Transcript Document

Informed Consent
Practical Considerations
Yusuf Yazıcı, MD
Assistant Professor of Medicine,
NYU School of Medicine
Director, Seligman Center for Advanced Therapeutics
NYU Hospital for Joint Diseases
Conflicts of interest
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Consultant / Speaker / Research Support
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Bristol-Myers Squibb
Celgene
Centocor
Genentech
Roche
UCB
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Topics
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Declaration of Helsinki
‘Seeding’ trials
Safety trials
Equipoise
Routine care registries/trials
– ‘opt in v opt out’
Declaration of Helsinki
– Declaration of Geneva
– International code of ethics (WMA)
– All based on
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No unnecessary risk to the participants
Unnecessary studies
Scientifically unsound studies
Poor planning
Declaration of Helsinki
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In medical research involving human subjects, the
well-being of the individual research subject must
take precedence over all other interests.
Details of the protocol
IRB
Special cases
Volunteering
Disclosure of study results, negative or positive
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Not only safety but also societal benefits?1
1-Goodyear MDE et al, BMJ 2008
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Physicians should consider the ethical, legal and
regulatory norms and standards for research
involving human subjects in their own countries as
well as applicable international norms and standards.
No national or international ethical, legal or regulatory
requirement should reduce or eliminate any of the
protections for research subjects set forth in this
Declaration.
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Medical research involving human subjects may only
be conducted if the importance of the objective
outweighs the inherent risks and burdens to the
research subjects.
This slide is not part of the presentation but I
need it here
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The controversies and national divisions over the text have continued. The US FDA
rejected the 2000 and subsequent revisions, only recognizing the third (1989) revision
(Wolinsky 2006), and in 2006 announced it would eliminate all reference to the
Declaration. After consultation, which included expressions of concern, [13] a final rule
was issued on April 28 2008 replacing the Declaration of Helsinki with Good Clinical
Practice effective October 2008. [14] This has raised a number of concerns regarding
the apparent weakening of protections for research subjects outside the United
States. [15] [16] [17] [18] [19] [20] [21] [22] [23] The NIH training in human subject research
participant protection no longer refers to the Declaration of Helsinki. The European
Commission refers to the fourth (1996) revision.
While the Declaration has been a central document guiding research practice, its
future has been called into question. Challenges include the apparent conflict
between guides, such as the CIOMS and Nuffield Council documents. Another is
whether it should concentrate on basic principles as opposed to being more
prescriptive, and hence controversial. It has continually grown and faced more
frequent revisions (Carlson 2004). The recent controversies undermine the authority
of the document, as does the apparent desertion by major bodies, and any rewording
must embrace deeply and widely held values, since continual shifts in the text do not
imply authority.
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The Declaration of Geneva of the WMA binds the
physician with the words, "The health of my patient
will be my first consideration," and the International
Code of Medical Ethics declares that, "A physician
shall act in the patient's best interest when providing
medical care."
History of Declaration of Helsinki
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Adopted by the 18th WMA General Assembly, Helsinki,
Finland, June 1964, and amended by the:
29th WMA General Assembly, Tokyo, Japan, October
1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September
1989
48th WMA General Assembly, Somerset West, Republic
of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland,
October 2000
53rd WMA General Assembly, Washington 2002 (Note of
Clarification on paragraph 29 added)
55th WMA General Assembly, Tokyo 2004 (Note of
Clarification on Paragraph 30 added)
59th WMA General Assembly, Seoul, October 2008
Informed consent
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Not only relevant at the beginning but has to be kept in mind at all
times
University based vs central IRBs
– Scrunity of private IRBs 1
– Fake protocol sent to 3 IRBs
• Rejected by two
– Last one over the last 5 years approved 355/356 protocols sent
• “If one accepted second one is free”
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Different site specific IC
IC can change during trial depending on AEs and othe
rconsideretions
– Lack of patients
– Local norm changes in treatment options
6th grade reading level
1-Lancet 2009
Protocol
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Does the study need to be done?
– ‘Equipoise’
– Past studies in the same area
– BMJ
‘seeding’ trials
– ADVANTAGE 1
– RADIUS
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Placebo concerns
Trial duration
What happens post trial
Early termination of the study
1-Hill KP et al. Ann Intern Med 2008
Equipoise
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Why is the study done?
If nothing new, interesting or different is not being
asked, why is it being done in the first place?
– Most important question in any protocol
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Equipoise
– Placebo tirals are hard to justify but can be if there is real
equipoise
Active controlled trials
– Especially when there are other options
• Bolivia surfactant trial
Early termination of trials
• Early benefit or harm detected
– Different exposure times, both treatment and control arms
– Usually initial size of benefit is not reproducible
– Neither are the harms
• Promise made to the patients
– Patients may be expecting certain benefits
– Volunteering to help advance science
– Help to over all society
Vıoxx vs Celebrex
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Vioxx - Celebrex
– ADAPT1
• Stopped because NIH asked for it
• No predetermined plan to stop the trial
• 2 years later 17 vs 23 vs 22
– Increased CRP and statins
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Unless there is very strong evidence trials should
not be terminated early, neither for benefit or
harm outcomes2
1-Nissen S. PLoS Clin Trials 2006
2-Pocock S. JAMA 2005
Safety trials
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Celebrex vs naproxen
20,000 OA patients, followed for 18m
Patient with preexisting cardiac risk factors
Primary outcome
– MI, death, nonfatal stroke
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What were the patients told exactly?
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What was the reason to the study in the first place?
– How detailed were the studies already available examined?
TEMPO
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Etanercept vs MTX vs etanercept+MTX
1 vs. 2 years
Why enroll patient who have used MTX in the past?
What were the patients told at 1 year?
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Were they offered “best available” treatment?
Klareskog L, et al. Lancet 2004
Baseline differences in cohorts
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Difference sin epileptic attack counts1
General internal medicine clinics
– Opt in is followed less frequently2
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NYU ARMD
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Every patient, every time, as part of routine care
The only way to collect consecutive patient data
Limits on what can be collected
An advantage over collecting nothing
• Learned helplessness
– Retrospective analysis of prospectively collected data
– DNA, blood
1-Al-Shahi R. et al. BMJ 2005
2-Junghans C. et al. BMJ 2005
‘opt in v opt out’
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Obtaining informed consent in routine care leads to different types of
cohorts when compared to the whole population of patients
Opt in
– Patient actively has to decide to be contacted for studies
Opt out
– It is assumed patients are interested in research and can opt out and not
participate after they are contacted
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When clinical data that is used in routine care is collected, possibly no need
for informed consent at the data collection phase
– May obtain for data analysis
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MDHAQ collected in all patients each visit for a consecutive patient data
base, much preferable to haphazard, selected patient database/registries
– Loss of some data
– 80% of data in 100% patients vs 100% of data in 10% of patients?
1-Al-Shahi R. et al. BMJ 2005
2-Junghans C. et al. BMJ 2005
Do patients have to participate in clinical trials?
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Autonomy over all
taxes
– Mandatory
– Can’t refuse
– Refusal leads to whole system collapse
Shared risk for shared benefits
Taxes can be left to only volunteers but not the ideal
system
Evans HM. J Med Ethics 2004
Considerations
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Best treatment option made available in the shortest
amount of time?
In specific circumstances mandatory participation can
happen
– Childhood cancers and parental decision making
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Not everything can be forced how beneficial they may
be but
– Energy use
– Helping the poor
Informed consent in routine care
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Patients may not refuse to be part of a clinical trial when:
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No known differences exist between treatment options
Every patient gets active therapy
Especially in government insurance /payment for treatment
Not the doctor but random assignment decides which patient gets
what
– Then the patient cannot refuse to be part of an observational
protocol
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All patients benefit from previous patients’ sacrifices
Tax
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Opportunity to learn about rare diseases
Comparative efficacy
AE reporting
Prevents choosing DMARDs with profit in mind
– Shared risk and shared benefit
Evans HM. J Med Ethics 2004
A proposal
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Research is risky
– We all benefit from previous trials
– Other patients volunteered and provided us with the benefit
– Any obligation on our part?
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If there are two active treatment options and no
differences among them as far as the doctor is aware
and the need for additional treatment is set, then?
TNF vs TNF?
Any comparative study?
Evans HM. J Med Ethics 2004
What can be learned from routine care databases
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Comparative studies
– Rare disease
– Small differences among treatment where large numbers are
needed
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Adverse event monitoring
No “other” incentives in picking one drug over
another
Conclusions
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Informed consent – needs to be part of clinical trial
registries
Not every study need to be approached the same
way
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Not every study frankly needs to be done
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Patient autonomy vs societal good