by James E. Lewis, PhD, an independent consultant and formerly a columnist for the Association of American Medical Colleges blog, Wing of Zock

A little known, but intentional, loophole in the federal regulations allows activities involving human subjects to be labeled “innovative care.” In spite of all that has been done since World War II to protect human subjects in clinical research, this ambiguity offers a mechanism through which unscrupulous individuals can avoid the ethical and regulatory obligations for the protection of human research subjects and the norms of professional and scholarly behavior. Recent cases demonstrating this dilemma can be found on the internet, but my purpose here is not to review any specific case but rather to bring broader attention to the generic question: “when is what appears to be human subjects research not research?” and the fundamental question: “how is it possible for such activities to occur without oversight?”

Let’s start by considering a hypothetical worst case scenario: A clinician, eager to investigate a self-generated hypothesis, decides to ignore everything anyone has ever said about protecting human subjects and undertake and fund an activity at his/her own discretion. The “innovative treatment” the physician is planning to implement is brought to the attention of the hospital and they determine, at the appropriate administrative level, that, based on the very limited information they’ve been provided, the activity does not meet the definition of human subjects research and does not require IRB approval. However, the hypothetical research subjects die. FDA is going to investigate. The Centers for Medicare and Medicaid Services is going to investigate because the subjects were Medicare eligible for inpatient coverage. This is the skeleton of a case study in which everything that could go wrong, does go wrong.

Cases such as the one described above bring several questions to the fore, including when does innovative and non-standard patient care become research and, thus, subject to the usually required and rigorous process of human subjects research review and approval? In thirty years of fairly close involvement with human research subjects protection in academic and community medical centers across the country, I have wondered from time to time about whether certain advances in surgical or other procedural techniques and instrumentation have been properly brought to the attention of the relevant IRB. And I have found myself left with the nagging question of whether there is a giant loophole in existing human subjects research regulations that allows researchers to avoid the policies and processes related to the protection of human research subjects through the use of phrases like “procedural experimentation” and “innovative care.”

Since I work nationally with institutions on IRB policy, requirements, and operations, the question of whether there is a category of exploratory activity involving human subjects that can be construed as innovative and non-standard, but not research and, therefore, legitimately be exempt from the IRB process is relevant to the quality and value of my advice. So I sent an email to the Office for Human Research Protections (OHRP) a few months ago asking for clarification on situations in which innovative and non-standard patient care is not research that requires IRB approval under the federal regulations. After about a month, I received the following response (emphasis added):

Please note that many ‘innovative treatments’ are part of research studies. However, if the activity involving the innovation does not meet the regulatory definition of research then those activities are not research under 45 CFR Part 46. However, they may be subject to regulation by the FDA or the state in which they are conducted.

OHRP also provided the regulatory definition of research at 45 CFR 46.102(d):

…a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes. For example, some demonstration and service programs may include research activities.

Unfortunately, that definition may generate more questions than it answers. What constitutes a systematic investigation? Does the use of the phrase in the regulatory definition of research encourage individuals seeking to avoid interaction with an IRB to engage in sloppy science? And what exactly constitutes generalizable knowledge? My colleagues, who are very active every day in IRB operations at the institutional level across the nation, point out that some individuals, who are bent on avoiding interaction with IRBs, will also cite the “contribute to generalizable knowledge” criterion to prove that there is no need for IRB involvement. With ambiguous terms such as “systematic investigation” and “generalizable knowledge,” the distinction between innovative and non-standard patient care and research becomes even less clear and paves the way for potential abuse.

The tenuous line between innovative care and research is one that can be seen in many key research ethics doctrines, including The Belmont Report, which served as the basis for much of 45 CFR 46. The Belmont Report seems to give much of medicine a free pass by waltzing around clinical experimentation and relying on review by “medical practice committees,” which may or may not exist let alone have any way of knowing when a clinician “departs in a significant way from standard or accepted practice.” The case I laid out at the beginning of this post offers a salient example of this. We can see what can happen when institutional oversight mechanisms for activities at the edge of research fail or don’t exist at all. How do institutions make decisions and communicate about what is and what is not human subjects research? And should it really be those institutions making those determinations? Perhaps, it is time for the leadership in this field to take a deep look at “clinical experimentation” qua “innovative treatment” and develop some new policies and regulations.