2005 issues: Stem cell research, noncompliance

PRIM&R panelist discusses issues on IRB radar 

The work of IRBs will not get easier this year, if predictions from panelists at the fall Public Responsibility in Medicine & Research (PRIM&R) conference are on point. Some issues are old hat — informed consent, conflict of interest — and others will arise out of the new frontier of stem cell research.

"There are several ongoing challenges," says J. Mark Waxman, JD, general counsel for CareGroup Healthcare System in Boston, including, "ensuring the quality of continuing reviews, meeting the eighth-grade understanding level in informed consent documents, and finding the resources to do all the work."

During the conference, Thomas Puglisi, PhD, senior consultant at PricewaterhouseCoopers LLP in Washington, DC, listed the following as "issues on the radar."

  • Systemic problems. Such problems include failures in the informed consent process, such as limited or no discussion of benefits or lack of a statement that informs subjects that the study is research; failure to conduct adequate continuing review; and failure to maintain adequate documentation of IRB activities — all items frequently listed in warning letters sent to institutions. According to Puglisi in his presentation, 1,120 citations of noncompliance were issued between 1998 and 2002.

He says good clinical practices and an effective evaluation process should be in place to ensure that IRB processes are in compliance with federal regulations.

Puglisi tells IRB Advisor, "If an IRB or institution discovers serious noncompliance, it should 1) take whatever immediate action is needed to safeguard current subjects; 2) self-report the problem to the FDA and/or OHRP; and 3) propose a corrective action plan to address the identified problem and any systemic issues to which the problem might be related."

The consequences of noncompliance range from suspension of the study to negative media attention to financial loss. "If discovered by OHRP, federally supported research could be halted until corrections are made," Puglisi says. "If FDA discovers the problem, the IRB could be prohibited from approving research until corrections are made. Clinical investigators could be sanctioned or even prosecuted if violations are serious enough."

  • Human and fiscal resources. It’s a common complaint: IRBs are shorthanded and overworked. "Generally, the amount of effort required is underestimated," says Waxman.

Further, many IRBs are dependent on institution support, points out Puglisi, and as institutions experience budget constraints, IRBs may be the first to feel the impact.

Two ways to solve the issue of lack of resources, says Stephen Kopecky, MD, medical director for the Rochester, MN-based Mayo Alliance for Clinical Trials, are to work smarter and charge for services. "An IRB has a huge job to do and requires a large amount of resources both in terms of finances, personnel, and information technology. I think for the near future, IRBs should focus on incorporating IT [information technology] processes that will streamline the protocol reviews and help educate investigators and coordinator as they are going through the steps."

Additionally, IRBs could pool resources he says. "One way to stretch resources is to have IRBs work together," Kopecky says. "For instance, if a study is done at 50 institutions around the country, then have one or two IRBs take the lead role in reviewing the study to ensure protection rather than having every individual IRB repeat the work. Groups such as the MACRO [Multicenter Academic Clinical Research Organization] group are working together with common IRB review protocols."

(Editor’s note: MACRO is a consortium of five institutions — Vanderbilt University, Washington University School of Medicine in St. Louis; the University of Pennsylvania; Baylor College of Medicine; and Partners HealthCare System, a Massachusetts-based health care delivery network — that have pooled IRB resources. Protocols are submitted to the group, and one institution is appointed lead reviewer. Though all participating institutions receive review documents, only the designated lead performs a full review.)

On the issue of financing activities, Kopecky says, "One way to recoup costs is to charge a fee for review of a protocol and for annual review. This is done commonly by centralized IRBs, and we should start to incorporate this more at academic institutions."

  • Rogue investigators. A rogue investigator, said Puglisi during his presentation, would include researchers who failed to adhere to the protocol approved by the IRB, failed to maintain adequate records, failed to report adverse events, or failed to provide appropriate information for informed consent.

Whereas a true rogue is highly unlikely, those who repeatedly make honest mistakes can create problems for an IRB or institution. Investigators who fail to comply typically tend to do so not out of malice but out of inadequate training, Puglisi said during his presentation at the PRIM&R conference. Investigator noncompliance also could be related to lack of adequate assistance from clinical trial coordinators, typically because they are overworked, and a sloppy monitoring program, Puglisi said.

  • Adverse events. "Adverse events are a challenge. Which ones are truly related to the trial and which are not continues to be a problem," says Waxman.

"IRBs receive a huge number of safety reports from the industry that are virtually impossible to interpret because the IRB does not receive sufficient context on the incident and/or sufficient information about the total number of subjects in the trial," Puglisi says.

"Adverse events are troublesome for an IRB in that they often see the numerator — how many patients have an adverse event at their institution — but don’t often see a denominator — total number of patient in the study at all institutions," says Kopecky. "The IRBs main role is to protect patients, and they should have data that helps them do this by looking at both the instance and the severity of the adverse event among the total patient population. IRBs often fall short because they don’t have access to this data."

One way to improve data gathering, Kopecky says, is to utilize data and safety monitoring boards (DSMBs). "It is the DSMB’s role to review adverse events and make suggestions regarding discontinuing the study as appropriate. IRBs should work closer with DSMBs, rather than repeating the role of the DSMB," he says.

  • Privacy of medical records. There are privacy concerns discussed in the Health and Human Resources IRB guidebook, and there is the Privacy Rule that came out of HIPAA. "Although they use similar language, the requirements of the HIPAA Privacy Rule and the human subject protection regulations are different in many important details." For example, the guidelines do not offer clear criteria for evaluating whether a protocol might involve an invasion of privacy or breach of confidentiality; they merely instruct members to take a sensitive, common-sense approach. HIPAA has specific criteria for when and how a subject’s private health information can be used.

Whether or not the Privacy Rule is adhered to is not an IRB responsibility, and the IRB shouldn’t make it one, Kopecky says. "The HIPAA rules are really here to ensure privacy of a patient’s records," he says. "IRBs are overwhelmed as it is and really can’t get into the role of policing and regulating privacy issues."

  • Stem cell research and gene transfer therapy. Both issues will appear on IRB radars this year, Puglisi said during the conference. "Multi regulatory and ethical issues surround the use of stem cells and gene transfer research," he tells IRB Advisor. Issues include questions about the level of protection human embryos deserve and at what stage of development, the appropriate use of stored biologic materials, and the possible mutation of vectors used in gene transfer therapy into active diseases.

"Clinicians are just scratching the surface on this and we need to have both clinicians and experts in gene issues involved when putting together guidelines," says Kopecky.

(Editor’s note: Puglisi suggests these web sites for more information on the ethical considerations related to stem cell research — www4.od.nih.gov/oba/; www.georgetown.edu/research/nrcbl/nbac/execsumm.pdf; or www.georgetown.edu/research/nrcbl/nbac/hbm_exec.pdf. Information on gene transfer therapy can be found at www.dnapolicy.org/genetics/transfer.jhtml.)

  • Accreditation. In 2001, the Association for the Accreditation of Human Research Protection Programs (AAHRPP) formed. AAHRPP is a voluntary accreditation program requiring that applicants meet a rigorous set of performance standards and submit to an on-site evaluation. To date, they have accredited 18 institutions.

Right around the same time, the National Committee for Quality Assurance (NCQA) developed an accrediting program for the Department of Veteran Affairs. In 2003, NCQA and the Joint Commission on Accreditation of Healthcare Organizations formed the Partnership for Human Research Protection (PHRP) accreditation program. To date, PHRP has accredited seven organizations, four of which are independent review boards.

"Accreditation remains an issue, but not a critical one. Right now, it is in the Wouldn’t it be nice’ phase, as opposed to We need to do it now.’ In three years, this may not be the case," Waxman says.

Accreditation should be global first, then individual, says Kopecky. "First is institutional accreditation; second is individual and coordinator [accreditation]. We have to be more diligent in educating our principal investigators as to the proper way to perform research. In the not-too-distant future, we will all understand that clinical research has to be done by individuals who are trained in it."