Putting the "ethics" back into research ethics: a process for ethical reflection for human research protection.

Introduction

"When persons prevent their emotions from overtaking their rationality, it is called reason. When persons prevent their rationality from overtaking their emotions, it is called compassion. When persons can do both, it is called wisdom."

--Ancient Chinese Saying

Research involving human subjects should be a partnership between the subjects who volunteer for the research, the public who hope to benefit from future drugs, devices, and biological products, investigators who design and conduct research, sponsors (institutions and companies that design, conduct, and sponsor or fund research), and IRBs who review research. I argue that "compliance with the regulations" governing research with human subjects has taken a front seat to broader ethical considerations of such research. While regulations contain practical applications of the ethical principles respect for persons, beneficence, and justice from such documents as the Belmont Report and Declaration of Helsinki, regulations do not explicitly reference these principles or provide procedures for ensuring that those who design, conduct, or review research have properly considered such matters.

Compliance is important, but it can become too focused on "checking off boxes" and the bureaucracy of documentation. As Dr. Gregory Koski (2003), former Director of the Office for Human Research Protections (OHRP), articulated, human research protection programs (HRPPs) need to move from a "culture of compliance" to a "culture of conscience" (p. $5). I argue that part of this shift in institutional culture involves re-discovering the ethical underpinnings of regulations for the protection of human subjects in such documents as the Belmont Report, the Nuremberg Code, and the Declaration of Helsinki. It is not enough to merely mention these documents in multi-center clinical trial protocols or IRB policy and procedure documents. Rather, the ethical principles in these documents need to be brought to life or enlivened during discussions of how to properly design, conduct, or review research.

Unfortunately, the number of findings from regulatory inspections from the Food and Drug Administration (FDA) and OHRP seems to indicate that there is a fundamental lack of training on the ethical principles themselves. The findings from such inspections consistently point to lapses in informed consent procedures and lack of investigator knowledge of human subject protection requirements. In addition, regulations provide little procedural guidance as to what the ethical substance of an IRB meeting should be like. However, regulations do provide checklists against which to document the presence or absence of certain required elements in protocols, informed consent documents, and recruitment materials.

Without training or experience in how to bring ethical principles to life, those who design, conduct, or review human subjects research will likely focus on ensuring compliance with regulatory requirements. In this way, they can at least be sure that the bare minimum of requirements has been met. This paper represents an attempt to supply those involved in designing, conducting, or reviewing human subjects research with a process of enlivening ethical principles by relying on a pragmatic framework for fostering moral discourse both within our own consciences and with others involved in these three research activities.

Origins of the Ethical Principles of Human Subjects Research

In 1979, the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research (the National Commission) produced, arguably, its most influential report. The Belmont Report, so named because the members of the Commission met at the Smithsonian Institute's Belmont Conference Center, articulated the ethical principles and philosophical basis for conducting research involving human subjects. The Report espouses three distinct ethical principles--respect for persons, beneficence, and justice--then provides practical measures for how these principles should be implemented in the design, conduct, and review of research (National Commission, 1979). The Report discusses the philosophical foundations of each of these principles and why each principle should be used in the research context. Discussion of these finer philosophical points is beyond the scope of this particular paper, but a multitude of philosophical sources, ranging from Aristotle, Immanuel Kant, John Stuart Mill, and David Hume, among others, find their thinking contained in the Belmont Report. The writers of the Belmont Report specifically intended and hoped that the Report and the three ethical principles would serve both as guideposts and reminders for those involved in designing, conducting, or reviewing human subjects research.

An "Ethics Gap" Between the Belmont Report and its Regulatory Offspring

It is not known, beyond mere anecdote, whether the Belmont Report enjoys wide dissemination to investigators (either in academic or medical settings or those in industry) nor to what extent the three ethical principles are part of education and training given to such groups. Moreover, it is not known whether those involved in reviewing research have read the Belmont Report, despite its free availability via the Internet on the FDA and OHRP websites.

What the Belmont Report provides in terms of philosophical justification and ethical analysis, it lacks in specific procedures for how its readers might employ the principles in designing, conducting, or reviewing research from an ethical perspective. Of course, that was and is not the purpose of the Belmont Report or the intent of its writers. Much of the practical import of the Belmont Report focuses on the translation of the ethical principles into their respective applications (respect for persons into the requirement to obtain informed consent, beneficence into the requirement to balance risks and benefits, and justice into the requirement of equitable subject selection). Current FDA, Department of Health and Human Services (DHHS), and international regulations governing human subjects research include each of the practical translations of the three ethical principles from the Belmont Report, yet no explicit mention of the ethical principles themselves appear in any of these regulations. Thus, there is a gap between the philosophical and the regulatory. Regulations mandate minimum requirements, but lack the specificity of procedural guidelines for how those who design, conduct, or review research should apply the ethical principles in their work. That is, and should not be, the purpose of regulations, for how would a government agency, institution, or company measure compliance with such an abstract notion as "ethical awareness."

To summarize, there is a paucity of evidence that those involved in human subjects research are aware of and utilize the ethical principles from the Belmont Report in their daily work. Moreover, the regulations do not directly address or mention the ethical principles themselves. Given these two pieces of information, it is not clear that reliance on regulations alone to carry out the ethical work required for appropriately designing, reviewing, or conducting research with human involvement is sufficient to ensure that the intent behind the Belmont Report can be met.

This "ethics gap" between the Belmont Report and the regulations might result in any of the following deficiencies in those who design, conduct, or review human subjects research:

1. Lack of awareness of particular ethical problems in the research;

2. Lack of ability or knowledge of how to apply ethical principles (and thus lack of acceptable resolutions to ethical problems in research); and

3. Focus on regulatory compliance rather than the broader ethical context and issues raised by the design or conduct of the research itself.

Bridging the "Ethics Gap:"Accreditation and Beyond

A series of research tragedies and scandals in the past decade have resulted in increased governmental scrutiny and focus on human subject protection regulatory compliance in the United States, both from OHRP and FDA. As a result, companies and institutions have become more focused on regulatory compliance as well. This focus might even be responsible for widening the "ethics gap" between regulations and ethics.

Fortunately, recent efforts to accredit human research protection programs (HRPPs) and thus the move away from exclusive focus on regulatory compliance to broader considerations in human research protections should help narrow this widening gap. At the time of the writing of this manuscript, two groups were offering accreditation of HRPPs--the Association for the Accreditation of HRPPs (AAHRPP) and the Partnership for Human Research Protection (PHRP). Both groups produced standards by which they will assess HRPPs, and both sets of standards explicitly address the ethical training not only of investigators but also IRB members and staff.

However, much like the Belmont Report, which articulates the ethical ideals to which those involved in research should aspire, the accreditation standards do not supply specifics on the mechanisms that institutions and companies should use to meet the standards. Thus, the purpose behind this paper.