20221209 DoH Expert Meeting-Wiesing

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The Declaration of Helsinki
in the bio-ethical literature
Urban Wiesing
Tel Aviv, Dec. 9, 2022
Institut für Ethik
und Geschichte der
Medizin
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The DoH in the literature
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und Geschichte der
Medizin
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The DoH in the literature
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und Geschichte der
Medizin
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The DoH in the literature
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und Geschichte der
Medizin
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The DoH in the literature
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und Geschichte der
Medizin
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The DoH in the literature
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und Geschichte der
Medizin
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The DoH in the literature
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und Geschichte der
Medizin
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The DoH in the literature
• Enormous number of references to the DoH
• The DoH itself: currently not a “hot spot” in the
bioethical literature!
• Other ethical issues are more discussed, e.g.,
~ 700 publications on conscientious objection
˃ 1000 on genome editing and ethics
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General critique (before and after 2013)
•Frequency of revisions:
– “living document” (Ndebele 2013)
or
– concentrated on a few “eternal”
principles – “tentative immortality”?
(Emanuel 2013)
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und Geschichte der
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General critique (before and after 2013)
• “Genuine ethical obligations do not change
every few years.”
(Emanuel 2013, p 1247)
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und Geschichte der
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“Does your organization adhere to a
specific version of the DoH?”
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und Geschichte der
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Skierka/Michels 2018, p 6
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General critique (before and after 2013)
•Outreach and mandate
• 2013, § 2: “Consistent with the mandate of the WMA,
the Declaration is addressed primarily to physicians.
The WMA encourages others who are involved in
medical research involving human subjects to adopt
these principles.”
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und Geschichte der
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General critique (before and after 2013)
•Outreach and mandate
Internal contradiction: The DoH addresses
– § 9: “physician or other health care professionals”
– § 23: “research ethics committees” (not all members
are physicians)
– § 34: “sponsors, researchers and host country
governments”
– § 36: “Researchers, authors, sponsors, editors and
publishers”
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General critique (before and after 2013)
•Outreach and mandate
• “[…] a statement of ethical principles does not
require a mandate from the people who ought
to follow those principles.”
(Millum et al. 2018, p 2143, also Emanuel 2013)
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General critique (before and after 2013)
•Terminology:
•“[…] the terms “human subjects”,
“patients”, “research subjects” and
“research participants” are used
interchangeably.”
(Muthuswamy 2014, p 4)
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Fundamental critique (before and after
2013)
•Legitimation?
• “merely […] ex cathedra declarations”
(Schüklenk 2015, p ii)
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und Geschichte der
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Fundamental critique (before and after
2013)
•The revision process:
• “[…] it should be that the normative
prescriptions are developed within a
collaborative dialogue between professionals
and patients, their families and advocates.”
(Woods/McCormack 2012, p 250)
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und Geschichte der
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Fundamental critique (before and after
2013)
•The revision process:
“[…] the present make-up of the committees
engaging in the process of reforming ethics
guidelines cannot be taken reliably to track the
interests of all those groups affected by the
guidelines”
(Smith/Weinstock 2017, p 318)
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und Geschichte der
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Fundamental critique (before and after
2013)
• Dissemination and worldwide adoption?
• DoH – a “minority report”? (Reider 2015, p 792)
• Prominent example: FDA/NIH
since 2008: ICH-guidelines, which refer to
the principles of the DoH.
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Positive commentaries to the DoH 2013
• Many commentators: positive
• “the most accepted and adopted ethical guideline”
(Skierka/Michels 2018, p 11)
• 2018 version “better organized, clearer and more
precise, received 12 subheadings”
(Hellmann et al. 2014)
• “a significant improvement over previous versions“
(Millum et al. 2013, p 2143)
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Important changes in the 2013 version
• Structure
• Vulnerable Groups
• Post-Study-Arrangements
• Research Ethics Committee
• Compensation
• Biobanks
• Placebo
• Registration
• publication and dissemination of results
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und Geschichte der
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Important changes in the 2013 version
• Structure
• Vulnerable Groups
• Post-Study-Arrangements
• Research Ethics Committee
• Compensation
• Biobanks
• Placebo
• Registration
• publication and dissemination of results
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und Geschichte der
Medizin
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§ 19, Vulnerable Groups
• Definition?
2013, § 19: “Some groups and individuals are
particularly vulnerable and may have an
increased likelihood of being wronged or of
incurring additional harm.
All vulnerable groups and individuals should
receive specifically considered protection.”
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§ 19, Vulnerable Groups
• General description or list of vulnerable groups?
(Millum et al. 2013)
• “separation between: disadvantaged populations;
vulnerability due to diminished decisional capacity or
undue influence by the recruiting researchers; and
vulnerability to risks of increased harms by nature of the
population under study.” (Moris 2013, p 1890)
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und Geschichte der
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§ 19, Vulnerable Groups
• The “[…] shift to an approach to vulnerable groups
based on wrongs or harms rather than labeling is to be
welcomed. One advantage of this approach is that it
allows tailored protections for different forms of
vulnerability, rather than blanket protections”
(Hurst 2014, p 1252)
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Vulnerable Groups, draft submitted to GA
• § 20: Medical research with a vulnerable group is only
justified if the research is responsive to the health
needs or priorities of this group and the research
cannot be carried out in a non-vulnerable group. In
addition, this group should stand to benefit from the
knowledge, practices or interventions that result from
the research. Consideration should be given to
ensuring that the community receives a fair level of
additional benefits.
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und Geschichte der
Medizin
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Vulnerable Groups, draft submitted to GA
• § 20: Medical research with a vulnerable group is only
justified if the research is responsive to the health
needs or priorities of this group and the research
cannot be carried out in a non-vulnerable group. In
addition, this group should stand to benefit from the
knowledge, practices or interventions that result from
the research. Consideration should be given to
ensuring that the community receives a fair level of
additional benefits.
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und Geschichte der
Medizin
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Vulnerable Groups, draft submitted to GA
• § 20: Medical research with a vulnerable group is only
justified if the research is responsive to the health
needs or priorities of this group and the research
cannot be carried out in a non-vulnerable group. In
addition, this group should stand to benefit from the
knowledge, practices or interventions that result from
the research. Consideration should be given to
ensuring that the community receives a fair level of
additional benefits.
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und Geschichte der
Medizin
Reasonable availability approach!
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Vulnerable Groups, draft submitted to GA
• § 20: Medical research with a vulnerable group is only
justified if the research is responsive to the health
needs or priorities of this group and the research
cannot be carried out in a non-vulnerable group. In
addition, this group should stand to benefit from the
knowledge, practices or interventions that result from
the research. Consideration should be given to
ensuring that the community receives a fair level of
additional benefits.
Institut für Ethik
und Geschichte der
Medizin
Fair benefit approach
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Vulnerable Groups, version accepted by GA
• § 20: Medical research with a vulnerable group is only
justified if the research is responsive to the health
needs or priorities of this group and the research
cannot be carried out in a non-vulnerable group. In
addition, this group should stand to benefit from the
knowledge, practices or interventions that result from
the research. Consideration should be given to
ensuring that the community receives a fair level of
additional benefits.
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und Geschichte der
Medizin
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§ 19, Vulnerable Groups
• The fair benefit approach was skipped by the
GA because of the fear of exploitation,
expressed by resource poor countries.
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und Geschichte der
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§ 19, Vulnerable Groups
• Critique: Without fair benefit approach no benefit is
possible for vulnerable people in phase 1 or 2 trials.
• “participants from poor countries with limited access to
medical services are unlikely to benefit”
(Millum et al. 2013, p 2144)
• The reasonable availability approach alone is
insufficient for vulnerable people!
• Contra: Fair benefit is not explicitly forbidden (Hurst 2014)
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§ 32: “biobanks or similar repositories”
• § 32: For medical research using identifiable human
material or data, such as research on material or data
contained in biobanks or similar repositories,
physicians must seek informed consent for its
collection, storage and/or reuse. […]
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§ 32: “biobanks or similar repositories”
• § 32: For medical research using identifiable human
material or data, such as research on material or data
contained in biobanks or similar repositories,
physicians must seek informed consent for its
collection, storage and/or reuse. […]
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§ 32: “biobanks or similar repositories”
• “More clarity is needed on issues related to biobanking.”
(Muthuswamy 2014, p 4)
• “more precise description of which samples and data
count as identifiable”
(Colledge/Elger 2013, p 150)
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§ 32: “biobanks or similar repositories”
• No explicit broad consent in the DoH!
• Detailed broad consent in the Declaration of
Taipei 2016!
• Relationship to the Declaration of Taipei?
• How detailed in the DoH when detailed in the
DoT?
• Reference to the DoT in the DoH?
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§ 33, placebo control
• The “never-ending” controversy!
• Historical background: HIV-transmission studies
in the 1990s in Africa, testing against placebo
• Proven intervention was available but too
complex to be used in resource poor settings.
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§ 33, placebo control
• Controversial ethical debate about different
standards
• “placebo orthodox” vs. “active control orthodox”
• In particular MLIC, South America: “active
control orthodox”
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und Geschichte der
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§ 33, placebo control
• DoH: Controversial since 2000
• DoH 2000, § 29: “The benefits, risks, burdens and
effectiveness of a new method should be tested against
those of the best current prophylactic, diagnostic, and
therapeutic methods. This does not exclude the use of
placebo, or no treatment, in studies where no proven
prophylactic, diagnostic or therapeutic method exists”.
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und Geschichte der
Medizin
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§ 33, placebo control
• DoH: Controversial since 2000:
• DoH 2000, § 29: “The benefits, risks, burdens and
effectiveness of a new method should be tested against
those of the best current prophylactic, diagnostic, and
therapeutic methods. This does not exclude the use of
placebo, or no treatment, in studies where no proven
prophylactic, diagnostic or therapeutic method exists”.
• (Similar since DoH 1975)
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und Geschichte der
Medizin
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§ 33, placebo control
• 2002 Note of Clarification added:
• “However, a placebo-controlled trial may be ethically acceptable,
even if proven therapy is available, under the following
circumstances:
• 1. Where for compelling and scientifically sound methodological
reasons it is necessary to determine the efficacy or safety of a
prophylactic, diagnostic or therapeutic method; or
• 2. Where a prophylactic, diagnostic or therapeutic method is being
investigated for a minor condition and the patients who receive
placebo will not be subject to any additional risk of serious or
irreversible harm.”
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und Geschichte der
Medizin
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§ 33, placebo control
• 2002 Note of Clarification:
• “However, a placebo-controlled trial may be ethically acceptable,
even if proven therapy is available, under the following
circumstances:
• 1. Where for compelling and scientifically sound methodological
reasons it is necessary to determine the efficacy or safety of a
prophylactic, diagnostic or therapeutic method; or
• 2. Where a prophylactic, diagnostic or therapeutic method is being
investigated for a minor condition and the patients who receive
placebo will not be subject to any additional risk of serious or
irreversible harm.”
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und Geschichte der
Medizin
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§ 33, placebo control
• 2002 Note of Clarification:
• “However, a placebo-controlled trial may be ethically acceptable,
even if proven therapy is available, under the following
circumstances:
• 1. Where for compelling and scientifically sound methodological
reasons it is necessary to determine the efficacy or safety of a
prophylactic, diagnostic or therapeutic method; or
• 2. Where a prophylactic, diagnostic or therapeutic method is being
investigated for a minor condition and the patients who receive
placebo will not be subject to any additional risk of serious or
irreversible harm.”
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und Geschichte der
Medizin
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§ 33, placebo control
• 2008, §33:
“[…] – 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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§ 33, placebo control
• 2 WMA-conferences on placebo control in Sao
Paulo in 2010, 2011, GA in Fortaleza 2013
• 2013 version:
• No change in ethics, but more systematic
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Placebo DoH 2013
• § 33: “[…] where for compelling and scientifically sound
methodological reasons the use of any intervention less
effective than the best proven one, the use of placebo,
or no intervention is necessary to determine the
efficacy or safety of an intervention
• and the patients who receive any intervention less
effective than the best proven one, placebo, or no
intervention will not be subject to additional risks of
serious or irreversible harm as a result of not receiving
the best proven intervention. […]”
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§ 33, first condition for placebo control
• “compelling and scientifically sound
methodological reasons […] to determine the
efficacy and safety of an intervention”
= vague, not precise
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§ 33, first condition for placebo control
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Skierka/Michels 2018, p 8
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§ 33, second condition for placebo control
• “no risk of serious and irreversible harm”
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§ 33, second condition for placebo control
• “no risk of serious and irreversible harm”
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Medizin
Skierka/Michels 2018, p 9
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§ 33, second condition for placebo control
• “no risk of serious and irreversible harm”
= absolute limit
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§ 33, second condition for placebo control
• § 28: “research subject who is incapable of
giving informed consent […] only minimal risk
and minimal burden”
= another absolute limit
(and criticised by Westra/de Beaufort 2013)
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§ 33, second condition for placebo control
• § 16: “if the importance of the objective
outweighs the risks and burdens to the research
subjects”
• = no absolute limit, but balancing!
• Internal contradictions regarding risk/benefit
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§ 33, double standard?
• “The term “best proven intervention” remains
ambiguous. Where is it applicable – locally or
globally?” (Muthuswamy 2014, p 1)
• But: Any wording in favour of the double
standard like “available best proven
intervention”, “locally available best proven
intervention” was not implemented!
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§ 33, double standard?
• “[…] the phrase ‘less effective than the best proven’
[allows] double standard in medical research in low-
resource countries.”
(Hellmann et al. 2014, also Hellmann et al. 2016)
• But: ‘less effective than the best proven’ does not allow
double standard!
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§ 33, double standard?
• Exceptions from best proven comparator only
allowed for scientific reasons,
• everywhere, not only in low-resource countries
• The DoH and WMA never supported a double
standard!
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§ 33, placebo control
• “placebo orthodox” for double standard:
• “The danger is that it may preclude vital research that
promises to improve the condition of the worst-off. […] A
future and better Declaration should allow such trials
under strict conditions, especially when no one is
deprived of treatment they would otherwise receive and
the research has the potential to save many lives and
improve the care of poor populations.”
(Millum et al. 2013, p 2144, also Millum/Grady 2013)
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§ 33, Paradox:
• The DoH never supported a double standard!
• The DoH is accused of supporting double
standard! (“active control orthodox”)
• The DoH is accused of not supporting double
standard! (“placebo orthodox”)
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§ 33, placebo control
• A symbolically charged political dispute
• The factual arguments have only limited
persuasive power!
• The current version: the best middle ground?
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§ 34, post trial provisions
• “In advance of a clinical trial, sponsors, researchers and
host country governments should make provisions for
post-trial access for all participants who still need an
intervention identified as beneficial in the trial.”
• Who is responsible?
(also for § 15, compensation; Hellmann et al. 2016)
• “how far it is practicable”?
(Shah 2014, p 63)
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§ 34, post trial provisions
• “should”: weakens the 2008 version: “are entitled to”
(Shah 2014, p 63)
• “This definition has diluted the provision in the 2008
version, according to which post-trial provisions signified
“access to interventions identified as beneficial in the
study or to other appropriate care or benefits.””
(Muthuswamy 2014, p 4)
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§ 34, post trial provisions
• “I criticize the disappearance of ‘access to other
appropriate care’ […] and the narrow scope given to
obligations of access to information after research.”
(Mastroleo 2016, p 80)
• “is drafted rather strangely”
(Malik/Foster 2016, p. 188, also Hellmann et al. 2016)
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§ 37, Unproven Interventions in Clinical Practice
• “perhaps the most philosophically intriguing [paragraph],
because it evokes the sometimes hazy distinction
between medical care and research”
(Reider 2015, p 792)
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§ 37, Unproven Interventions in Clinical Practice
• 2013, § 37: “In the treatment of an individual patient, where
proven interventions do not exist or other known interventions have
been ineffective, the physician, after seeking expert advice, with
informed consent from the patient or a legally authorised
representative, may use an unproven intervention if in the
physician’s judgement it offers hope of saving life, re-establishing
health or alleviating suffering. This intervention should
subsequently be made the object of research, designed to evaluate
its safety and efficacy. In all cases, new information must be
recorded and, where appropriate, made publicly available.”
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§ 37, Unproven Interventions in Clinical Practice
• 2013, § 37: “In the treatment of an individual patient, where
proven interventions do not exist or other known interventions have
been ineffective, the physician, after seeking expert advice, with
informed consent from the patient or a legally authorised
representative, may use an unproven intervention if in the
physician’s judgement it offers hope of saving life, re-establishing
health or alleviating suffering. This intervention should
subsequently be made the object of research, designed to evaluate
its safety and efficacy. In all cases, new information must be
recorded and, where appropriate, made publicly available.”
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§ 37, Unproven Interventions in Clinical Practice
• “The need to revise the Helsinki Declaration”
(Asplund/Hermeren 2017, p 1190)
• Not strict enough! Cases of abuse!
• “opens a Pandora’s box” (Shah 2014, p 64)
• “[…] only safeguards listed in the DH – expert advice
and informed consent – do not seem to provide
sufficient protection for patients”
(Borysowski et al. 2018, p 505).
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§ 37, Unproven Interventions in Clinical Practice
•Better: Guidelines for stem-cell research and clinical
translation by the International Society for Stem Cell
Research (ISSCR)
–
written plan: procedure, scientific rationale and justification,
reasonable chance of success, preclinical evidence efficacy and safety
– approved through a peer-review process
– voluntary informed consent
– action plan for adverse events
– reporting of outcomes (including negative outcomes and adverse
effects), enabling critical review of the intervention by the scientific
community
– (Asplund/Hermeren 2017, p 1190)
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DoH: Ethical problems not addressed
• “Furthermore, ethical issues in human
enhancement research are still being
uncovered.”
(Hellmann et al. 2014)
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•How should the DoH react
to new technologies?
• Digitalization, data, AI, Genome-editing,
biobanks, personalized medicine
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Literature review
• Shall the DoH be revised because of
• digitalization? no results!
• AI? no results!
• genome editing? no results!
• CRISPR/cas? no results!
• personalised medicine? no results!
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Literature review
“Declaration Helsinki” and “data”
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The 17 articles are confirming that the research with data has to be
performed according to the DoH.
No revision of the DoH regarding research with data is required!
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General consideration: New principles or
further explanation?
• “The current effort, as has been the case with
previous revisions, is aimed not at changing
core ethical principles but at determining
whether additional guidance is needed.”
(Cecil B. Wilson 2013, former President of the WMA)
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Summary: DoH in the literature
• Many comments to the 2013 version: positive!
• General criticism:
– frequency of revision
– mandate/outreach
– internal contradictions
– terminology
– revision process
– legitimation
– dissemination/adoption
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Summary: DoH in the literature
• Main criticism to the 2013 version:
– vulnerable groups
– post-trial provision
– biobanks
– placebo
– unproven intervention
• Shall the DoH react to new technologies? So far
not addressed in the literature!
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Summary
The best answer to criticism?
Quality!
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The Declaration of Helsinki
in the bio-ethical literature
Urban Wiesing
Tel Aviv, Dec. 9, 2022
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und Geschichte der
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