Safety concerns slow new drug review and approval processes


FDA is struggling to implement a host of new drug safety policies and programs and still meet review time frames set by the Prescription Drug User Fee program (PDUFA).

Key Points

FDA is struggling to implement a host of new drug safety policies and programs and still meet review time frames set by the Prescription Drug User Fee program (PDUFA). Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), acknowledges a slowdown in drug approvals as the agency works to meet these challenges. FDA's Amendments Act (FDAAA) of 2007 added new requirements for assessing post-market studies and determining the need for Risk Evaluation and Mitigation Strategies (REMS) at the time of approval, she said, but with no extension in review times.

CDER has hired more staff and is implementing new procedures to make the review process more efficient. Electronic submission and review systems for drug applications would help, but these innovations remain far from reality. The result is that many applications take more than one review cycle to gain market approval.

One consequence is that the United States may be falling behind Europe in approving innovative therapies for patients. At a meeting in September, sponsored by the Institute of Medicine (IOM) to evaluate safety initiatives established by FDAAA, Merck Executive Vice President, Peter Honig, noted that first-cycle approval trends are down and that user-fee approval dates are "routinely missed" due to increased scrutiny of safety issues. FDA is "clearly struggling" with post-market safety demands, he said, suggesting that "drug lag" may be appearing once more as European regulators approve some new drugs for market faster than has been done in the United States.

The good news is that manufacturers are submitting more NDAs to FDA and that the approval numbers are going up. Parexel cites 147 NDAs pending at FDA at the beginning of this year (2009), a notable increase from the 86 under review a year earlier. The number of applications for new molecular entities (NMEs) is holding steady, but the percentage enjoying first-cycle reviews has been dropping slightly but steadily.


A Safety First initiative provides the process to help CDER implement the multiple FDAAA post-marketing safety requirements, including the high-profile Risk Evaluation and Mitigation Strategies (REMS) program. CDER has approved 63 new REMS since March 2008: 47 require only distribution of Medication Guides for pharmacists to give patients; 10 REMS have additional communication plans that usually involve letters to healthcare professionals about product risks; and 6 REMS include Elements to Assure Safe Use (ETASU), which may impose restrictions on prescribers or patients, limits on drug distribution, or additional patient monitoring requirements.

The process of devising, proposing, and implementing a REMS is complex and time-consuming for all parties. The long-awaited draft guidance on REMS content and format for innovator drugs, which FDA issued Sept. 30, 2009, describes how pharma companies should submit an REMS proposal to FDA that explains product risks, program goals, materials involved, and how and when the plan will be implemented. A REMS supporting document should provide more detail on program rationale and how elements and tools in the REMS will mitigate risks. A MedGuide-only REMS requires a manufacturer to explain why such a moderate post-marketing strategy is sufficient to enhance safety product use, while a more restricted REMS program involves considerable analysis to develop and implement.

An important REMS component is a timetable for assessing the program after 18 months, 3 years, and 7 years, or more often if warranted. There are detailed procedures for modifying a REMS after it is approved and adopted if goals are not met, and FDA may unilaterally modify a REMS if new safety or effectiveness information emerges. Manufacturers are under pressure to negotiate reasonable and practical REMS goals and timetables; they face hefty fines for violating a REMS requirement (up to $10 million), along with the possibility of FDA pulling the product off the market. But valid assessment is based on the assumption that sponsors and FDA will be able to devise ways to measure whether a REMS is effective or successful. It's fairly straightforward to conduct surveys, collect prescriber information, or establish active surveillance programs, but much harder to assess how risk information actually influences prescriber and patient behavior. And pharmaceutical companies correctly note that they can't compel physicians to report adverse events or to limit inappropriate prescribing if practitioners ignore advisories and restrictions.


REMS assessments also include updated information on post-approval studies or clinical trials undertaken by the sponsor, including the status of the study, the expected completion date, and information about any difficulties encountered in meeting set goals. This information similarly is provided in annual reports on post-approval studies, as required by FDAAA to address perennial complaints that pharmaceutical companies failed to complete agreed-upon post-marketing studies in a timely manner. Under the new law, FDA reviewers now have to determine the scope and timing of post-marketing studies as part of the application review process, instead of merely vetting study proposals from manufacturers.

This scrutiny of post-marketing studies seems to be having a notable effect. FDA's latest annual report on the program showed considerable manufacturer progress in achieving "on schedule" status for fulfilling post-marketing study obligations. About 20% of these studies are ongoing (started on schedule) or submitted to FDA, while most are "pending"-that is, not yet started, but not delayed. This category includes many studies involving pediatric populations, which have to wait until all other safety information is submitted and reviewed.

Because some post-marketing studies are likely to involve thousands of patients, CDER plans to ask advisory committees to weigh in on acceptable trial designs, numbers of patients, and end points. These advisory sessions will address study designs for classes of drugs, not for each individual product, which would only extend approval times even more. The agency hopes that broader public buy-in for innovative studies may reduce second-guessing later on if post-market research is delayed or changed.

FDAAA also authorizes FDA to require additional post-marketing studies for already approved drugs and to require changes in labeling when new safety information emerges. The agency sent out 14 letters requiring additional studies from mid-2008 to mid-2009 and issued 18 safety-labeling notification letters during that period, additional tasks that tap agency resources.


Woodcock hopes that a 21st century review initiative at CDER will deal with these added challenges by better managing the drug review process. The aim is to compress application review times at the start in order to provide more leeway at the end of the review period to address safety issues and resolve internal and external disputes. This is a considerable challenge, though, as the average NDA consists of 10 gigabytes of material; the data may no longer come in truckloads, but CDER reviewers still have to digest a massive amount of information.

CDER conducted a pilot program last year that reviewed 17 applications for NMEs under the new review process. The program is being extended to most NMEs and new biologics license applications, with plans to streamline reviews for all applications and supplements by 2012. The new review process involves upfront FDA meetings with sponsors to identify key issues. There are earlier internal deadlines for establishing multi-disciplinary review teams, for identifying application deficiencies, and for reviewing product labeling. FDA will assess faster the possible need for an advisory committee meeting, potential post-market safety requirements, and other possible "showstoppers" that could delay the approval process.

There's optimism in some quarters that these efforts, along with staff expansion and training, will get CDER back on track with review goals and deadlines. But any changes have to support FDA's capability for assessing and preventing drug safety problems and ensuring safe drug use throughout the product life cycle.

Ms Wechsler is a Washington-based reporter specializing in federal and state healthcare issues.

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