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More Information on Ethics and Clinical Trials

Comments on Draft HHS Report on the Globalization of Clinical Trials

July 5, 2001

Comments by Peter Lurie, M.D., M.P.H., Deputy Director
and Sidney M. Wolfe, M.D., Director 
Public Citizen's Health Research Group
on the Draft Health and Human Services Inspector General's Report: 
The Globalization of Clinical Trials (OEI-01-00-00190)

While this report highlights the important issue of the increasing internationalization of medical research, it is lacking in three regards: 1. The report fails to draw adequately upon prior research in this area; 2. It fails to adequately emphasize the deficiencies of the data collected by the U.S. Food and Drug Administration (FDA); 3. The recommendations are too weak, even falling below those of the National Bioethics Advisory Commission (NBAC).

Moreover, it cannot be too strongly emphasized that the report's findings apply only to studies intended to result in FDA approval. Particularly because other government agencies may not be as attentive to ethical issues as the FDA and because some research occurs entirely without government oversight, it is important to change the report's title to clarify that it applies only to FDA-regulated studies. Nonetheless, the report's basic conclusion is irrefutable: more and more research is being conducted abroad and the great weight of existing evidence suggests that ethical review in foreign countries, particularly those with limited experience with research, cannot be demonstrated to be equivalent to U.S. review.

1. Failure to draw upon prior research 

While an exhaustive review of published articles is beyond the scope of this report, the failure to include even a cursory review results in a document that is diminished inasmuch as it fails to establish that it is addressing a significant public health problem. In the absence of even a summary of evidence in the report that researchers are, for example, conducting research without adequate informed consent or taking advantage of the lack of available medical care to recruit patients and then not providing medically indicated treatment, the finding that there is much more international research is of interest, but does not generate the level of concern that is appropriate. Despite its omission from the report, there is a great deal of evidence of improper research in foreign studies, ranging from HIV vaccine preparedness studies in which informed consent was inadequate[1] to the Asian and African perinatal HIV prevention studies,[2] Ugandan tuberculosis prophylaxis study[3] and the proposed Latin American surfactant study,[4] in which known effective treatments were, by design, withheld from poor patients. At least some of these examples must be mentioned. Similarly, the report must at least acknowledge the possibility that research in developing countries is attractive to pharmaceutical companies because costs and ethical protections are lower.

Recently, the NBAC released its report on the ethics of international research. Volume II of the report contains abundant and clear evidence of the deficiencies of both sponsoring and developing country Institutional Review Boards (IRBs).[5] This evidence, too, is lacking from the draft report, a deficiency of particular note because systematic studies of international research practices are few and far between. For example, U.S. researchers responding to the survey indicate that only 22% of pharmaceutical company/biotech studies were reviewed by U.S. IRBs. Elsewhere, the report clearly documents the inadequacies of developing country IRBs. As one developing country researcher stated, "They [local IRBs] are not really concerned about ethical issues, they are looking [at] technical [issues]. And you know, and who [is] giving you money, how much are you getting ... But now [we need to look at] the ethical aspects, what people are doing, is it right." Added another: "... but in terms of who is running these bodies and who is controlling what's really happening, you will be amazed. It is mostly people who have no idea about this. They just know it [ethics] is a word."

The NBAC report states that researchers should attempt to secure availability of effective treatments to both trial participants and members of the general community. Moreover, the NBAC concluded that "clinical trials in developing countries should be limited to those studies that are responsive to the health needs of the host country."[6] These are at the heart of claims that developing country study participants are sometimes exploited by multinational pharmaceutical companies. The absence of any discussion of this issue greatly undermines the report's credibility.

2. Failure to adequately emphasize data deficiencies 

This report makes more clear than any previous report just how limited the data on the internationalization of biomedical research really are -- and this in the area (FDA-regulated studies) where the data are among the strongest. Even as there remains little question that more research on drugs intended for approval in the U.S. is being conducted abroad, and that an increasing proportion of the foreign trials are being conducted in developing countries with fledgling ethics infrastructures, the authors of the report can marshall little hard data on these trends. Even the data that do exist are subject to many caveats that emphasize the weakness of the FDA's oversight abilities, but many of these limitations are unfortunately relegated to the footnotes of the draft report. To emphasize the extent of the data drought, these footnotes should be elevated to the report's main body. To summarize, the report finds that:

Lack of data on foreign investigators 

  • The FDA only has data on investigators conducting research under Investigational New Drug (IND) applications
  • Not all research on new drugs is conducted under an IND; the FDA first learns of some research only when the sponsor submits a New Drug Application (NDA)
  • IND investigators, domestic and foreign, are required to submit a signed attestation confirming that they will comply with the basic tenets of human subjects research
  • These attestations form the basis for the Inspector General's assessment of the growth in foreign clinical trials
  • No attestation is required of research not conducted under an IND
  • However, even foreign investigators operating under INDs do not always sign such attestations
  • Sponsors are not required to submit the attestations to the FDA
  • Despite these missing data elements, the number of non-U.S. clinical investigators increased 17-fold between 1990 and 1999
  • These data show particularly high rates of growth in the number of investigators from Eastern Europe and Latin America

Lack of data on New Drug Applications 

  • FDA's database on NDAs does not track information by the location of the research
  • Consequently, the FDA cannot describe the trends in NDAs containing data from foreign trials

Lack of data on foreign inspections 

  • The FDA does not know how many foreign clinical trial sites there are
  • Therefore, there are no data on the proportion of foreign sites that are inspected as part of the evaluation of an NDA
  • These inspections occur primarily to assure the integrity of the data, not to assure the protection of the volunteers
  • Such inspections generally occur only after the study has been completed -- too late to correct any unethical practices
  • Despite the data limitations, there has been an estimated seven-fold increase in the number of foreign clinical investigator inspections between 1990 and 1999
  • Many of the inspections appear not to be in the countries with emerging research programs: Poland had 100 investigators registered with the FDA in 1994-1996 and 190 in 1997-1999, but none of these have ever been inspected. Similarly, none of the 122 Argentinean investigators registered between 1994 and 1996 or the 271 registered between 1997 and 1999 has ever been inspected
  • Although the FDA has such power, the report does not give any instances of foreign data being rejected because the study investigators did not collect the data ethically (this is an NBAC recommendation) or because an investigator refused to permit an inspection

Lack of data on foreign Institutional Review Boards 

  • Although there were 250 U.S. IRB inspections in 2000, the FDA has never inspected a foreign IRB
  • FDA officials are unaware of a single regulatory agency outside of the U.S. that inspects IRBs
  • Thus, the FDA does not know how many foreign IRBs there are, where they are located or how many IND protocols these IRBs have reviewed

Lack of data on foreign study participants

  • The FDA cannot track how many participants have enrolled in foreign sites or any trends over time

3. Failure to issue sufficiently strong recommendations 

Although the report describes the situation as "serious" and acknowledges that "FDA cannot assure the same level of human subject protections in foreign trials as domestic ones," the recommendations offered are not commensurate with the problems identified.

Recommendations regarding foreign Institutional Review Boards 

Ideally, researchers working with INDs outside the U.S. would be required to provide the FDA with the name of the IRB from which they plan to obtain ethical approval and some evidence of its structure and rigor. The FDA could then work with foreign regulatory authorities and the foreign IRB itself to confirm the credibility of that IRB; those foreign regulatory authorities should actually inspect the IRB, something that has not been their custom to date, perhaps in conjunction with the FDA. The report's recommendation that the FDA merely "examine ways in which it can obtain more information about the performance of non-U.S. [IRBs]" falls well short of what is needed.

Recommendations regarding U.S. Institutional Review Boards 

Here the problem with the report is not the presence of an inadequate recommendation, but the absence of any recommendation. Current U.S. regulations do not require U.S. companies conducting research in foreign countries to submit their study protocols to a U.S. IRB in addition to the foreign IRB. The NBAC clearly endorsed the need for double-IRB approval: "The Food and Drug Administration should not accept data from clinical trials conducted in developing countries unless those trials have been approved by a host country ethics review committee and a U.S. Institutional Review Board."6 (emphasis in original) This recommendation from the NBAC would actually be an improvement over existing ethical protections; the Inspector General should strongly endorse this recommendation.

Recommendations for the Food and Drug Administration 

The report recommends that the FDA "encourage" sponsors to ensure that attestations are signed. We can see no reason that IND researchers should not be required to sign these attestations, regardless of where the research is conducted. Sponsors should be required to send all attestations to the FDA.

The report presents more than enough data to conclude that any detailed attempt to track trends in international research by the FDA under the present schema is doomed to failure. Some of the report's ideas -- such as the retrospective entry of data from NDAs and extending IRB registration to include foreign boards -- are laudable. Yet, the report's recommendations are couched in polite terms such as "could" and "consider." There is simply no sense of urgency in the report's recommendations, despite the data-collection disaster it describes.

Finally, the report notes that sponsors of gene therapy research are required to submit their monitoring plans to the FDA before the research is conducted. This requirement should be extended to all developing country research conducted with INDs. In addition, the FDA should be responsible for ensuring that all foreign research conducted with an IND is responsive to the health needs of the community and that the researchers have made good faith efforts to assure post-trial availability of effective treatments to the study participants and the general community, as recommended by the NBAC.

Recommendations for the Office for Human Research Protections (OHRP) 

The report endorses the OHRP's proposed voluntary approach to IRB accreditation, both domestically and abroad. We can see no advantage to a voluntary approach over a mandatory one, particularly for domestic IRBs. Accreditation of foreign IRBs should also be pursued by requiring sponsors to provide detailed information on their study's IRB to the FDA when they apply for an IND. Sponsors would have a strong incentive to comply with such a regulation.


References

[1] 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.

[2] Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. New England Journal of Medicine 1997; 337:853-6.

[3] Whalen CC, Johnson JL, Lkwera A, et al. A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. New England Journal of Medicine 1997;337:801-8.

[4] Lurie P, Wolfe SM, Klaus M. Letter to Tommy Thompson, Secretary of Health and Human Services, regarding planned placebo-controlled surfactant study in Latin America. Available at: http://www.citizen.org/hrg1558

[5] 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: Commissioned Papers and Staff Analysis. Bethesda, MD, May 2001.

[6] National Bioethics Advisory Commission: Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries. Volume I: Report and Recommendations of the National Bioethics Advisory Commission. Bethesda, MD, May 2001.

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