CIOMS AND HELSINKI ON PLACEBO CONTROLS

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CIOMS AND HELSINKI ON PLACEBO CONTROLS

• Robert J. Levine
• Professor of Medicine, Lecturer in Pharmacology,
• Co- Chair Interdisciplinary Bioethics
  Program
• Yale University
• Santiago, October 17, 2003

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HELSINKI REQUIRES REVISION

• Illogical therapeutic vs. nontherapeutic
  research not todays topic
• Out of touch with contemporary ethical thinking
  placebo controls
• Widely disregarded
• Loss of authority

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HELSINKI ARTICLE II.3

• every patient including those of a control
  group, if any should be assured of the best
  proventherapeutic method. This does not
  excludeplacebo where no proven method exists.

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ARTICLE II.3 FORBIDS 1

• Development of all new therapies for conditions
  for which there are proven therapies
• Peptic ulcer belladonna alkaloids preclude trial
  of H2 receptor antagonists
• Hypertension ganglionic blocking agents preclude
  further developments

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ARTICLE II.3 FORBIDS 2

• Placebo controls in clinical trials in which
  there is virtually no risk from the withholding
  of the best proven therapy
• Analgesics, hypnotics, benzodiazepines
• Antihypertensives, oral hypoglycemics

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ARTICLE II.3 FORBIDS 3

• Research designed to develop for use in resource
  poor countries relatively inexpensive
  alternatives to expensive therapies used in
  industrialized countries
• Recent example of short duration AZT

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HELSINKI REVISION 2000

• 29.Thenew method should be tested againstthe
  best current prophylactic, diagnostic, and
  therapeutic methods. This does not exclude the
  use of placebo, or no treatment, in studies where
  no proventherapeutic method exists.

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WMA November 2001
"The WMA hereby affirms its position that a
placebo controlled trial should generally only
be used in the absence of existing proven
therapy. However, a placebo-controlled trial may
be ethically acceptable, even if proven therapy
is available Where for compelling and
scientifically sound methodological reasons its
use is necessary to determine the efficacy or
safety of a therapeutic method, or - 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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HELSINKI STILL REQUIRES REVISION

• Illogical therapeutic vs. nontherapeutic
  research
• Out of touch with contemporary ethical thinking
  placebo controls
• WMA clarifications 2000-2001 failed to secure
  consensus.
• Some think it went too far.
• Some deplore loss of substantive standard.
• Some think it incomprehensible
• Widely disregarded
• Loss of authority

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NBAC INTERNATIONAL REPORT

• Limited to RCTs
• Established effective treatment
• Escape clause provided for ethical justification
  of withholding EET
• No therapeutic research

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GUIDELINE 11

• General requirement to provide each subject with
  established effective intervention EET.
• Replaced standards
• Best proven therapeutic (preventive or
  diagnostic) method. Helsinki
• Best current intervention. (CIOMS drafts).

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PLACEBO MAY BE USED1

• 1. No proven intervention exists.
• 2. Withholding EEI results in only temporary
  discomfort and no serious harm.
• 3. EEI as comparator would not yield
  scientifically reliable results.

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PLACEBO MAY BE USED2

• 4. Studies designed to develop an effective
  alternative to an EEI that is not locally
  available.
• Usually for economic or logistic reasons.
• Ethical justification
• Responsive to health needs.
• EEI as comparator would not yield scientifically
  reliable results.
• Reasonably available sustainable.

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DISSENT ON 3 GROUNDS

• Placebo control could expose subjects to
  preventable harm.
• Not all scientific experts agree on whether and
  when use of EEI as a comparator would not yield
  reliable results.
• Economic reasons for unavailability of EEI cannot
  justify placebo-controlled trial in a country
  with limited resources when it would be unethical
  to conduct the same study where population has
  general access to the EEI outside the study.

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CLINICAL EQUIPOISE

• Initial statement of no difference in
  anticipated outcomes. A B
• Considers both risks and benefits.
• Old criterion for justification considered only
  primary outcome measures.
• Designed to enforce the physicians fiduciary
  obligation to the patient/subject. Undivided
  loyalty

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CLINICAL EQUIPOISE

• Rigid application when stakes are high
  meaningful possibility of death or disability.
• Placebo controls are permissible when withholding
  of known effective therapy is not associated with
  a meaningful risk of serious adverse consequence.
• De minimis non curat lex the law does not
  concern itself about trifles or insignificant
  matters.

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The meaning of a green slide

• This is my own opinion.
• When I write guidelines I am responsible for them
  to the extent that to the best of my ability they
  represent the position taken by the group that
  participated in their writing to the point I
  turned them over to another to continue the
  writing.
• UNAIDS Guidance Document Semifinal draft.
• WMA Declaration of Helsinki Report of Working
  Group to propose a revision to the 1996 edition.
• CIOMS International Ethical Guidelines Final
  version of 1993 and 2002 publication.
• In the case of the CIOMS 1993, I presented my
  critique in 1992 at a conference published in
  1996 in a book edited by H. Vanderpool The
  Ethics of Research Involving Human Subjects
  Facing the 21st Century.

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CLINICAL EQUIPOISE

• Rigid application when stakes are high
  meaningful possibility of death or disability.
• Placebo controls are permissible when withholding
  of known effective therapy is not associated with
  a meaningful risk of serious adverse consequence.
• De minimis non curat lex the law does not
  concern itself about trifles or insignificant
  matters.

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FIDUCIARY and NONBENEFICIAL PROCEDURES

• Pathogenesis
• Pathophysiology
• Epidemiology
• All forbidden by Helsinki Article 28

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DOUBLE STANDARD?

• No!
• The single standard is that the results of the
  research should be responsive to the health needs
  and priorities of the community of the subjects
  and the products developed must be made
  reasonably available.

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PLACEBO CONTROLS JUSTIFICATION

• If there is a known effective therapy for the
  specific indication, placebo controls may be
  justified if not associated with increased risk
  of death or disability
• Symptomatic relief
• Fail-safe escape eg, antihypertensive
• Standard tried and failed
• Standard rejected eg blood product
• Standard in low resource country should satisfy
  Guideline 11 as determined by authorities in both
  sponsoring and host countries.

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PLACEBO CONTROLS

• AZT for AIDS
• Gancyclovir in CMV retinitis
• ARA A in herpes encephalitis
• BCPT Tamoxifen

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PLACEBO CONTROLS II

• UCLA Schizophrenia Study
• AZT in perinatal transmission of HIV
  (protocol 076)
• AZT in perinatal transmission of HIV in
  technologically developing countries