Transcript No Slide Title

Clinical Research Overview
Kathryn Candler M.A.
VCU Massey Cancer Center
Bone Marrow Transplant Program
November 13, 2008
Why is research important?
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Why is research important?
Just about every drug, test and intervention done in BMT is the
direct result of clinical research
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What are the goals of this presentation?
What is research?
Why is research important?
What research is being done here?
How does a research idea get implemented?
How do clinical trials lead to drug development?
Why and how is research regulated?
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What is the definition of research?
According to the code of federal regulations it is “a
systematic investigation…designed to contribute to
generalizable knowledge”
So, innovative therapy, off-label use of medications, and any
other practice changes designed to treat a specific patient are
not defined as research if the intent is not to contribute to
generalized knowledge
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What research is done in the BMT program?
Industry sponsored trials in phases I, II, III, and IV
Chemotherapy agents – Vidaza
Antifungals – Voriconazole and combination therapies
Antivirals – Maribavir
Drugs to control side effects of treatment – KGF, Osiris
Mobilization regimens – AMD 3100
Investigator initiated studies
Vidaza to transplant – McCarty
Non-myeloablative transplantation – Toor
Cooperative group studies
CALGB, SWOG, BMT CTN,
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Why is research regulated?
Remember - According to the code of federal regulations
research is “a systematic investigation…designed to contribute
to generalizable knowledge”
Therefore, the subject in a study is the means to achieving the goals
of the research (this means that the study subject is exposed to risk
for the benefit of others) and is thus vulnerable to exploitation
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Where did current regulations come from?
• 1947 Nuremburg Code – written in response to nazi experiments on prisoners;
required the voluntary consent of human subjects, absence of coersion,
reasonable scientific goals and concern for the wellbeing of study subjects
• 1964 Declaration of Helsinki – written by the World Medical Association to
further clarify acceptable practices; defines the ability of children and the
mentally disabled to participate as research subjects with extra safeguards on
their treatment
• 1979 Belmont Report - rather than produce another list of rules about what was
acceptable and what was not this report defines the basic ethical principles that
should underlie the conduct of human subjects research
• 2001 Common Rule – code of federal regulations dealing with research
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How is research regulated?
The federal government has passed a number of laws that lay out very
specific rules for the process of drug development, the purpose and
function of Institutional Review Boards (IRB), the process for obtaining
informed consent, and the overall protection of subjects in research
These began with guidelines designed to address inappropriate
behavior and have progressed to include very detailed federal
regulations and guidance meant to ensure that the rights of subjects are
protected
They assign the FDA to enforce these laws and to perform audits of
clinical sites to ensure that the regulations are followed and that
subjects are protected
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What are the phases of drug development?
Pre Clinical
Studies
Synthesis and development of promising compounds, testing in lab and possibly
animal models to obtain information about efficacy, toxicity, pharmacokinetics
Phase I
Normally a small group of healthy volunteers, in cancer treatment trials often a small
group with the disease under study, used to determine appropriate dosing and not
designed to look at efficacy, may include pharmacokinetic studies to assess how the
drug is metabolized and excreted
Phase II
Assess how well the new drug works and continue safety assessments – usually
done with larger groups
Phase III
Usually very large randomized multi-center trials aimed as definitive assessment of
how effective the new drug is compared with standard of care
Phase IV
Post marketing surveillance – may be required by the FDA to evaluate drug
interactions, combination therapies or prompted by the pharmaceutical company to
assess new populations such as children
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Drugs are expensive, this is why…
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How does a research idea get implemented?
• Ask a question in
a systematic way
Have an idea
Write a
protocol
• Decide on who
will be included,
what and how to
measure
• Include required
elements of
consent
Write a consent
form
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How does a research idea get implemented?
• Review for
scientific validity
and feasibility
Submit to Massey
P.R.M.S.
Submit to IRB
• Celebrate
• Review for
appropriate
treatment of
subjects
Get regulatory
approval
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How does a research idea get implemented?
• Train staff to carry
out study
Train staff
Enroll
subjects
• Informed consent
process
• Enter subjects in
study
• Ensure required
information is
collected
Collect data
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How does a research idea get implemented?
Interpret data
• Analyze for
investigator
initiated study
Analyze and/or
submit data
• What do results
mean, were
assumptions
correct?
• Communicate
methods, subject
details, results,
analysis
Write results
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How does a research idea get implemented?
• Need to
repeat for
each phase of
development
Repeat as
necessary
Submit data
to FDA
• Send data for
review
• Marketing
begins
• Have pens
printed
Drug is
approved
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What is the Institutional Review Board (IRB)?
An IRB is a group of people designated to review research, the board
must have at least five members with varying backgrounds, some in
science others non scientists
At VCU there are multiple IRB boards who meet regularly to review new
and ongoing research
The IRB must review the study protocol and the informed consent
process to ensure that adequate safeguards are in place to protect
human subjects, that any risks of the research are balanced by the
potential benefits and that any potential conflicts of interest are
disclosed to the subjects
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What is Informed Consent?
Subjects must be given the opportunity to determine what happens to
them (to the degree they are able), this is insured by obtaining informed
consent. To have all the necessary elements of consent the subject
must:
 Be provided all necessary information
 Comprehend the information
 Agree to participate voluntarily
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What is the informed consent form?
Federal regulations require 8 elements in consent form
What is the purpose and duration of participation?
What are the risks?
What are alternatives to participating in the research?
What are the potential benefits of the research?
How will confidentiality of records be assured?
What is the plan for compensation if there are injuries?
Who is the person to contact with questions?
Participation is voluntary and they have the right to withdraw
The consent is documented on an IRB approved informed consent form
(ICF) but the overall process is much more involved than just signing
the form.
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What makes clinical research ethical?
• EJ Emanuel, Chairman of the Department of Clinical Ethics at NIH has proposed a
series of 7 ethical principles that, if followed minimize the potential for exploitation
Ethical requirement
Explanation
Social or scientific value
Evaluation that will improve health or increase
knowledge
Scientific validity
Use of science in a way that will produce reliable and
valid data
Fair subject selection
Selected so that vulnerable subjects are not selected for
risky research and that powerful subjects are not
favored for potentially beneficial research
Favorable risk / benefit ratio
Minimize risk, enhance possible benefits, risks to the
subject are proportionate to benefit to society
Independent review
Review of study design, subject population and risk /
benefit ratio by individuals unaffiliated with the study
Informed consent
Provide information about study to subjects about
purpose of the research, risks, potential benefits,
alternatives so that subject understands the information
and can make a voluntary decision
Respect for subjects
Permit withdrawal, protect privacy, inform subjects of
new information about risks / benefits, inform subjects of
results of research, maintain overall welfare of subjects
JAMA May 24/31 2000- Vol. 283, No 20
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The Clinical Trial Volunteer’s Bill of Rights
To be told the purpose of the clinical trial
To be told all the risks, side effects or discomforts that might be
reasonably expected
To be told of any benefits that can be reasonably expected
To be told what will happen in the study and whether any procedures,
drugs or devices are different than those that are used as standard
medical treatment
To be told about options available and how they may be better or worse
than being in a clinical trial
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The Clinical Trial Volunteer’s Bill of Rights 2
To be allowed to ask any questions about the trial before giving consent
and at any time during the course of the study
To be allowed ample time, without pressure, to decide whether to consent
or not to consent to participate
To refuse to participate, for any reason, before and after the trial has
started
To receive a signed and dated copy of the informed consent form
To be told of any medical treatments available if complications occur
during the trial
Getz, K., & Borfitz, D. (2002). Informed Consent. Boston, MA: Thomson CenterWatch
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How do we enroll a BMT patient to a study?
• At weekly meetings we discuss whether a patient might be eligible for a
specific study
• BMT physicians meet with the potential subject to discuss the study
• The potential subject asks questions and discusses the consent form
and the study procedures with the physician
• If the subject agrees to participate they are asked to sign the informed
consent form
• The research staff begins testing for eligibility and if appropriate enrolls
the subject in the study
• If new information about risks, benefits or procedures develops the
subject is informed and if required another consent form is signed
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What have we covered?
•Informed consent form
•Placebo controlled
•Double blind
•FDA
•Randomized
•IRB
•Subject / Patient
•Phases of drug development
•Historical factors in the practice of
clinical research
•Ethical principles used to make
determinations about research
•Regulatory agencies involved in
research
•Definition of consent process
•Limitations of consent
•Cooperative group
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What is the bottom line?
Our purpose is to carry out clinical research
to enhance patient care while insuring the
protection of human subjects
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