oxford handbook of bioethics

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of Helsinki (1996). The standard of care for control groups, the use of placebos, and post-trial benefits were and still are intensely debated. These involve issues about responsibilities, obligations during and after research, justice, and exploitation.

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CL ASSIC CASES

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The first cases to reveal the importance of establishing guidelines in research ethics were the abuses during the Second World War. Nazi physicians forced people to drink seawater to find out how long a man could survive without fresh water. In Dachau, Russian prisoners were immersed in icy waters to see how long a pilot might live when shot down over the English Channel and to find out what kinds of protective gear or warming techniques were most effective. At Fort Ney, near Strasbourg, fifty-two prisoners were exposed to phosgene gas, a biologicalwarfare agent, in 1943 and 1944 to test possible antidotes. Again in Dachau, Ernst Grawitz infected prisoners with a broad range of pathogens to test homeopathic preparations. Nazi military authorities were worried about exotic diseases that German troops might contract in Africa or eastern Europe, and physicians in the camps reasoned that the ‘human materials’ at their disposal could be used to develop remedies. Hundreds of people died in these experiments, and many of those who survived were forced to live with painful physical or psychological scars (Annas and Grodin 1992).

These experiments were perpetrated during wartime and by Nazis. Germany at that time was scientifically highly advanced, and these experiments were conducted by German physician – researchers. In contrast to what was asserted in post-war apologies, physicians were never forced to conduct these experiments (Annas and Grodin 1992). However, these experiments represent aberrations in the field of nontherapeutic research; research subjects were prisoners of war in a situation of total subordination without any question of consent.

Variations on these kinds of abuse in times of peace and prosperity are the cases that were conducted during the so-called ‘gilded age of research’ in the United States. These cases were revealed by the anesthesiologist Henry Beecher in 1966 (Rothman 1991). For example, researchers explored different physiological responses, in one case inserting a special needle through a bronchus into the left atrium of the heart. This was done in an unspecified number of subjects, some with cardiac disease, some with normal hearts. The technique was a new approach whose hazards at the beginning were quite unknown. The subjects with healthy

hearts were used, not for their personal benefit, but for that of patients in general. In other cases researchers experimented to determine the period of infectivity of infectious hepatitis. Artificial induction of hepatitis was carried out in an institution for mentally defective children in which a mild form of hepatitis was endemic. As part of a study of cancer immunity live cancer cells were injected into twenty-two human subjects. According to a recent review, the subjects (hospitalized patients) were ‘merely told they would be receiving ‘‘some cells’’ . . . the word cancer was entirely omitted’ (Rothman 1991). All of these cases risked the lives and health of the individuals without their consent or approval. Beecher reported that only two of the original fifty protocols mentioned obtained consent; thus, his cases do not represent simply a few rare examples, but describe how mainstream investigators in the period between 1945 and 1965 exercised their broad discretion.

Baruch Brody illustrates this same point and adds data from other sources and countries. For example, he cites M. H. Pappworth, who published Human Guinea Pigs (Pappworth 1967), in which he alleged similar problems in British research. In Canada much attention was focused in the 1960s on the Halushka case, in which a subject in a study who had not received adequate information about what was involved suffered serious injury after the use of a new drug and invasive monitoring. In New Zealand investigations in the 1980s focused on research in the 1960s and 1970s in which women with cervical cancer were left untreated in order to study the natural history of the disease. As was expected, many developed invasive carcinoma, from which some died (Rothman 1991).

This is not merely a matter for nontherapeutic research. It concerns therapeutic research, isolated populations, and subjects with a deficient education who were being misled. All of these cases occurred in so-called ‘industrialized countries’ and express a characteristic problem of early bioethics: that of inadequate respect for the autonomy of the research subjects, where a solution would have been to enforce informed consent as a means of avoiding these mistakes. It is interesting that AIDS, in its early period, takes this model of research ethics to an extreme. AIDS patients – research subjects proposed that informed consent should be the only element to restrict research ethics (Merrigan 1990). However, the model does not hold: research ethics cannot be reduced to informed consent; even if it is a necessary condition for all research, it is not sufficient (see Luna 2001a).

During these early cases some safeguards were brought in, constituting the basis of early research ethics. The most relevant were: informed consent, the risk – benefit ratio, ethics committees, and confidentiality.

CL ASSIC PROBLEMS

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Research ethics initially focused on informed consent. The celebrated Nuremberg Code (1947), a consequence of the trials following the atrocities of the Nazi

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physicians, broke new ground. The document, produced by lawyers, focused on nontherapeutic research. Its obligation of informed consent was quite demanding and required that the subject be legally capable.

However, informed consent in itself has lost its privileged place: it was the first article of the Nuremberg Code but in the Declaration of Helsinki it is to be found in Article I.9 (WMA 1996). Informed consent is unquestionably one of the fundamental factors in research ethics. Based on the principle of respect for persons as outlined in the Belmont Report (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979), it implies the recognition of the autonomy of research subjects and the need for their authorization to participate in a clinical trial. It is worth stressing the emphasis on informed consent that is given in the analyses of research ethics stemming from the above cases (Brody 1998). But note that, despite the long tradition in implementing informed consent, it still poses problems. For example, we have to consider the amount and kind of information that must be presented — some consents appear to overwhelm the research subjects rather than inform them. Even if there is consent; respect for voluntariness appears to evade the rules in the case of research subjects who are so needy that the trial is their only access to treatment; or in the case of rural or very isolated communities where certain members have no decision-making power, for example, women.

However, as was mentioned earlier, consent alone cannot serve as the sole condition for acceptable research ethics. Other fundamental elements have begun to play important roles. One is the risk – benefit ratio (based on the principle of beneficence described in the Belmont Report). This implies two assessments: the first, to minimize possible risks; the second, to ensure that the possible benefits outweigh the possible risks to subjects (Brody 1998). It is a difficult assessment that deals with various factors, for example, the seriousness of the disease, the available alternative treatments, or the adverse effects of such treatments. Thus, the risk – benefit ratio of a treatment for AIDS at the onset of the epidemic when no treatment existed and the only alternative was death was different than it is today with drugs that improve patients’ quality of life.

Another factor that has begun to play an interesting role is the need for independent review, for example, through research ethics committees. These committees must assess the research protocols and check whether the ethical requirements have been thoroughly fulfilled. This practice began in the United States with the so-called institutional review boards (IRBs) and is currently accepted worldwide, although variations exist (Brody 1998).

Finally, among the crucial factors, confidentiality is key, for example, in the case of some diseases that can stigmatize patients such as psychiatric illness or the sexually transmitted diseases such as AIDS.

It is interesting to note how during this first period these analyses were shared internationally. After examining the Nuremberg Code, the Declaration of Helsinki,

the International Ethical Guidelines for Biomedical Research Involving Human Subjects, also known as the CIOMS Guidelines (CIOMS – WHO 1993), as well as some European and international documents, Baruch Brody says:

A clear-cut consensus has emerged in all of these official policies about the basic conditions for the permissibility of research on human subjects. Procedurally, such research needs to be approved in advance by a committee that is independent of the researchers. Substantially, informed voluntary consent of the subjects must be obtained, the research must minimize risks and involve a favorable risk – benefit ratio, there should be an equitable non-exploitative selection of subjects and the privacy and the confidentiality of the data must be protected. (Brody 1998)

I I

SO CIO-ECONOMIC CHANGES AND ACTORS IN

RE S E ARCH

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Nowadays, this broad consensus on protections and obligations to research subjects has disappeared (Schuklenk¨ 2004). To understand the dynamics and complexity of research today, the current debate, and the impact research has on developing countries, let us briefly examine the interests, concerns, and influence of the various actors in international research. They share the objective that clinical trials should be conducted correctly, although their agendas, interests, and main concerns may differ.

The Research Subject

One of the main actors in clinical trials is the person who constitutes the ‘research subject’. Obligations toward research subjects will depend on our conceptualization of them. Judith P. Swazey and Leonard Glantz examine society’s conception of its ethical obligation to research subjects and argue that the social concept of moral obligation may vary depending on whether we consider them altruistic heroes, gift-givers, willing contractors, or victims (Swazey and Glantz 1982). They propose these models on the specific issue of compensation for injured subjects. However, their analysis can be examined in a broader context, that is, in relation to our conception of a research subject in general. The altruistic hero or gift-giver is not a useful image to determine obligations. Heroes volunteer and assume risks for someone else’s sake. Since heroes are not supposed to seek reward, society has

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no obligation to compensate heroic research subjects. Likewise, with gift-givers, although such donors may not be morally entitled to compensation, society may desire to return the favor by compensating their injuries. In the following I shall only consider the cases of the contractor and the victim, which may be more relevant to the conception of a research subject than the above.

Willing contractors follow the model of the businessman striking a bargain: so long as the negotiation process is just, the contractors have a right to no more than what they bargained for. Victims are those who are treated unjustly or harmed without their consent. They can be especially vulnerable or the target of exploitative behavior and can do little to avoid these harms.

Is the willing contractor model acceptable? It appears to be so in the case of English or Swedish research subjects who can access a universal healthcare system. However, issues to consider are problems like ‘therapeutic misconception’ (that is, believing that research procedures have therapeutic aims) (Appelbaum et al. 1987), as well as the emotional stress caused by the extent of available therapeutic alternatives. Patients with access to current therapies are better off than those without; they can test the best current therapy or participate in a trial, weigh the risks and benefits, and decide. This may be an accurate description if we do not consider the severity of some diseases and the stress that the patient may be undergoing. However, aside from the accuracy of the situation of the Swedish research subject, this is not the case for someone who lives in absolute poverty and/or in a poor country. We have to be very careful when assessing the suitability and limits of informed consent in these situations. There might be variables (for example, extreme needs or distress) that can pose serious challenges to informed consent. How can patients negotiate when their only access to treatment is a clinical trial? Note that these are not perfect contracts. They occur in the real world and depend on the negotiating power of the actors. Onora O’Neill indicates the importance of the possibility of refusal or renegotiation in order to ascertain that consent is not a mere formality (O’Neill 1996). In cases such as this the possibility of refusal is fundamental in order to avoid a merely formal and vacuous consent. Even if it is not always a question of an unjust offer that someone cannot refuse (Wertheimer 1996), such proposals are closely related to potential exploitation. In regard to this possibility Thomas Pogge points out the limits of informed consent, especially in situations of extreme distress. The otherwise impermissible harming of another is not rendered permissible by this person’s prior rational consent when such consent is exacted as a condition of saving her from a horrible predicament or as a condition of giving her some chance of being so saved (Pogge 2003).

Should we endorse, then, the image of the victim? Swazey and Glantz assume a total lack of consent (for example, victims of the Nazis or from Tuskegee). The latter are clearly unethical models. On this view, victims appear to be entitled to assistance, having a strong moral claim to compensation, especially where society

has facilitated the research or benefited by it (Swazey and Glantz 1982). However, Swazey and Glantz’s proposal, focusing solely on the formality of informed consent, appears to take a narrow view of the concept of victim: other, subtle factors seem to weigh, for example, vulnerability.

The CIOMS – WHO Guidelines refer to vulnerable groups as ‘people receiving welfare benefits or social assistance and other poor people and the unemployed . . .

some ethnic and racial minority groups . . . members of communities unfamiliar with modern medical concepts’ (CIOMS – WHO 2002). According to this definition, many research subjects in countries with scarce resources may be deemed vulnerable. The Guidelines specify that to the extent that these and other classes of people have attributes resembling those of classes identified as vulnerable, the need for special protection of their rights and welfare should be reviewed, and applied where relevant.

Having been born destitute also conveys the situation of victim: people are not responsible for the social situation into which they have been born. The ‘social lottery’ can generate victims (though several analyses of justice try to avoid these ‘circumstances’ and ‘social lottery’ factors; Dworkin 1971; Rawls 1971; Sen 1980; Cohen 1993). The situation prior to informed consent may be unjust, and considerations about injustice and exploitation should be taken into account. Even if we cannot modify the initial conditions of the social lottery, we should not profit from its imbalance.

However, choosing one particular image of the research subject may prove simplistic. Neither the image of the willing contractor nor that of the victim is completely applicable to real-world research subjects, and something of each should be reflected in the concept. On the one hand, the individual is a willing contractor (hence the importance of informed consent), but in many cases, the person may also share the features of a victim (hence the importance of proper protection). Thus, in each research situation the model should be reevaluated for whether the individual is a willing contractor or a victim. This will help to establish the correct safeguards.

Who, then, are the actors in clinical research who can provide such an evaluation and protection if applicable?

Researchers

Researchers are principal actors in this process. They can design or influence the design of clinical trials. They also conduct the trials and are responsible for their implementation. Thus, it is in their interest that trials are conducted properly.

They may have diverse personal interests. Academic researchers may be particularly interested in publication, in making brilliant discoveries, or in raising their prestige. If they have been hired by the drugs industry, they may also be interested in matters of salary or in economic incentives.

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Another issue that merits examination is the role of the researcher on the ‘periphery’ of a trial. Given the structure of multicentric trials, researchers in developing countries play a different role from those involved in the ‘original’ design, which is done at the site that originated the research — generally in a industrialized country. As the same study must be replicated in different populations, there is little flexibility for researchers at other sites — generally in developing countries — to modify the design; thus, their role is quite marginal. This may also apply to researchers in industrialized countries who were not initially involved in the design.

In addition, we should not forget that scientific research has undergone a powerful transformation in recent decades. The paradigm of altruistic research in the name of the ‘progress of humankind’ has given rise to a kind of highly profitable research governed by market rules. Eloquent article titles illustrate this: ‘Academia and Industry: Increasingly Uneasy Bedfellows’, ‘Uneasy Alliance: Clinical Investigators and the Pharmaceutical Industry’ (Weatherall 2000; Bodenheimer 2000).

As Marcia Angell says:

The ties between clinical researchers and industry include not only grant support, but also a host of other financial arrangements. Researchers serve as consultants to companies whose products they are studying, join advisory boards and speakers’ bureaus, enter into patent and royalty arrangements, agree to be the listed authors of articles ghostwritten by interested companies, promote drugs and devices at company-sponsored symposiums, and allow themselves to be plied with expensive gifts and trips to luxurious settings. Many also have equity interest in the companies. (Angell 2000)

In fact, prestigious journals have referred to this troubling relationship between science and academia. For example, 27 per cent of discoveries could take over six months to be published; unforeseen or problematic findings may never be published. One problem is under-reporting (Pitch et al. 2003; Antes and Chalmers 2003). Researchers must sign strict confidentiality agreements with the drug companies (Angell 2000). In an attempt to solve these conflicts some of the more prestigious medical journals have begun to hold researchers responsible for the content of their articles, and they request that conflicts of interest be duly explained (Angell 2000).

Sponsors

Another category of actor in the research process comprises the pharmaceutical industry and private companies. These sponsors prioritize successfully developed research in order to obtain approval from the new drugs or procedures by regulatory agencies. However, the context and the rules are determined by the market. A day’s delay costs the pharmaceutical industry approximately $US1.3 million, so speedy approval is of key importance. Patents expire quickly, although they have recently been extended from fifteen to twenty years. The industry applies for a patent during

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need reliable information to consider adverse effects since they are responsible for preventing potentially harmful drugs from being launched on the market. The congruence and validity of the information and the design of the research are essential to matters of precision and safety.

One factor that regulatory agencies must consider is their responsibility to the population who will be using the new drug. The main concern of these agencies is to safeguard public health, and incorrect evaluation can affect the life and health of many people. This applies particularly to agencies in industrialized countries since they are responsible for approving the great majority of drugs that are launched worldwide. Regulatory agencies in developing countries have a low rate of approval for new drugs. Drugs generally approved have already been accepted in industrialized countries with high standards of pharmacovigilance. Thus, they do not face the same pressure in analyzing the data.

When approving a new drug, one of the main goals of the regulatory agencies is public health. At the same time, agencies draw up regulations and conduct inspections to protect research subjects. (An example of this is the concern of the US Food and Drug Administration (FDA) for the ‘self-satisfied’ choice of committees — ‘IRB shopping’; Dotzel 2002.) These conflicting demands — for the population in general as against the research subjects — create a degree of tension, if not possible conflicts in responsibilities. However, this issue is still to be thoroughly considered.

Research Ethics Committees

We have seen that many of the actors in clinical research — in addition to their particular interests and concerns — share the aim of ensuring that the research process develops appropriately, but can these safeguards guarantee that research subjects are protected?

If we accept the above conception of a research subject, we need an agent that can evaluate the individual’s need for protection and provide safeguards. In one way or another the above-mentioned actors are concerned with the well-being of research subjects, but there is one more category of actor whose main objective is to protect research subjects; this is the research ethics committee.

The glossary of the ‘Good Clinical Practices Consolidated Guideline’ specifies that it is the responsibility of research ethics committees

to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving/providing favorable opinion on the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subject. (International Conference on Harmonization 1996)

This is accomplished by analyzing and assessing the ethical elements in the research protocol with the help of guidelines and international ethics documents — hence the importance of ethical documents such as the Declaration of Helsinki and the CIOMS Guidelines.

The most recent revision of the Declaration of Helsinki (2000) introduces, in addition, the option for committees to monitor the research process itself. Thus, the responsibility of ethics committees is substantial, though they do not have the power that other actors have, such as regulatory agencies and drug companies. This is an issue that should not be overlooked.

In general, research ethics committees face many obstacles. A frequent concern refers to the gap between what laws or regulations stipulate and what actually occurs (Luna 2002). Another problem focuses on the inadequate constitution of these committees, which are made up mostly of researchers and physicians (Luna 2002). Unlike the model in northern Europe, which has a high percentage of lay members of the community, many Latin American committees, for example, experience serious difficulties in incorporating representatives of the community. This may be because of their highly authoritarian culture and the prevalence of the medical model discourse that filters through this, making members of the community, nongovernmental organizations, and groups of patients difficult to include. In addition, a common problem in many developing countries is the poor training of some of the members, as well as the lack of resources for infrastructure (for example, subscriptions to journals, photocopies, and books) and administrative backup, which undermines the efficacy of the committee. Part of the problem lies in the lack of qualified committees and the lack of a system that can assess the performance of the ethics committees and the accuracy of their work. In contrast to the strong responsibility and demands implied in approving a research protocol, there is a lack of institutional support (for example, committee members may not be given time off work to sit on the committees; physicians or hospital staff may have to attend patients at the same time; or there may be a lack of secretarial support). This is closely related to the status of these committees, but it also has to do with the scarce resources and revenue to finance some of their tasks.

A further complication regarding the adequate functioning and protection of committees is the dissimilarity of policies among ethics committees themselves, even in the same country, region, or city. A South African committee illustrates this point clearly: ‘Our committee, established in 1966, is the oldest and most experienced in South Africa and is known to be conservative. Protocols not accepted by us, we know, have been readily approved in the private sector or at other institutions’ (Committee for Research on Human Subjects (Medical) 1997). This leads to another flaw in the opportunity for good protection: ethics committee shopping. Research ethics committees’ main goal is to protect research subjects.