Nexus Oncology

The Declaration of Helsinki:

Is it still relevant in the Ethical Conduct of Clinical Trials?

K Clayton 02 Dec 09

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Plan of Presentation

• Introduction: History, scope & Development

• Current Controversy• Ethical Problems• Arguments in support of FDA decision to

abandon DoH• Arguments against FDA Decision• Conclusion: Is DoH still relevant to ethical

conduct of Clinical Trials?

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What is the Declaration of Helsinki?

• Set of ethical principles• Developed by WMA for medical

community re: human experimentation• Followed Nuremberg Code (1947)• Regarded as cornerstone document of

human research ethics• Included within clinical trial protocols

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History of Declaration of Helsinki

• Adopted in June 1964• Has undergone 6 revisions• 2 clarifications• First significant effort by medical

community to regulate research• Prior to Nuremberg Code only specific

countries had national policies (Germany for example)

• Forms basis of most subsequent documents

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Scope of Declaration of Helsinki

• Developed 10 principles first stated in Nuremberg Code

• Linked to Declaration of Geneva (1948)• Statement of physicians ethical duties• DoH specifically addressed clinical

research• Relaxed need for IC which Nuremberg

Code deemed ‘absolutely essential’

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Development of Declaration of Helsinki

• First Revision 1975• Second Revision 1983• Third Revision 1989• Fourth Revision 1996• Fifth Revision 2000• Clarifications of Articles 29 & 30 2002 &

2004• Sixth Revision 2008

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First Revision 1975

• 11 years after first adoption of DoH• Introduced idea of oversight by independent committee• Led to development of IRBs/RECs• Issues relating to IC developed – more prescriptive• Duty to individual given greater weight over duty to

society• Ideas of publication ethics introduced• Comparison of trial treatment to best available treatment• Access to treatment following trial completion• Mandatory for protocols to state they adhered to the DoH

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Second & Third Revisions 1983 & 1989

• Fairly minor revisions• Consent of minors• Further developments re: independent

committees• CIOMS & WHO published International

Ethical Guidelines for Biomedical Research involving Human Subjects developed in 1982

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Fourth Revision 1996

• Allowed for use of placebo controlled trials• Only in cases where no proven diagnostic or therapeutic

method existed• Followed AIDS study publication 1994• Maternal-Infant HIV Transmission & effect of Zidovudine• Drug showed 70% reduction in transmission rate and

became standard of care• Subsequent HIV studies - US patient had unrestricted

access to AZT• Patients in developing countries still randomised to

placebo controlled arms

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Fourth Revision (cont)

• Conflicting guidance• 1994 WHO “Placebo controlled trials offer

the best option for a rapid and scientifically valid assessment of alternative antiretroviral drug regimens to prevent transmission of HIV”

• CIOMS – Ethical standards in developing countries should be no less exacting than those adopted within country initiating research

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Consequence of Fourth Revision

• FDA ignored this revision – continued to refer to 1989 version

• EU cited fourth revision in Clinical Trial Directive of 2001

• Adopted into UK national law in 2004

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Fifth Revision 2000

• Extensive revision to structure of document

• Extensive debate, symposia & conferences

• No reference to research where there is no potential benefit to participants

• Article 29 – placebo controlled studies• Article 30 – After care of trial participants• Led to clarification points of 2002 & 2004

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Sixth Revision 2008

• Followed general review• Comparatively Minor Revisions• Extensive debate & consultation re: 5th &

6th revisions led to concerns• ? Ethical strength of DoH weakened

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Points of controversy

• Article 29 states:

• “The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention, except in the following circumstances: The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or, Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.”

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Points of controversy (cont)

• Article 30 states:• “At the conclusion of the study, patients

entered into the study are entitled to be informed about the outcome of the study and to share any benefits that result from it, for example, access to interventions identified as beneficial in the study or to other appropriate care or benefits”

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Current Controversy

• April 2008 FDA Abandons requirement for clinical trials conducted outside of US to adhere to Declaration of Helsinki

• Disturbing ethical implications

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Potential Ethical Problems

• Possibility that placebo controlled trials might be allowed in emerging countries

• Concerns re: availability of optimal care of patients

• Able to use argument that ‘standard’ treatments not normally available within emerging country

• Financial incentives for Pharma companies

• Ethical Hypocrisy

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Arguments in support of FDA Decision (1)

• DoH was designed for regulation of physicians but:

“Although the Declaration is addressed primarily to physicians, the WMA encourages other participants in medical research involving human subjects to adopt these principles”

• DoH morally binding but not legally enforceable• Subsequent guidelines likely to be just as

effective

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Arguments in support of FDA Decision (2)

• Hasn’t prevented ‘unethical’ practices continuingTuskegee study ended 1972US Radiation experiments ended 1974CNEP studies in prem babies at North Staffs Hospital in1990sAlder Hay late 1980s & early 1990s

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Arguments in support of FDA Decision (3)

• Other guidelines/regulations have since been developedWHOCIOMSICH GCP (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice)

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Arguments in support of FDA Decision (4)

• DoH is now outdated by newer guidelines• Developed from DoH• More Comprehensive Guidelines• Should not assume pharma companies

are morally corrupt

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Arguments against the FDA Decision (1)

• Have to agree DoH was primarily aimed at physicians and not legally enforceable

• So too was Hippocratic oath (revised in Declaration of Geneva)

• None would doubt the moral weight this carries• “Physicians should consider the ethical, legal and

regulatory norms and standards for research involving human subjects in their own countries as well as applicable 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 the Declaration”

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Arguments against the FDA Decision (2)

• Continuing unethical practicesTrue but abandoning DoH and adopting other guidelines unlikely to cause such aberrations to miraculously stop

• Development of other GuidelinesFundamental concerns with ICH GCP

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Arguments against the FDA Decision (3)

• ICH GCP Guidelines driven by ‘interested parties’

• ICH consists of drug regulators from US, EU & Japan, reps from pharma from same 3 areas and 3 observers (WHO, EU Free Trade Committee & Health Canada)

• Risk that guidelines may be relaxed to facilitate Clinical Research

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Arguments against the FDA Decision (4)

• Guidelines not legally binding in all countries• ‘Slippery Slope Argument’• Adoption and reliance upon ICH GCP depends

on pharma companies regulating themselves• Demanding concept given huge financial

pressures and incentives• Remember Germany was leader in introducing

national policy on medical research – afforded little protection to those who suffered in WW2

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Ethical Hypocrisy

• Major argument against FDA decision• Globalisation of Clinical Research due to

prohibitive cost of studies within the western world & access to standard treatments

• Unacceptable to allow differing standards as suggested by drug companies when they refer to best standard of care in that area

• Ethical tenets should be consistent and universal• If study unethical in US then it would also be

unethical in Brazil

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Is the Declaration of Helsinki still relevant for the ethical conduct of Clinical Trials?

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YES

• Remains morally binding for physicians over and above national/local laws and/or regulations

• Less influenced by interested parties than ICH GCP guidelines

• Provides basis for conduct of CTs and has a focus on protection of subjects/participants

“In medical research involving human subjects, the well being of the individual research subject must take precedence over all other interests” (Paragraph 6)

• Upholds Kantian respect for persons and view that individuals should not be treated simply as a means to an end

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References

• WMA - Declaration of Helsinki – 2000 version (including notes of clarification 2002 & 2004)

• WMA - Declaration of Helsinki – 2008 version• Human, D. & Fluss, S. (July 2001) “The World

Medical Association’s Declaration of Helsinki: Historical and Contemporary Perspectives”

• The Social Medicine Portal (1st June 2008) “FDA Abandons Declaration of Helsinki for international clinical trials” http://www.socialmedicine.org/2008/06/01/ethics (accessed 20 Feb 2009)