Streamlining Clinical Research Oversight

June 1, 2004
Jill Wechsler

Jill Wechsler is ACT's Washington Editor

Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-06-01-2004,

Federal agencies seek to curb redundant IRB procedures and encourage voluntary accreditation of research organizations.

Federal agencies seek to curb redundant IRB procedures and encourage voluntary accreditation of research organizations.


The lengthy and cumbersome process of gaining research protocol approvals from IRBs (institutional review boards) is prompting regulators and advisory panels to seek strategies for making the review process more efficient. Federal agencies that oversee human research activities want to reduce the number of adverse event reports (AERs) filed with review boards. Officials are also encouraging IRBs and research institutions to seek voluntary accreditation to enhance credibility and gain more insight into efficient operating practices.

Meanwhile, as government health care programs seek more evidence on the value of new drugs, sponsors and researchers face pressure to produce more outcomes and more cost-effectiveness data (see sidebar).

Bernard Schwetz, recently named director of HHS's Office of Human Research Protections (OHRP) after serving in an acting capacity for a year, plans to issue more guidances to clarify policies in several areas. Formerly acting commissioner of the Food and Drug Administration, Schwetz believes that he is well-positioned to work closely with FDA to gain consensus on key policy issues. Schwetz wants to move away from OHRP's "gotcha" image and create an environment where members of the research community more readily come to the agency for assistance. He also wants to help IRBs become more efficient by addressing their lack of resources and familiarity with operational best practices. Schwetz is working with FDA and the HHS Secretary's Advisory Committee on Human Research Protections (SACHRP) to encourage IRBs and research organizations to implement streamlining opportunities.

Reducing AERs
One current initiative is to reduce the overwhelming volume of adverse event reports (or external AERs) filed with IRBs. Schwetz estimates that only about 5% of AERs really warrant IRB review; he believes that about 70% of the reports are of little concern to review panels, and only the remaining 25% fall into a gray area that requires some kind of assessment or triage. One problem is that sponsors file duplicate reports with all IRBs involved in multisite trials; pharmaceutical companies in particular usually opt to report even minor AERs as broadly as possible to reduce liability exposure.

Schwetz and others at the March SACHRP meeting discussed options for decreasing the IRB review burden. One approach is for data safety monitoring boards (DSMBs) to triage adverse events for multisite trials. SACHRP chairman Ernest Prentice supported a proposal from several academic institutions to have principal investigators analyze AERs and decide which ones to send on for additional IRB review. He considers investigators well positioned to assess the significance of an adverse event.

However, some objected that this merely shifts the burden of evaluating adverse events to already overburdened investigators. Moreover, such an approach could raise conflict-of-interest concerns because PIs might be inclined to minimize problems related to their own site. Another issue is whether FDA policies permit investigators instead of sponsors to decide whether or not to file an AER with the IRB.

At the April National Medical Research Summit in Baltimore, Prentice said that sponsors and DSMBs should file only those AERs that require:

  • modifications of a protocol to address new safety concerns
  • revision of consent forms to include new risk issues
  • disclosure of other risk issues affecting the study.

Prentice noted that no HHS regulations require sponsors to inform all IRBs of adverse events, but that the practice has developed due to over-interpretation of the rules. He urged OHRP and FDA to promptly issue clear guidance on which AERs should be filed with IRBs, and Schwetz agrees on the need for clarification in this area, particularly regarding submission of adverse event reports for multisite studies.

Meeting standards
Schwetz and SACHRP members also are encouraging IRBs and research organizations to apply for voluntary accreditation, particularly commercial IRBs eager to document independence and credibility. At its March meeting, SACHRP concluded an examination of private sector accreditation programs and praised the process as likely to significantly improve research protections. However, the advisory panel decided that it was premature for government agencies to offer additional incentives for institutions to seek accreditation or to endorse any specific accreditation program.

SACHRP subcommittee chairman Tom Adams, who heads the Association of Clinical Research Professionals (ACRP), predicted that pressure from pharmaceutical companies will spur research organizations and IRBs to seek accreditation as a good business practice. Of the still-low number of research organizations awarded accreditation so far, about half are IRBs. Schwetz expects that in the near future, sponsors of commercial clinical trials will contract primarily with accredited review boards and research firms.

The panel's decisions was disappointing to accrediting organizations, which had looked for a stronger support from SACHRP to spur more research organizations to sign up for this admittedly expensive and time-consuming process. Even without additional regulatory "carrots," though, the Association for the Accreditation of Human Research Protection Programs (AAHRPP) predicted that most major academic research centers and teaching hospitals will be accredited in five years.

AAHRPP and the Partnership for Human Research Protections (PHRP), formed by the National Committee on Quality Assurance and the Joint Commission on Accreditation of Healthcare Organizations, combine self-assessment activities with site visits in their accreditation procedures. AAHRPP's program is considered more subjective and easier for academic institutions to utilize. It recently announced accreditation of Cedars-Sinai Medical Center in Los Angeles and the Dana-Farber/Harvard Cancer Center in Boston, among others.

PHRP's process is regarded as more quantitative and useful for high-profile organizations that want to document compliance with regulations. It gained its start by providing an accreditation program for the Veteran's Administration's troubled clinical research program and has accredited two independent IRBs in recent months, along with other organizations.

Further insight into the value of accreditation is expected to come from an effort by the Centers for Disease Control and Prevention (CDC) to assess the role of accreditation in enhancing the protection of participants in public health research. CDC recently contracted with AAHRPP to develop a set of measures for determining the effectiveness of accreditation programs and their impact on IRB performance. CDC supports a broad range of research involving health services, behavioral interventions, epidemiologic trends as well as traditional biomedical research and clinical trials.

AAHRPP plans to develop pilot measures this summer and perform a validation study next year. The aim is to assess whether such measures can improve the ability of the public health infrastructure to assess and monitor research involving human subjects. Members of the research community have expressed concern that AAHRPP's involvement in this evaluation effort might support measures most suitable to its accreditation methods. Schwetz and SACHRP have asked CDC officials to clarify more fully their objectives for the study and concerns about research protections. The results of this three-year assessment most likely will provide an opportunity for SACHRP to revisit the role and impact of accreditation overall.

SIDEBAR: Push for More Outcomes Research
Mark McClellan, now administrator of the Centers for Medicare and Medicaid Services (CMS), is seeking more evidence on how drugs and medical products affect patients in clinical settings. McClellan says that his first priority is to use the new Medicare pharmacy program, starting with the drug discount card, to lower spending on pharmaceuticals. One strategy for doing so is to determine which therapies are most effective for certain patients in order to curb unnecessary outlays.

At an American Medical Association (AMA) conference in March, McClellan complained that the government does not have a good system for collecting evidence on real-world uses of new technologies. He asked physicians to help provide data on the value of certain products prescribed for patients, and also called for more information on the effects of medicines used under off-label conditions, particularly whether off-label uses generate interactions with other treatments or create problems for certain patient subgroups.

Such comments are prompting FDA acting commissioner Lester Crawford to anticipate increased pressure on the agency to encourage broader analysis of drug effectiveness and value. FDA officials traditionally have maintained that outcomes studies should be done in postmarket settings to avoid delaying approval of new safe and effective therapies. Congress similarly has rejected expansion of FDA authority to require evaluation of economic factors as part of the new drug approval process.

But with Medicare about to become a major purchaser of prescription drugs, Crawford acknowledges that FDA may be called on to seek more data on the comparative value of new medical treatments. The agency is better equipped to move in this direction than in the past, moreover, due to additional in-house economic expertise brought in by McClellan.

More outcomes analysis of pharmaceuticals also may get a boost from a provision in the Medicare Modernization Act (MMA) that increases funding for the Agency for Healthcare Research and Quality (AHRQ) to support clinical effectiveness, cost-effectiveness and outcomes research on new medical technology. AHRQ director Carolyn Clancy is working with an HHS steering committee to develop a comparative-effectiveness research agenda. The research priorities list for 2005, which is due in June, aims to evaluate existing cost-effectiveness research and identify gaps, with a focus on prescription drugs. Proposals for the 2006 priorities list are due July 1 and may address additional health care services and strategies for managing and delivering health care products and services. Continued AHRQ involvement in this area, however, will require Congress to appropriate the $50 million proposed in the MMA but not included in current budget plans.-JW