR 50.54.
Code of Federal Regulations, Subpart D Additional Protections for Children Involved as
Subjects in Research of Title 45—Public Welfare, Subtitle A—Department of Health and
Human Services, Part 46 Protection of Human Subjects, DHHS; 45 CFR 46.404 to 45
CFR 46.407
CT State Statutues. The following Sections: Section 17a-101, Section 17a-101a,
Section 19a-14c, Section 46b-150.
Shaddy, R. E., Denne, S.C. (2010). Clinical report guidelines for the ethical conduct of
studies to evaluate drugs in pediatric populations. Pediatrics, 125, 850-860. (Pediatrics
is the Official Journal of the American Academy of Pediatrics.)
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