In the Nuremberg Code, find at least one point that focused on the research subject’s welfare and one point that focused on the research subject’s autonomy. 2. In the Belmont Report, find at least on

After Helsinki: Unresolved Issues in International Research Ruth Macklin

Kennedy Institute of Ethics Journal, Volume 11, Number 1, March 2001, pp. 17-36 (Article)

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MACKLIN • UNRESOLVED ISSUES IN INTERNATIONAL RESEARCH

[ 17 ] Kennedy Institute of Ethics Journal Vol. 11 No. 1, 17–36 © 2001 by The Johns Hopkins University Press

Ruth Macklin

After Helsinki: Unresolved Issues in International Research

ABSTRACT. Following a long process of revision, a new version of the Declara- tion of Helsinki was approved by the World Medical Association in 2000. Two provisions of the Declaration address ongoing international controversies regard- ing research sponsored by industrialized countries and conducted in developing countries. Despite the issuance of the final version of the Declaration, opponents remain locked in debate. Moreover, the Declaration remained silent on other prominent controversies concerning international research. An analysis of these current controversies reveals reasons why they are not likely to be readily re- solved, despite apparent agreement by opponents on overarching ethical principles.

AREVISED VERSION OF THE Declaration of Helsinki was fi- nally approved by the World Medical Association in October 2000, well over two years after the process of revision began.

But it would be a mistake to think that the newly revised Declaration lays to rest a spate of ongoing controversies and unresolved issues in interna- tional research, especially studies that an industrialized country sponsors or conducts in a developing or resource-poor country. One reason why the revised Declaration has not accomplished that task is that opponents in the fiercest controversies over key provisions remain locked in debate.

Probably the two most contentious points are embodied in paragraph 29: (1) “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnos- tic, and therapeutic methods.” And (2) “This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diag- nostic, or therapeutic method exists” (World Medical Association 2000). A close runner-up for contentiousness is the statement in paragraph 30: (3) “At the conclusion of the study, every patient entered into the study

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should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.” In analyzing what is at stake in these ongoing debates, I argue that opponents are not likely to reach a resolution because of their adherence to fundamentally different and incompatible premises.

A second reason why the Declaration, even in its current revision, can- not resolve ongoing controversies is that it simply does not address other aspects of international research about which people disagree. Included in this category are: (4) the question of what, precisely, is owed to the community or country where the research is conducted after the trial is over; and (5) what specific mechanisms for prior review of research pro- tocols and monitoring of studies already in progress can best protect the research participants. In seeking to identify the underpinnings of the de- bates surrounding these points, I will argue that like the earlier items, these are unlikely to be easily resolved.

I intend to spare readers of this article any further analysis of the pla- cebo-controlled, mother-to-child HIV transmission studies conducted in Thailand, Uganda, and other developing countries in the late 1990s (al- though of necessity, I will refer to that controversy in what follows). Those clinical trials may well have surpassed the infamous Tuskegee study in the number of articles that have described, analyzed, and argued about them (see, e.g., Angell 1997; Lurie and Wolfe 1997; Varmus and Satcher 1997; Annas and Grodin 1998; Crouch and Arras 1998; Grady 1998; Glantz et al. 1998; C. Levine 1998; Resnik 1998; Lie 1998; Schüklenk 1998; Tho- mas 1998; Del Río 1998; Brennan 1999; Benatar and Singer 2000; Greco 2000; Schüklenk and Ashcroft 2000; London 2000; Rothman 2000). I will begin by identifying several premises on which opponents in these various controversies appear to agree.

First, there is widespread agreement that research should be responsive to the health needs of the population in the country or region where the research is conducted. Second, research is needed in developing countries on common and serious diseases that rarely occur in industrialized coun- tries–e.g., malaria–and on those that pose a huge risk to life and health even if the same diseases do exist in industrialized countries–e.g., HIV/ AIDS, tuberculosis. Third, it is unethical to exploit vulnerable popula- tions or individual participants in the conduct of research. Fourth, it is unacceptable to lower the ethical standards adopted in the industrialized world when carrying out research in developing or resource-poor coun- tries. Despite the apparent consensus on these fundamental propositions,

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once we peel off the layer of harmony we confront unanswered ques- tions, as well as stark disagreements.

RESPONSIVENESS TO THE HEALTH NEEDS OF THE POPULATION

How should the first premise on which there is ostensible agreement be interpreted? Is research “responsive” to the health needs of the popula- tion just so long as it addresses a health problem that is prominent in the country or region? Or must some steps be taken before the research is initiated to seek to ensure that successful products are made available to the population at the conclusion of the research? Opposing replies to these question point to one of the gaps in the revised Declaration of Helsinki identified above: (4) the question of what is owed to the community or country where the research is conducted after the trial is over. The 2000 revision of the Declaration contains a provision not included in the ear- lier versions. Paragraph 19 states: “Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research.” Although the provision as stated is laudable, it leaves wide open what are the crite- ria for determining “likelihood,” and what degree of likelihood is neces- sary. This is precisely the point on which opponents disagree.

The CIOMS International Ethical Guidelines for Biomedical Research (1993), also undergoing revision at the present time, contain two sepa- rate provisions that address this point:

Guideline 8: As a general rule, the sponsoring agency should ensure that, at the completion of successful testing, any product developed will be made reasonably available to inhabit ants of the underdeveloped community in which the re- search was carried out. (CIOMS 1993, p. 26)

Guideline 15: As a general rule, the sponsoring agency should agree in advance of the research that any product developed through such research will be made reasonably available to the in habitants of the host community or country at the comple- tion of successful testing. Exceptions . . . should be justi- fied and agreed to by all concerned parties before the re- search begins. (CIOMS 1993, p. 45)

A discussion paper issued by the Nuffield Council on Bioethics (1999) says of these provisions in the CIOMS Guidelines that “they may be dif- ficult to follow in practice.” The paper observes that such research is generally undertaken without any guarantee that the treatment in ques-

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tion would be provided to the participants in the event of a possible out- come. An obvious response to this observation is that the province of ethics is not simply to describe what generally occurs but rather, to pre- scribe what ought to take place. The Nuffield discussion paper was a report on a conference sponsored by the Council in February 1999 in London. At the conference, some participants contended that the “rea- sonable availability” provisions in the CIOMS Guidelines are too strong, as they would either prevent research from going forward or lead to in- tolerable delays if made a condition of initiation of the research. Other participants took an opposing view, saying the provision is too weak as it fails to guarantee availability of the successful products of research to the population. One researcher from Chile cited the example of Norplant, a product researched and developed in her country well over a decade ago, but that still is not generally available to Chilean women.1

One prevailing view holds that as long as research projects investigate health problems of the population from which subjects are drawn, and if the study adheres to proper ethical rules for the conduct of research in- volving human subjects, then sponsors or researchers have no additional obligation to ensure availability of any resulting products. Others reply that failure to ensure in advance that products are made reasonably avail- able in a timely manner to the participants and others in the community or country is a violation of distributive justice, and could constitute a reason not to embark on a trial at all (Crouch and Arras 1998; Glantz et al. 1998; Page [unpublished] 2000). Opponents agree on the underlying premise that research must be responsive to the health needs of the popula- tion; yet they disagree in their interpretation of what that premise entails.

Opponents in the much discussed placebo-controlled, HIV maternal- to-child transmission studies also agreed on the fundamental premise yet disagreed over whether an alternative trial design would be responsive to the health needs of the population. Defenders of the placebo-controlled studies argued that to compare the shorter, cheaper experimental regimen with the treatment that is the “gold standard” in the United States and Western Europe would fail the “responsiveness” test, since the costly, much more complex preventive regimen could never be implemented in resource- poor countries or those lacking the health care infrastructure to adminis- ter the treatment (Levine 1999). Critics could reply that the alternative research design was nonetheless responsive since the “short-course” regi- men being tested was the one that could be made available (which has

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occurred in Thailand, but not in Uganda, for which even the cheaper treatment remained too costly).

It is evident that the substantive views held by opponents in both de- bates—what is owed to research subjects during a trial, and what is owed to the country or community after a trial is completed—determine just how they interpret the uncontroversial premise that research must be re- sponsive to the health needs of the population in which the studies are conducted. Beyond that lies a deeper question about the nature of ethical guidelines. Should they be “pragmatic” or “aspirational”? Adherents of the view that statements such as the Declaration of Helsinki and docu- ments like the CIOMS International Guidelines must be “pragmatic” are likely to rely on current and past practices as a guide to what is possible. The pragmatists dismiss “aspirational” guidelines as too lofty and, there- fore, unrealistic (Grady 1998; Levine 1999). For their part, the “aspirationists” tend to be reformers who judge past or current practices to be ethically insufficient to ensure that the highest standards for re- search apply everywhere, not just in wealthy, industrialized countries (Glantz et al. 1998; Greco 2000; Schüklenk 1998; Rothman 2000).

NEEDED RESEARCH IN DEVELOPING COUNTRIES

Agreement is virtually universal that research is needed in developing countries on common and serious diseases that rarely occur industrialized countries and on those that pose a huge risk to life and health even if the same diseases do exist in industrialized countries. Yet despite that consen- sus, sharp disagreement exists on a range of specific questions: Must the research design of a clinical trial demonstrate that a proposed treatment is better than nothing in resource poor countries that lack a current, standard treatment available in wealthier countries? Or would an equivalency trial be satisfactory, showing that an experimental treatment is as good, or almost as good, as the current treatment used in the wealthier country (Lurie and Wolfe 1997; Lie 1998; Brennan 1999)? If studies with proven benefits have been conducted in one or more countries, when does it be- come ethically unacceptable to repeat those studies in still another coun- try, instead of providing the proven treatment to the population in the country where no trials have taken place? Are observation studies of the “natural history” of diseases ethically permissible in resource-poor coun- tries where effective treatments are not affordable to the majority of the people, even when effective treatments for that same condition are avail- able in the country sponsoring or conducting the research (Rothman 2000)?

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Answers to the above-noted questions are provided in paragraph 29 of the 2000 revision of the Declaration of Helsinki: “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic, or therapeutic method exists.” As we shall see below, this answer is not without ambiguity. Moreover, despite the apparent clarity with which this proposition is stated, critics have determined that it may warrant a rejection of the standing of the Declara- tion of Helsinki. Participants in a conference held at the National Institutes of Health (NIH) during the last week of November 2000 debated the Declaration’s ban on the use of placebos in research except when no proven treatment exists. Robert J. Temple, director of medical policy at the Food and Drug Administration’s Center for Drug Evaluation and Research and a long-standing defender of placebo-controlled trials, said that the revised Declaration of Helsinki takes an absolute position. “It would bar using placebos, for example, to evaluate a new drug for hay fever or migraine. But testing such a medicine against another drug approved to treat such condi- tions generally doesn’t measure its effectiveness as well as testing it against a placebo” (Okie 2000, p. A03). Robert J. Levine, who has argued strongly for abandonment of the “best proven treatment” provision in the earlier Declaration of Helsinki (Levine 1999), was quoted as saying: “Forbidding the use of placebos rules out development of all new therapies for condi- tions for which there are proven therapies. . . . If researchers had followed such rules in the past, he said, drugs currently used to treat high blood pressure or stomach ulcers never would have been developed because of the existence of older, less-effective treatments” (Okie 2000, p. A03). Levine and Temple were countered by Kenneth J. Rothman, who defended the Declaration of Helsinki’s position on placebos, saying the interests of the individual patient always should supersede the goals of science or society.

In a telling comment, Levine said: “The United States and most other countries have been ignoring the Declaration of Helsinki for years. I don’t know why people think this revision . . . is going to bring about a great change in behavior.” Change of behavior aside, Levine’s comment prompts two questions: first, why has the United States (presumably, U.S. researchers and IRBs) been “ignoring” the Declaration of Helsinki; and second, if that is the case, should we conclude that the United States and other countries have been unethical in so doing or instead, agree with Levine and Temple that there must be something wrong with the Declaration of Helsinki?

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If it is true–and it probably is–that the United States has been ignoring the Declaration of Helsinki, it may well be because the Federal Regula- tions governing research involving human beings are so detailed in their procedural aspects that researchers and IRBs see no need for another, different set of ethical rules for research. Furthermore, the U.S. regula- tions are just that–official regulations promulgated by a federal agency, with enforcement mechanisms and sanctions for noncompliance. The Dec- laration of Helsinki, on the other hand, is simply a “declaration,” issued by an international association of medical professionals, which has no enforcement mechanisms and no sanctions for noncompliance. The United States has declined to become a signatory even to international instru- ments issued by the United Nations—human rights documents like the Covenant on Economic, Social, and Cultural Rights and the Convention on the Elimination of All Forms of Discrimination Against Women. So it is hardly surprising that researchers, ethical review bodies, and govern- mental agencies do not consider the Declaration of Helsinki to be a neces- sary adjunct to the “official” Common Rule, which governs most feder- ally funded research in the United States. While the U.S. federal regulations are almost entirely procedural in their provisions, the Declaration of Helsinki tends toward a more substantive approach to ethical principles governing human subjects research.

What, then, should we conclude about whether the United States is behaving unethically in ignoring the Declaration of Helsinki? It is obvi- ous that critics of paragraph 29 believe that the “best current” provision and the rejection of placebo controls for the vast majority of clinical trials are unreasonable, if not hopelessly aspirational, and therefore, it is not unethical to ignore them. Defenders of those provisions would conclude that U.S. researchers and IRBs are remiss for not adhering to the Declara- tion of Helsinki in addition to complying with the U.S. federal regula- tions. Once more, people’s views on the substantive ethical issues at stake determine how they view the relevance of the Declaration of Helsinki to research conducted in the United States or elsewhere in the world.

Here again we face the question of whether ethical guidelines should be “aspirational” or “pragmatic.” Those who refer to guidelines as “aspirational” imply that they are impossibly ideal, not able to be real- ized in practice; whereas “pragmatic” conveys the sense that the guide- lines are truly usable in the practical world. The connotations of these terms implies the answer: pragmatic is better than aspirational. But there is another way to describe the nature of guidelines. Are they prescriptive,

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stating what ought to be the case even if current practices fall quite short? Or are they merely descriptive of what is, in fact, done most of the time? The quotation cited earlier from the Nuffield Council on Bioethics dis- cussion paper illustrates the confusion between these rather obviously different activities of prescribing and describing.

In sum, then, agreement about the need for research in developing coun- tries is a thin reed compared to the wide disagreement about acceptable research designs in attempts to fulfill that need.

EXPLOITATION OF VULNERABLE POPULATIONS

The third point of clear agreement is on the proposition that is unethi- cal to exploit vulnerable populations or individual participants in the con- duct of research. No one is in favor of exploitation, so it is easy to come to apparent agreement on this point. Yet, here again, agreement evapo- rates once we examine various allegations in specific cases. With regard to the obligation following successful trials, discussed earlier, some com- mentators are unequivocal in alleging that exploitation occurs if success- ful products are not made “reasonably available.” For example, “. . . if the results of a clinical trial are not made reasonably available in a timely manner to study participants and other inhabitants of a host country, the researchers might be justly accused of exploiting poor, undereducated sub- jects for the benefit of more affluent populations of the sponsoring coun- tries” (Crouch and Arras 1998, p. 29). And another, “[i]f developed coun- tries use inhabitants of underdeveloped countries to create new products that would be beneficial to both the developed and the underdeveloped country, but the underdeveloped country cannot gain access to the prod- uct because of expense, then the subjects in the underdeveloped countries have been grossly exploited” (Glantz et al. 1998, p. 39).

The specific example of exploitation cited by the latter commentators is that of the short-course AZT studies in Africa. Unlike the situation in Thailand, where the Thai government had made a commitment to pro- vide the AZT before the trials began, no such discussion apparently took place in the African countries where even the short-course regimen turned out to be too costly to provide in Uganda. Yet those who maintained that the Uganda trials were ethically defensible surely would reject the contention that any exploitation was involved. The defense against this allegation of exploitation turns out to be a procedural one: Ugandans reviewed and approved the studies so they must have been ethically acceptable to Uganda and, therefore, no exploitation was involved. Drs. Danstan Bagenda and

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Phillipa Musoke-Mudido of Uganda were quoted in the Washington Post as saying: “The ethical issues in our studies are complicated, but they have been given thought by the local community, ethicists, physicians, and activists. . . . We are suspicious of those who claim to speak for our people, yet have never worked with them” (Grady 1998, p. 37).

There remains a profound uncertainty about the ethical sufficiency of the procedural steps that involve in-country involvement in the design, approval, and implementation of research. One article defending the pla- cebo-controlled AZT trials quoted from a letter written to NIH by Ed- ward K. Mbidde, chairman of the AIDS Research Committee of the Uganda Cancer Institute. In his letter, Mbidde vigorously defended the IRB he chairs in Uganda, stating that “It is a wrong assumption that we do not have the vision to deal with such issues” (Letter from Edward K. Mbidde to Dr. Harold Varmus, then Director of NIH, 8 May 1997).2 Pulling out a trump card in ethical argumentation, Mbidde charged that it is “ethical imperialism” for outsiders to dictate to Ugandan researchers and IRBs what sort of research is ethical or unethical for Ugandans to carry out on their own people. Despite the unfortunate use of this inflammatory accu- sation, Mbidde raises a crucial issue for international collaborative re- search: How adequate are the protections for research subjects in devel- oping countries? A procedural defense prompts the obvious question whether a charge of exploitation can be defeated simply by pointing out that persons from the developing country where the research took place had a role in designing, approving, and conducting it.

Although relatively little hard data exists, there appears to be a wide variation among developing countries, and even within the same country, regarding both the existence and application of ethical laws, regulations, or guidelines, and the existence and quality of ethical review committees at the institutional or national levels. Among the countries known to have regulations or guidelines requiring prior ethical review of research by an independent committee are Uganda, India, Nepal, Thailand, Zimbabwe, Zambia, and South Africa. Less is known about the actual operation of these committees—their membership requirements, terms of reference, and operating procedures. A report commissioned by the National Bio- ethics Advisory Commission (NBAC) included a recommendation that ethics boards in countries where the U.S. sponsors or conducts research should gain additional experience in ethics. The report states that “[m]any U.S. researchers voiced concerns that host country boards had little fa- miliarity with ethics. Thus, when ethics boards convened, they focused

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on other issues where they felt more comfortable, such as the scientific design or the budget” (Kass and Hyder 2000, p. 7).

Review and approval of a study provides no guarantee of its ethical soundness, whether the review body is a U.S. IRB or a research ethics committee in another country. In my role as consultant to the Joint United Nations Programme on HIV/AIDS (UNAIDS) and in other review capaci- ties, I have studied an admittedly relatively small sample of protocols, approved by U.S. IRBs, for research to be conducted in developing coun- tries. Some of these approved protocols revealed that the IRB did not notice or ignored serious risks to research subjects, that it failed to take account of significant psychosocial risks to subjects, overlooked the need for confi- dentiality protections during the course of research, or approved informed consent documents that had grossly inadequate disclosures to the subjects of the procedures to be undertaken and contained myriad other shortcom- ings. In addition, as Rothman (2000) notes, U.S. IRBs have little familiar- ity with developing countries. Nor is it the case that involvement of host- country researchers in the design and implementation of a study can ensure that all features of the research comply with the highest ethical standards, or even minimally acceptable ones. Adherence to correct procedures is a necessary condition for ethical conduct but surely not a sufficient condition.

So, although everyone agrees that exploitation is a serious moral wrong that must be avoided, there is no consensus on what constitutes exploita- tion and little in the way of sustained analysis of the concept in the con- text of international research.3 One commentator offers the following, almost tautologous account: “Exploitation occurs when an individual or group use [sic] unethical means to obtain a benefit from another indi- vidual or group” (Resnik 1998, p. 306). Another account, slightly more illuminating, observes that all research subjects face some risk of exploi- tation: “They face the possibility that researchers may regard them purely as a means to benefit society or, more subtly, enroll them when the soci- etal benefits to be gained from the research do not justify the risks that subjects face” (Wendler 2000, p. 312). In the absence of a fuller account on which opponents in these different controversies can agree, an appeal to exploitation will accomplish no more than to identify the chief grounds for criticizing a particular study.

ETHICAL STANDARDS AND “STANDARD OF CARE”

What substantive ethical standards ought to apply to research con- ducted in developing countries? This question brings us to the fourth point

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on which there is apparent consensus: It is unacceptable to lower the ethical standards adopted in the industrialized world when carrying out research in developing or resource-poor countries. Some commentators have maintained that exactly the same standards should be employed the world over, whereas others contend that different standards are required because different circumstances obtain. But does “different” necessarily mean “lower”? What is the relevance of “standard of care” arguments used to defend or criticize the care and treatment research participants receive during a trial? The conflicting ways in which the terms “stan- dard” and “standard of care” have been interpreted demonstrate that agreement on the basic principle can nonetheless yield conflicting judg- ments about which research is ethically acceptable and which is not. In answer to the question “Should there be one ethical standard for research conducted in industrialized countries and another for resource-poor coun- tries?,” a variety of intriguing and apparently contradictory answers have been proposed; they are quoted and numbered below for ease of refer- ence in the discussion that follows.

(1) Opponents [of placebo-controlled trials] contend that reference to the “standard of care” in developing countries to justify placebo-controlled trials is ethically suspect. When people receive no treatment at all, there can be no “standard” of care. Defenders say that women in the trial who receive placebo are not being made worse off than they would be if they we