FDA announces advisory committee reform, supports adaptive trial designs; HHS report criticizes FDA postmarketing study policies

In response to criticism about the composition of its independent advisory committees, FDA announced it would modify its procedures dealing with committee appointments and clarify the circumstances under which waivers for conflicts of interest occur.

Steps to be taken in the next few months include:

These steps are in addition to an ongoing internal assessment by the agency's Center for Drug Evaluation and Research (CDER) of its procedures and involvement with the advisory committees.

"It would be a significant step backwards if our primary criterion for selecting members to our committees becomes their lack of private sector work, if we exclude people for deep experience rather than embrace them for it," Dr Gottlieb said in a speech before the Center for Science in the Public Interest Conference on Government Advisory Committees in Washington, DC. "I'm particularly worried that the value of these committee meetings could be eroded, as well as our ability to attract the experts we need, if some current legislative proposals become law."

In his speech, Dr Gottlieb stressed that top experts on the committees would have various research relationships, receive grants, or serve on data monitoring safety boards that often present the appearance of a conflict of interest. These relationships often lead FDA to grant conflict of interest waivers by FDA in cases in which the relationships "while significant enough to warrant proper disclosure, are not deemed to be the kind that would affect their judgment or impartiality or outweigh the benefits offered by their participation," according to Dr Gottlieb.

"The system we have now can be improved upon," Dr Gottlieb said. "But the system works, and works well."

ADOPTING ADAPTIVE TRIALS

In a speech given at the 2006 Conference on Adaptive Trial Design, Dr Gottlieb said the agency was open to allowing "adaptive" trials as an alternative to the standard double-blind, placebo-controlled clinical trials.

In contrast with the highly rigorous and "inflexible" design that is the cornerstone for drug development today, adaptive trials could provide more insight into the safety and efficacy of medications in less time, while exposing fewer patients to experimental treatments and decreasing costs, he said.

"The ability to fail faster is an important advance in science," Dr Gottlieb said. "Establishing that a placebo pill doesn't treat a cancer better than an active drug in our highly empiric approach often doesn't maximize our learning about a new medicine, and it surely doesn't help the patient who gets the sugar pill."

According to Dr Gottlieb, adaptive trial designs could provide a more efficient path to the marketplace for medications and quicker benefits for patients from effective therapies. The ability to adjust sample size also would allow for more accurate information in dosing and variations in study power.

"But adaptive approaches are not a panacea to all of our challenges and enabling them is not a sure thing," Dr Gottlieb said. "Adaptive procedures are more complicated to design and to analyze, and in some settings are more difficult to implement."

FDA's openness to adopting adaptive trials is an offshoot of its Critical Path initiative, launched 2 years ago to help encourage a more rapid approval process for new medications. Led by Janet Woodcock, MD, deputy commissioner, the initiative has lately focused on measuring the safety and toxicity of new medications, as well as on the creation of predictive biomarkers.

FDA is currently working on the first in a series of 5 guidances that will further define adaptive trial designs, according to Dr Gottlieb. These guidances will aid study sponsors in:

The guidance covering studies with multiple end points is being drafted and is expected to be available in January 2007.

A 2-day workshop in November and public meetings will also help FDA to develop the guidances.

"If we are successful in better adapting scientifically rigorous information that helps predict response into the clinical trials themselves, the results will be clinical development programs that tell doctors a lot more about which patients are likely to benefit from a new medicine," Dr Gottlieb said. "It will enable the day when we are able to reliably deliver the right drug in the right dose to the right patient."

HHS REPORT CRITICIZES POSTMARKETING PROCEDURES

A report by the US Department of Health and Human Services (HHS) Office of Inspector General (OIG) criticized FDA's handling of postmarketing study commitments (PMCs) after finding that 35% of the annual status reports (ASRs) required by FDA to provide information about PMCs in fiscal year 2004 were either missing or contained no information.

"FDA cannot readily identify whether or how timely postmarketing study commitments are progressing toward completion," OIG said in the report, citing the "limited utility" of information in ASRs and a lack of an effective management information system in addition to the missing reports. "Monitoring postmarketing study commitments is not a top priority at FDA."

Andrew von Eschenbach, MD, acting FDA commissioner, disagreed with the report's findings in a written response, saying that the agency takes its duties to monitor the progress of PMCs and to make that information available to the public "very seriously." He cited FDA's efforts to maintain a database with PMC information, a training program for specialists to validate and review the ASRs, and the administration's hiring of an outside contractor to analyze FDA's handling of PMCs as indications of FDA's commitment to the process.

PMCs can be required from drug applicants by FDA under circumstances such as accelerated approval of a medication. FDA also can request PMCs, which then are agreed upon by the applicant. FDA received further powers of oversight from the Food and Drug Administration Modernization Act of 1997 (FDAMA) that requires FDA to receive the ASRs from applicants, which are then reviewed by CDER to monitor the progress of the studies and validate the reports'accuracy.

Information from PMCs can then be used by FDA to change a medication's label, approve new uses for a medication, make a request for changes in a medication's manufacturing process, or even seek a medication's withdrawal from the market.

The OIG's report reviewed all PMCs-also known as phase 4 commitments-for new drug applications approved by FDA from fiscal year 1990 through 2004 by using information available from FDA's database and documents submitted by drug applicants for fiscal year 2004. Interviews with project managers from CDER also were performed, as was a review of FDA policies and procedures in handling PMCs.

Overall, new molecular entities tended to have more PMCs associated with them than other NDAs.

A more in-depth examination by OIG of the 336 ASRs submitted by drug applicants in fiscal year 2004 found that 27% of ASRs lacked or had no information about open PMCs, while 8% of ASRs were not submitted by drug applicants (92 ASRs and 27 ASRs, respectively).

Validation for the majority of ASRs in fiscal year 2004 took place within 180 days of submission, with 29 of the 65 reports (45%) receiving validation in ≤90 days. Nineteen additional validations occurred between 91 and 180 days after receipt by FDA, according to OIG. FDA's goal is to have CDER's Office of New Drugs review and validate the information in ASRs within 90 days of receiving them.

Broad recommendations from OIG to FDA to improve tracking of PMCs include:

FDA disagreed with the initial recommendation, saying that current regulations for ASRs already set forth content and formatting requirements and that any request for new information would require additional regulations to be drafted.

The agency concurred with OIG's other recommendations and detailed the steps it was taking to address them, but the need for solid reform remains, according to OIG.

"We appreciate that FDA has taken steps to improve its monitoring of postmarketing study commitments," OIG said in the report. "However, our review of the postmarketing study commitment database and annual status reports, as well as our interviews with agency officials demonstrated that FDA cannot readily identify whether or how timely postmarketing study commitments are progressing toward completion for the period of our review."

SOURCES FDA announces plan to strengthen advisory committee processes [press release]. Washington, DC: US Food and Drug Administration; July 24, 2006. Available at: http:// http://www.fda.gov/bbs/topics/news/2006/new01416.html. Accessed July 25, 2006.

Gottlieb S. Speech before the Center for Science in the Public Interest Conference on Government Advisory Committees; July 24, 2006; Washington DC. Available at: http:// http://www.fda.gov/oc/speeches/2006/conference0724.html. Accessed July 25, 2006.

Gottlieb S. Speech before 2006 Conference on Adaptive Trial Design; July 10, 2006; Washington DC. Available at: http:// http://www.fda.gov/oc/speeches/2006/trialdesign0710.html. Accessed July 20, 2006.

Department of Health and Human Services Office of Inspector General. FDA's monitoring of postmarketing study commitments. Washington, DC: Department of Health and Human Services; 2006. Available at: http://oig.hhs.gov/oei/reports/oei-01-04-00390.pdf. Accessed July 20, 2006.