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More consultations with sponsors promise to drive drug development, but also impose a growing burden on FDA.
The new drug review offices at the Food and Drug Administration are "drowning in meetings," according to FDA officials, and the volume may grow even faster if the agency adopts recommendations from a new report on factors that slow drug development and application approval. FDA is taking steps to make sponsor meetings more productive and more uniform among its many drug review divisions. The agency also is looking for more resources to support the time and effort involved in preparing for and conducting meetings, a topic that is on the table in negotiating renewal of the Prescription Drug User Fee Act (PDUFA) next year.
As drug development has become more complex and more costly, sponsors have sought to meet earlier and more often with FDA drug review staffs. They seek to ensure that research protocols fit agency requirements and that study results will support the approval of a new drug application (NDA). The result is an "exponential growth rate in meetings during the last five years," pointed out John Jenkins, director of the Office of New Drugs (OND) at FDA's Center for Drug Evaluation and Research (CDER). He noted at a January workshop on FDA meetings sponsored by the Drug Information Association that CDER and CBER (Center for Biologics Evaluation and Research) scheduled more than 2000 formal presubmission meetings with sponsors in 2005, up from about 1500 in 2001.
The PDUFA agreement of 2002 encourages early and frequent communication between FDA and sponsors as a way to improve the quality of drug development. Sponsors are not required to meet with FDA at all, but those that want to ensure that research will yield a marketable product increasingly are taking advantage of FDA's willingness to discuss study protocols and filing requirements. The user fee program sets time frames for FDA to respond to sponsor requests and to schedule meetings at set "milestones" in the pharmaceutical development process:
Additional meetings may occur at the end of Phase I to assess clinical testing of fast-track products or unique therapies. Companies developing new chemical entities (NCEs) or products with special manufacturing issues also may request a separate EOP2 meeting to discuss chemistry, manufacturing, and controls issues. After filing, some applications may be discussed at advisory committee meetings, and FDA usually meets with sponsors to negotiate final product labeling. A company also may request a special meeting to discuss a stalled development program or to address other specific issues.
As part of the effort to improve FDA–sponsor communication on development issues, the agency also provides feedback on a growing number of Special Protocol Assessments (SPA; 346 in 2004 vs. 125 in 2000). Under this PDUFA initiative, a sponsor that has an EOP2 meeting may later ask FDA to evaluate specific questions about protocol designs in specific areas: carcinogenicity studies, efficacy claims in pivotal trials, and stability studies. A written SPA evaluation commits FDA to accept the resulting data as the basis for its approval of the product.
These assessments, plus the task of preparing for and conducting hundreds of meetings, has become a serious drain on FDA resources. Drug review divisions hold an average of nine meetings each day, and each session requires 200 to 500 FDA staff hours for preparation. FDA is meeting PDUFA time frames for scheduling and holding milestone meetings, but seeks more resources to handle the growing burden. Agency staffers particularly would like to streamline the administrative task of tracking and documenting that it meets these scheduling goals.
With so much time and effort committed to meetings, FDA wants to ensure that these sessions are productive and encourage efficient drug development and approval. To this end, FDA's OND seeks to clarify and standardize how its 17 review divisions handle meeting requests, internal pre-meeting discussions, and subsequent communication with sponsors. Under the current system, OND review offices follow varying policies for sharing information with sponsors on their internal deliberations; some offices permit sponsors to review draft meeting minutes, while others are reluctant to do so.
To gain more uniformity in this area, OND is developing a guidance on Good Meeting Management Practices, which it hopes to issue later this year. An OND process improvement team has been examining best practices among divisions, and several offices have been piloting new meeting management approaches. Jenkins expects to allow deviations in practices when justified, but aims to reduce differences based largely on personal whims.
The guidance aims to clarify:
Despite FDA complaints of meeting overload, the volume could increase even more if the agency implements recommendations from a report on FDA's First Cycle Review Performance by Booz, Allen, Hamilton [available at www.fda.gov/OHRMS/DOCKETS/98fr/OC05257-rpt0001.pdf]. As part of a broader evaluation of ways to improve the drug approval system, the report examines those factors that permit FDA to approve an NME (new molecular entity) in one cycle versus multiple review cycles. The main conclusion is that more early agency–sponsor meetings make a difference in developing quality applications that do not require additional information later from the sponsor.
The Booz, Allen, Hamilton report found that 52% of companies that held an EOP2 meeting with FDA gained application approval in the first review cycle; only 29% of sponsors that did not have presubmission meetings benefited from speedy reviews. Early consultation with FDA often fails to resolve all problems, but presubmission meetings seem to help.
The data comes from a retrospective analysis of 77 NMEs submitted to FDA during 2002–2004: almost half (47%) were approved in the first review cycle, 23% experienced multicycle reviews, and 22 were still pending (i.e., "approvable") at the end of the study. Although many factors—product characteristics, quality of the clinical program, the need to negotiate postmarketing commitments—affected the review process, early communication with FDA correlated most clearly to one-cycle reviews.
In fact, the analysts suggest adding a mid-Phase III meeting to the milestone meeting schedule. The aim would be to review data, discuss problems, and refine protocols when it is still possible to alter studies to address any inadequacies. Booz, Allen, Hamilton recommended that FDA define a formal four-meeting presubmission schedule (pre-IND, EOP2, mid-phase III, and pre-NDA) to replace the current ad-hoc meeting process that relies on sponsor requests. The consultants also encourage the development of checklists to guide meeting discussions for each therapeutic category and urge more follow-up to meetings based on review of minutes, similar to actions that OND already is looking to address in its upcoming guidance.
All these activities will consume more of FDA's precious resources, which the agency hopes to augment from increased user fees. FDA officials anticipate additional confirmation of these approaches from ongoing assessments of the costs and benefits of new meeting management approaches, and the Booz, Allen, Hamilton report ratifies such efforts to expand and improve the FDA meeting process.
Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 firstname.lastname@example.org