266 CHAPTER 4

CLINICAL TRIALS I N DEVELOPING COUNTRIES

RESEARCH IN DEVELOPING COUNTRIES: TAKING BENEFIT SERIOUSLY Leonard If. Glant:. George J. Antlas, Micl~ael A. Grodin, and Wendy K. Mariner

The authors confront the issue of whether it can be acceptaide for researchers in wealthy countries to enroll citizens of developing countries in clinical trials. Citing guidelines published I>y the Council for International Organizations of Medical Sci- ences, the authors argue that t o justify such trials, the risks or burdens imposed o n trial participants must be offset by the prospect of actual benefit to the inhabitants of the developing country. Thus, if the trial yields beneficial knowledge, benefits l l l ~ ~ s t i~ctually reach individuals in the country in which the trial took place; other- wise, the subjects will have been exploited. A practical implication of this approach is that "an essential prerequisite to designing ethical research in underdeveloped countries is identifying the source and amount of funding for providing the fn~ i t s of the research to the people of the developing countryn-a moral requirement that was not satisfied in recent African AZT studies. The authors then consider and reply to a wide range of objections to the ethical standard they propose.

An April 1998 New York Times Magazine article de- scribed Ronald Munger's efforts to obtain blood samples from a group of extremely impoverished people in the Philippine Island of Cebu.' Munger sought the blood to study whether there was a ge- netic cause for this group's unusually high incidence of cleft lip and palate. One of many obstacles to the research project was the need to obtain the coopera- tion of the local health officer. It was not clear to Munger, or the reader, whether the health officer had a bona fide interest in protecting the populace or was looking for a bribe. The health officer asked Munger a few perfunctory questions about informed consent and the study's ethical review in the United States, which Munger answered. Munger also explained the benefits that mothers and children would derive from participating in the research. The mothers would learn their blood types (which they appar- ently desired) and whether they were anemic. If they were anemic, they would be given iron pills. Lunch would be served, and raffles arranged so that fami- lies could win simple toys and other small items.

Reprinted with pertnission of Leonard H. Glaritz al~d lhe publisher from Hrt.$rirlgs CEII~PI. Repor!, vol. 28 (November-December 1998). pp. 3842. Copyright 0 1998 by The Hasr~ngs Center.

Munger told the health officer that if his hy- potheses were correct, the research would benefit the population of Cebu: if the research shows that in- creased folate and vitamin B6 reduces the risk of cleft lip and palate, families could reduce the risk of facial deformities in their future offspring. The re- porter noted that the health officer "laughs aloud at the suggestion that much of what is being discovered in American laboratories will make it back to Cebu any time soon." Reflecting on his experience with another simple intervention, iodized salt, the health officer said that when salt was iodized, the price rose threefold "so those who need it couldn't afford it and those who didn't need it are the only ones who could afford it."

The simple blood collecting mission to Cebu il- lustrates almost all the issues presented by research in developing countries. First is the threshold ques- tion of the goal of the research and its importance to the population represented by the research subjects. Next is the quality of informed consent, including whether the potential subjects thought that partici- pation in the research was related to free surgical care that was offered in the same facility (although it clearly was not) and whether one could adequately explain genetic hypotheses to an uneducated popu-

HUMAN AND ANIMAL RESEARCH 267

lace. Finally, there is the question whether the popu- lation from which subjects were drawn could bene- fit from the research. This research intervention is very low risk-the collection of 10 drops of blood from affected people and their family members. The risk of job or insurance discrimination that genetic research poses in this country did not exist for the Cebu population; ironically, they were protected from the risk of economic discrimination by the pro- found poverty in which they lived.

Even this simple study raises the most funda- mental question: "Why is it acceptable for re- searchers in developed countries to use citizens of developing countries as research subjects?" cau- tionary approach to permitting research with human subjects in underdeveloped countries has been rec- ommended because of the risk of their inadvertent or deliberate exploitation by researchers from devel- oped countries. This cautionary approach generally is invoked when researchers propose to use what are considered "vulnerable populations," such as pris- oners and children, as research subjects.' Vulnerable populations are those that are less able to protect themselves, either because they are not capable of making their own decisions or because they are par- ticularly susceptible to mi~treatment.~ For example, children may be incapable of giving informed con- sent or of standing up to adult authority, while pris- oners are especially vulnerable to being coerced into becoming subjects. Citizens of developing countries are often in vulnerable situations because of their lack of political power, lack of education, unfamil- iarity with medical interventions, extreme poverty, or dire need for health care and nutrition. It is the dire need of these populations that may make them both appropriate subjects of research and especially vulnerable to exploitation. This combination of need and vulnerability has led to the development of guidelines for the use of citizens of developing countries as research subjects.

CIOMS GUIDELINES

lines for the appropriate use of research subjects from "underdeveloped comrn~nities."~

Like other human research codes, the CIOMS guidelines combine the protection of subjects' rights with protection of their welfare; as subjects become less able to protect their own rights (and therefore become more vulnerable), researchers and review- ers must increase their efforts to protect the welfare of s ~ b j e c t s . ~ Perhaps the most important statement in these guidelines is what appears to be the injunc- tion against using subjects in developing countries if the research could be carried out reasonably well in developed countries. Commentary to guideline 8 notes, for example, that there are diseases that rarely or never occur in economically developed countries, and that prevention and treatment research therefore needs to be conducted in the countries at risk for those diseases. The conclusion to be drawn from the substance of these guidelines is that in order for re- search to beethically conducted, it must offer the po- tential of actual benefit to the inhabitants of that developing country.

In order for underdeveloped communities to de- rive potential benefit from research, they must have access to the fruits of such research. The CIOMS com- mentary to guideline 8 states that, "as a general rule, the sponsoring agency should ensure that, at the com- pletion of successful testing, any product developed will be made reasonably available to inhabitants of the underdeveloped community in which the research was carried out: exceptions to this general requirement should be justified, and agreed to by all concerned par- ties before the research is begumw6 This statement is directed at minimizing exploitation of the underdevel- oped community that provides the research subjects. If developed countries use inhabitants of underdevel- oped countries to create new products that would be beneficial to both the developed and the underdevel- oped country, but the underdeveloped country cannot gain access to the product because of expense, then the subjects in the underdeveloped countries have been grossly exploited. As written, however, this CIOMS guideline is not strong or specific enough to prevent exploitation. Exemplifying this problem are recent

In 1992, the Council for International Organizations short course zidovudine (AZT) studies in Africa that of Medical Sciences (CIOMS), in collaboration with were approved and conducted despite the existence of the World Health Organization, published guide- the CIOMS guidelines.'

T H E AFRICAN MATERNAL-FETAL H I V TRANSMISSION STUDIES

The goal of the short course AZT studies was to see if lower doses of the drug AZT than those used in the United States could reduce the rate of maternal-child transmission of HIV. It was well established that doses of AZT that cost $800 (not taking into account screening and other related costs) reduced maternal- fetal transmission of HIV by as much as two-thirds in the United state^.^ If the developed countries had been willing to subsidize the cost of this regimen in Africa, no additional research would have been needed. But because many African countries could not afford this expense, the decision was made to at- tempt to see if lower (and therefore cheaper) doses would prevent maternal-fetal HIV transmission. Several impoverished countries were chosen as re- search sites. The justification for conducting re- search in those countries was not that they suffered from a disease that did not afflict people in devel- oped countries, and not because no treatment ex- isted, but because their impoverishment made an existing therapy unavailable to them (as long as de- veloped countries refused to subsidize the costs).1°

The issue, as always, is to determine the ethical acceptability of the proposed research before it is conducted. In acase like this, where the researchable problem exists solely because of economic reasons, the research hypothesis must contain an economic component. The research question should be formu- lated as follows:

( 1) We know that a given regimen of AZT will re- duce the rate of maternal-child transmission of HIV.

(2) Maternal-child transmission of HIV in many African countries is a serious problem but the effec- tive AZT regimen is not available because it is too expensive.

(3) If an effective AZT regimen costs $X, then it will be made available in the country in which it is to be studied.

(4) Therefore, we will conduct trials in certain African countries to see if $X worth of AZT will ef- fectively reduce maternal-child transmission of HIV in those countries.

The most important part of the development of this research question is number 3. Without knowing what dollar amount X actually represents, it is im-

possible to formulate a research question that can lead to any benefit to the citizens of the country in which the research is to be conducted. There is no way to determine what $X represents in the absence of committed funding. Therefore, an essential pre- requisite to designing ethical research in underde- veloped countries is identifying the source and amount of funding for providing the fruits of the re- search to the people of the developing country in which it is to be studied as a condition of the re- search being approved.

If a study found, for example, that $50 worth of AZT has the same effect as $800 worth of AZT, it would greatly benefit the developed world. Devel- oped countries, which currently spend $800 per case on drugs alone, could pay substantially less for this preventive measure, and, because the research was conducted elsewhere, none of their citizens would have been put at any risk. At the same time, if the un- derdeveloped country could not afford to spend $50 any more than it could spend $800, then it could not possibly derive information that would be of any benefit to its population. This is the definition of exploitation. "

It is only now that an effort is being made to de- termine how to raise the money to actually provide AZT to prevent maternal-child HIV transmission (as 3

well as the other costly services that go with the ap- 5 propriate administration of the drug) to the impover- j ished African countries that provided the human i subjects.I2 These efforts began after parallel studies j conducted in Thailand reported that lower doses of I AZT reduced maternal-fetal transmission of HIV.'~ !

r' The Thai government had committed to providing 5 the AZT before its trials began. In the African trials, 1 however, no one "ensured" that at the completion of successful testing the product would be made rea-

4

i sonably available, thereby violating the CIOMS 4 guidelines.14 The guidelines say that there can be ex- t ceptions to this general requirement, but that excep- ; tions must be "justified" and "agreed to by all concerned parties." It is not clear to whom the ex- J ception must be "justified" or on what grounds. I

Moreover, if the "concerned parties" are the sponsor and/or the Investigator and the host country, they may not adequately represent the interests of the re- search subjects. The fact that representatives of the

HUMAN AND ANIMAL RESEARCH 269

community and officials of the host coun- search only has the potential to benefit the limited tries agree to exploit the population does not make number of individuals who participate in the study, the research any less exploitive.I5 it cannot offer the benefit to the underdeveloped

country that legitimizes the use of its citizens as re- RULES RESEARCH IN search subjects. It should be emphasized that re- DEVELOPING COUNTRIES search whose goal is to prevent or treat large We believe the standards for research in developing countries should include the following.

There should be a rebuttable presumption that researchers from developed countries will not con- duct research in developing countries unless it can be shown that a direct benefit will be bestowed upon the residents of that country if the research proves to be successful. The person or entities proposing to conduct the study must demonstrate that there is a realistic plan, which includes identified funding, to provide the newly proven intervention to the popu- lation from which the potential pool of research sub- jects is to be recruited. In the absence of a realistic plan and identified funding, the population from which the research subjects will be drawn cannot de- rive benefit from the research. Therefore, the bene- fits cannot outweigh the risks, because there are, and will be, no benefits. Only by having committed funding and a plan to make a successful intervention available can it be determined that there will be suf- ficient benefit to justify conducting research on the target population. The distribution plan must be re- alistic. Where the health care infrastructure is so un- developed that it would be impossible to deliver the intervention even if it were free, research would be unjustified in the absence of a plan to improve that country's health care delivery capabilities.

Some might argue that this standard is too strict and that it would reduce the amount of research that could be conducted in certain countries. The answer, of course, is that if the benefits of the research are not made available to the inhabitants of that country, they have lost nothing by the lack of such research. Others might argue that research in underdeveloped :ountries is justified if it might benefit the individ- ~ a l research subjects, even if it will not benefit any- me else in the population. However, research is, by lefinition, designed to create generalizable knowl- :dge, and is legitimate in a developing country only f its purpose is to create generalizable knowledge hat will benefit the citizens of that country. If there-

populations is fundamentally public health research, and public health research makes no sense (and thus should not be done) if its benefits are limited to the small population of research subjects.

It might be argued that there is no requirement that such a plan be devised prior to conducting re- search in the United States, and, therefore, that by adopting such a requirement we would be imposing a higher standard for research conducted in develop- ing countries than we do for research conducted in the United States.

This argument only further demonstrates the dif- ferences between wealthy and poor countries. The re- ality in the United States is that regardless of the very significant gaps in insurance and Medicaid coverage and the health care discrepancies between the rich and poor, medical interventions are relatively widely available, especially when compared to developing countries. Upon the successful completion of the re- search that demonstrated the effectiveness of the 076 regimen in reducing maternal-child transmission, the primary beneficiaries of this new preventive interven- tion in the United States were poor women and their newborns. Unlike the United States, absent a plan to pay for a new intervention and lacking the infrastruc- ture to deliver an intervention, it is virtually guaran- teed that the intervention will not be generally available in a developing country.

The more accurate analogy to the African AIDS trials would be if investigators proposed the 076 pro- tocol in the United States knowing that only poor women would be recruited as research subjects and that, if successful, the intervention would not be made generally available to poor women. Such re- search would be clearly unethical. Not only would this be a gross violation of the ethical principle of distributive justice, it would be a violation of the regulatory obligation of the equitable selection of subjects.16

A further objection is that one cannot always trust what a government or another potential funder

promises. What is to prevent the promisor from reneging? The answer is, nothing. One can try to ex- pose the funder to embarrassment and other pres- sures that might cause it to live up to the promise upon which researchers and subjects relied. How- ever. the potential unethical behavior in the future by the funder is no excuse for not having a realistic plan at the outset. Furthermore, if we take this obligation seriously, this should only occur once per funder. Af- ter reneging once, they cannot be relied upon again to justify research in the future.

An additional objection to our position is that it will restrict access to new interventions because once a new intervention is developed, the price will come down and therefore the intervention will be- come available to the people of the impoverished country. The answer is to ask those who control the pricing of interventions if this will be the case in any particular instance. One could have asked Glaxo if it would reduce its price once it was shown that lower doses of AZT were effective. If the answer is yes, one can proceed. If the answer is no, or "we have not decided," there seems to be no justification to pro- ceed if the current price would significantly restrict availability. There is nothing magical about pricing. Pricing is in the absolute control of manufacturers and there is no need to guess or speculate about what will happen to price. Indeed, this objection to our ar- gument would justify conducting the full 076 trial it- self in developing countries. The price might come down enough so that determining the efficacy of short course AZT regimens might not be needed at all. Such speculation should not be sufficient to put subjects at risk.

Finally, it might be argued that there are dis- eases that only affect people in developing countries for which there are no effective treatments, but that the treatments that might be discovered could be ex- pensive. The argument continues that it is not right to fail to develop treatments that could benefit some affected people because it will not be available to most affected people. This objection raises quite a different issue from the one addressed in this article. The impetus for such research is the absence of ef- fective treatment and not the absence of economic resources. We have discussed research intended to

determine whether effective but unaffordable inter- ventions would work if used in lower, less expensive dosages. The researchable issue arises from an eco- nomic circumstance. The only way such research could offer any benefit is by "curing" the economic problem by establishing that the less expensive form of the intervention will be affordable and available. Absent knowledge of financial resources, one might well be creating a new unaffordable. and therefore useless, intervention. In contrast, in the case in which one is developing a new intervention, not be- cause of poverty, but because no known effective in- tervention exists, and the disease is prevalent in a particular geographic area, the issue is quite differ- ent. In such a case one is not conducting research to try to "cure" the effects of poverty but rather because of the need to create new knowledge to treat a cur- rently untreatable disease. However, even this case may raise problems similar to the ones addressed here. If one were to try to develop an intervention for such a condition and chose research subjects from impoverished segments of a society, knowing that only the richest segment of that society could bene- fit from that intervention, such subject selection would be unethical for many of the reasons we have discussed.

Our proposal to require researchers and their funders to develop realistic plans to make their in- terventions available to the relevant population of the developing country in which the research is pro- posed should not be controversial. It is well accepted in principle not only by groups like CIOMS, but by the funders of many of the African HIV trials, in- cluding the Centers for Disease Control and Preven- tion and the National Institutes of ~ e a l t h . " The principle is often honored in the breach, however. Research funders who hope that their studies will yield beneficial knowledge may neglect the steps necessary to ensure that the benefits will be made available. Ethical codes have not been sufficiently specific or enforceable to protect research subjects from exploitation. It is essential to replace vague promises with realistic plans that must be reviewed and approved before the research commences.

In at least one other instance it has been sug- gested that economic issues be addressed in the re-

HUMAN AND ANIMAL RESEARCH 27 1

view of proposed research projects. The U.S. Na- 6 Bankowski and Levine, EfhicsnndRe.~ecm.h, p. 26

tional Research Council's Committee on Human Emphasis added. 7 George Annas and Michael Grodin, "Human Rights and

Genome Diversity recommended that "Arrange- Maternal-Fetal HIV Transmission Prevention Trials in ments regarding financial interests in the products or Africa." Anzericnn Journal o f Public Health. 88. no. 4 outcomes of the research should be negotiated as (1998): 560-63.

part of the origirlal project review and informed- 8 Edward Connor. Rhoda Sperling. Richard Gelber et al..

consent proce~s." '~ "Reduction of Maternal-Infant Transmission of Human Immunodeficiency Virus Type 1 with Zidovudine

It is essential that the wealthier countries of the Treatment," NEJM 33 ( 1994): 173-80,

world use their resources, both financial and techno- 9 c.~ecommendation of the U.S. public ~ ~ ~ l ~ h service ~~~k logical. to help resolve the health problems that af- Force on the Use of Zidovudine to Reduce Prenatal

tlict the D O O ~ of the world. Doing SO will Transmission of Human lmmunodeficiency Virus," MMWR – undoubtedly require research. But research is a Morbidity and Mortality Weekly Reports 43 (1994): 1-20,

10 Harold Varmus and David Satcher, "Ethical Complexities of means to solving health problems, not an end in it- Conductine Research in Develo~int? Countries." NEJM 337 – . – self. The goal must be to create interventions that (1997): 1003-1005. ~. will benefit the people of the countries in which the 11 The per capita health care expenditures of most of the research is conducted. They will benefit onlv if the African countries involved in mother-to-child HIV

knowledge gained produces interventions that are transmission prevention trials range from $5 to $22 U.S. World Bank Sector Strategy Health Nutrition and

affordable and accessible. This needs to be deter- Population, 1997. mined as a condition of approval before research is 12 M. Bunce. wChirac Seeks Worldwide Relief f o r A I ~ S in conducted so that limited research funds are not Africa," Boston Globe, 8 December 1997.

wasted, and research subjects are not drawn from 13 "Administration of Zidovudine During Late Pregnancy and

populations that will not be able to benefit from the Delivery to Prevent Perinatal HIV Transmission-Thailand 1996-1998," MMWR Morbidity and Mortality Weekly

research. Reports 47. no. 8 (1998): 15 1-54. The editorial note states

REFERENCES

1 Lisa Belkin, "The Clues Are in the Blood," New York 7imes Magazine, 26 April 1998.

2 M~chael Grodin and Leonard Glantz, eds., Children as Research Subjects: Science. Ethics, and Law (New York: Oxford University Press. 1994).

3 Wendy K. Mariner, "Distinguishing 'Exploitable' from 'Vulnerable' Populations: When Consent Is Not the Issue," in Erhics and Research on Human Subjects: Proceedings, ed. Zbigniew Bankowski and Robert J. Levine (Geneva: CIOMS, 1993), pp. 44-55.

4 Zbigniew Bankowski and Robert 1. Levine. eds., Ethics and Research on Humun Subjects: lnternarional Guidelines (Geneva: CIOMS. 1993, pp. 25-32.4346.

5 Sharon Perley, Sev S. Fluss, Zbigniew Bankowski, and Francoise Simon. "The Nuremberg Code: An International Overview," in The Nazi Doctors and the Nuremberg Code, ed. George J . Annas and Michael A. Grodin (New York: Oxford University Press, 1992). pp. 149-73.

, . that "to implement these findings, ministries of health, donor agencies, and other interested agents should develop policies and practices to strengthen access to prenatal care, testing and counseling for HIV infections, and provision of ZDV for HIV-infected pregnant woman."

14 Bankowski and Levine, E~hics and Research, p. 45. 15 As the National Research Council's Committee on Human

Genome Diversity properly put it, in the context of research on human subjects, "rslensitivity to the special practices and beliefs of a community cannot be used as a justification for violating universal human rights." Committee on Human Genetic Diversity, Evaluating Human Genetic Diversity (Washington, D.C.: National Academy Press. l997), p. 65.

16 45 CFR 46.1 11 (a)(3). 17 Varmus and Satcher, "Ethical Complexities of Conducting

Research in Developing Countries." 18 Evaluating Human Genetic D i v e r s i ~ , at pp. 55-68.

Emphasis added.