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Worries about safety of approved drugs have pushed post registration research (phase IV) to become the fastest growing drug research phase. Until recently, phase IV studies were mainly conducted for marketing purposes and run much like a phase III trial—at institutions with experienced investigators and a list of inclusion and exclusion criteria. Innovative phase IV studies involve ordinary physicians in research naïve communities. This brings ethical issues familiar to medical research into clinical practice. As a consequence, individual physicians are challenged to protect scientific integrity and to secure the ethical conduct of research. Several ethical issues need to be addressed in the process of developing a scientifically sound and ethically high principled practice of phase IV research.
Essential to phase IV research is the focus on how drugs work in the real world. The research goal may be to explore a specific pharmacological effect, to establish the incidence of adverse reactions, or to determine the effects of long-term administration of a drug. They may also be designed to establish a new clinical indication for a drug.1 Subjects may or may not be randomised, and the studies typically involve large numbers of patient-subjects and physicians.
Doubts concerning the scientific rigor and clinical value have put postmarketing research in a poor light. However, high quality phase IV research is badly needed to further pharmaceutical science. First, because it can provide reliable data on the effectiveness, safety and optimal use of a drug in treated populations.2 3 In pre-registration clinical trials (phase I–III), a pharmaceutical product is studied under unrealistic circumstances. Under-representation of women and elderly are common and the concomitant use of medicines is usually extremely restrictive in these trials.4 Second, phase IV can provide much needed data for evidence-based guidelines. In the European Union, assessment of the (added) therapeutic value of most new medicines was impossible at the moment of marketing authorisation. Practicing clinicians however, need comparative data to guide choices among registered alternatives.5
The current system of postmarketing safety monitoring is falling short. According to the FDA, of all 1259 open postmarketing commitments for new drugs, 71% was classified as “pending”, which means that the study has not been initiated.6
Moral issues that are well known in research ethics manifest themselves differently in the renewed phase IV practice. To explore these issues, we point out two paradigms in research ethics.
First, the protection paradigm, which has its roots in tragedy and scandal in medical experimentation. As a consequence, the emphasis of research ethics is on protection of individuals against the risks and burdens of research. Central to the protection paradigm is the view that a patient considering research participation is potentially vulnerable and in need of protection.
The second paradigm is that of distributive justice. At the heart of this paradigm is the principle of equitable distribution of burdens and benefits of medical research. This became important in the 1990s, when profound moral issues arose with the globalisation of pharmaceutical research. It comprises rules of distributive justice among groups of people in research (ie rich-poor, men-women). In addition, this paradigm attracts attention to the benefits of research participation. Fair and equitable access to research and to the results of research is a main concern.7
Starting from these ethical perspectives, we highlight several issues concerning phase IV.
Protection of research subjects
Issues related to protection can be divided in two categories: problems of informed consent and issues of protection of subjects against risk.
Informed consent and voluntariness
All prominent medical and research codes and international rules of ethics hold that informed consent must be obtained of patients and subjects—or their legal representatives—prior to any substantial intervention. Problems with voluntariness are likely to occur when there is a dependent relationship between the potential subject and the researcher, or when the subject consents under duress. The Declaration of Helsinki explicitly refers to these situations and urges physicians to be particularly cautious in obtaining informed consent (paragraph 23).
In general, adopting a dual role of treating physician and researcher should be avoided because it creates a dependency of potential patient-subjects. In community-based phase IV research, the roles of treating physician and investigator will be hard to separate—for patients and doctors. Furthermore, mixing research with care is associated with the therapeutic error. This occurs when a research subject—or her physician—falsely believes that participation in a clinical trial is in her best medical interest and this belief leads her to enrol in the trial. This poses an ethical problem, because enrolment is based on the wrong premise.8
Finally, attractive offers, such as access to new treatment for a life threatening disease can leave a person without choice. In 2006, the American Centers for Medicare and Medicaid Services designed the so called coverage with evidence development.9 Patients insured through Medicare who have an indication for a new technology would either have to pay out of pocket or enrol in a phase IV clinical trial. When incentives for potential research subjects are forceful, the role of physician-researchers in protecting the freedom of potential research subjects is at stake.
Protection against risk
If the risks involved in a study do not outweigh the potential benefits, the conduct of the study is unethical. There are some specific risks involved in modern phase IV research that need consideration from physicians and review committees. First, clinical practitioners participating in phase IV research will serve the interests of new parties. In clinical practice, the physician has a clear obligation to the patient. In research, this obligation remains, but may come into conflict with other obligations and incentives. Currently, the majority of clinical studies are funded by pharmaceutical companies and this results in the pursuit of supporting evidence concerning medications that are actively marketed by the companies. In the end, this leaves us with an undesirable and even dangerous mix of science and commerce.10
Second, the uncontrolled circumstances under which the research is carried out make it difficult to manage. Physicians who are not trained investigators play a significant role in the conduct of research. Thus, violations of trial conduct and fraud are harder to uncover.
Review committees should protect potential participants (patients and doctors) from research that is not designed to contribute to prophylactic, therapeutic or diagnostic possibilities, by withholding their approval. Physician-investigators need to be aware of the influence of research participation on their clinical decision making. For example, a study among general practitioners showed that participation in a large trial with asthma drugs increased the participating physician’s preference for and prescription of the trial sponsor’s drug. The results of this asthma trial were not published.11
It is unethical to let people carry the burdens of research when they are excluded from the benefits. Furthermore, injustice is caused by systematic neglect of certain diseases and populations.
It is a good thing that the under-representation of certain groups in pre-registration research can be compensated by phase IV trials in treated populations. Nevertheless, injustice due to selection occurs any time when vulnerability, privilege, or other factors unrelated to the purposes of the research, are the primary basis for determining the groups and individuals that will be recruited and enrolled.12 The size of phase IV studies imply that a large group of individual physicians is responsible for inclusion of subjects. Potential research subjects can be denied access to research when their physician is biased. The uncontrolled circumstances under which the research is carried out make it difficult to uncover such mechanisms.
Globalisation of pharmaceutical research has led to participation of subjects from resource-poor settings. The benefits of pharmaceutical research hardly reach these populations. An estimated 10% from the US $70 billion spent is used for research into 90% of the world’s health problems.13 All stakeholders in pharmaceutical research have a growing moral obligation to bridge this 10/90 gap. Phase IV research may help improve drug use in resource-poor settings. For example, when the objective is to differentiate pharmaceutical products in such a way that they fit the cultural and socio-economic context of formerly neglected populations. On the other hand, if the practice of phase IV focuses on study outcomes that are only relevant to rich, Western communities, the gap will be widened.
Innovative phase IV research is essential for optimal use of medicines and it has gained methodological rigor. However, a main source of ethical concern is the mix of medical research and clinical practice in this post registration phase. Problematic aspects are related to voluntariness, informed consent, risk management, conflicts of interest and the responsibilities of the physician in shaping a high principled research practice. A proactive strategy to accompany the further development of phase IV by an ethic of innovation can help pave the path for valuable pharmaceutical research.
Competing interests: None.
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