Uniformity Sought for Research Standards

Research experts, patient advocates, and government officials have examined options for improving oversight of human subject research for years, often in response to periodic scandals involving patient abuse and unethical conduct that heighten public interest in the clinical research process. Now federal officials have put a major reform proposal on the table, with an eye to enhancing protections for research subjects while also reducing burdens, delays, and ambiguity for investigators. The change involves a lengthy and detailed proposal for revising the Common Rule, which was published in July by the Department of Health and Human Services (HHS), in coordination with the White House Office of Science and Technology Policy (Federal Register, 76 (143), 44,512-44,524 (2011). HHS is receiving comments to the Advanced Notice of Proposed Rulemaking until October 26, and the breadth and depth of the proposal is sure to generate a considerable response.

Jill Wechsler

The Common Rule generally requires investigators and sponsors to obtain and document informed consent by research participants and to undergo review by institutional review boards (IRBs), spelling out a host of requirements for investigators and review board operations in the process. It was developed and revised through the 1970s and 1980s and adopted in 1990 by 14 federal agencies as the Common Rule for the protection of human research subjects.

The long and convoluted process for establishing these standards, though, has led to a policy that can be overly burdensome and bureaucratic, often accused of driving up study costs and failing to protect research participants. Although the Common Rule directly affects research funded by the US government, the contemplated changes stand to shape policies for industry-sponsored studies regulated by the Food and Drug Administration. Proposals to streamline informed consent, adverse event reporting, and IRB oversight could make the research process more efficient, while new standards governing data privacy and disclosure could require new approaches to clinical trial conduct.

The reform proposal is timely, according to HHS, because the scope and nature of clinical research has changed notably since the last revision of the Common Rule 20 years ago. Research has shifted from academic medical centers to hospitals and doctors' offices, while sophisticated software and mobile technology have altered the landscape for protecting the privacy of research data. Investigators and sponsors, moreover, are conducting more clinical studies overseas, which only adds to the confusion over which standards to follow.

An added impetus for proposing this broad regulatory reform initiative is the campaign launched in January by President Obama to identify, eliminate, or modify those federal regulations found to be excessive. Revising the Common Rule fits that mandate, even though it could mean added regulation in some situations.

Parallel efforts

HHS officials were able to move quickly to publish this extensive reform proposal because of a long history in examining human subject research practices and policies. Over the last few decades, the Institute of Medicine, the Government Accountability Office, and the National Bioethics Advisory Commission have offered multiple reports with a range of recommendations for revising oversight and review of research.

In addition, the HHS Office for Human Research Protections (OHRP), which was formed in 2000 to address concerns about inadequate oversight of clinical research by the National Institutes of Health (NIH) and other HHS agencies, has evaluated and proposed multiple policy changes governing oversight of federally funded research. The Secretary's Advisory Committee on Human Research Protections (SACHRP), which OHRP manages, has examined ways to harmonize and clarify rules governing informed consent, conflicts of interest, safety assessment, and IRB operations, among many other issues. SACHRP subcommittees continue to explore problems related to federal policies and to harmonize diverse federal standards, particularly differences between HHS and FDA policies.

Moreover, the Presidential Commission for the Study of Bioethical Issues is reviewing how well US research regulations protect human research subjects in response to a formal request from President Obama. Concerns about US policies emerged last year following revelations that a US-funded study in the 1940s in Guatemala deliberately infected people with sexually transmitted diseases and in some cases withheld treatment [see Applied Clinical Trials, View from Washington, April 2011]. In addition to assessing the Guatemala study specifically, the panel is examining the scope and sufficiency of controls and regulations governing US-funded research. In the process, the commission seeks to assemble a database on federally supported scientific studies, including how many people are enrolled and how much money the government expends in this field.

At its May 2011 meeting, Christine Grady, Deputy Chief of the Department of Bioethics at the NIH Clinical Center, described how the common rule differs from FDA good clinical practices regs (GCPs) and how the proliferation of federal guidelines can be overwhelming and frustrating to investigators. The sheer number of rules and guidances can discourage scientists from conducting clinical research at all, she acknowledged, and burdensome rules can delay approval of new studies for years, with potential harm to patients.

Murray Lumpkin, FDA Deputy Commissioner for International Programs, outlined how the growth in foreign clinical trial data submitted to support US marketing applications has expanded the agency's role in ensuring that data from foreign clinical trials is obtained in an ethical manner. With half of clinical investigators involved in FDA-regulated studies now based outside North America, he noted, the agency finds it increasingly challenging to inspect clinical sites to ensure that studies meet GCPs and have appropriate oversight by independent ethics boards. Lumpkin agreed with Grady that GCP guidelines developed by the International Conference on Harmonization (ICH) have become an international standard, but that US researchers have to understand local differences in key issues such as standard of care and legitimate consent.

Risk-based approach

In this latest effort to update the Common Rule, HHS officials seek to take a more risk-based approach to research oversight, permitting expedited IRB review and less continuing review for studies categorized as "minimal risk." At the same time, HHS proposes to extend Common Rule oversight to a much broader scope of research. Instead of applying only to those studies that receive government funding, research standards would cover all research at institutions that receive any federal funds. The aim is to bring more social science and behavioral research under the Common Rule umbrella, but the change could affect industry sponsored research with sites at hospitals, clinics, or academic research centers.

An important change for sponsors of multi-site studies is new flexibility to designate a central IRB of record, a move that would reduce IRB workloads and permit them to focus on more critical oversight activities, while also simplifying compliance for investigators. Oversight also would be enhanced by an electronic system for reporting adverse events that would feed all safety information from federally-regulated studies into a comprehensive database. This would utilize a harmonized data set for adverse event reporting developed by FDA, NIH, and other agencies and now being tested by NIH and FDA in a harmonized reporting system for gene-transfer studies.

Similarly, the reformers seek to improve informed-consent requirements and the consent process. The proposal cites ways to reduce the length and legalese in these documents to help subjects make informed decisions about study participation. An important issue is the need for consent for future use of biospecimens and research information. Current rules permit investigators to use blood and tissue samples in subsequent research without added consent because such material is not individually identified; now HHS proposes that researchers obtain explicit permission from tissue donors for future use of such material because new DNA sequencing technology makes it possible to link tissues to specific donors.

HHS justifies looser controls and less oversight of certain research activities on its plan to extend privacy protections to research data. The proposed rule seeks to establish uniform security standards for research data modeled on the protections provided by the Health Insurance Portability and Accountability Act for medical records. Related to this, IRBs no longer would have to evaluate privacy and confidentiality standards for research studies, a fairly recently added responsibility that has been difficult for most review boards to carry out.

For the most part, industry sponsors and investigators adhere to FDA standards that are more specific than those for academic researchers. OHRP has been working with FDA on harmonization efforts for more than a decade, but legal requirements limit how much FDA can modify its policies. Officials at these agencies are keeping pretty mum about the implications of the rule changes until they see what kind of response they get from the research community and patient advocates. Changes of this magnitude will take years, but some could make clinical research more efficient and effective.

At the May bioethical commission meeting, Wellesley College Professor Susan Reverby, who uncovered the controversial Guatemala study, raised concern that the resulting discussion about unethical research practices could make people afraid to participate in clinical studies, which make "a huge difference in the lives of every person on this planet."

Jill Wechsler is the Washington Editor of Applied Clinical Trials, (301) 656-4634 jwechsler@advanstar.com