The Declaration of Helsinki

The Declaration of Helsinki

www.myclinicalresearchbook.blogspot.com

Plan of Presentation

• Introduction: History, Scope & Development
• Ethical Problems
• Arguments in support of FDA decision to
abandon DoH
• Arguments against FDA decision
• Conclusion


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


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


Scope of DoH
• Developed 10 prinicples 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’


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 General Assembly


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


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 of trial treatment to best available
treatment
• Access to treatment following trial completion
• Mandatory for protocols to state they adhered to th
DoH


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


4th 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
randomized to placebo controlled arms


4th 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


Consequence of 4th 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


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


6th Revision 2008
• Followed general review
• Comparatively minor revisions
• Extensive debate & consultation re: 5th & 6th
revisons led to concerns
• ? Ethical strength of DoH weakened


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.”


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”


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


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


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”


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


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


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)


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


Decision (4)
• DoH is now outdated by newer guidelines
• Developed from DoH
• More Comprehensive Guidelines
• Should not assume pharma companies are
morally corrupt


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


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


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

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)


Thank
you


The Declaration of Helsinki

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