United States: Clinical Researchers — Heads up! HHS’ Proposed Rules Focus on Clinical Research Enterprise

The clinical research enterprise faces several potential federal initiatives relating to the protection of human subjects, research misconduct, and investigational drugs, as reflected in the June 28, 2004, semiannual regulatory agenda of the U.S. Department of Health and Human Services ("HHS"). The agenda provides a brief description of rulemaking actions now under development, or ongoing review, by HHS, and is designed to provide notice to interested parties in order that they may participate the regulatory process and submit comments. Participation in the rulemaking process may be critical to later protests to the regulations, because of the recent Ninth Circuit decision in Universal Health Services v. Thompson, which held that the providers had no right to challenge a regulation in court, having failed to submit comments during the proposed rulemaking phase.

Below we discuss the proposed rules designed to address: the protection of human subjects; research misconduct; expansion of the uses of investigational drugs for which a sponsor may charge; and the ability of patients to obtain investigational drugs for treatment. Among the areas of particular agency focus are allegedly inadequate institutional review board ("IRB") oversight and related inadequacies in the protection of vulnerable patient populations.

In recent years, federal regulatory agencies have suspended clinical research studies at several prestigious institutions due to assessed deficiencies in the institutions' human subject protection systems. In some cases, these deficiencies were alleged to have contributed to the deaths of trial participants. These cases also led to an increased concern that the human research protection programs had failed to protect the volunteers from unacceptable research risks. As a result, the regulatory agenda reflects several provisions designed to increase the potential for federal oversight of the operations of IRBs.

IRB registration. On July 6, 2004, the Office for Human Research Protections ("OHRP") published a proposed rule which would require IRBs that review research conducted, or supported, by HHS under a federal wide assurance ("FWA") of compliance to register with HHS. A FWA is an organization's assurance to the federal government that human subject research, conducted at a particular site, is in compliance with federal human subject protection regulations, and applies broadly to all human subjects research conducted or supported by HHS, as well as to human subjects research conducted or supported by most of the other federal departments and agencies.

The FDA simultaneously published a separate proposed rule that would require IRBs that review FDA regulated clinical investigations to register.

The proposed OHRP and FDA registration requirements are generally the same and would create a single electronic HHS registration system. The proposed rules, if adopted, will have a significant impact on the clinical research community because of the increased level of public disclosure and potential federal oversight.

The current OHRP registration system requires IRBs to provide certain information, while other information is optional. Under existing FDA regulations, depending on the product involved the clinical investigation, sponsors or clinical investigators may be required to identify the IRB involved in the review of the study. Uder the proposed rules, all registration information would be mandatory.

The mandatory registration information would include the name of the IRB, the institution operating the IRB, the approximate number of active protocols involving FDA regulated products, and/or HHS funding, a description of the types of FDA regulated products (if applicable) involved in the protocols, accreditation status, and (for OHRP only) the IRB membership roster and number of full time administrative staff. While only the name of the IRB, institution, and IRB registration number would be available via internet, other IRB registration information would be subject to public disclosure under the federal Freedom of Information Act ("FOIA").

The proposed IRB registration requirements would make it easier for HHS to identify IRBs for inspection and for oversight purposes, and to send educational and other information to IRBs. The information would also enable HHS to determine, if problems have been identified at one IRB, whether similar problems exist at other IRBs affiliated with that institution.

OHRP indicated that it plans to use the information acquired from the registration to determine if the IRB's staffing is adequate in relationship to its workload. In the past, OHRP has cited institutions for failing to manage the IRB workload.

Initially, IRBs would be required to register and, thereafter, to renew their registrations every three years. If the IRB changes its contact person or chairperson, the IRB will need to update the registration information within 90 days of the change. HHS is particularly interested in comments on how it could best ensure that sponsors and investigators only use registered IRBs. For example, should sanctions be imposed on sponsors and investigators who use unregistered IRBs? Should FDA amend its regulations to authorize suspension of a study if the sponsor or investigator uses an unregistered IRB? Moreover, under the proposed rule, OHRP explained that it would not approve a FWA that lists an unregistered IRB.

HHS is also specifically seeking comments on: whether foreign IRBs should be required to register; the value of collecting information on IRB accreditation status; and whether it should require electronic registration and discontinue written registration procedures after a period of time.

Comments on the proposed rules must be submitted by October 4, 2004. HHS plans to issue a final rule in December 2004 and have the online (internet) registry operational in 2005.

IRB education. HHS plans to issue a Notice of Proposed Rulemaking ("NPRM") that would require institutions engaged in research conducted or supported by HHS under a FWA, to ensure that institutional officials, RB chairpersons, and administrators receive appropriate training and education about the institution's assurance of compliance. In addition, IRB chairpersons, members, and staff; investigators, and others involved in the conduct or oversight of human subject research would be required to receive appropriate training and education about human subject protection requirements. HHS has determined that better trained investigators and IRB members will help protect the interests of human subjects.

Additional safeguards for children in clinical investigations of FDA regulated products. The FDA also plans to issue a final rule in November 2004 that would finalize its April 2001 interim rule, providing additional protections for children enrolled in clinical investigations of FDA regulated products.

Existing HHS regulations provide safeguards for children involved in federally funded research. However, if an FDA regulated clinical investigation is commercially sponsored, the pediatric research is not subject to the HHS regulations. While some safeguards exist for pediatric research, the FDA regulations do not specifically address enrollment of children in clinical investigations. In the interim rule, the FDA adopted the safeguards established by HHS for pediatric research with minor changes. These additional pediatric safeguards would take on even greater significance in light of the Pediatric Research Equity Act ("PREA") which was passed in December 2003. The PREA gave FDA the authority to require drug manufacturers to conduct clinical trials of certain drugs and biologicals on children, and, as a result, the number of children enrolled in clinical trials is expected to increase.

Additional protections for adults with impaired decisionmaking. HHS plans to issue an advance notice of proposed rulemaking ("ANPRM") in September 2004 seeking comments on whether it is necessary to develop additional safeguards to protect adults with impaired decisionmaking capacity who are potential research subjects, and, if so, what the appropriate safeguards might be. The goal of the ANPRM is to continue the important research on the cause and treatment of mental disorders, while ensuring the protection of vulnerable patients who participate as subjects in such research.

Foreign clinical trials. On June 10, 2004, the FDA issued a proposed rule that would revise the standards for FDA acceptance of foreign clinical trials not conducted under an investigational new drug application ("IND"). The proposed rule would replace the current standard that such trials be conducted in accordance with the principles of the Declaration of Helsinki (a statement of ethical principles governing human subject research) with a requirement that the studies be conducted in accordance with good clinical practices ("GCP"). The GCP standard, which has been incorporated in FDA guidances, shares many of the ethical principles set forth in the Declaration of Helsinki, but also provides more specific principles, such as monitoring of the trial, reporting adverse events, and review and approval by an independent ethics committee. In addition, under the proposed rule, FDA must be able to validate the data from the study through an onsite inspection, as deemed necessary.

The objective of the proposed rule is to update the standards for the acceptance of non-IND clinical trials and help ensure the quality and integrity of data obtained from such studies.

Comments on the proposed rule must be submitted by September 8, 2004. FDA expects the final rule to be issued by June 2005.

Public Health Services policies on research misconduct. On April 16, 2004, HHS published a proposed rule that would substantially revise the existing regulations governing research misconduct at institutions applying for, or receiving, Public Health Service ("PHS") research funds, and broaden the scope of the federal government oversight and enforcement of federally funded research. One significant change would be to replace the current definition of "scientific misconduct" with the broader term of "research misconduct." Under the proposed definition of "research misconduct," misconduct occurring during the research review process, such as the peer review of an application or a journal article, would now be covered by the regulation. As a result individuals who plagiarize PHS funded research could be liable for research misconduct even if the individual or individual's research did not receive PHS funding.

The proposed rule would clarify and codify the institutional and federal responsibilities in handling research misconduct allegations. Institutions would continue to have primary responsibility for conducting inquiries and investigations. The proposed rule would also replace the existing ad hoc appeals process with a formal administrative hearing procedure. An appeal would first be heard by an administrative law judge ("ALJ"), rather than a three-person panel under the existing appeals process. The ALJ's final ruling constitutes a recommended decision to the Assistant Secretary for Health, who will then take final agency action on PHS research misconduct appeals, either affirming, reversing or modifying the ALJ's recommended decision. The respondent may then seek judicial review in federal court.

If an institution fails to comply with policies and procedures required by the proposed rule for inquiring and investigating allegations of research misconduct, it may be subject to an array of enforcement actions by HHS, including written reprimand, special oversight by HHS, specific corrective actions, and a requirement that the institution adopt an institutional integrity agreement. The comment period the NPRM ended June 15, 2004.

PHS standards for the protection of whistleblowers of research misconduct. In conjunction with the PHS policies on research misconduct, HHS plans to finalize the NPRM issued in December 2000 that would require institutions that receive PHS funds to follow a nonretaliation policy against whistleblowers involved in cases of possible research misconduct. The final rule is slated to be issued in December 2005.

The regulatory agenda also includes proposed actions that are favorable to drug manufacturers and clinical trial sponsors.

Charging for investigational drugs. FDA plans to issue a NPRM in December 2004 that would amend FDA's investigational new drug exemption regulations concerning charging for investigational drugs. The NPRM would describe the types of investigational uses for which a sponsor may be able to charge, and would expand the other uses for which a sponsor may charge. The NPRM would also establish the criteria for permitting charging for the identified investigational uses, and outline the types of costs that may be recovered by the sponsor.

Treatment use investigational drugs. Finally, the FDA plans to issue an NPRM in December 2004 that would amend FDA regulations governing investigational new drug exemptions to describe the process by which patients may obtain investigational drugs for treatment outside of a clinical trial. Under the NPRM, treatment use of investigational drugs would be available to individual patients (including emergency situations), intermediate size groups of patients, as well as larger patient populations under a treatment protocol or IND.

As evidenced by the proposed rulemaking action aimed at clinical research, the research enterprise faces heightened federal oversight and enforcement, and additional protections for human research subjects. Research institutions, IRBs, investigators and clinical research sponsors should monitor the proposed rules to determine any potential adverse impact their respective activities or goals. And we strongly advise active participation in the rulemaking process in order to preserve future legal rights.

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.