DoH

1. The Declaration of Helsinki
Sreenu Thalla
Assistant Professor

2. What is Declaration of Helsinki?
• Set of ethical principles
• Developed by WMA for medical community for human
experimentation
• Followed Nuremberg Code (1947)
• Regarded as cornerstone document of human research ethics
• Included within clinical trial protocols

3. History of DoH
• 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

4. Scope of DoH
Developed 10 principles Nuremberg Code
• Linked to Declaration of Geneva (1948)
• Statement of physicians ethical duties
• DoH specifically addressed clinical research
• Relaxed need for ICwhich Nuremberg code deemed
‘absolutely essential’

5. Development of DoH
18th WMA General Assembly
Helsinki, Finland, June 1964
1. 29th WMA – Tokya, Japan,Oct-1975
2. 35th WMA – Venice, Italy,Oct-1983
3. 41st WMA – Hong Kong,Sep-1989
4. 48th WMA – Somerset West, RSA,Oct-1996
5. 52nd WMA – Edinburgh, Scotland,Oct-2000
6. 59th WMA – Seoul,Oct-2008
• Clarifications of Articles 29 & 30 in 2002 & 2004, 53rd & 55th WMA
GeneralAssembly

6. Basic Principles
• Confirm to the moral and scientific principles
• Based on laboratory and animal experiments
• Conducted onlyby scientifically qualified persons
• Objective Vs. Inherent risk
• Special caution should be exercised by the doctor

7. First Revision 1975
• 11 years after first adoption of DoH
• Introduced idea of oversight by Independent Committee
• Led to developments of IRBs/IECs
• Issues relating to IC developed – more prescriptive
• Duty to individual given greater weight over duty to society
• Ideas of publication ethics introduced
• Comparison oftrial treatment to best available treatment
• Access to treatment following trial completion
• Mandatory for protocols to state they adhered to the DoH

8. 2nd & 3rd Revisions 1983 & 1989
• Fairly minor revisions
• Consent of minors
• Further development – Independent committees
• CIOMS (Council for International Organizations of Medical
Sciences) & WHO published International Ethical Guidelines
for Biomedical Research Involving Human Subjects
Developed in 1982

9. 4th Revision1996
• 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 randomized to placebo
controlled arms

10. • 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

11. Consequence of 4th Revision
• FDA ignored this revision – continued to refer to 1989 version
• EU cited fourth revision in clinical directive of 2001
• Adopted into UK National law in 2004

12. 5th Revision2000
• 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 trial participants
• Led to clarification points of 2002 & 2004

13. 6th Revision2008
• Followed general review
• Comparatively minor revisions
• Extensive debate & consultation re: 5th & 6th revisions led to
concerns
• Ethical strength of DoH weakened

14. 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.”

15. • 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”

16. 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

17. 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

18. Arguments in against of 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”

19. Arguments in support of FDA Decision (2)
• Hasn’t prevented ‘unethical’ practices continuing
• Tuskegee study ended 1972
• US Radiation experiments ended 1974
• CNEP studies in premature babies at North Staffs Hospital in1990s
• Alder Hay late 1980s & early 1990s

20. Arguments in against of FDA Decision (2)
• Continuing unethical practices
– True but abandoning DoH and adopting other guidelines unlikely
to cause such aberrations to miraculously stop
• Development of other Guidelines
– Fundamental concerns with ICH GCP

21. Arguments in support of FDA Decision (3)
• Other guidelines/regulations have since been developed
• WHO
• CIOMS
• ICH GCP (International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for
Human Use Good Clinical Practice)

22. Arguments in against of 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

23. Arguments in support of FDA Decision (4)
• DoH is now outdated by newer guidelines
• Developed from DoH
• More Comprehensive Guidelines
• Should not assume pharmacompanies are morally corrupt

24. Arguments in against of 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

25. 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

26. Is the DoH still relevant for the ethical conduct of
Clinical Trials?
• 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