1 / 23

CIOMS AND HELSINKI ON PLACEBO CONTROLS

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. HELSINKI REQUIRES REVISION.

suzette
Download Presentation

CIOMS AND HELSINKI ON PLACEBO CONTROLS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 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

  2. HELSINKI REQUIRES REVISION • Illogical [therapeutic vs. nontherapeutic research]: not today’s topic • Out of touch with contemporary ethical thinking [placebo controls] • Widely disregarded • Loss of authority

  3. HELSINKI ARTICLE II.3 • “…every patient – including those of a control group, if any – should be assured of the best proven…therapeutic method. This does not exclude…placebo where no proven method exists.”

  4. ARTICLE II.3 FORBIDS1 • Development of all new therapies for conditions for which there are ‘proven’ therapies • Peptic ulcer: belladonna alkaloids preclude trial of H2receptor antagonists • Hypertension: ganglionic blocking agents preclude further developments

  5. ARTICLE II.3 FORBIDS2 • 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

  6. ARTICLE II.3 FORBIDS3 • 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

  7. HELSINKI REVISION 2000 • 29.The…new method should be tested against…the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven…therapeutic method exists.

  8. 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.

  9. 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

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

  11. 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).

  12. 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.

  13. 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.

  14. 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.

  15. 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 physician’s fiduciary obligation to the patient/subject. [Undivided loyalty]

  16. 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.

  17. 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 EthicalGuidelines: 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.

  18. 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.

  19. FIDUCIARY and NONBENEFICIAL PROCEDURES • Pathogenesis • Pathophysiology • Epidemiology • All forbidden by Helsinki Article 28

  20. 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’.

  21. 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.

  22. PLACEBO CONTROLS • AZT for AIDS • Gancyclovir in CMV retinitis • ARA A in herpes encephalitis • BCPT Tamoxifen

  23. PLACEBO CONTROLS II • UCLA Schizophrenia Study • AZT in perinatal transmission of HIV (protocol 076) • AZT in perinatal transmission of HIV in technologically developing countries

More Related