Informed ConsentPractical Considerations

Yusuf Yazıcı, MD

Assistant Professor of Medicine,NYU School of Medicine

Director, Seligman Center for Advanced TherapeuticsNYU Hospital for Joint Diseases

Conflicts of interest

• Consultant / Speaker / Research Support– Bristol-Myers Squibb– Celgene– Centocor– Genentech– Roche– UCB

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Topics

• Declaration of Helsinki

• ‘Seeding’ trials

• Safety trials

• Equipoise

• Routine care registries/trials– ‘opt in v opt out’

– Declaration of Geneva

– International code of ethics (WMA)

– All based on• No unnecessary risk to the participants• Unnecessary studies• Scientifically unsound studies• Poor planning

Declaration of Helsinki

• 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

• Not only safety but also societal benefits?1

Declaration of Helsinki

1-Goodyear MDE et al, BMJ 2008

• 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.

• 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.

• 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.

This slide is not part of the presentation but I need it here

• 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."

• Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the:29th WMA General Assembly, Tokyo, Japan, October 197535th WMA General Assembly, Venice, Italy, October 198341st WMA General Assembly, Hong Kong, September 198948th WMA General Assembly, Somerset West, Republic of South Africa, October 199652nd 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

History of Declaration of Helsinki

• 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”

• 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

Informed consent

1-Lancet 2009

• Does the study need to be done?– ‘Equipoise’– Past studies in the same area– BMJ

• ‘seeding’ trials– ADVANTAGE 1

– RADIUS

• Placebo concerns

• Trial duration

• What happens post trial

• Early termination of the study

Protocol

1-Hill KP et al. Ann Intern Med 2008

Equipoise

• 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

• 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 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

Early termination of trials

Vıoxx vs Celebrex

• 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

• Unless there is very strong evidence trials should not be terminated early, neither for benefit or harm outcomes2

1-Nissen S. PLoS Clin Trials 20062-Pocock S. JAMA 2005

Safety trials

• Celebrex vs naproxen

• 20,000 OA patients, followed for 18m

• Patient with preexisting cardiac risk factors

• Primary outcome– MI, death, nonfatal stroke

• What were the patients told exactly?

• What was the reason to the study in the first place?– How detailed were the studies already available examined?

TEMPO

• 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?

• Were they offered “best available” treatment?

Klareskog L, et al. Lancet 2004

Baseline differences in cohorts

• Difference sin epileptic attack counts1

• General internal medicine clinics– Opt in is followed less frequently2

• NYU ARMD– 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 20052-Junghans C. et al. BMJ 2005

‘opt in v opt out’

• 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

• 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

• 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 20052-Junghans C. et al. BMJ 2005

Do patients have to participate in clinical trials?

• 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

• Best treatment option made available in the shortest amount of time?

• In specific circumstances mandatory participation can happen– Childhood cancers and parental decision making

• Not everything can be forced how beneficial they may be but– Energy use– Helping the poor

Informed consent in routine care

• Patients may not refuse to be part of a clinical trial when:– 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

• All patients benefit from previous patients’ sacrifices• Tax

– Shared risk and shared benefit• Opportunity to learn about rare diseases• Comparative efficacy• AE reporting• Prevents choosing DMARDs with profit in mind

Evans HM. J Med Ethics 2004

A proposal

• Research is risky– We all benefit from previous trials

– Other patients volunteered and provided us with the benefit

– Any obligation on our part?

• 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

• Comparative studies– Rare disease– Small differences among treatment where large numbers

are needed

• Adverse event monitoring

• No “other” incentives in picking one drug over another

Conclusions

• Informed consent – needs to be part of clinical trial registries

•

• Not every study need to be approached the same way

• Not every study frankly needs to be done

• Patient autonomy vs societal good