Clinical trials: unique aspects of
clinical-based grants
Grant-Writing Series
June 12, 2012
Marian Limacher, MD
Senior Associate Dean for Faculty Affairs
and Professional Development
AHA Endowed Professor of
Cardiovascular Research
The challenges of patient oriented
research
• Complex, hard to do – lots of regulations
• Takes a long time
• High cost
• You will underestimate your ability to recruit
subjects
• You will overestimate your effect size
Human Subjects Research
• What is “clinical research”?
NIH Director's Panel on Clinical
Research, 1997
• (a) Patient-oriented research. Research conducted
with human subjects (or on material of human
origin such as tissues, specimens and cognitive
phenomena) for which an investigator (or colleague)
directly interacts with human subjects. This area of
research includes:
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Mechanisms of human disease
Therapeutic interventions
Clinical trials.
Development of new technologies
• (b) Epidemiologic and behavioral studies
• (c) Outcomes research and health services
research.
Not “clinical research”:
• in vitro studies that utilize human tissues but
do not deal directly with patients.
• In other words, clinical or patient-oriented
research is research in which it is necessary to
know the identity of the patients from whom
the cells or tissues under study are derived.
• For funding, the emphasis is on research
concerned with examining patients.
• Mixed grant applications, as in program
projects in which one element of the proposal
is an animal model and one is a human model,
may also be classified as clinical research
Spectrum of Research
What is a clinical trial?
• a clinical trial is a "research study to answer
specific questions about vaccines, new therapies
or new ways of using known treatments. Clinical
trials (also called medical research and research
studies) are used to determine whether new
drugs or treatments are both safe and effective.
• Carefully conducted clinical trials are the fastest
and safest way to find treatments that work in
people."
Source: Clinicaltrials.gov
Types of Clinical Trials
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Treatment trials test new treatments, new combinations of
drugs, or new approaches to surgery or radiation therapy
Prevention trials look for better ways to prevent disease in
people who have never had the disease or to prevent the disease
from returning. Approaches may include medicines, vitamins,
vaccines, minerals or lifestyle changes
Screening trials try to find a better way to detect certain
diseases or health conditions
Quality of life trials explore ways to improve comfort and
quality of life for individuals with chronic illness
Nontherapeutic trials hope to answer specific research
questions without using any type of treatment on participants.
This may be accomplished by reviewing medical records, doing
certain types of medical tests or asking participants questions in a
survey.
Design Issues
• What type of study will best answer the
question?
• What type of study will I be able to do?
Observational Studies
• Is there a comparison or “control” group?
Yes = “analytical”
No = “descriptive”
• For analytic studies -- determine time
sequence
What is a control?
• "a control is the standard by which
experimental observations are
evaluated. In many clinical trials, one
group of patients will be given an
experimental drug or treatment while
the control group is given either a
standard treatment of the illness or a
placebo."
Source: Clinicaltrials.gov
Cohort Study
looking forward, aka “prospective”
Exposure
(Risk Factor)
Outcome
(Disease)
Time
Cohort Studies
• May establish -– Incidence of the outcome over time
– Risk factors
– Protective factors
• Downsides
– Not useful for rare diseases
– Expensive
– May contain biases
Case-Control Study
Exposure
(Risk Factor)
Outcome
(Disease)
Time
Case-Control Example
• Investigating a food-borne illness on a ship
• Question all those who became ill
• Identify what they ate, medicines, underlying
conditions
• Identify a number of other shipmates and ask
same questions
• Analyze what was more common among those
who became ill
• Final result: it was the German potato salad
Case-Control
• Useful for
– Rare diseases
– Conditions that develop over a long time (heart
disease)
– “easier” than cohort studies, less time, effort and
fewer subjects needed
• Downside
– Appropriate “control” group can be difficult to identify
– Recall bias (relies on subject memory of some risk
factors)
Cross-Sectional Study
Exposure
(Risk Factor)
“Snapshot”
In time
Outcome
(Disease)
Time
Other research reports
• Case study
– Report of a single case (patient) with unusual,
interesting findings that illustrate a lesson in
diagnosis, treatment or outcome
• Case series
– Several case studies of the same condition
– Consecutive cases, e.g. reporting outcome
with a new surgical technique
Deciding which study to answer the
question(s)
• Descriptive studies
– Describe the features of a new disease
– Frequency of the condition
– Determinants of the condition
• First description of Legionnaire’s disease
• First report of Toxic Shock syndrome
• No comparison or control group
• No ability to determine associations or
causes
Randomized, Controlled Clinical
Trial (RCT)
• Considered the “gold standard” among clinical
research designs
• Can best identify whether “X” results in
improved outcomes
• Rather than some characteristic(s) of the
participants and not the intervention itself
– Reduces bias
• Selection
• Confounding
• informational
Sample size
• Do it!
• Consult a statistician – at the design phase
• Include an analysis plan in your methods
Planning for Drop out
• Increase sample size
• Decide in the analysis plan how they will be
handled
• Another issue for your statistician
The Regulatory Aspects
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IRB
RAC
HIPAA
Reporting
Fundamentals of Human Subject Protection
and the IRB Process
Ensuring That All Research Involving Human Subjects Meets Federal, State,
and Institutional Guidelines
Tiffany Danielle Pineda
Education Coordinator
tiffany.danielle@ufl.edu
(352) 273-9604
Responsibilities in Research
• Institutional Responsibilities
• Institutional Review Board Responsibilities
• Investigator Responsibilities
Institutional Responsibilities
– Federalwide Assurance
• Under Federal regulations, any institution engaged in
Federally-supported human subjects research must
commit itself in writing to the protection of those
subjects.
• UF guarantees adherence to Title 45, Part 46, of the
Code of Federal Regulations.
• UF will review ALL research involving human subjects.
IRB Responsibilities
• UF Utilizes 4 IRBs
IRB01: Health Science Center
IRB02: Behavioral/Non-Medical
IRB03: Jacksonville
IRB04: Western IRB (Industry Sponsored)
• Review all proposed human subject research at
the University of Florida in accordance with
established guidelines.
IRB Responsibilities Cont.
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Authority to approve, request modification in, and/or
disapprove research.
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Authority to suspend or terminate previously approved
research that is not being conducted in accordance with
the IRB’s requirements, or that has been associated with
unexpected serious harm to subjects.
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To observe, or have a third party observe, the conduct of
the research.
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To observe, or have a third party observe, the consent
process.
Investigator Responsibilities
Investigators have the primary responsibility for
protecting the rights and welfare of human
research subjects and are responsible for
complying with all applicable provisions of their
institution's Assurance.
Investigator Responsibilities Cont.
Investigators are expected to be knowledgeable
about the requirements of the Federal regulations,
applicable state law, their institution's Assurance,
and institutional policies and procedures for the
protection of human subjects.
Investigator’s Responsibilities Cont.
• Conducting their research according to the IRB
approved Protocol.
• Ensuring that each potential subject understands the
nature of the research.
• Providing a copy of the IRB-approved Informed
Consent document to each subject at the time of
consent.
Investigator Responsibilities Cont.
• Promptly submitting proposed changes for
review prior to implementation.
• Promptly reporting any unanticipated
problems and adverse events.
• Submitting the continuing review and study
closure forms.
Research Requiring IRB Approval
All research that involves intervention/interaction
with human subjects or their identifiable
protected health information must be reviewed
by the IRB BEFORE it is conducted.
Ethical and Regulatory Considerations
• Would I let a family member take part in the study?
• Is the study design ethical?
• Are the risks worth taking?
• Why is a special population or site included or
excluded?
Study Procedures
• In ample detail, establish what really happens, and
the risk to subjects.
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Time commitment.
Setting or site.
Are “routine” agents used?
How is the data analyzed?
Logical, chronological, rationalized, and prioritized.
Make sure the Consent and Protocol match.
Consent form is written at 8th grade reading level.
Qualifications of the Staff
• Confirm the study staff’s duties, qualifications,
and roles.
Subject Selection/Enrollment
• How are subjects identified ?
Ads, charts, referrals, own clinic, support groups, public
• How many subjects are needed?
Is there enough to answer the question
records, etc.
posed?
• How, when and by whom are subjects first contacted about
the study?
Letter? In person? By whom?
Safety Monitoring
• How is data monitored and by whom?
– Every study needs a safety monitoring PLAN!
– Provide objective criteria for withdrawal of subject for
safety reasons!
– Make sure to have stopping rules.
– Submit necessary reports to IRB!
(adverse events, deviations/non-compliance,
unanticipated problems, revisions, and such)
Risks and Discomforts
• Listed clearly, quantitatively, and in order of
seriousness.
• Also consider:
– The costs and risks of withdrawal of current medications!
– The non-medical risks (social and psychological).
– Always guard against potential loss of confidentiality.
Benefits
• Monetary compensation is NOT a benefit.
• State the benefits to individual then to society.
Consent
• Consent is a process not a form but the Form is the
formal record/document
• Consent is ongoing
• Timing is important - the details should be submitted
• Anyone who signs a Consent form is considered formally
enrolled or whose records are accessed under an
approved Waiver
Consenting Cont.
• Adults >18 years of age, sophisticated teens
may read adult Form. ( Must be written at the
8th grade reading level)
• All minors require parent/guardian to sign
Consider who you have doing the
Consenting
• Consent for activities corresponds with their typical
clinical practice in medicine.
• Examples:
– (Breast Study) Mammogram Technologist.
– (Investigational drugs/devices) Licensed MD -
8 Mandatory ICF Elements
• A statement that the study involves research, an explanation of the
purposes of the research and the expected duration of the subject's
participation, a description of the procedures to be followed, and
identification of any procedures which are experimental;
• Description of Risks;
• Description of Benefits;
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Alternatives to Participation;
• How Privacy and Confidentiality of records will be maintained;
ICF Mandatory Elements Cont.
• An explanation as to whether any compensation and medical
treatments are available if injury occurs and, if so, what they
consist of, or where further information may be obtained;
• Who to contact for answers about the research, research
subjects' rights, and research-related injury; and
• A statement that participation is voluntary, refusal to
participate will involve no penalty or loss of benefits to which
the subject is otherwise entitled, and the subject may
discontinue participation at any time without penalty or loss
of benefits to which the subject is otherwise entitled.
IRB Submission
http://irb.ufl.edu/
Research Administration & Compliance
Health Science Center Research
Billing Risks
Edy Zettler, BS
Education & Training Coordinator
Broad Building, Room 102-H
(1300 Center Drive at Mowry Road)
ezettler@ufl.edu
352-273-6244
Health Science Center (HSC) Policy
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All research conducted in the HSC will be in
compliance with applicable State & Federal
regulations.
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All PIs & their designees will provide necessary
information to appropriate service personnel to
ensure proper billing procedures.
Why is this Pertinent?
Clinical Research Study Policy addressing
billing/claims established by Center for
Medicare and Medicaid Services (CMS) in 2000!
Audits (internal and external) – refunds.
Institution can be liable for damages & fines.
PI, institution, billing providers subject to a
fraud investigation.
HSC Research Billing Risks
Two areas of risk:
Billing Claims
Fiscal Language
Billing Claims Risks
Cannot bill out items that are paid for or
provided by sponsor – Tracking essential!
Care must be taken to ensure billable items can
be billed out per Medicare Rules.
Fiscal Language
 Informed Consent Language must accurately reflect
Study’s fiscal obligations (cannot conflict with
protocol, contract, budget).
 Discrepancies can have financial implications for
PI’s department, UF, Shands and/or the participant.
Patient Costs
Subject Injury
What Does RAC Do?
Research Administration & Compliance (RAC)
Responsibilities
 Multiple reviews of HSC studies that involve Human
Subjects and Services.
 Education & Training to promote billing compliance.
 Financial Language Assessment (FLA) Forms.
 Audit research activity & provide guidance for
reconciliation.
 Investigate/address billing noncompliance allegations.
Where can I get help?
Resources & Contact Information
– RAC Liaisons (273-5398)
– RAC Education & Training Staff (273-5946)
– DSR Representative in RAC (273-5392)
– RAC Auditors (273-5946)
– Monthly Roundtables & AD Hoc Meetings
– RAC Newsletters
Where can I get help?
Websites
– http://ctc.health.ufl.edu/
– http://www.med.ufl.edu/research/rac/
Where can I get help?
Training & Classes
– Mandatory Online Training Module
– Research Billing Crash Course: The Essentials
– To Bill or Not to Bill: What is the Difference?
– Service Provider Communication
– Building a Great Detailed Budget
– Navigating the Clinical Trials Compliance Website
– Why Track Services Now? Save Time and Money Later!
– Study Registration & Initiation
Sign up through MyUFL
UF Resources
• Clinical and Translational Science Institute
National Consortium
of 60 Academic Health Centers
The UF CTSI is supported in part by NIH awards UL1
RR029890, KL2 RR029888 and TL1 RR029889
A Catalyst for Collaboration
CTSA
consortium
Corporate
Partners
16 UF
Colleges
UF
CTSI
University
Partners
Health Care
Systems
Community
Partners
The UF CTSI is supported in part by NIH
awards UL1 RR029890, KL2 RR029888 and
Regulatory Knowledge and Research Support
• Overarching goal
– To increase accessibility of information by providing
expert investigator assistance via Research Project
Navigators, and provide prompt access to research
and training resources ensuring rapid activation of
research
• Services provided
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Trial design and database (RedCap)
Quality assurance
Clinical and research ethics
Regulatory affairs
IRB assistance
Contract negotiations
Billing and budgeting
Technology transfer
The UF CTSI is supported in part by NIH awards UL1
RR029890, KL2 RR029888 and TL1 RR029889
Wajeeh Bajwah, PhD
Research Design and Analysis
• Overarching goal
– Consult, collaborate and conduct
research and educate on study design
and biostatistical issues in CTS.
• Activities
– Study Design – clinical trials,
observational studies, cohort, chart
review, qualitative, epidemiologic
– Power Analysis
– Study Analysis
– Data presentation and visualization
The UF CTSI is supported in part by NIH awards UL1
RR029890, KL2 RR029888 and TL1 RR029889
Jon Shuster, PhD
CTSI web portal
• www.ctsi.ufl.edu
• To request a consultation on any topic related to
clinical and translational science or any of the
programs, services or activities of the UF CTSI,
please call 352-273-8700.
• Research Project Navigators:
– Teresa D’Angelo, RN, BSN, CCRC
(danget@shands.ufl.edu) – (352) 265-0032 H. Robert
Kolb, RN, BS, CCRC (kolbhr@ufl.edu) – (352) 2738882 Douglas Theriaque, MS (theriaqu@ufl.edu) –
(352) 273-8877
Key recommendations
• Background:
– Demonstrate experience with recruitment
– Provide convincing evidence of an adequate, suitable population
• Methods:
– Provide the complete subject protocol
– Organize by time – provide table, which interventions at which
time/visit
– Also provide a full study timeline
– Work with a statistician, include an analysis plan
• Have IRB approval at the time of submission, if possible
• Must include a safety and monitoring plan
• Address possible pitfalls - honestly
Want more?
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Introduction to Clinical/Translational Research
2 week course: July 13-27, 2012
2:00 – 5:00 pm
Didactics – covering the spectrum of CTR
Small group projects
Check CTSI website to register
Or contact: Eve Johnson 273-9307