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More Information on Ethics and Clinical Trials

Letter Opposing U.S. Government Efforts to Declare Some Foreign Ethics Approval Procedures Equivalent to Those in the U.S.

May 31, 2005

Ms. Gail Carter
Division of Policy and Assurances
Office for Human Research Protections
1101 Wootton Parkway
Suite 200
The Tower Building
Rockville, MD 20852

Re: Protection of Human Subjects, Proposed Criteria for Determinations of Equivalent Protection

Dear Ms. Carter:

The Office for Human Research Protection’s (OHRP’s) proposal[1] to develop criteria to recognize the equivalence of research protections offered by foreign institutions or governments is the first step in its clear overall objective: to eliminate, at least for some studies, ethical review in the United States of studies subject to U.S. regulation.  With research studies increasingly being conducted abroad,[2],[3] particularly in developing countries with relatively poor ethical infrastructures, the proposal would lead to a lowering of ethical standards at just the moment that they should be strengthened.  One can understand why corporations and researchers might want to see government oversight of their activities reduced; why that part of the government charged with protecting patients would be a party to such an effort is much less clear.

U.S. regulations currently allow that, for research in a foreign country subject to U.S. regulations, “if a Department or Agency head determines that the procedures prescribed by the [foreign] institution afford protections that are at least equivalent to those provided in this policy, the Department or Agency head may approve the substitution of the foreign procedures in lieu of the procedural requirements provided in this policy.”[4]  The only agency known to have developed equivalence criteria is the U.S. Agency for International Development, but these have never been put into practice, to our knowledge.   In effect, therefore, the equivalency language has never been utilized.  Instead, foreign institutions have been required to obtain Single Project Assurances, which describe the process for local review for a particular study, but which do not supplant U.S. review.

We are certainly in favor of any effort to expand the capacity of developing (or other developed) countries to conduct ethical review.  Anything that converts international research studies into efforts more closely resembling true, equal collaborations in every aspect of the trial, including ethical review, is to be supported. But the uncomfortable fact, as documented clearly in the National Bioethics Advisory Commission (NBAC) report (see below), is that there remain enormous deficiencies in both developing and industrialized country review processes.  Even many developed countries have regulatory structures much less elaborate than our own.  To entrust the review of studies only to institutions in foreign countries may comport with aspirations for future developing (or developed) country ethical review capacities; it does not comport with the NBAC-documented reality.

Data on Equivalence of Foreign Research Protections

In research conducted for the NBAC, Johns Hopkins University researchers collected useful quantitative data, which have since been published.[5] Developing country researchers who responded to the survey (203 of 550 or 38%) indicated that U.S. Institutional Review Boards (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=0.004), to comment on the need for a local language consent form (84% vs. 58%; p=0.006) 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. The NBAC consultants calculated that this could represent 15% of studies, about one-third of which were funded by the U.S.  These researchers conclude: “Ethics review in both the host and the donor country should be standard in collaborative research.”

In other research conducted for the NBAC by Johns Hopkins, U.S. researchers were surveyed about their experiences in developing countries.[6]  According to the Johns Hopkins report, “79 percent of U.S. researchers believed that host country ethics boards were more concerned with politics than with protecting research subjects.”  Among the 12% of U.S. respondents who had engaged in research that represented more than a minimal risk to participants, the U.S. IRB was more likely than the foreign IRB to raise questions about whether the intervention was too risky (18% vs. 2%), procedures for the control group (35% vs. 15%), use of placebos (32% vs. 7%), whether benefits offered might compromise voluntariness (25% vs. 8%), relevance of the research to the developing country (59% vs. 27%), post-trial availability (52% vs. 17%), complexity of the informed consent form (66% vs. 42%), and need for a local language consent form (84% vs. 63%). All findings listed here were statistically significant at p=0.02 or less.

The Johns Hopkins survey of U.S researchers includes the following observations by U.S. researchers:

Some of [the developing country IRBs] do really quite a decent job, just as you would want them to be. And there are others that are completely rubber stamps, and nothing else ... Yes, there’s an IRB, [but] I don’t have any faith that there was any real review.

[Local IRB members] may be people that are not all equipped intellectually, culturally, scientifically to deal with the issues you are asked to deal with.   And therefore, you introduce a false sense of security and conformity with the rule, with the letter, when the spirit is actually vacant.

In some cases, the developing country ethical review is actually a process of seeking permission to conduct research, and no ethical questions are raised at all.  Developing country review boards are often more concerned about the financial aspects of the study than about ethics.

Specific Comments on the Proposed Criteria

As mentioned, our preferred approach is to simply not permit ethical review in a foreign jurisdiction to supplant U.S. review.  Nonetheless, we would like to offer some observations with the criteria proposed.

First, to ensure the highest levels of ethical protection, we believe that any finding of substantial equivalence should take place at the institutional (e.g., university, hospital), not the country, level.   If an institution has not formalized its ethical structure, it is unlikely to be able to guarantee adequate human subjects protection, no matter what high-minded principles have been adopted at the national level. 

Second, we would strongly support the continued requirement for Assurances.  With this major weakening of ethical review contemplated by OHRP, the Assurance process will have to take on much of the load previously shouldered by IRBs. To eliminate the Assurance process and the requirement for U.S. IRB review will essentially eliminate U.S. oversight.

Third, according to the proposal, only those human subjects protections codified under Subpart A of 45 CFR 46 need be considered in the determination of equivalent protection.  This eliminates from consideration the protections for pregnant women and neonates, prisoners, and children codified under Subparts B, C, and D, respectively.

Finally, while the areas covered by the criteria seem broadly to be the correct ones, the criteria themselves are maddeningly vague and, like the Code of Federal Regulations, focused on process rather than outcome. Perhaps it cannot be otherwise — but then that’s precisely the reason we do not believe U.S. review should be eliminated. 

On the other hand, U.S. regulations are at times very specific about certain aspects of research review.  The contents of informed consent forms, definitions of minimal risk, and membership on IRBs come readily to mind.  How similar to the U.S. regulations will the foreign standards have to be to be declared equivalent?  Given the intent of the present deregulatory drive, we have little confidence that the threshold for declaring protections to be equivalent will be high.

The NBAC report contains multiple tables comparing the ethics regulations in 15 countries, including the U.S.[7]  The tables highlight the complexity and diversity of these regulatory structures and demonstrate just how formidable any attempt to establish equivalence would be.   For example, while U.S. regulations require that the selection of subjects be equitable, nine of the 15 countries (including Australia, France and Thailand) do not.  U.S. regulations address treatment and compensation for injured human participants, but Canada, Denmark, Finland, Thailand and the United Kingdom do not.  U.S. regulations have the force and effect of law, but this is not the case in South Africa and the United Kingdom.  The Chinese regulations do not even require IRB review.  Without even considering the details of their regulations, 11 of the 15 countries are clearly different from the U.S. on at least one of just these four elements of their regulations.

Conclusion

In another report,[8] the NBAC identified a major problem: not all U.S. research is subject to U.S. regulations.  Only biomedical research that is funded by the U.S. government or is intended to lead to approval at the Food and Drug Administration is covered.  (In practice, academic research institutions receiving federal funds customarily apply U.S. regulations to all their research.)  Thus, research by U.S. pharmaceutical companies or other private sector scientists that does not fall into one of the two categories above is not covered.  In the NBAC report, only 22% of studies conducted overseas by U.S. researchers for pharmaceutical or biotechnology firms underwent U.S. IRB review. [6]  Rather than address this major deficiency by seeking to extend the reach of U.S. regulations, as the NBAC recommended, the OHRP has instead gone down the deregulatory route.  In so doing, it risks the entire image of U.S. research.  For when the inevitable ethical controversy over a particular research project conducted by U.S. researchers beyond our shores erupts, much attention will be paid to a double standard whereby U.S. researchers follow one set of principles at home and another (often weaker) set abroad.

The OHRP proposal directly contradicts the Council for International Organizations of Medical Sciences (CIOMS) ethics document which requires:“Committees in both the country of the sponsor and the host country have responsibility for conducting both scientific and ethical review, as well as the authority to withhold approval of research proposals that fail to meet their scientific or ethical standards.”  [9]  It also is weaker than the Canadian requirements: “Research to be performed outside the jurisdiction or country of the institution which employs the researcher shall undergo prospective ethics review both (a) by the [Research Ethics Board (REB)] within the researcher’s institution; and (b) by the REB, where such exists, within the legal responsibility and equivalent ethical and procedural safeguards in the country or jurisdiction where the research is to be done.”[10]

We realize that any findings of equivalence are likely to begin with a country with a relatively well developed ethical structure.  Even in this circumstance, we consider the added effort (and benefits) associated with U.S. review well worth the time expended.  Certainly, U.S. ethical review is less than ideal, having been heavily criticized by the government’s own Inspector General for inadequately protecting participants.[11]  But the most appropriate standard is a simple one: no researcher should ever perform a project that was not approved in his or her country of origin.

Sincerely,

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

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


References

[1] 70 Fed Reg 15322-7, March 25, 2005.

[2] Office of the Inspector General. Recruiting human subjects: pressures in industry‑sponsored clinical research. Department of Health and Human Services, June 2000.

[3] Schmit J. Costs, regulations move more drug tests outside USA. USA Today, May 17, 2005.

[4] 45 CFR 46.101(h).

[5] Hyder AA, Wali SA, Khan AN, Teoh NB, Kass NE, Dawson L. Ethical review of health research: a perspective from developing country researchers. Journal of Medical Ethics 2004;30:68-72.

[6] Kass N, Hyder AA. Attitudes and experiences of U.S. and developing country investigators regarding U.S. human subjects regulations. In: National Bioethics Advisory Commission. Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries, Volume II.  Bethesda, MD, May 2001.

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

[8] National Bioethics Advisory Commission. Ethical and Policy Issues in Research Involving Human participants.   Bethesda, MD, August 2001.

[9] Council for International Organizations of Medical Sciences, World Health Organization. International ethical guidelines for biomedical research involving human subjects. Geneva, 2002.

[10] Tri-Council Policy Statement, Ethical Conduct for Research Involving Humans, 2004. Available at: http://www.pre.ethics.gc.ca/english/policystatement/section1.cfm#1H.

[11] Office of the Inspector General. Institutional Review Boards: a time for reform. Department of Health and Human Services, June 1998.

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