Research Ethics, Clinical J H Solbakk, University of Oslo, Oslo, Norway, and University of Bergen, Bergen, Norway

S M Vidal, United Nations Educational, Scientific and Cultural Organization, Montevideo, Uruguay

ª 2012 Elsevier Inc. All rights reserved.

Glossary Dignity The quality or state of being worthy of esteem

or respect. Dignity is often used in biopolitical

discussions and in discussions about ethics and human

rights to signify an inherent noble condition that entitles

a human being to respect and ethical treatment. When

proclaimed in such discussions, dignity is rarely given

an explicit definition.

Epistemology From ancient Greek (episteme), meaning

‘knowledge,’ ‘science’ þ ‘logos,’ meaning ‘the word by

which the inward thought is expressed,’ ‘the inward

thought or reason itself.’ As a branch of philosophy,

epistemology or theory of knowledge is concerned with

the nature of knowledge, its presuppositions and

foundations, and its extent and validity.

Ethos From ancient Greek, originally meaning

‘accustomed place,’ ‘custom,’ ‘habit,’ or ‘usage.’ Ethos

is often used to depict disposition, character, or

fundamental values peculiar to a specific person,

people, institution, social organization, culture, or

movement. Based on this understanding, ethos is here

used in the meaning of accepted epistemological and

ethical norms and principles employed within the

institution of medical research and practice.

Exploitation The instrumental utilization of a person’s or

a group of persons’ assets or capacities merely for the

advantage or the sake of interests of other involved parties.

Ghostwriter One who writes for and gives credit of

authorship to another.

North–South A geographical division whereby the

North represents the richer countries of North America,

Europe, Japan, Australia and New Zealand, and the

South represents the poorer majority of countries in

Africa, Asia and Latin America. North–South

Cooperation (NSC) is thus the development cooperation

between the North (the developed countries) and the

South (the developing countries).

Placebo Any dummy medical treatment; originally, a

medicinal preparation having no specific

pharmacological activity against the patient’s illness or

complaint given solely for the psychophysiological

effects of the treatment; more recently, a dummy

treatment administered to the control group in a

controlled clinical trial so that the specific and

nonspecific effects of the experimental treatment can

be distinguished.

South–South Cooperation (SSC) A broad concept

that covers a wide range of collaborations among

developing countries. It refers more specifically to

cooperative activities between newly industrialized

southern countries and other, less developed nations

of the South.

Standard Something that has been established by

relevant authorities (governmental, scientific, professional,

etc.) through habits of custom or by general consent to

serve as a type, model, norm, pattern, or reference.

Standard of care A diagnostic and treatment

process that a clinician should follow for a certain

type of patient, illness, or clinical circumstance. In

legal terms, the level at which the average, prudent

provider in a given community would practice. It is

how similarly qualified practitioners would have

managed the patient’s care in the same or similar

circumstances.

Introduction What are the epistemological and ethical norms and values underlying and guiding clinical research? What is their nature? From where do they originate? To what extent can clinical research be of help in protecting and promot­

ing basic human rights? In what ways may clinical research inadvertently violate or abuse human rights? These are some of the questions addressed in this article.

More precisely, the article aims to provide a narrative about the inherent tensions between the epistemological

ethos of clinical research, that is, the generation of effective diagnostic, treatment, and prevention methods, and the ethical ethos of the same enterprise, that is, the attempt to protect the interests and well-being of patients and healthy individuals involved in such research. Ethos is here used in the meaning of ‘accepted standards,’ to emphasize that in research two different types of norms and principles are at play: epistemological norms and principles (e.g., truth, prob­

ability, coherence, relevance, fruitfulness, and utility) and ethical norms and principles (e.g., autonomy, justice,

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beneficence, nonmaleficence, truthfulness, trust, vulnerabil­ity, and solidarity). In summary, this account aims to provide a picture of

•

• the factors that may help to explain these tensions;the ethical norms and principles that actually underlay and should

guide clinical research; and

• how this normative system relates to the framework of values witnessed in relevant human rights documents.

Brief History of the Ethics of Clinical Research

Since the onset of medicine, concerns and questions have been raised about what the limits of actions leading toward new knowledge should be when they involve human beings. This history of research ethics is the result of the interplay and interaction between three different domains: the system of ethical principles and norms that guide medical practices (the ethical domain), the ways of obtaining new knowledge in medicine (the epistemologi­cal domain), and the norms and rules of civil society (the social and political domain). The concerns and questions that emerged from these interactions have molded the development of different periods in the history of research ethics. Most of these questions were related to the limits of research, but in recent years an additional question has been raised – the question about who should be entitled to establish these limits.

Research Scandals and the Emergence of Ethical Codes of Conduct in Clinical Research

This discussion focuses on the history of research ethics in the twentieth century; in fact, the historical scope is limited to the development of clinical research ethics since the disclosure of the atrocities and medical crimes committed by Nazi physicians during World War II and the later disclosure of similar crimes committed by Japanese researchers with war prisoners and also by researchers in the United States during the same period with prisoners, patients in mental hospitals, and mentally retarded persons.

The Nuremberg Code, the final document issued in 1947 by the court in the so-called ‘Doctors’ Trial’ in Nuremberg, together with the creation during the same year of the World Medical Association and the adoption in 1948 of the Universal Declaration of Human Rights (UDHR) formed the basis for a new international order with regard to research involving human beings.

The Nuremberg Code (hereafter called the Code) represents one of the first documents providing the inter­national research community with a normative framework aimed at protecting the rights and well-being

of subjects undergoing biomedical research. It was fol­lowed by other equally or even more significant normative documents known as the ‘international ethical norms for biomedical research.’ However, the emergence of these different normative codes and declarations did not take place without criticism and obstacles.

The Code, for instance, proved to have little impact on the medical communities, especially regarding research practices, because it was widely perceived as a code to mark out barbarian doctors and not as a guide intended to be followed by responsible doctors. Likewise, between 1945 and 1965, several medical organizations developed guidelines for human experimentation that addressed the Code. However, they had a minimal impact on the prac­tice of medical research and little attention was paid to them. In fact, it was not until the 1970s that the procedural measure of voluntary consent, first articulated in the Code, was seriously taken into account.

In the 1950s and 1960s, some articles in medical jour­nals emphasized the importance of relying on a normative framework for research involving human beings, but the Code did not seem to have any direct influence on the conduct of medical research. The boundary between cor­rect and incorrect research behavior was still perceived as up to the ethical consciousness of individual researchers to determine, and the practices were ruled by an internal research code based on the model of moral neutrality or the so-called scientific purity of science. During these years, studies not only ignored informed consent but also exposed research participants to serious risks and harm. Some of these studies were conducted in secret, such as those with radiation for national defense purposes or for the sake of understanding human physiology, with both kinds of studies conducted by researchers on behalf of the U.S. Defense Department.

In 1964, after 2 years of debate, the World Medical Association adopted the Declaration of Helsinki. This declaration became the subject of fierce debate in profes­sional medical journals, and it was viewed by many physicians as an intrusion on the moral consciousness of researchers and as an attempt to force compulsory beha­vior upon them.

In fact, it was not until the disclosure of a whole range of additional medical experiments in the United States of an appalling ethical nature, such as the studies conducted at the Jewish Chronic Disease Hospital in Brooklyn and at Willowbrook School, both included in the cases addressed in 1966 by H. Beecher, that it became clear that violations of people’s rights were commonplace even in the country of rights.

After the disclosure of the Jewish Chronic Disease study in 1964, an internal committee was appointed by the National Institutes of Health to review issues con­cerning involvement of human beings in medical experimentation. In its report, the commission stated

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that in a situation in which a patient is involved in a research project, the sole judgment of the investigator is not a sufficient basis to reach a decision concerning the moral issues raised by the researcher–patient relation. Thereby, it put aside an axiom that until then had ruled medical research practices – that is, that the researcher’s consciousness is the most suitable instance to assess the ethical aspects of a biomedical experiment.

In 1974, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was established by the U.S. Department of Health, Education and Welfare, mirroring the new ethical awareness that had emerged in the wake of the many documented research scandals, including the scandal raised by the revelation of the Tuskegee Syphilis Experiment. In its final report in 1978, the Belmont Report, the commission did not make reference to one interna­

tional norm as the source on which it based its recommendations, and it dismissed the rules suggested in previous guidelines and declarations as being too gen­

eral and therefore inadequate as a normative basis for biomedical research. Instead, it suggested a new founda­

tion for research ethics based on three basic ethical principles – the principles of respect for persons, benefi­

cence, and justice – that could be applied to deal with ethically conflictive situations involving research with human beings. The basic ethical principles proposed in the report were a clear reflection of the Anglo-American liberal tradition, especially its emphasis on the notion of individual autonomy. The recommendations were promptly adopted and backed by the American Medical Association and other medical organizations in the United States, and in practice it became a much more influential normative document than previously suggested codes and declarations. This influence is also evident in declarations and guidelines that emerged later, such as the International Ethical Guidelines for Biomedical Research Involving Human Subjects issued by the International Council of Medical Sciences in 1993 (revised in 2002).

Whereas in the United States the emergence of a code of conduct for medical researchers was strongly influ­

enced by a liberal pragmatic tradition, embracing a principlist approach, in Europe the Nuremberg Code and the UDHR gave rise to an approach based on human rights.

This human rights-based approach is clearly traceable in the conflictive story of the Declaration of Helsinki. Although the 8th General Assembly of the World Medical Association in 1954 adopted the Resolution on Human Experimentation: Principles for Those in Research and Experimentation, it was not until the final adoption of the committee’s draft code of ethics for human experimenta­

tion at the 18th World Medical Assembly in Helsinki in 1964 that the Declaration of Helsinki became a reality.

Besides the physician origin of the Declaration, the main difference between these guidelines and the Nuremberg Code is that in the original version of the Declaration an explicit distinction is made between clinical research combined with professional care involving sick persons and clinical research carried out on healthy sub­jects for the advancement of scientific knowledge.

It is worth noting, however, that the first version of the Declaration of Helsinki did not make any mention of peer review or a system of ethics committees. Also, although the Declaration emphasized the scientific standards that should govern good research, the previously mentioned distinction allowed for a weakening of the Code’s strong requirement with regard to voluntary consent, giving more freedom to the physicians to omit the application of consent procedures in special circumstances. This indi­cates that the welfare and safety of the involved research subjects were still considered to be the full responsibility of the individual investigator. In fact, it was not before the revision of the Declaration of Helsinki in 1975 that assess­ment of research protocols by an independent ethics committee was included in the Declaration as a require­ment. With the revision in 1975, it seemed that biomedical research involving human beings finally had been furnished with a firm system of internationally accepted norms and principles.

However, in 1997, a fierce debate broke out about the ethical acceptability of using placebo as a comparative alternative to established effective treatment (‘standard of care’) in trials conducted in poor and low-income coun­tries for the purpose of preventing perinatal HIV transmission. This debate had a direct impact on the further development of the Declaration of Helsinki, in the sense that some of its strongest commitments with regard to protecting the interest and welfare of individual research participants and vulnerable communities came under fierce pressure from different voices that repre­sented research and policy institutions in the United States and Europe and the international pharmaceutical industry. For these reasons, the Declaration of Helsinki underwent substantial revisions in 2002 and 2008 to try to accommodate the interests of these powerful voices and facilitate the conduct of clinical trials in poor and low-income countries. These revisions – such as the facil­itation of the use of placebo, the dilution of the requirements of care in such situations, and the reduction of sponsors’ post-trial responsibilities toward research participants and host communities – have been heavily criticized as ethically untenable, as being contrary to the idea of human’s dignity and human and social rights, as offending people’s integrity, and as injuring the Declaration of Helsinki’s own notion of justice. For these reasons, it has also been suggested to abandon the sixth version of the Declaration of Helsinki and instead embrace the Universal Declaration on Bioethics and Human Rights

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(2005) as an appropriate ethical and normative frame of reference.

The Universal Declaration on Bioethics and Human Rights

The first explicit reference to biomedical research within the framework of an international human rights document is found in the second Covenant of the Universal Declaration of Human Rights – that is, in the International Covenant on Civil and Political Rights (1966). In Article 7 of this cove­nant, the core principle laid down in the Nuremberg Code – the principle of consent – figures prominently as a condition that needs to be met before involving any human being in medical or scientific experimentation.

In 1997, the Council of Europe’s Convention on Human Rights and Biomedicine was adopted, and in October 2005 the 33rd session of the General Conference of the United Nations Educational, Scientific and Cultural Organization adopted by acclamation the Universal Declaration on Bioethics and Human Rights (UDBHR). This declaration is the first international ethics instrument that deals with the linkage between bioethics and human rights. In addition, it represents the first normative instru­ment that provides the international community with global bioethics standards.

Despite the fact that this declaration has been unan­imously adopted by all the 192 member states of the United Nations, it has been the subject of harsh criticism in the scholarly literature in bioethics. For example, in 2005 the journal Developing World Bioethics devoted a com­plete issue to discussing the declaration, and in the editorial section serious questions were raised regarding the academic quality of the experts that had participated in the drafting of the declaration, ignoring both the long and fully involved process that resulted in the final docu­ment and the scholars who had participated in the drafting process. Finally, the claim was made that the human rights baseline of the declaration was more of an ideology, defending the criticism that had already been formulated by other authors regarding the lack of useful­ness of the notion of dignity for medical ethics and disregarding the meaning of international law of human rights and its implications for national legislations, espe­cially with regard to biomedical practices.

These reactions against the declaration seemed to indicate that its normative content was perceived as affecting the interests of certain powerful groups. Another possible interpretation of this criticism – albeit a very negative one – is that it represented a new attempt at expanding the sensitive limit beyond which biomedical interventions should be considered a vulneration of the rights of persons.

Finally, it seems appropriate to add to this historical account that several attempts have recently been made to

develop consensus documents and guidelines in research ethics that are of a doubtful legitimacy and with sugges­tions for the implementation of new ethical standards for the conduct of clinical research in poor and low-income countries.

Evidence and Facts about a Practice in Crisis: A New International Order

A brief analysis of the situation of clinical research in the international field after the 1990s indicates that significant changes have taken place with regard to the model of clinical research, mainly reflecting the growing influence and marketing strategy of pharmaceutical companies. These changes have inserted conflicts of interest in almost every link of the medical chain, from the research and development of drugs to the trade and consumption of them. Also, many claims about highly irregular situations have been made related to agreements to patent and register new medicines and to the means used by the pharmaceutical industry to increase profits by influencing those who prescribe drugs – for example, through the information they make accessible, through the establish­ment of so-called ongoing medical education programs, through direct payments and rewards for every prescrip­tion, through briberies, as well as through the use of massive advertising campaigns targeting users. In this section, some prevalent signs and symptoms characteristic of the current situation of clinical research are addressed.

The Growth of Multinational Research and the Globalization of Clinical Research

Progressive growth of research in poor and low-income countries has occurred. There are several possible expla­nations for this development. First, stricter regulations were implemented to protect the rights of vulnerable subjects especially in the United States following the report of the Advisory Committee on Human Radiation Experiments in 1995, and regulatory systems in many countries in the affluent part of the world have become increasingly bureaucratic and expensive.

Second, the lack of wide heterogeneity or flexibility of normative standards and regulations in poor and low-income countries allows for research employing different standards from the ones required in the countries of origin (e.g., the use of different versions of the same protocols).

Another factor that adds to the creation of a more favorable research climate in these countries is that the ethical evaluation of many research ethics committees is less rigid, partly due to poor training of committee mem­bers. Moreover, the search for new markets on the part of the industry is easier in areas of the world with lower costs and with fewer risks of legal actions because the amounts

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to be paid to insurance companies are less in poor and low-income countries than in affluent countries.

An additional factor that can help to explain this development is that in many poor and low-income coun­tries, there is a willingness of a large percentage of the population – and notably without the application of rigid consent procedures – to enroll in research, which helps ensure and accelerate the recruitment process.

Finally, the openness on the part of many physicians in these countries to become involved in research practices that may offer personal prestige as well as significant profits may help to explain the ever-increasing involve­ment of populations in poor and low-income countries in clinical research. This situation has also helped to pave the way for the use of different ethical standards in clin­ical research – an issue that is explicitly addressed later.

The Privatization Process of Clinical Research

The biomedical research model called ‘privatized’ has moved substantial parts of clinical research from aca­demic centers to private institutions, contract research organizations (CROs), or directly to individual research­ers. The tasks of CROs range from designing the trial to hiring health care professionals, developing a strategy to recruit patients, supplying a research ethics committee, and providing the means for protecting the subject of research.

This model has changed the research payment system from academic investment or incentives for university researchers – the valid system until the early 1990s – to a direct payment system, occasionally of significant amounts, to researchers in the private sector. Most of the researchers contracted from these centers are not named in the final publications, and many of them have hardly any research experience in the field under investigation.

Direct funding of clinical research on the part of the pharmaceutical industry may have several impacts on the research conducted. First, it may direct the research toward primarily reaching business goals. Second, it may reduce the chance of sharing of research results. Third, it may lead to a premature ending of the studies and to the suppression of publications. Also, it may foster the pub­lication of papers overestimating the positive results of the trial drug, and it makes it easier to involve ‘ghost’ writers in the production of research papers.

In addition, the increasing influence of the pharma­ceutical industry on clinical research and development may impact the decisions of editorial boards of medical journals through their financial ties to highly renowned experts serving on these boards and on committees pro­viding advice to national and international health authorities and organizations. Also, the pharmaceutical industry funds a great deal of the so-called continuous

medical education programs of physicians; for example, in the United States, approximately 60% of this type of funding originates from the pharmaceutical industry.

Prevalent Health Needs and the 10/90 Gap in Medical Research

Most clinical trials conducted in poor and low-income countries are not aimed at addressing the particular health needs in these countries. These health needs are evalu­ated according to the impact of certain risk factors on the cause of disease and death in each country and region. It is well known that in poor and low-income countries, and to a certain extent in affluent countries, many diseases are associated with social determinants of health – that is, with social factors directly determining the life condi­tions in these communities. Some of these factors are gender, youth, social exclusion, unemployment, drug addiction, stress, poor food habits, and poor transportation facilitations.

Recently, regulatory agencies have included in their drug registers only a few genuinely new innovations, many of which are targeting diseases in extreme situations or low-incidence diseases. At the same time, most of the ‘new’ drugs reaching the market are not new drugs but, rather, variations of old drugs – the so-called ‘me too’ drugs.

On the other hand, the treatment of diseases such as Chagas, paludism, or hemorrhagic fever is not among the priorities of pharmaceutical companies or public research institutions. Since 1996, this discrepancy between prevalent health needs and research priorities has been labeled the 10/90 gap. This metaphor was introduced to depict the major inequity in the world with respect to who’s diseases are favored in ongoing or planned research programs. In concrete terms, this means that at least 90% of the economic resources spent annually on medical research are targeting the health needs of the richest 10% of the world’s population, which implies that the needs of 90% of the world’s population have to be met from the remaining 10% of research funding. Unfortunately, studies on the so-called globalization of clinical research indicate that this gap has not diminished, although during approximately the past 15 years the number of people from poor and low-income countries enrolled in clinical trials has substan­tially increased. On the contrary, evidence from these studies suggests that during this trial period, the relativeavailability of new drugs to populations in poor and low-income countries has not increased, whereas the gap between wealthy nations and poor and low-income countries with regard to who benefits from the advances of clinical research and development has continued to widen.

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The Regulatory Situation and the Quality of the Ethics Evaluation Procedures in Poor and Low-Income Countries

In many poor and low-income countries, the develop­ment and implementation of normative standards and systems of regulations of clinical research, including the establishment of research ethics committees, is a rela­tively recent venture. In addition, there is often inadequate funding to secure sustainable functioning of these systems of regulation as well as heterogeneity with regard to the interpretation of the regulatory norms and standards employed.

Several factors may help to explain these weaknesses. First, people in charge of designing, implementing, and applying the normative standards and principles are not always fully qualified for the task. Sometimes the norms are the result of needs alien to the country in which the studies are conducted. Also, the system of norms and standards used to evaluate and regulate clinical research is separated from – and often at odds with – the broader health policy in the country in question, including iden­tified or unacknowledged research priorities.

In addition, the methods and procedures employed for recruiting patients for research are very heterogeneous. Whereas in some centers or large hospitals patients are recruited and research projects are carried out in accor­dance with internationally accepted normative standards for research and in compliance with the research priori­ties of these institutions, in other places patients are recruited by young and inexperienced researchers in first- and second-level centers, in consulting rooms, in rural areas and communities, and without following inter­nationally accepted standards for recruitment.

Another factor is that many research ethics committees lack sufficient training or experience to assess certain protocols. They rarely consider topics such as distributive justice or the imposition of the burdens of the research to the most vulnerable for the sake of the most privileged. Also, in many countries there is no opportunity to per­form a methodological assessment of the protocol, which is the first step for any ethical assessment.

Finally, citizens are often totally unaware of the legal, ethical, and social implications of the clinical trials carried out, particularly with regard to their own rights as parti­cipants in such trials.

Scientific Misconduct and Ethical Fractures in Clinical Medicine

During recent years, it has become clear that lack of scientific honesty, often conceptualized as ‘scientific mis­conduct,’ ‘research misconduct,’ or ‘scientific fraud,’ is more common than widely believed.

Many of these irregularities are related to studies funded by the pharmaceutical industry and strongly linked with the interests of this industry and its wide field of influence. For example, a considerable amount of these trials are never published and for different rea­sons, such as errors in the design of the study, failures in the recruitment process or in the sample size, low statis­tical power of the trial, financial cuts by the sponsor, or unfavorable results for the sponsor in question. Today, it is widely known that findings of a number of studies that were concealed for commercial reasons could have, if made public, resulted in the prevention of injury and death among patients.

Other forms of irregularity relate to trial reports using erroneous statistical methods with the aim of drawing other conclusions than those warranted by the available data, distorted interpretation of results or distortion of conclusions, selective and undisclosed rejection of unde­sired results, and reporting of increased favorable results due to the comparison of the drug under study only against placebo or a non-gold standard drug.

Apart from being scientifically unethical, distortions of medical evidence or withholding of unfavorable results or adverse effects may result in serious damage to patients, not only to those who participate in the study but also to patients who may ‘benefit’ from the drug once it has reached the market. One notable example was the removal of rofecoxib from the market after more than 80 million patients had used it and after the company produ­cing the drug had obtained a profit of nearly $2.5 billion dollars per year.

All the examples provided here give reason for deep concern with regard to the current clinical research situation.

Values and Principles That Should Guide the Practice of Clinical Research

The Normative Bedrock of Clinical Research: The Primacy of the Research Subject

Whereas the focus of the previous sections was on histor­ical and current factors that may help to explain the inherent tensions between the epistemological ethos of clinical research and the ethical ethos of the same enter­prise, this section addresses the values and principles that should underlie and guide all clinical research. We first discuss a formulation that for decades, albeit in slightly different versions, has been considered the normative bedrock of clinical research – that is, that the interests and welfare of the individual should have priority over the sole interest of science or society (UDBHR, Article 3.2). Despite multiple revisions of the Declaration of Helsinki, the core of this formulation has also prevailed in this influential normative document (Article 6). This

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formulation demonstrates in a succinct way that in clin­ical research not only are the interests of several stakeholders at play but also the interest of one of these ‘players’ – the individual research participant – should take precedence over all other interests. Except for the explicit reference made to the welfare or well-being of individual research participants, it is not immediately clear from these formulations what other interests are envisaged or what kind of interests research participants are in need of being protected from. Recalling the nature of scientific inquiry and the history of clinical research, however, it is not difficult to understand that although clinical research may be said to be driven by two aims or desires – scientific curiosity and the generation of empiri­cal knowledge that might benefit patients and society – there is always the danger that ethical boundaries might be transgressed in the attempt to achieve tangible benefits. For this reason, it is also clear that it is not sufficient for a clinical research project to comply with the episte­mological requirements of scientific validity to be deemed ethically justifiable. What is needed in addition is that the project is committed to respecting and protecting the interests and welfare of research participants, that it is fair to them, and that it is found to be morally acceptable by the implicated community (Council for International Organizations of Medical Sciences (CIOMS), Guideline 1). In UDBHR, this commitment to respecting and protecting the interest and welfare of research participants is given a triple justification: (1) as a recognition of the dignity, human rights, and fundamental freedom of research subjects (Article 3.1), (2) as an institution for protecting the integrity and interests of individuals and groups of special vulnerability against the interests held by the majority or by those in power (Articles 6.3 and 8), and (3) by linking the search for knowledge in clinical research to the principles of harm and benefit (Article 4).

The Interests of Science and Society

Before addressing other relevant ethical principles aimed at respecting and protecting research participants, some additional observations and remarks concerning potential interests of the two other stakeholders mentioned in the previous formulation – that is, science and society – that may infringe upon the integrity, interests, and welfare of research participants seem warranted. Ideally, clinical researchers and research communities should be com­mitted to the core values of scientific research, in the sense that their research should give rise to new forms of beneficial knowledge, new truths, and new probabil­ities. Consequently, clinical research should aim at something more than control or confirmation of already established facts. This does not, however, mean that confirmatory clinical research should be deemed unim­portant; it only represents a qualification of primary

research findings in terms of their newness compared to secondary research. Furthermore, it should be observed that although so-called phase 4 trials, also known as post-marketing surveillance trials, are deemed justifiable in order to assess the safety and long-term side effects of newly marketed prescription drugs – and thus may be viewed as in the protective interest of patients – a number of these studies are conducted not because they have been required by regulatory authorities but because the spon­soring pharmaceutical company is trying to find a new market for the drug. Consequently, there is also the dan­ger that economic interests may come to influence the scientific ethos of physicians involved in such trials, including the inclusion of new groups of patients.

Another example from clinical research that illustrates how the interests of scientific stakeholders – and their industrial sponsors – may come to represent an infringe­ment on the interests and welfare of research participants as well as on the interests of communities in which the research is carried out relates to the increased involve­ment of populations of poor and low-income countries in clinical research originating from affluent countries. Although it is important to recognize that the so-called globalization of clinical research can bring benefits to poor and low-income countries, particularly in countries capable of imposing regulations that put local individual and public interests above private and public ‘scientific’ interests of affluent countries, findings indicate that many of these studies are conducted in communities that are not intended to be major markets for the products under testing. It is difficult to understand how such studies could be said to be in compliance with the normative bedrock of clinical research.

A third example relates to the debate about the use of ‘double standards’ in international clinical research. The ethical core of this controversy is whether it might be justifiable under certain socioeconomic conditions, such as when standard of care is neither available nor afford­able for the countries and communities in question, to allow for the use of placebo in the control group. The main critique against the use of placebo as a comparative alternative in such situations is that it implies an inten­tional withholding of a well-documented superior treatment – that is, the ‘standard of care’ regimen – from one group of research participants (i.e., the control group). On the other hand, advocates of the use of placebo con­trols in such situations argue that the only way to proceed in order to generate treatment options that in a foresee­able future will prove to be efficient as well as affordable for patients living in such communities is to employ a placebo-controlled research design. Furthermore, they hold that the main counterargument employed against the placebo controls – that is, the withholding of a well-documented superior treatment (the standard of care regimen) from the patients in the control group – can be

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used to invalidate the use of standard of care as an ethi­cally appropriate control regimen because this would imply that the patients in the intervention group would be deliberately precluded from access to the best treat­ment option. This controversy provides a vivid illustration of the tensions that might be at play in clinical research between epistemological and ethical considera­tions and the ethical complexities of acquiring knowledge of treatment options that are scientifically sound and at the same time responsive to the medical needs and eco­nomic capabilities of people living in poor and low-income countries. On the other hand, if one takes into account the revisions of the Declaration of Helsinki and CIOMS’ International Ethical Guidelines for Biomedical Research Involving Human Subjects allowing for the use of double ethical standards in such situations, it seems appropriate to state that today’s international research ethics runs the risk of making individual research partici­pants and populations in poor and low-income countries victims of exploitation and of alterable forms of vulner­ability – that is, forms of vulnerability that could have been dealt with through affirmative and context-sensitive forms of actions of a social and remedial kind. A less negative reading of this controversy is that it has given rise to two different ethical standards, one that considers all human beings as equals (without taking into account the particularities of communities implicated in research) and another that is more flexible regarding different socioeconomic contexts, especially in poor and low-income countries.

The Principles of Benefit and Harm

It remains to consider some potential interests of the third stakeholder referred to in the bedrock formulation men­tioned previously – that is, the community in which the research is carried out. These interests relate to the prin­ciples of benefit and harm, specifically to the distinctions made between direct and indirect benefits and between benefits to research participants and benefits to the com­munity during and after a study has been carried out. Disagreement related to this issue concerns mainly how study participants and involved communities should ben­efit. The intention here is not to give a content-full account of envisageable ways of benefiting research par­ticipants and involved communities but, rather, to illustrate how the normative bedrock of clinical research also sets limits with regard to the interests of the commu­nity. This is of particular relevance when research is carried out in poor and low-income communities – that is, communities suffering from alterable forms of vulnerability – because in such situations it might be tempting for community leaders to sacrifice some of a community’s individuals as research participants for the negotiated benefits of the community at large of serving

as host for internationally sponsored research projects. Examples of such benefits are ancillary health services, health care capacity development, or even employment and economic activity. Also with regard to such benefits, it is clear that the interest and welfare clause made in relation to the individual research participant is applic­able with regard to deciding in what situations and to what extent such benefits or forms of compensation for the community at large might be deemed justifiable. Thereby, it is also clear that the principle of benefit in clinical research should not be applied in isolation; it is firmly tied to the principle of harm and to the nature and size of the risks involved, which implies that every attempt at maximizing potential benefits of a research project – for science and society as well as for research participants – must always be balanced against the attempt to minimize any possible harm for the research participants implicated in the project.

A final remark concerning the principles of benefit and harm relates to the previously addressed problem of scientific misconduct in clinical research. That is, the lack of scientific integrity in clinical research may give rise to two deep fractures in the practice of medicine: an epistemological fracture and an ethical fracture. The implication of this for the practice of medicine is that when new clinical recommendations are based on a dis­tortion of medical evidence or on the withholding of unfavorable results or adverse effects, physicians will not be able to fulfill their commitments to their patients, in the sense of maximizing potential benefits and minimiz­ing any possible harm to them.

The Principle of Vulnerability

Of the other relevant ethical principles aimed at respect­ing and protecting research participants, the principle of vulnerability is probably one of the most disputed. Since it was indirectly alluded to in 1979 in the Belmont Report, vulnerability has been attributed with a steadily increas­ing role and prominence in national and international guidelines and policy documents applicable to medical research, health care, and bioethics. The culmination in this regard was marked in 2005 by the integration of this concept as a principle into the UDBHR. Also in the scho­larly literature in bioethics and health care ethics, the principle of vulnerability has been the focus of vivid attention and scrutiny.

In considering these debates, it is possible to trace the emergence of two seemingly conflicting orientations. On the one hand, an understanding of vulnerability is pre­valent in guidelines and policy documents applicable to medical research, health care, or bioethics and promoted by Anglo-American scholars in bioethics. This orientation has given rise to a whole range of restrictive or minimalist conceptions of vulnerability aimed at identifying and

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categorizing individuals, groups, and populations as vul­nerable and tracing the different forms of vulnerability that need to be overcome. On the other hand, a human rights-based approach to vulnerability has emerged, taking its inspiration mainly from continental European philosophy and differentiating between inalterable forms of vulnerability that require state protection and accidental forms of vulnerability (i.e., susceptibility) that need to be handled by additional measures of protection. Thus, the formulations in Article 8 of the UDBHR may rightly be seen as an attempt to bring under the same hat two competing conceptions of vulnerability and, conse­quently, also two distinct moral regimes of protection. The first one is a human rights-based regime aimed at protecting persistent or universal vulnerability, whereas the second regime aims at handling accidental states and situations of increased vulnerability – that is, vulner­ability requiring additional measures of protection as well as identification of the particular persons and populations in need of protection against forms of harms and wrongs not covered by human rights-based regimes of protection.

Informed Consent

In this attempt to provide a reliable account of relevant ethical principles aimed at respecting and protecting research participants, we must include the principle or procedural measure that for decades has been considered one of the most crucial in clinical research ethics – informed consent. It was installed to serve several func­tions, three of which are mentioned here: to protect research participants from any form of abuse, to respect the autonomy of research participants and ensure that they are themselves in control of decisions concerning their own health and life, and to help maintain the public’s trust in the institution of clinical research. Four questions may help to indicate what is entailed in this principle and how freedom from abuse and liberty to choose is envisaged to be safeguarded by employing this principle: Are the research subjects fully informed about the pur­pose of the envisaged study? Have they understood the information provided to them? Have they given their free and informed consent? Have they been informed about their right to withdraw from the study at any time and to have all data about themselves, including blood samples and biological material, deleted or destroyed? These questions draw attention to an important epistemological asymmetry characteristic of the researcher–research par­ticipant relationship: As a researcher, one is obliged to provide comprehensive reasons for starting a clinical study and inviting patients to participate in it. A patient, on the other hand, can say ‘yes’ or ‘no’ to participating in a study or withdraw from a study for any reason and at any time, without telling why and without risking any disad­vantage or prejudice by doing so.

The limits of informed consent with regard to respect­ing the autonomy of research participants and protecting them from any form of abuse are evident when function­ally illiterate people are involved as research participants, which is often the case in poor and low-income countries. Their illiteracy makes them practically incapable of providing adequate consent.

Regarding the involvement of children or other persons without the capacity to consent in clinical research, addi­tional measures of protection are required, such as authorization from a legally authorized representative or from an independent research ethics committee. In addi­tion, there are restrictions with regard to what kind of research can be carried out on such persons. For example, research without potential direct health benefit for persons unable to consent should only exceptionally be carried out, such as in situations in which the research in question cannot instead be carried out with persons able to consent, and only when such research might benefit other persons belonging to the same category of persons without the capacity to consent (Declaration of Helsinki, Article 27; CIOMS, Guideline 9; UDBHR, Article 7).

Prognosis: The Future of Clinical Research

Here, some tentative reflections about the future of clinical research are presented by reemphasizing the importance of the core principle of clinical research concerning the pri­macy of the interest and welfare of research participants and by drawing attention to three articles in the UDBHR that so far have received little attention in clinical research ethics: Article 10 on equality, justice, and equity; Article 13 on solidarity and cooperation; and Article 15 on sharing of benefits. The principles suggested in these articles have not been taken into account in previous declarations, at least not with the same force in their application.

Since 1996, all member states of the United Nations as well as the global community of medical researchers have been aware of the so-called 10/90 gap in clinical research. In view of this situation, the bioethics debate has been marked for more than a decade by a much broader focus on the need for protection of the interests and welfare of poor and low-income communities, which also resulted in the inclusion of the three articles mentioned previously in the UDBHR. This inclusion actualizes the question of what could be the science policy implications for clinical research of pursuing the principles of justice, solidarity, and benefit sharing. One implication signaled in the arti­cle on benefit sharing is that even when clinical research is conducted in affluent countries in Europe and in the United States, these UN member states have committed themselves to sharing the benefit of this development not only among themselves but also with poor and

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low-income countries. For a sustainable ethics of benefit sharing to be realized, however, it is not sufficient to develop a global medical science policy and research strategy that takes into account the particular research for health needs of poor and low-income countries. What is needed in addition is the development of national research policies in the richer areas of the world that include sustainable plans for how the benefits resulting from these research programs can be shared efficiently with poor and low-income countries. How can poor and low-income countries become actively involved in the co-evolution of a fair and sustainable global policy on scientific literacy and benefit sharing in clinical research? One possibility is to focus attention on ways to involve stakeholders from poor and low-income countries – such as academic stakeholders, members of national bioethics committees, and policymakers – in the design, conduct, and evaluation of national research programs in affluent areas of the world. A second possible strategy is to focus attention on national research programs that aim at forms of benefit directly transferable to poor and low-income countries. A third possibility is to give priority to national research programs that aim to investigate the role and risks of respect for cultural diversity and pluralism (UDBHR, Article 12) in the design, conduct, and evalua­tion of national research programs.

At the same time, it is of urgent importance for the poorest countries to develop their own national systems of research ethics evaluation in a completely independent way, which means not only having research ethics com­mittees able to evaluate all research protocols but also having a network of ethics evaluation with adequate ethi­cal norms and procedures, as well as a register of research and researchers and national ethics advisory bodies.

Finally, through the establishment of a north–south and a south–south collaboration between national ethics advisory bodies, a forum could be created in which repre­sentative ethics stakeholders from poor and low-income countries could work together with equivalent represen­tatives from the affluent areas of the world to create a global medical science policy and research-for-all strat­egy that could lay the foundation for a fairer distribution of available resources for clinical research throughout the world as well as of the research benefits that, it is hoped, will be generated from such a redistribution.

In conclusion, the best way to ensure genuine protection of human beings who participate in clinical research is to implement a human rights-based approach to research ethics. In addition, to heal some of the current fractures of clinical research and reduce the inherent tensions between the epistemological ethos and the ethical ethos of clinical research, it seems necessary to install a new pact of trust between science and society, which implies a deeper com­mitment of individual researchers and research institutions to the principles of trust, independency, and transparency.

In this way, the promotion of scientific advances committed to human needs and within the frame of respect to human dignity and the promotion of global solidarity could become a tangible reality.

See also: Applied Ethics, Challenges to; Benefit Sharing; Clinical Ethics; Codes of Ethics; Community Consent; Conflict of Interest; Developing World Bioethics; Dignity; Economic Globalization and Ethico-Political Rights; Economies and Trust; Exploitation; Forgery and Plagiarism; Global Access to knowledge; Global Ethics, Approaches; Global Ethics, Overview; Human Rights; Human Research Subjects, Selection of; Improper Payments and Gifts; Informed Consent; Intellectual Property Rights; Justice in International Research; Medical Ethics, Use of Empirical Evidence in; Organizations and Guidelines; Payment of Research Subjects, Ethical Issues in; Poverty; Principlism; Professional Ethics; Randomized Trials; Research Ethics Committees; Research Funding and Academic Freedom; Research Governance; Scientific Responsibility and Misconduct; Social Responsibility Principle; Solidarity.

Further Reading

Angell M (2006) The Truth about the Drug Companies. How They Deceive Us and What to Do About It, pp. 75–95. New York: Random House.

Beecher HK (1966) Ethics and clinical research. New England Journal of Medicine 274: 28–30.

Elliott C (2004) Pharma goes to the laundry: Public relations and the business of medical education. Hastings Center Report 34(5): 18–23.

Emanuel EJ, Grady C, Crouch RA, Lie RK, Miller FK, and Wendler D (eds.) (2008) The Oxford Textbook of Clinical Research Ethics. New York: Oxford University Press.

Glickman SW, McHutchison JG, Peterson E, et al. (2009) Ethical and scientific implications of the globalization of clinical research. New England Journal of Medicine 360(8): 816–823.

Jonsen A (1998) The Birth of Bioethics. New York: Oxford University Press. Landman W and Schu clenk U (2005) UNESCO ‘declares’ universals on

bioethics and human rights – Many unexpected universal truths unearthed by UN body. Developing World Bioethics 5(3): iii–vi.

Lexchin JR (2005) Implications of pharmaceutical industry funding on clinical research. Annals of Pharmacotherapy 39(1): 194–197.

Lie RK (2002) The HIV Perinatal Transmission Studies. In: Lie RK and Schotsmans PT (eds.) Healthy Thoughts. European Perspectives on Health Care Ethics, pp. 189–206. Paris: Peeters.

London AJ (2005) Justice and the human development approach to international research. Hasting Center Report 35(1): 24–37.

Lurie P and Wolfe SM (1997) Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. New England Journal of Medicine 337: 801–808.

Patra o Neves M (2009) Respect for human vulnerability and personal integrity. In: ten Have HAM and Jean MS (eds.) The UNESCO Universal Declaration on Bioethics and Human Rights. Background, Principles and Application, pp. 155–164. Paris: United Nations Educational, Scientific and Cultural Organization.

Petryna A (2006) Globalizing human subjects research. In: Petryna A, Lakoff A, and Kleinman A (eds.) Global Pharmaceuticals: Ethics, Markets, Practices, pp. 33–60. Durham, NC: Duke University Press.

Solbakk JH (2010) The principle of respect for human vulnerability and global bioethics. In: Chadwick R, ten Have HAM, and Meslin E (eds.) Handbook of Health Care Ethics. London: Sage.

ten Have HAM and Jean MS (eds.) (2009) The UNESCO Universal Declaration on Bioethics and Human Rights. Background, Principles

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and Application. Paris: United Nations Educational, Scientific and Cultural Organization.

Relevant Websites

http://www.cioms.ch/publications/layout_guide2002.pdf – Council for International Organizations of Medical Sciences, ‘International Ethical Guidelines for Biomedical Research Involving Human Subjects.’

http://conventions.coe.int/Treaty/EN/Treaties/html/164.htm – Council of Europe, ‘Convention for the Protection of Human Rights and Dignity of the Human Being with Regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine. Oviedo, 4.IV.1997.’

http://bioethics.georgetown.edu/nbac/pubs.html – National Bioethics Advisory Commission, ‘Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries.’

http://ohsr.od.nih.gov/guidelines/belmont.html – National Institutes of Health, Office of Human Subjects Research, ‘The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research.’

http://www.nuffieldbioethics.org/go/ourwork/ developingcountries/publication_309.html – Nuffield Council on Bioethics, ‘The Ethics of Research Related to Healthcare in Developing Countries.’

http://portal.unesco.org/shs/en/ev.php-URL_ID¼1883& URL_DO¼DO_TOPIC&URL_SECTION¼201.html – United Nations Educational, Scientific and Cultural Organization, ‘Universal Declaration on Bioethics and Human Rights.’

http://www.unesco.org.uy/shs/fileadmin/templates/shs/ archivos/DeclaracionCordoba.pdf – United Nations Educational, Scientific and Cultural Organization Latin American Network – Redbioetica, ‘Declaration of Cordoba.’

http://www.hss.energy.gov/healthsafety/ohre/roadmap/ achre/report.html – U.S. Department of Energy, Office of Health, Safety and Security, ‘Advisory Committee on Human Radiation Experiments: Final Report.’

http://whqlibdoc.who.int/hq/1996/TDR_GEN_96.2.pdf – World Health Organization, Ad Hoc Committee on Health Research Relating to Future Intervention Options, ‘Investing in Health Research and Development.’

http://www.wma.net/en/30publications/10policies/b3/ index.html – World Medical Association, ‘Declaration of Helsinki.’

Biographical Sketch

Jan Helge Solbakk is trained as a physician and a theologian at the University of Oslo. He holds a Ph.D. in ancient philosophy from the same university. Since 1996, he has been Professor of Medical Ethics at the Section for Medical Ethics, University of Oslo. During the same period, he has been Adjunct Professor of Medical Ethics at the Centre for International Health, University of Bergen. From February 2007 to August 2008, he served as Chief of Bioethics at the United Nations Educational, Scientific and Cultural Organization (UNESCO) headquarters in Paris. He is chair of ISSCR’s Ethics and Public Policy Committee. Since January 2006, he has been a member of an ethics committee set up by the European and Developing Countries Clinical Trial Partnership, and since August 2008 he has also served as member of UNESCO’s task force of experts set up in connection with the project Assisting Bioethics Committees. He is also a member of the Biomedical Ethics Funding Committee of the Wellcome Trust, United Kingdom. He has published extensively and is involved in several inter­

national research projects dealing with ethics teaching and with the ethical implications of biobanking, genetics, nanotechnol­

ogy, synthetic biology, and stem cell research.

Susana M. Vidal is trained as a physician with specialization in internal medicine. She has also a specialization in fundamental bioethics and holds a master’s degree in bioethics from the University of Chile/PAHO. She is Programme Specialist and in charge of Bioethics and Ethics of Science for Latin America and the Caribbean, SHS Sector of UNESCO in the UNESCO Montevideo Office, Uruguay. She also works as coordinator of the Permanent Education Programme in Bioethics, Redbioetica UNESCO, and she is a member of the Executive Board of Redbioetica UNESCO. From 1996 to 2008, she was chief of the Bioethics Area of the Ministry of Health of Cordoba, Argentina, and of the regional network of Clinical Ethics Committees. From 2001 to 2003, she was coordinator of the Commission of Research in Health Ethics of Cordoba, Argentina, and until 2008 she was member of the Council of Ethics Research Evaluation in Cordoba. She is also a member of the Bioethics Committee of the High Court of Justice of Cordoba. Finally, she is one of the founding members of the Argentinean Bioethics Society and Honorary Member of the Bioethics Society of Cordoba. She has published extensively in bioethics, clinical ethics, and the ethics of medical research.