Ethics in healthcare 4

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 were not in the trial at all. That is what is meant by “standard of care” in this context. (C. Levine 1998, p. 47)

(2) In developing countries, the standard of care . . . is not based on a consideration of alternative treatments or previous clinical data, but is instead an economically determined policy of governments that cannot afford the prices set by drug companies. . . . Acceptance of a standard of care that does not conform to the standard in the sponsoring coun- try results in a double standard in research. Such a double standard, which permits research designs that are unacceptable in the sponsoring country, creates an incentive to use as research subjects those with the least access to health care. (Lurie and Wolfe 1997, p. 855)

(3) “Standard of care” is a concept borrowed from the medical-legal con- text, denoting the level of conduct against which a physician’s or health provider’s treatment of a patient will be judged in determining whether such conduct constitutes negligence. It generally means: “what a rea- sonably prudent physician (or specialist) would do in the same or simi-

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lar circumstances” (Annas 1993, p. 4). Defined in this way, it can mean- ingfully describe the types or level of treatments provided to patients in the clinical setting, but it might not serve as a justification for what ought to be provided to participants in research. (NBAC 2000, p. 13)

(4) Firstly, there has been a failure to define adequately the “standard of care.” Secondly, it has been incorrectly assumed that the standard set by developed countries can be considered the norm. . . . It is arbitrary and not justifiable to select only one [requirement] . . .–for example, which drugs are used–to compare the standard of care in developed and developing countries. . . .The United States’s standard of care should not be emulated throughout the world. (Benatar and Singer 2000, pp. 824-25)

(5) [T]his debate has been complicated by some unrecognized ambiguities in the notion of a standard of care. . . . [T]his concept is ambiguous along two different axes, with the result that there are at least four possible standard of care arguments that must be clearly distinguished. (London 2000, p. 381)

(6) There are strong practical as well as principled reasons for Americans to follow American ethical standards when they do research abroad. (Rothman 2000, no page number)

(7) We can also see why we should not expect a single standard of research to govern all study designs. There are a variety of ethical principles that apply to research on human subjects, and they sometimes conflict. . . . In order to achieve an optimal balance of these different ethical stan- dards, we need to take into account various social, cultural economic, political, as well as scientific factors. . . . One might even argue that it is unjust, unfair, and insensitive to demand that the exact same standards of research that govern study designs in developed nations should also be implemented in developing countries. (Resnik 1998, pp. 304-5)

(8) When Helsinki calls for the “best proven therapeutic method” does it mean the “best therapy available anywhere in the world”? Or does it mean the standard that prevails in the country in which the trial is conducted? . . . [T]he best proven therapy standard must necessarily mean the standard that prevails in the country in which the clinical trial is carried out. (R. Levine 1998, p. 6)

(9) It is clear that the pressures to lower the ethical standards set by the DoH [Declaration of Helsinki] are primarily economic–it costs less to

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run a trial where you do not have to provide for medical care. . . . So let us push to keep the highest ethical standards applied everywhere . . . . (Greco 2000, p. 97)

(10) Just because the obligation to make research products available to the host country after the trial is over is not the prevailing international standard does not mean it is not an ethical standard to which we should aspire. (Page 2000, p. 20)

What are we to make of these assorted claims? Is the question of what ethical standard should prevail in international research a hopeless sea of confusion? Is it an ethical domain like some others, in which reasonable people can disagree? Or are some of the opponents in this debate simply unreasonable? One good starting point would be to identify and seek to clear up ambiguities that lurk in the terms of these debates. Three of the sources of the statements quoted above strive to do just that.

In the first of these (3), the National Bioethics Advisory Commission’s report distinguishes between the original (and typical) context in which “standard of care” is invoked–the clinical setting–and questions whether the concept can be uncritically imported into the research setting. The NBAC report makes a further observation:

. . . an ambiguity lurks in the term “standard,” which sometimes means “what is normally done,” as in “standard practice.” In this meaning, “stan- dard practice” in some countries—such as reusing syringes or other dispos- able equipment—would not be acceptable to U.S. researchers and would not constitute a justification to employ the local, unsafe practice. But “stan- dard” can also refer to a level that must be attained, as in “a standard for admission to medical school,” or “the standard for maintaining hygienic practice in treatment and research.” In this latter sense, U.S. researchers would be bound by the proper medical standard that prohibits the reuse of disposable equipment, even if reuse is standard practice in some countries. (NBAC 2000, p. 13)

In the second source (4), the authors propose a new analysis of “stan- dard of care,” arguing that equal standards of medical care during re- search could be taken to mean any one or a combination of several re- quirements, encompassing more than simply medications or other “proven” therapies. Among the five elements specified in this “expanded” concept for standard of care are “[r]esearch undertaken by a team of the same culture and language group as the subjects, so that the same degree of effective communication, trust, and genuine informed consent is

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achieved through a legitimate informed decision making process;” and “[c]are provided by a research team with equivalent qualifications, train- ing, and expertise” (Benatar and Singer 2000, p. 824). The authors also propose an “alternative” concept of standard of care, one they contend could be achieved globally despite existing or future economic inequali- ties. This alternative concept is geared toward clinical trials in developing countries, and includes undertaking only such research that will be of benefit to the community being researched, and translating research find- ings into components of accessible care in the community being researched (Benatar and Singer 2000, p. 825).

The third and most sustained analysis (5) identifies four different inter- pretations of “standard of care” culled from the literature. The first two interpretations arise as a result of two different relevant reference points, harking back to the quotation cited above in (8): Does “best proven therapy” mean the “best therapy available anywhere in the world”? Or does it mean the standard that prevails in the country in which the trial is conducted? These two reference points are termed “global” and “local” and give rise to two different judgments of what “standard of care” means. However, limiting the debate to these two reference points is simplistic and fails to capture a more subtle yet crucial distinction found in the second pair of interpretations. This latter pair is termed “de facto” and “de jure.” The de facto interpretation uses “standard of care” to mean that the standard of medical practices in a community is determined by the actual medical practices in that community. In other words, the stan- dard of care is no more than a description of what, in fact, occurs. The de jure concept, on the other hand, interprets the “standard of care” as that determined by the judgment of experts in the medical community regard- ing which diagnostic and therapeutic practices have proven most effective.

Full details of this complex analysis cannot be reproduced here. The author concludes by opting for the “local, de jure” interpretation of “stan- dard of care” because it rejects the “bad, if not perfidious” local, de facto standard while still permitting research to go forward that may not meet the stringent requirements of the “global de jure” standard. However, the local, de jure standard would not permit researchers knowingly to deny subjects care that has proven effective for their illness in their population, and thus ensures that subjects of clinical research in developing countries are not exploited. At the same time, this standard requires attention to substantive differences in social, cultural, and economic contexts and their impact on the permissibility of international research.

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SEEKING RESOLUTIONS

Armed with these proposed new definitions and multiple interpreta- tions of the terms “standard” and “standard of care,” are opponents in the controversies over international research likely to resolve their differ- ences? Alas, I fear not. My pessimism stems from several factors. First and foremost is the prevalence of “the method of tenacity” (borrowed from the philosopher, Charles Sanders Peirce (1955))4 in maintaining a belief system. Defenders of the view that the local, de facto standard of care is ethically appropriate because subjects are not being made worse off are not likely to alter their position when confronted with a de jure standard that may require more by way of care or treatment than re- search subjects would receive outside a trial. What counts for the de facto group is simply that research subjects are not made worse off as a result of their participation than they were before the research began. Similarly, those who interpret the Declaration of Helsinki in terms of the global, de jure standard–requiring the best current methods “anywhere in the world”– are not likely to be persuaded by the subtlety of arguments that would permit the local de jure standard in some circumstances.

A second factor that makes resolution of disagreements unlikely is the limited power of persuasive definitions. Those who understand “stan- dard of care” in its narrowest meaning—referring only to which drugs are used for a control group in a clinical trial—are not likely to abandon that meaning in favor of an expanded or alternative concept proposed by even the most thoughtful bioethicists who argue both for the need to attend to morally relevant considerations of context and for the equally important need to reduce the huge inequities in global health (Benatar and Singer 2000).

Still another reason why opponents in at least some debates over the ethics of international research will not come to agree is that they accord higher priority to different ethical principles that come into conflict. Resnik (1998, p. 305) says of the disputed placebo-controlled perinatal trans- mission studies that “the conflict can be viewed as beneficence and in- formed consent versus scientific rigor, justice and social utility.” Brennan (1999) also identifies a conflict of ethical principles, this time the conflict is utilitarianism (understood as efficiency) versus distributive justice and “the investigator’s moral duty to the research subject.” However, since Resnik comes down on the side of defending those trials, he considers that justice supports them. Brennan, on the other hand, comes down on

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the side of opposing the disputed trials, and finds justice to be on his side of the controversy. Obviously, people are not willing to concede that jus- tice lies anywhere but on the side they support.

This result is not surprising, since “justice” is not an unambiguous concept and there is not a single, unequivocal principle of justice that can be applied in assessing the ethics of international research (Macklin 1998). According to one interpretation, it is unjust to use a particular study de- sign in a developing country when that same study design could not be used in the industrialized country sponsoring the research because it vio- lates the precept, “treat like cases alike, different cases differently.” An alternative interpretation contends that the cases are not alike since facts and circumstances differ in the developed and developing countries. This is an interesting philosophical debate, one that involves a deeper analysis than can be provided here (Macklin 1998).

Concluding that a resolution to these controversies might require philo- sophical analysis is not without its dangers, however. To appreciate the cynicism with which philosophers and bioethicists are viewed in some quarters in mainstream medicine, one has only to look at the comments in an editorial entitled “The Ethics Industry” that appeared in The Lan- cet. The editorial accuses “the ethics industry” (that’s us) of being “oddly parochial” and “rooted in armchair moral philosophy.” And further: “De- partments of ethics that are divorced from the medical profession, wal- lowing in theory and speculation, are quaintly redundant” (Editorial 1997, p. 897). Most interesting, however, is The Lancet’s quick and certain judg- ment of the most controversial studies of the past decade:

Most of the dilemmas upon which ethicists thrive can be solved by appeal to principles fundamental to medical practice worldwide—that doctors do no harm to patients, that doctors do their best for patients. . . . It does not require recourse to the opposing arguments of 18th century philosophers to work out that the placebo-controlled trials of antiretroviral drugs to prevent perinatal transmission of HIV infection…infringe the first prin- ciple. Women in the placebo-treated group were harmed by receiving no effective treatment to prevent transmission of HIV to their children (Edito- rial 1997, p. 897).

Without recourse to novel interpretations of “standard of care” or pro- posed new definitions, without appeal to debates about the proper role of efficiency and economics in international research, and surely without recourse to philosophical principles of justice, The Lancet drew its con-

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clusion about the ethics of the placebo-controlled trials. All it needed was an appeal to the “first principle” of medical practice worldwide—“that doctors do no harm to patients.”

To end on a more positive note, let me return to the earlier discussion of exploitation. It serves as a reminder of why research in developing countries raises somewhat different (or at least more serious) problems than research conducted in the United States or other industrialized countries. The earlier discussion drew the unsatisfying conclusion that what is required is a full account of exploitation in the context of international research, one that opponents in these various disputes could be likely to agree upon. But the problem noted there is that the very factors that give rise to the dispute are the ones that will lead critics of the research to make the charge of exploita- tion and defenders to reject that allegation. A different approach focuses not so much on what constitutes exploitation, but instead on criteria for deter- mining the vulnerability of subject populations or individual subjects.

A UNAIDS Guidance Document takes this approach in two of its guid- ance points (UNAIDS 2000). Guidance Point 3 lists factors that may in- crease vulnerability to exploitation of host countries and communities, including: the level of the proposed community’s economic capacity; a community’s experience with and/or understanding of scientific research; a community’s level of experience and capacity for conducting ethical and scientific review; and the local infrastructure, personnel, and techni- cal capacity for conducting the proposed research (UNAIDS 2000, pp. 15-16). Guidance Point 7 lists additional factors that create conditions for possible exploitation or increased vulnerability among research participants. These include social and legal marginalization of groups from which partici- pants might be drawn; limited availability, accessibility, and sustainability of health care and treatment options; limited ability of individuals to un- derstand the informed consent process; and limited ability of individuals to be able to give freely their informed consent in the light of prevailing class, gender, and other social and legal factors (UNAIDS 2000, p. 23).

If researchers, sponsors, and ethical review bodies were to undertake a systematic review of these conditions prior to preparing a research proto- col to implement in developing countries, it might provide a better way to assess vulnerability to exploitation in advance of initiating the research rather than opening it up to allegations once the research is underway. This type of prior investigation of the context in which the research is to be conducted will not appeal to those who seek to begin research as quickly as possible, either in order to reach scientific conclusions about safety

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and efficacy or, in the case of industry, to reap the maximum possible profits. As one thoughtful researcher has put it:

The proclaimed and real urgency of many countries is for an efficacious vac- cine, drug, preventive or diagnostic method and not for a clinical trial—these trials can be done in other countries/regions/communities with similar inci- dences of infection or disease, but without the vulnerability of the already destitute. In certain situations even the government and the investigators may be considered vulnerable—e.g., the possibility of getting research money and of enhancing one’s career may act as inducers for doing trials” (Greco 2000).

If some resolution of these controversies in international research comes down to the age-old battle between economics and efficiency on one side, and ethics on the other, then let ethics win out.

NOTES

1. I was a participant in the conference and these observations are taken from my notes. The comments of the Chilean researcher were not reflected in the published Discussion Paper.

2. Dr. Mbidde’s letter was sent to Dr. Varmus in response to the Public Citizen News Release of 22 April 1997. Public Citizen subsequently faxed copies of Dr. Mbidde’s letter to individuals on their mailing list.

3. For a full analysis of the general concept of exploitation, see Alan Wertheimer (1996).

4. Although the phrase, “the method of tenacity” is borrowed from Peirce, his explanation of the method is somewhat different from my description here.

REFERENCES

Angell, Marcia. 1997. The Ethics of Clinical Research in the Third World. New England Journal of Medicine 337: 847-49.

Annas, George J. 1993. Standard of Care. New York: Oxford University Press. ———, and Grodin, Michael A. 1998. Human Rights and Maternal-Fetal HIV

Transmission Prevention Trials in Africa. American Journal of Public Health 88: 560-63.

Benatar, Solomon R., and Singer, Peter A. 2000. A New Look at International Research Ethics. British Medical Journal 321: 824-26.

Brennan, Troyen A. 1999. Proposed Revisions to the Declaration of Helsinki– Will They Weaken the Ethical Principles Underlying Human Research? New England Journal of Medicine 341: 527-31.

MACKLIN • UNRESOLVED ISSUES IN INTERNATIONAL RESEARCH

[ 35 ]

CIOMS. Council for International Organizations of Medical Sciences. 1993. In- ternational Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: CIOMS.

Crouch, Robert A., and Arras, John D. 1998. AZT Trials and Tribulations. Hastings Center Report 28 (6): 26-34.

Del Río, Carlos. 1998. Is Ethical Research Feasible in Developed and Developing Countries? Bioethics 12: 328-30.

Editorial. 1997. The Ethics Industry. The Lancet 350: 897. Glantz, Leonard H.; Annas, George J.; Grodin, Michael A.; and Mariner, Wendy

K. 1998. Research in Developing Countries: Taking “Benefit” Seriously. Hastings Center Report 28 (6): 38-42.

Grady, Christine. 1998. Science in the Service of Healing. Hastings Center Re- port 28 (6): 34-38.

Greco, Dirceu B. 2000. Revising the Declaration of Helsinki: Ethics vs. Econom- ics or the Fallacy of Urgency. Canadian HIV/AIDS Policy & Law Newslet- ter 5 (4): 94-97.

Kass, Nancy, and Hyder, Adnan. 2000. Attitudes and Experiences of U.S. and Developing Country Investigators Regarding U.S. Human Subjects Regula- tions. In Ethical and Policy Issues in International Research, Part F, Na- tional Bioethics Advisory Commission. Paper prepared for NBAC and avail- able in Vol. II.

Levine, Carol. 1998. Placebos and HIV: Lessons Learned. Hastings Center Re- port 28 (6): 43-48.

Levine, Robert J. 1998. The “Best Proven Therapeutic Method” Standard in Clinical Trials in Technologically Developing Countries. IRB: A Review of Human Subjects Research 20 (1): 5-9.

———. 1999. The Need to Revise the Declaration of Helsinki. New England Journal of Medicine 341: 531-34.

Lie, Reidar K. 1998. Ethics of Placebo-Controlled Trials in Developing Nations. Bioethics 12: 307-11.

London, Alex John. 2000. The Ambiguity and the Exigency: Clarifying “Stan- dard of Care” Arguments in International Research. Journal of Medicine and Philosophy 25 (4): 379-97.

Lurie, Peter, and Wolfe, Sidney. 1997. Unethical Trials of Interventions to Re- duce Perinatal Transmission of the Human Immunodeficiency Virus in De- veloping Countries. New England Journal of Medicine 337: 853-56.

Macklin, Ruth. 1998. Justice in International Research. In Beyond Consent: Seek- ing Justice in Research, ed. Jeffrey Kahn, Anna Mastroianni, and Jeremy Sugarman, pp. 131-46. New York: Oxford University Press.

KENNEDY INSTITUTE OF ETHICS JOURNAL • MARCH 2001

[ 36 ]

NBAC. National Bioethics Advisory Commission. 2000. Ethical and Policy Is- sues in International Research. Washington, DC: NBAC.

Nuffield Council on Bioethics. 1999. Ethical Issues in Research In Developing Countries. Discussion paper.

Okie, Susan. 2000. Health Officials Debate Ethics of Placebo Use. Washington Post (24 November): A03.

Page, Alice. Unpublished (2000). Prior Agreements in International Clinical Tri- als: Ensuring the Provision of Drugs and Other Research Benefits to Devel- oping Countries. Background paper prepared for the National Bioethics Advisory Commission.

Peirce, Charles Sanders. 1955. The Fixation of Belief. In Philosophical Writings of Peirce, ed. Justus Buchler, pp. 5-22. New York: Dover Publications.

Resnik, David B. 1998. The Ethics of HIV Research in Developing Nations. Bio- ethics 12: 286-306.

Rothman, David J. 2000. The Shame of Medical Research. New York Review of Books (30 November): PDF file, unpaginated. Available at: http:// www.nybooks.com/nyre/WWWfeatdisplay.cgi?20001130060F.

Schüklenk, Udo. 1998. Unethical Perinatal HIV Transmission Trials Establish Bad Precedent. Bioethics 12: 312-19.

———, and Ashcroft, Richard. 2000. International Research Ethics. Bioethics 14: 158-72.

Thomas, Joe. 1998. Ethical Challenges of HIV Clinical Trials in Developing Countries. Bioethics 12: 320-27.

Varmus, Harold, and Satcher, David. 1997. Ethical Complexities of Conducting Research in Developing Countries. New England Journal of Medicine 337:1003-5.

UNAIDS. 2000. Ethical Considerations in HIV Preventive Vaccine Research: UNAIDS Guidance Document (May). Geneva, Switzerland: Joint United Nations Programme on HIV/AIDS.

Wendler Dave. 2000. Informed Consent, Exploitation and Whether It Is Possible to Conduct Human Subjects Research Without Either One. Bioethics 14: 310-39.

Wertheimer, Alan. 1996. Exploitation. Princeton, NJ: Princeton University Press. World Medical Association. 2000 [1964]. Declaration of Helsinki, as amended

by the WMA 52nd General Assembly, Edinburgh, Scotland, October 2000.