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More Information on Ethics and Clinical Trials

Letter on CIOMS's Draft Ethical Guidelines

July 13, 2001

Dr. Jack Bryant, President
Council for International Organizations of Medical Sciences
c/o World Health Organization
CH-1211 Geneva 27
Switzerland

Dear Dr. Bryant: 

The current draft revision of the Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines for Biomedical Research Involving Human Subjects should be called what it is: a bald-faced and dangerous attempt to reverse the gains in the protection of research participants accomplished in the October 2000 version of the World Medical Association’s (WMA’s) Declaration of Helsinki (DOH).[1]  The pharmaceutical industry and its allies in the U.S. government and academia failed in their efforts to insert the “standard of care argument” (researchers are obligated to provide to research participants no more treatment than what is otherwise available locally) into the DOH.  They are now apparently hoping that through the CIOMS process they can accomplish this.  The current draft is also an assault on the more general restrictions on placebo use in clinical trials that were also part of the revised DOH.  

Historically, the CIOMS document has often been seen as an elaboration on the Declaration of Helsinki.  Yet the current draft goes out of its way to contradict the DOH, particularly on the standard of care issue; other important elements of the DOH are simply ignored.  The apparent intent is to create a “war of the documents,” so that researchers will be able to pick a study design acceptable to them and then have an array of different ethical codes from which to justify their behavior (document shopping?).  To an extent, this has already been accomplished through the International Conference on Harmonisation (ICH); its monograph on Choice of Control Group in Clinical Trials[2] is also intended to bolster the inappropriate use of placebos and is actively hostile toward active-controlled trials).  Our critique of a draft of that document is attached.[3]  

Guideline 2: The research protocol (New Guideline)  

This new section is mainly acceptable, except that it is insufficiently prescriptive on conflict of interest.  The DOH requires that “The researcher should also submit to the [ethical review] committee, for review, information regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and incentives for subjects.” (Article 13)  With researchers (and even universities) now commonly owning stock in the companies for which they are conducting research or sitting on their advisory boards,[4],[5] such disclosure is critical.  Yet CIOMS requires less than both the DOH and what is necessary; the protocol need only include “The organization that is sponsoring the research and a detailed account of the sponsor's financial commitments to the research institution, the researchers, the research subjects, and, when appropriate, the community.”  Thus, relationships between the researcher and the sponsor that are outside the particular study in question would not need to be disclosed in the protocol.  

In our view, in certain circumstances disclosure would not be enough.  Some conflicts are so crass that they should simply be precluded, not “managed,” in the currently popular vernacular.  There is growing evidence of the relationship between funding source and reported research outcome.[6],[7]  Except for investments of minimal value, therefore, researchers should not be allowed to conduct research for companies in which they have investments.[8] 

Finally, although the DOH has an affirmative requirement for reporting adverse events to the Institutional Review Board (IRB) (Article 13), we see no mandate for this in the current draft of the CIOMS document. 

Guideline 3: Ethical review committees (Old Guideline 14) 

The discussion of this Guideline goes well beyond legitimate ethical topics to include a plea for a “hands-off” approach to regulation: “Sanctions imposed by institutional, governmental, professional or other authorities possessing disciplinary power should be employed as a last resort. Preferred methods of control include cultivation of an atmosphere of mutual trust, and education and support to promote in researchers and in sponsors the capacity for ethical conduct of research.”  Such a regulatory policy may be desirable for the research industry (including the IRB industry), but it is poor public policy and inappropriate in an ethics document.  Surely, each country should be free to set its own regulatory policies?  Is CIOMS not recommending a form of Regulatory Imperialism? 

The DOH clearly requires that “Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.” (Article 27)  The draft CIOMS document, on the other hand, seems intent on watering this down: “Editors should consider refusal to publish the results of research conducted unethically, and drug regulatory authorities should consider refusal to accept unethically obtained data submitted in support of an application for marketing authorization of a product. Such sanctions, however, deprive of benefit not only the errant researcher or sponsor but also that segment of society intended to benefit from the research; such possible consequences merit careful consideration.” 

Finally, the ability of IRBs to act independently would be enhanced if they were required to include scientific representatives from other relatively nearby institutions. 

Guideline 6: Research in populations and communities with limited resources (Old Guideline 8) 

The most important aspect of this draft Guideline is not what is present, but rather what was excised from the current CIOMS document: “persons in underdeveloped communities will not ordinarily be involved in research that could be carried out reasonably well in developed communities.”  Of course, research can only be carried out in countries where the disease is reasonably prevalent.  Developing country research is also readily justified if there is a clear, scientifically based reason to believe that local social conditions, viral strains or human genetics differ enough from those in developed countries to likely change the study results significantly.  But, as a practical matter, the clear result of this change in language (and, we fear, its intent) is to open the developing world up to studies that could easily be conducted in the industrialized world: studies of hypertension, diabetes or some common infectious conditions.  Particularly because practically all the important recommendations in the current draft come handily equipped with exceptions, a likely result is a major increase in studies that could easily be done in an industrialized country, but where the participants are denied optimal medical care and the products are not made available afterward.  The benefits to the pharmaceutical industry are obvious: potentially lower costs, less red tape, larger pools of “naïve” subjects and lower ethical requirements.  Thanks to the exceptions in the draft document, there is simply no guarantee of benefit to either the developing country volunteers or their countrymen and women. 

The DOH makes clear that the poor are vulnerable and thus must be protected from exploitation: “Some research populations are vulnerable and need special protection. The particular needs of the economically and medically disadvantaged must be recognized.” (Article 8)  Although there are obviously different aspects to their vulnerability, it is interesting that the draft CIOMS document has retained the requirement for seeking alternative research populations to children and those who cannot give informed consent due to a mental disorder (Guidelines 14 and 15), but has excised this requirement for residents of developing countries. 

It is encouraging that the notion that effective interventions must be made “reasonably available” after the trial is retained in the current draft.  In fact, it is now supported, for the first time, by a discussion of prior agreements, which is a step forward.  

Guideline 7: Placebo-controlled studies (New Guideline)

The central thrust of the new draft CIOMS document is to dilute the revised DOH’s recommendations on placebo use.  Ever since the DOH required that “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods,” (Article 29) the research industry and their flag-bearers at the U.S. Food and Drug Administration have been leading the charge to reverse this provision.  To a certain extent, they have a point.  As we have frequently asserted, there is a legitimate role for the use of placebos even when effective treatment has been identified, as long as the disease in question is mild.  Placebo-controlled trials of treatments for mild headache, seasonal rhinitis and cough are acceptable.  To the extent that the current DOH would preclude studies of these conditions, we agree that it should be modified. 

But the commentary on Guideline 7 would include a host of other classes of drugs for which placebo-controlled trials would be deemed acceptable: analgesics (not only mild analgesics [which would be acceptable] but, at least as written, powerful ones such as morphine), anti-emetics (at least as written, including for vomiting due to chemotherapy) and to “prevent diseases caused by smoking or other harmful habits related to lifestyle.”  There are two problems with this list.  First, the issue in deciding the appropriateness of placebo use is not the drug class, but the severity of the condition being treated and the effectiveness of existing therapy.  Second, it is completely inappropriate to allow potentially more dangerous studies to be conducted on patients simply because the patient’s lifestyle may have contributed to their risk for a disease.  This kind of “blame-the-victim” mentality has no place in any document, let alone a document billing itself as an ethics document.  We should remember that the issue of whether conditions are considered to be related to lifestyle has deep social and historical roots.  It is not so long ago that schizophrenia was thought to be a consequence of the patient’s lifestyle.  Even in the recent past, injection drug users seeking treatment for opiate addiction have been randomized to placebos, despite the existence of methadone.[9]  Placebos should be deemed appropriate based on the severity of the disease and the effectiveness of current treatment — not on often evidence-free judgments about whether the patient is making a choice to engage in the lifestyle. 

The other obvious purpose of Guideline 7 is to make it easier for researchers to use the poverty of their participants to justify the withholding of effective therapies.  A variety of statistical arguments have been made to support this unethical position; we will not critique them here, but rather attach our comments on the ICH guideline on this subject.3   The second major justification for placebo use in this setting is that an active-controlled study may, in the words of the draft, “yield no reliable scientific results.”  Obviously, “reliable” is a subjective judgment, permitting the researchers to assert that results obtained through an active-controlled trial fall short of the magical placebo-controlled trial “gold standard” and are therefore unreliable.   

But the real question is whether an alternative trial design would provide adequate results, while treating all patients.  Let us revisit the issue of the Thailand and African perinatal HIV prevention studies, in which the placebo-controlled trial was said by the trials’ defenders to be the only way to obtain reliable results.  Ironically, the U.S. National Institutes of Health, which funded more of these unethical trials than any agency, also funded an active-controlled trial.[10]  In that study, the researchers randomly assigned 1,437 HIV-positive pregnant women to groups in which the women received either long (12 weeks) or short (5 weeks) regimens of AZT before delivery and the infants received either long (6 weeks) or short (3 days) regimens of AZT.  There were thus four groups: long-long (similar to a regimen called ACTG 076 proved effective in the U.S. and France in 1994); long-short; short-long; and short-short. All women received AZT during labor, usually by mouth.  The HIV transmission rate in the short-short arm (10.5%) was so high that the researchers prematurely terminated that arm.  Even so, the short-short arm was so much better than the placebo arms in all of the unethical studies (and better than the rates of transmission in other non-treatment studies conducted before AZT was proved effective for this purpose) that there was no difficulty concluding that short-short was better than nothing. The placebo in the other studies was therefore unnecessary and dangerous.  The transmission rates for the long-long (6.5%), long-short (4.7%) and short-long (8.6%) were statistically indistinguishable.  The study provides clinicians with much better guidance as to which part of the AZT regimen is critical than do most of the other placebo-controlled trials. 

It is interesting, too, that representatives of the U.S. National Bioethics Advisory Commission (NBAC), which endorsed limited exceptions to the DOH’s position on placebo use, have rejected the standard of care argument when it applies to life-threatening conditions.  The only justification for exceptions to the DOH, they write, would be situations “in which the only useful research design, from the host country’s perspective, required a less effective intervention in the control group, if the condition being studied was not life-threatening and if the trial received approval from an ethics review committee in the host country as well as one in the United States.”[11] (emphasis added)  They then go on to discuss the notorious Surfaxin trial (which would have randomized some infants with often fatal Respiratory Distress Syndrome to placebo instead of one of four approved surfactants),[12] concluding that “In studies of this kind — involving a disease that is life-threatening and one for which an established, effective treatment is available — a placebo control is not permissible.” 

Let us consider another example.  For years it has been known that treatment with at least some antihypertensive medications can reduce mortality.  Yet between 1987 and 1990, Bayer-funded researchers in China compared the efficacy of nifedipine to placebo in 1600 patients.[13]  The result was 45 more cardiovascular events in the untreated group (77 in the placebo group vs. 32 in the nifedipine group).  Such a study would (we hope) never be countenanced in an industrialized country.  Is this the new face of medical research that CIOMS wishes to endorse?  

As scientists and persons interested in ethics, we should shy away from developing ethical standards based on terms such as “standard of care” that have no scientific meaning but are instead reflective of economic concerns.  From a scientific perspective, there are only two kinds of medicines: those that have been proved to work and those that haven't.[14]  The DOH assures all patients of the former, while the proposed CIOMS document will consign some patients (specifically poor patients) to the latter.  This is not standard of care; it is substandard care and, at times, no care at all.  

Guideline 9: Essential information for prospective research subjects (Old Guideline 2) 

The CIOMS draft fails to require two crucial pieces of information: 1. Investments of the researchers and the university in the company whose product is being tested and service on company advisory committees (see our comments on Guideline 2); and 2. That the participants be told the study results.  The draft simply requires that participants learn whether or not they will be told the study results.  Participants who have put their bodies on the line for science deserve better than that. 

The draft also misses a golden opportunity to argue for tests of comprehension of the information provided, instead of the mere signing of often-incomprehensible and sometime misleading  [15] documents.  We believe that, particularly in large clinical trials, a random sample of participants should actually be surveyed to see if their understanding of the trial is sufficient to meet a reasonable standard of informed consent. If adequate levels of knowledge about the trial cannot be demonstrated, the trial should either be stopped or, preferably, its informed consent process should be redesigned to address the deficiencies identified in the survey. In the absence of real measurements of the outcomes of the informed consent process, the claim that informed consent was given will be an empty one, particularly given the well-documented examples of unacceptably low levels of informed consent in several recent developing country studies.[16],[17],[18] 

Material in Volume II of the NBAC report suggests widespread support for the concept of incorporating tests of participant understanding into the research process.  Eighty-three percent of responding international researchers and 65% of U.S. researchers favored such tests, although only 27% of international and 16% of U.S. researchers had actually administered them.[19]  CIOMS is missing a golden opportunity to actually advance the ethical conduct of clinical trials. 

Finally, the draft would have researchers provide effective interventions after the trial “unless the ethical review committee agrees that there are good reasons not to do so.”  This is far too vague.  At a minimum, this exception should be restricted to “good scientific reasons.”  It would be still better if the document clearly spelled out a very limited exception here.  

Guideline 10: Obligations of researchers regarding informed consent (Old Guideline 3)

The draft document would create an exemption from the informed consent requirement for emergency situations.  Here, again, the DOH is being watered down.  Considering its length, the CIOMS document has very little to say about the procedural safeguards for this rare circumstance.  Moreover, the DOH clearly requires, appropriately, that “Research on individuals from whom it is not possible to obtain consent, including proxy or advance consent, should be done only if the physical/mental condition that prevents obtaining informed consent is a necessary characteristic of the research population.” (Article 26)  This wise admonition is missing from the CIOMS document. 

We note, too, that the clear requirement in the DOH that independent physicians obtain consent when the potential participant is also a patient of the physician-researcher (Article 23) is lacking in the draft CIOMS document. 

Guideline 19: Safeguarding confidentiality (Old Guideline 12) 

Under the draft CIOMS Guidelines, researchers must assure confidentiality of research data, but the phrase “during the research process” has now been added.  There can be no justification for this.  Certainly, researchers can not be expected to retain research records indefinitely, but the requirement to protect confidentiality should extend indefinitely, beyond the life of the research project. 

Guideline 20: Right of subjects to compensation (Old Guideline 13) 

This Guideline again ushers in a change guaranteed to put a smile on the faces of the research industry.  While the current CIOMS document requires that compensation for injuries incurred during the study must be provided and that “The right to compensation may not be waived,” the draft allows IRBs to waive this entitlement.  There is no attempt to justify this proposed change, except the observation in the commentary accompanying the Guideline that “in some societies this right to compensation is not acknowledged.”  While this is no doubt true, the failure of a country to require a particular practice (e.g., having an IRB) does not prevent foreign (or local) researchers from insisting upon it.  

Guideline 22: Ethical review of externally sponsored research (Old Guideline 15)

We are gratified to see that the draft, more clearly than the current version, requires review by IRBs in both sponsoring and host countries.  If actually followed, this would represent a marked improvement over current practices: only 22% of pharmaceutical/biotech studies in developing countries received review from a U.S. IRB, according to the NBAC.[19]  The NBAC report also makes clear that at present many developing countries (and some industrialized ones) have inadequate capacity for ethical review.  

However, the commentary accompanying the Guideline contemplates a kind of division of responsibility in which the industrialized country IRB would merely be responsible for “ensuring compliance with broadly stated ethical standards,” while the developing country IRB would be reviewing the “detailed plans for compliance.”  This might make sense in some ideal world where we know longer needed the capacity building the document acknowledges is necessary in Guideline 21.  But developing country researchers who responded to the NBAC survey (approximately 200 of 500 or 40%) indicated that U.S. IRBs were more likely than developing country IRBs to indicate that confidentiality protections in the index study were inadequate (42% [U.S.] vs. 18% [developing country]; p=0.005), to comment on the need for a consent form in the local language (84% vs. 58%; p=0.0065) and to raise concerns about the complexity of the informed consent form (64% vs. 45%; p=0.070). Twenty-five percent of developing country respondents indicated that their studies were reviewed by neither the Ministry of Health nor by an IRB or equivalent.[19] Full review by IRBs in all involved countries is therefore necessary. 

Guideline 23: Obligations of external sponsors to provide health-care services (New Guideline)

It is progress of a sort that a new Guideline addressing this issue has been added.  But the Guideline raises as many questions as it answers.  For one thing, it states that, despite the plea for capacity building in Guideline 21, providing such services is merely “morally praiseworthy,” not ethically mandatory.  For another, it is clearest on the requirement to refer patients for treatment for diseases unrelated to the research.  Of course, what has raised much controversy lately has been the treatment of diseases that are related to the research.  These include the provision of antiretroviral drugs to participants who become infected during HIV vaccine trials[20] and in studies that monitor HIV progression.[21]  This is where the researcher’s conflict of interest arises and where a clear CIOMS statement of the need to treat such conditions would be helpful.  

Conclusion 

We are not surprised that the CIOMS and ICH documents are so much weaker than the DOH.  Particularly in the latter phases of the DOH revision, there were multiple opportunities for public input and the revisions were put to a vote of the full membership.  In contrast, the ICH consists entirely of the regulatory agencies and pharmaceutical industries of Europe, the U.S. and Japan.  CIOMS is an organization without clear membership criteria and no accountability which has met and developed drafts of this document over a period of two years in complete secrecy, all the while excluding those known to disagree with the intent of the research industry.  The draft CIOMS document is concerned with the process of research; without considerably more transparency in the process of drawing up this research ethics document, it will have little credibility. 

Yours sincerely, 

Peter Lurie, M.D., M.P.H.
Deputy Director 

Sidney M. Wolfe, M.D.
Director
Public Citizen’s Health Research Group

 


 

References

[1] World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Adopted by the 18th World Medical Assembly, Helsinki, 1964 and revised by the 29th World Medical Assembly, Tokyo, 1975, the 35th World Medical Assembly, Venice, 1983, the 41st World Medical Assembly, Hong Kong, 1989, the 48th World Medical Assembly, Somerset West, 1996 and the 52nd World Medical Assembly, Edinburgh, 2000.

[2] International Conference on Harmonisation. Choice of Control Group in Clinical Trials. Available at: http://www.ifpma.org/ich5e.html#Design.

[3] Lurie P, Wolfe SM. Comments on Draft Guidance on Choice of Control Group in Clinical Trials. Available at: http://www.citizen.org/documents/1503.pdf.

[4] Boyd EA, Bero LA. Assessing faculty financial relationships with industry: a case study. Journal of the American Medical Association 2000;284:2209-14.

[5] Birch DM, Cohn G. The changing creed of Hopkins science. Baltimore Sun, June 25, 2001.

[6] Barnes DE, Bero LA. Why review articles on the health effects of passive smoking reach different conclusions. Journal of the American Medical Association 1998;279:1566-70.

[7] Cho MK, Bero LA. The quality of drug studies published in symposium proceedings. Annals of Internal Medicine 1996;124:485-9.

[8] Dame L, Mendelson LS, Wolfe SM. Letter to U.S. Food and Drug Administration on Financial Disclosure by Clinical Investigators, April 29, 1996. Available at: www.citizen.org/documents/1390.pdf.

[9] Johnson RE, Eissenberg T, Stitzer ML, Strain EC, Liebson IA, Bigelow GE. A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence. Drug Alcohol Dependence 1995;40:17-25.

[10] Lallemant M, Jourdain G, Le Coeur S, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. New England Journal of Medicine 2000;343:982-91.

[11] Shapiro HT, Meslin EM. Ethical issues in the design and conduct of clinical trials in developing countries. New England Journal of Medicine 2001;345:139-42.

[12] Lurie P, Wolfe SM, Klaus M. Letter to Tommy Thompson, Secretary of Health and Human Services regarding unethical surfactant trial in Latin America. Available at: http://www.citizen.org/hrg1558.

[13] Gong L Zhang W, Zhu Y, et al. Shanghai trial of nifedipine in the elderly (STONE). Journal of Hypertension 1996;14:1237-45.

[14] Angell M; Kassirer JP. Alternative medicine — the risks of untested and unregulated remedies. New England Journal of Medicine 1998;339:839-41.

[15] Pelton T. Asthma study violated safety rules, FDA says. Baltimore Sun, July 3, 2001.

[16] Karim QA, Karim SSA, Coovadia HM, Susser M. Informed consent for HIV testing in a South African hospital: is it truly informed and truly voluntary? American Journal of Public Health 1998;88:637-40.

[17] Sloat B, Epstein K. Living proof: Ugandans in American-run study expected treatment, but some pills were dummies. Cleveland Plain Dealer, November 9, 1998, pp. 1-A, 8-A, 9-A.

[18] French HW. AIDS research in Africa; juggling risks and hopes. New York Times, October 9, 1997, p. A1, A8.

[19] National Bioethics Advisory Commission. Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries. Volume II: Commissioned Papers and Staff Analysis. Bethesda, MD, May 2001.

[20] UNAIDS. Ethical Considerations in HIV Preventive Vaccine Research. Geneva, May 2000.

[21] Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. New England Journal of Medicine 2000;342:921-9.

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