Modernizing the Human Subjects Regulations

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Given its importance in scientific development, human subjects research requires close regulatory attention.

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Every day individuals around the world take part in research studies, including biomedical and behavioral experiments.

As a result of decades of research regulation development, most of these studies maintain high ethical standards and can be of considerable importance for advances in science, medicine, and technology. But the ways in which the federal government will choose to respond to new research issues of pressing concern, like the development of personalized medicine or the use of novel neuro-technologies, remain unclear.

The regulations that provide for oversight of human subjects experimentation were shaped by collective responses to profound tragedies, among them the Nazi medical atrocities during World War II, the Tuskegee syphilis study (a horrifying decades-long clinical study conducted by the U.S. Public Health Service), and human radiation experiments performed on U.S. service members.

Responses to these atrocities included the Nuremberg Code, a set of ethical principles for human experimentation developed in 1947, and the Declaration of Helsinki, a cornerstone document on human research ethics released in 1964 by the World Medical Association.

In the United States, key responses included the creation of the Office for Protection from Research Risks (OPRR), later replaced by the U.S. Department of Health and Human Services (HHS) Office for Human Research Protections in 2000.

OPRR recommended establishing independent bodies to oversee experiments, now known as institutional review boards (IRBs). Basic regulations governing the protection of human subjects in research were first issued by HHS in 1974, and the National Research Act established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.

The National Commission published the Belmont Report in 1978, identifying three fundamental ethical principles for research involving human subjects: respect for persons, beneficence, and justice. The report also identified these principles’ primary areas of application: informed consent, assessment of risks and benefits, and subject selection. Guided by the Belmont Report and related work, HHS revised and expanded its human experimentation regulations.

In 1981, the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research called on all federal agencies to adopt the HHS regulations then in effect for the protection of human subjects of research. In 1982, the head of the White House Office of Science and Technology Policy (OSTP) appointed a committee including the relevant federal departments and agencies to address these recommendations.

Nine years later, sixteen federal departments and agencies adopted a common set of regulatory provisions protecting human subjects of research, generally known as the Common Rule. These shared provisions relate to IRBs, consent, and compliance. Broader regulations also provide additional protections, not shared in common by all agencies, for pregnant women, human fetuses, infants, children, and prisoners.

Since the original release of the Common Rule, concerns have surfaced about many unintended consequences created by the rule’s heightened protections of human subjects.

These unintended consequences include: excessive attention to minimal-risk research; possible misapplication of the regulations—also known as “mission creep”—to areas such as journalism and oral history; problems with the consent process; the complexity of multi-site experiments; and the appropriate gathering and use of physical materials like cells and other biospecimens, as discussed in Rebecca Skloot’s book, The Immortal Life of Henrietta Lacks.

In July 2011, OSTP and HHS announced their intention to create a rule with the goal of modernizing protections for human research subjects while also reducing burden, delay, and ambiguity for investigators.

After several years, there were reports that this modernization process had stalled, and, in 2014, there were concerns that it might be abandoned. President Barack Obama tasked OSTP with expediting the effort, with the goal of releasing a final rule before the end of his Administration, if feasible.

A short-term interagency group called The Common Rule Modernization Working Group was created in February 2014 and co-chaired by OSTP, OHRP, and the National Science Foundation.

Membership in The Common Rule Modernization Working Group included representatives from the Common Rule agencies and departments, providing the first opportunity for interagency discussion beyond HHS over modernization of the regulations. The process of drafting a notice of proposed rulemaking commenced.

Input on the proposed rule came in from a variety of sources, including universities, professional societies, advocacy groups, the National Academies, and the public, including previous responses to the 2011 announcement.

The “final” rule to revise the Common Rule was published on January 19, 2017, the next to last day of the Obama Administration.

As is often the case with a change in administrations, the regulatory steps taken by the Obama Administration resulted in additional scrutiny from the incoming Trump Administration, particularly for those rules like the Common Rule revision that were released near the end of the term. In addition, the rule revision was amended twice, delaying the compliance dates to allow for appropriate implementation.

After an almost eight-year-long regulatory process, and almost thirty years after its original adoption, the modernized Common Rule officially took effect on January 21, 2019.

Key changes in the revised version of the Common Rule include the following: no longer requiring continuing review for some minimal-risk research; requiring informed consent to incorporate “key information” at the beginning of the consent form and including new consent elements and a “broad consent” option for biospecimen use; including new categories of exemptions and clarifying existing categories; and requiring a single IRB of record in most cases starting January 20, 2020.

What is the future of the Common Rule and other related regulations? It is important to keep in mind that scientific, medical, and technological landscapes are constantly changing and often engender challenges in research ethics and regulation.

As an example, when the Obama Administration was developing the White House BRAIN Initiative, it was clear to participants in that process that they needed to take seriously ethical issues relating to emerging neuro-technologies. Accordingly, we reached out to the Presidential Commission for the Study of Bioethical Issues, chaired by Amy Gutmann, to consider such matters.

Specifically, President Obama asked the Presidential Commission to establish core ethics standards to address developments in neuroscience research and ethical issues raised by applications of such research. The Presidential Commission’s work resulted in two detailed reports.”

Other examples of new technological developments raising emerging ethical issues include gene editing, personalized medicine, and big data and algorithmic bias in artificial intelligence systems, along with social interactions with artificial intelligence.

It is important to have broad and constant conversations and input on a wide range of issues that go beyond the biomedical when considering research ethics.

Many concerned parties will be dissatisfied with the modernized Common Rule—which is to be expected. In part, this dissatisfaction reflects the complexity of the process and the diversity of opinions about the system and desired goals. The opinions and preferences of a wide range of stakeholders need to be heard.

At the federal level, I hope that, if it has not already been done, an interagency group on research ethics will be revived, perhaps within the National Science and Technology Council. I also hope that the public and policymakers are provided with opportunities to participate interactively and meaningfully in this important and ongoing conversation.

Philip E. Rubin

Philip E. Rubin is the Chief Executive Officer emeritus of Haskins Laboratories and an adjunct professor at the Yale University School of Medicine.

This essay is part of a 12-part series, entitled What Tomorrow Holds for U.S. Health Care.