The previous analysis focused on the PP in pre-2000 versions of the DoH. This section offers a very brief overview of major normative changes that occurred at the turn of the twentieth and twenty-first centuries in the ethical foundations of the DoH, and in the ethics of biomedical research on humans in general. This section investigates as well the implications of those changes for the interpretation of the PP.
By 2000, the DoH has risen in prominence as the guiding document for the ethics of biomedical research involving human subjects (Carson et al. 2004). It has been widely endorsed, implicitly or explicitly, as one of the cornerstones of international and national instruments regulating research on humans (Human and Fluss 2001). In parallel, in the mid-1990s heated debates over the standard of care owed to participants during and after research, especially those conducted in developing countries, and the ethics of placebo controlled trials started (Rothman and Michels 1994; Freedman et al., 1996a, 1996b; Angell 1997; Lurie and Wolfe 1997; Annas and Grodin 1998; Ellenberg and Temple 2000; Temple and Ellenberg 2000). Those debates revealed that the ethical paradigm of similarity position, and its “logical offspring”—clinical equipoise and “active control orthodoxy”—were not universally shared by academic ethicists, researchers (sponsors), and the relevant public authorities and policy-making bodies. To the contrary, they were rather a minority view (Lie et al. 2004). By the end of the 1990s the necessity for a change of the DoH had become evident also for the WMA. Accordingly, in 2000, after over two years of heated discussions, the 52nd WMA General Assembly adopted the fifth revision of the DoH, which proved to be the most far reaching and controversial modification of the document to date (Carlson et al. 2004; Kuroyanagi 2009). It resulted in a major normative and logical re-framing of the DoH as well as complete restructuration of the text. There is no need or space to discuss every aspect of the introduced modifications. It is, however, necessary to note that, although the references to the Declaration of Geneva and the International Code of Medical Ethics remained intact, the 1964–1996 distinction between therapeutic and non-therapeutic research was dropped. The DoH got a new internal three-part structure: “Introduction”, “Basic principles for all medical research”, and “Additional principles for medical research combined with medical care”. There was no longer a separate section dealing with non-therapeutic research. Such studies were subject to ethical standards for all medical research; now therapeutic research was awarded an additional regulation. In consequence, the 1975–1996 wording and the location of the PPs were modified. The PP was no longer mentioned twice in the 2000 DoH, nor in two separate paragraphs. It was “codified” in paragraph 5 of the introductory section as one of the top ethical considerations regarding research on humans. This is the textual and normative position that the PP has been occupying since then in the DoH (2008, 2013) and various other instruments setting standards for biomedical research involving humans.
It is also important to note that, despite major amendments proposed during the DoH review process, the 2000 revision did not introduce any significant changes in the overall ethical guidelines for placebo use (Kuroyanagi 2009). However, in response to the growing criticism against the “active control orthodoxy” of the DoH, in 2002 the WMA made an unprecedented move and added “Note of clarification” to the placebo-regarding paragraph. The “Note” enumerated two scenarios, in which a placebo-controlled trial could be ethically acceptable, even if proven therapy was available: (i) where the use of placebo control was necessary for compelling and scientifically sound methodological reasons; or (ii) where the trial investigated a method for a minor condition and “the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm”. Evidently, the Note did not clarify, but did significantly modify requirements for the use of placebo controls. With the added “Note”, the DoH abandoned “active control orthodoxy” and moved to the “middle ground” position (Emanuel and Miller 2001), which at that time, was already adopted by many international standards as well as numerous advisory and regulatory bodies (Lie et al. 2004). Thus, the DoH was no longer entirely faithful to the therapeutic orientation and the principle of clinical equipoise. Crucial cracks appeared in its normative foundations as well as in the ethical authority of the DoH guidelines.
Those (and other) ethical inconsistencies in the 2000 DoH mirrored the ongoing discussions on the need to revise ethical foundations of biomedical research involving human subjects. The debates were stimulated by rapid changes taking place both in research practice and research governance (e.g., growing patients’ activism and engagement in research, commercialization and globalization of research, local communities involvement in research, increasing regulatory demands for randomized double blind placebo control studies). All those new phenomena undermined theoretical and practical accuracy of the similarity position as “the reigning paradigm in the ethics of clinical trials” (Miller and Brody 2003, p. 24). Due to space limit, in what follows, three main “revolutionary” tendencies will be briefly discussed.
Beyond beneficence and respect for autonomy
At the end of the twentieth century, the similarity position, with its focus on the therapeutic obligation of a physician-researcher towards an individual research subject, turned out to be too narrow to embrace important ethical and social commitments represented by multiple facets of the principle of justice.
In the last two decades of the last century, the focus of research ethics and research oversight shifted from the protection against research to considerations regarding the just conduct of and access to research (cf. Emanuel and Grady 2006). Participation in research was no longer perceived as inherently dangerous, harmful or exploitive. It began to be viewed as a unique opportunity for treatment. The risks of research were deemphasized, the benefits highlighted, and “fair access to research (both participation in research and access to the results of research) became as important as protection from exploitation” (Beauchamp and Childress 2001, p. 227). Concomitantly, growing number of research conducted in developing countries by researchers and sponsors from developed countries created a demand for involving host communities in collaborative partnership to avoid their exploitation in research and to ensure their just share in research benefits (cf. Emanuel and Grady 2006).
That shift towards justice considerations was reflected in the 2000 version of the DoH, especially in paragraph 30 (requiring the post-trial access to the best proven method identified by the study for every patient-subject; eventually significantly weakened by the second “Note of Clarification” adopted in 2004) and paragraph 19 (requiring study benefits to accrue also to the host populations). Nevertheless, justice-based concerns remained of secondary importance for the drafters of the 2000 DoH. The document maintained its predominant focus on the individual researcher’s duties derived from the principles of beneficence and of respect for autonomy. And—to a large extant—it ignored problems of justice and injustice in research practice (i.e., questions of: fair selection of research subjects and host communities, just distribution of research risks and benefits between individuals and communities, fair access to research and its results, fair benefit sharing).
The shift towards justice considerations found, however, strong expression in the third version of the International Ethical Guidelines for Biomedical Research Involving Human Subjects adopted by the Council for International Organizations of Medical Sciences in 2002. The Guidelines were built upon ethical standards laid down by the DoH and the Belmont Report (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979), but they paid special attention to ethical challenges of research involving vulnerable individuals or communities as well as to dilemmas posed by multinational or transnational research conducted in low-income countries. Guideline 1 clearly stated that the production of socially valuable knowledge is “ethically justifiable only if it is carried out in ways that respect and protect, and are fair to, the subjects of that research and are morally acceptable within the communities in which the research is carried out” (CIOMS 2002). This has been repeated and developed further in the current version of the CIOMS Guidelines of 2016. The commentary on the 2016 Guideline 1 stresses that the respect for rights and welfare of individual participants and communities in which research is carried out, requires research to be (among others) “sensitive to issues of justice and fairness. This concern is manifest in choosing whose health needs are investigated; how risks, burdens, and anticipated benefits of individual studies are distributed; and who will have access to any resulting knowledge and interventions”.
Although specific demands of justice in research are not always evident or uncontroversial, all modern ethical standards for biomedical research include numerous, widely accepted requirements regarding the fair treatment of potential and actual research participants and relevant communities. A comprehensive discussion of these requirements lies beyond the scope of this article. One general imperative is however certain: research subjects’ interests should be protected against non-equal consideration and/or unfair treatment, especially when such a treatment aims at promoting interests of others (e.g., interests of researchers in minimizing inconveniences and maximizing efficacy and money-saving). This constitutes a justice-driven facet of the PP.
Under the umbrella of human dignity and human rights discourse
One more paradigm shift occurred towards the end of twentieth century—the practice of medicine and medical research got embraced by the international human rights discourse based on the concept of inherent and unalienable human dignity (Thomasma 2001; Knowles 2001; Beyleveld and Brownsword 2001; Schroeder 2005; Andorno 2009, 2013). The recourse to the human dignity and human rights in the field of global bioethics was particularly strong in regulatory instruments developed under the auspices of the United Nations Educational, Scientific, and Cultural Organization (UNESCO) and the Council of Europe.
In 1997, after five years of drafting process, the Council of Europe adopted the 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, also known as the Oviedo Convection, since it was opened for signature in Oviedo, Spain (1997a). Seven years later, the Council of Europe adopted the Additional Protocol to the Convention concerning biomedical research (2005a) to “address the ethical and legal issues raised by present or future scientific advances through the further development, in specific fields such as biomedical research, of the principles contained in the Convention” (Council of Europe 2005b, para.11). The Convention (with subsequently added further additional protocols) was the very first and still is the only international legally binding human rights instrument entirely dedicated to biomedicine.
Both the Oviedo Convention and the Additional Protocol concerning biomedical research aim at protecting “the dignity and identity of all human beings and guarantee everyone, without discrimination, respect for their integrity and other rights and fundamental freedoms with regard to the application of biology and medicine” (Council of Europe 1997a, Article 1), and specifically with regard to any biomedical research involving interventions on human beings (Council of Europe 2005a, Article 1). The Preamble to the Additional Protocol clearly states that biomedical research contrary to human dignity and human rights should never be carried out, and stresses that the paramount concern should be the protection of the human being participating in research, particularly those who are vulnerable.
Importantly for this analysis, both the Oviedo Convention and the Additional Protocol concerning biomedical research create a strong link between the value of human dignity—which “constitutes the essential value to be upheld …[as] it is at the basis of most of the values emphasized in the Convention” (Council of Europe 1997b, para. 9)—and the PP. In both documents the PP is expressed in the very first substantive article, immediately following introductory provisions. Both documents stipulate that the interests and welfare of the human being, especially of the human being participating in research, shall prevail over the sole interest of society or science (Council of Europe 1997a, Article 2; Council of Europe 2005a, Article 3). Although a more detailed explanation of the PP is absent, it is evident that the PP sets limits of freedom of biomedical research. The scientific freedom is valuable, but not absolute. It is limited by the participants’ welfare and interests as well as the concept of human dignity and fundamental rights, expressed by the Additional Protocol, the Convention and “by other legal provisions ensuring the protection of the human being” (Council of Europe 2005a, Article 4; Council of Europe 2005b, para. 23). The Explanatory Reports to the Additional Protocol and the Convention clarify further that both documents are “inspired by the principle of the primacy of the human being, and all [their] Articles must be interpreted in this light” (Council of Europe 1997b, para. 22; Council of Europe 2005b, para. 21). Thus, under the Council of Europe bioethical framework, the PP plays two main roles: it is a general rule aiming at protecting humans (research subjects) against being sacrificed on the altar of science, and the fundamental, interpretative rule stating: if a provision is open to more than one interpretation, the interpretation which serves the human being’s interests and welfare in the most effective way should prevail.
In 2005, the UNESCO adopted the Universal Declaration of Human Rights and Bioethics (2005). The Declaration is not the first, but definitely it is the most important instrument adopted by the UNESCO dealing with biomedicine from the human right perspective. Similar to the Oviedo Convention, the Declaration assigns a very central role to the notion of human dignity and human rights, and it makes a direct link between this notion and the PP. The PP is spelled out in Article 3 of the Declaration titled “Human dignity and human rights”. Paragraph 1 of Article 3 states: “Human dignity, human rights and fundamental freedoms are to be fully respected”, and paragraph 2 reads: “The interests and welfare of the individual should have priority over the sole interest of science or society”. Thus, it should come as no surprise that numerous commentators of the Declaration consider the PP to be a normative offspring of the idea of human dignity (Andorno 2009, 2013; cf. Parker 2010; Simonsen 2012). Robert Andorno claims: “The primacy of the human being over science is indeed a direct corollary of the principle of respect for human dignity and aims to emphasize two fundamental ideas. First, that science is not an end in itself but only a means for improving the welfare of individuals and society. Second, that people should not be reduced to mere instruments for the benefit of science” (Andorno 2009, p. 228).
Obviously, the two ideas mentioned by Andorno do not exhaust all that is to be said on the dignity-derived PP. In order to fully understand the normative content of this PP, it would be necessary to discuss the meaning of human dignity. For obvious reasons, this is beyond the scope of this paper. Nevertheless, despite the vagueness and ambiguity of the notion of human dignity, it seems safe to conclude that in the context of global bioethics this notion includes two conceptions: the conception of human dignity as empowerment, which emphasizes human rights, especially the right to pursue one’s autonomously chosen goals, and the conception of human dignity as constraint, which is more concerned with human duties. These duties comprise “not only a duty to respect the dignity of others but also a duty not to compromise our own dignity, as well as to act in a way that is compatible with respect for the vision of human dignity that gives a particular community its distinctive cultural identity” (Beyleveld and Brownsword 2001, p. 1). Thus, human dignity as constraint is based on a shared vision of what constitutes valuable human life and what is owed to the individual—to her intrinsic worthiness, integrity, and identity. These dignity-driven duties fuel the PP which aims at protecting interests of human being participating in research, even against autonomy of the individual concerned.
Towards a “difference position”
The heaviest criticism against the similarity position was launched at the beginning of the twenty-first century by a group of influential American research ethicists (Franklin G. Miller and his collaborators) which questioned its ethical and practical validity (Miller and Brody 2003, 2007; Miller and Rosenstein 2003). They argued that the very idea of researchers having a therapeutic obligation to research participants rests on a fundamental confusion—a “’therapeutic misconception” concerning the ethics of biomedical research (Miller and Brody 2003, p. 20), and it should be rejected. Their claim was based on the following reasoning: (i) “the basic goal and nature of the activity determines the ethical standards that ought to apply” (22); (ii) ultimate goals of medical practice and medical research are entirely different—physicians are devoted to promote the best medical interest of their individual patients; researchers aim at producing generable knowledge to improve medical care for the future patients; (iii) the goals of medical practice and medical research are “logically incompatible”, since “it is impossible to maintain fidelity to doing what is best for patients in the context of RCT [randomized clinical trials] because these are not designed for, and may conflict with personal care” (25); therefore (iv) medical research should be governed by ethical standards appropriate for goals and nature of the practice, which are distinct from the principle of therapeutic beneficence (and non-maleficence).
Miller’s et al. extended their critique of the similar position further to the requirement of clinical equipoise which, given the inappropriateness of applying the principle of therapeutic beneficence to research practice, provided a “solution” to a non-problem. Consequently, they claimed that: “Clinical equipoise is neither necessary nor sufficient for ethically justifiable RCTs [randomized clinical trials]. The use of placebo controls when proven effective treatment exists violates clinical equipoise … Nevertheless, it is the unacceptable level of risk, not the violation of investigators’ alleged “therapeutic obligation”, that makes these trials unethical” (Miller and Brody 2003, p. 25).
Thus, Miller and colleagues argued for abandoning both the similarity position and the clinical equipoise, and for adopting instead a “difference position” to the ethics of biomedical research involving humans, which would not conflate the ethics of research with the ethics of therapeutic medicine. They considered the “non-exploitation framework”, developed by Ezekiel Emanuel, David Wendler, and Christe Grady (2000), to be a strong candidate for such an alternative framework for the ethics of biomedical research.
The “non-exploitation framework” aims at protecting research participants from exploitation by setting seven requirements for all clinical research: (1) social value; (2) scientific validity; (3) fair subject selection; (4) favorable risk–benefit ratio; (5) independent review; (6) informed consent; (7) respect for potential and enrolled subjects (by “permitting withdrawal from research; protecting privacy through confidentiality; informing subjects of newly discovered risks and benefits; informing subjects of results of clinical research; maintaining welfare of subjects”; Emanuel et al. 2000, p. 2703). These requirements are justified by the following ethical values and social commitments: reasonable use of scare resources (1, 2); avoidance of exploitation (1, 2, 4); justice as equal treatment, justice as fairness in distribution of research risks and benefits (3); beneficence and non-maleficence (4, 7); public accountability and minimization of influence of potential conflicts of interests (5); respect for the subject’s autonomy (6, 7). This framework rejects the idea of researchers having any therapeutic obligations towards participants. It “holds instead, that researchers have the somewhat weaker duty to non-exploitation” (London 2007, p. 102).
The “non-exploitation framework” does not involve the PP. Perhaps, it is due to the PP original affiliation with the already rejected principle of therapeutic beneficence. In this context, it is interesting to mention that Ezekiel Emanuel has developed a proposal for a revision of the current version of the DoH adopted in 2013. The PP contained in the 2013 DoH reads: “While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects” (para. 8). Paragraph 9 adds: “It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of research subjects. The responsibility for the protection of research subjects must always rest with the physician or other health care professionals and never with the research subjects, even though they have given consent”. Emanuel proposed to replace both provisions by one paragraph stating: "Purpose of Ethical Principles Guiding Research: The primary purpose of ethical principles to guide research in biomedical and other sciences involving human participants is to promote socially valuable studies while minimizing exploitation, the unfair distribution of benefits and burdens of the conduct and results of research. It should minimize the likelihood that the life, well-being, health, self-determination, privacy, and confidentiality of the participants’ personal information, might be adversely affected and minimize the consequences if they are” (Emanuel 2013, Supplementary appendix).