NDA Reviews To Be Studied Prospectively To Identify Best First-Cycle Practices

FDA is planning a prospective study on the root causes of multiple-cycle drug and biologic reviews as part of an effort to improve the review process, Commissioner Mark McClellan, MD/PhD, announced Jan. 31.

As part of the multi-center initiative, the agency plans to award a contract for a "prospective evaluation of process and communications" that will identify FDA and industry best practices that facilitate effective first-cycle reviews.

"Better cycle review performance doesn't automatically translate into more rapid availability of safe and effective new products," McClellan wrote in a ¹ Jan. 30 memo. "In many cases, multiple cycles are unavoidable. But in some cases, there may be steps that FDA can take to help us get applications that 'get it right the first time.'"

"Key elements of this strategic initiative are to identify and address, in collaboration with industry sponsors, the 'root causes' of poorly designed and executed drug development programs and inefficient first-cycle review performance for all medical products," the agency wrote in an accompanying report.

The announcement follows McClellan's Jan. 29 speech to the Generic Pharmaceutical Association outlining plans to collaborate with the generics industry to reduce the number of multiple-cycle ANDA reviews.

The agency's "First-Cycle Review" initiatives will provide drug and biologic sponsors with "notification of deficiencies prior to the goal date for 50% of submitted applications in FY '03, 70% of applications in FY '04 and 90% of applications in FY '05-'07."

As part of the reauthorization of the Prescription Drug User Fee Act, FDA will inform sponsors of application deficiencies identified during a review's first 60 days.

Under another PDUFA initiative, FDA plans to publish a good review management principles draft guidance in the spring and hopes to issue final guidance by the end of FY 2003 (² (Also see "PDUFA III “Good Review Management Principles” Stress Early FDA Action" - Pink Sheet, 18 Mar, 2002.), p. 20).

"The GRMPs call for more consistent communication of issues identified during the review that may affect the approval of the application, with emphasis on early communication of easily correctable deficiencies, including appropriate use of discipline review letters, anticipating/planning for advisory committee meetings, and planning to provide labeling comments and scheduling time for feedback to sponsors before the action goal date, and training of review staff," FDA says.

In a retrospective study, the Center for Drug Evaluation & Research found the primary reason for first-cycle review delays for new molecular entities receiving standard review was inadequate demonstration of the product's safety. By contrast, the leading reason for first cycle delays for priority NMEs was chemistry, manufacturing and controls issues.

The study looked at standard applications approved in 2000 and 2001 that took longer than 12 months and priority applications approved between Jan. 1, 2000 and Aug. 31, 2001 that took longer than six months.

As a second part of the initiative to improve reviews, FDA announced the completion of a draft good review practices document related to the review of safety information; the document has been under development for several years.

Other ongoing quality systems efforts include refuse-to-file and clinical hold review committee discussions and initiation of "regulatory briefings to bring difficult regulatory issues to center leadership for discussion."

The agency also notes it is "committed to undertaking aggressive efforts to recruit and retain the best and the brightest review scientists."

"FDA believes that this can be accomplished by highlighting the public health importance of the work done by FDA reviewers, providing opportunities, protected time and funding for training and professional development and continuing ongoing agency efforts to enhance compensation and other quality of work life initiatives," the agency says.

CDER will develop a "continuous improvement/ quality management approach" to the premarket process, according to FDA.

Quality system elements to be implemented over the next several years, with the help of a contractor, include: training managers on the institution and maintenance of a quality system; identifying and addressing staff's scientific and medical continuing training and educational needs; and enhanced training for reviewers and managers on good review practices.