Safety First in Biotech Development

Published on: 
BioPharm International, BioPharm International-11-01-2009, Volume 22, Issue 11
Pages: 40–45

Heightened attention to product safety issues is slowing the approval process for new therapies.

The task of implementing a host of new drug safety policies and programs as required by the FDA Amendments Act (FDAAA) is having a troubling impact on the Food and Drug Administration's capacity to approve new drugs in a timely manner. Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), acknowledges that drugs are getting approved, but more slowly. FDAAA added new requirements for assessing postmarket studies and determining the need for risk evaluation and mitigation strategies (REMS) at the time of approval, but with no extension in review times. The FDA has hired more staff and is implementing new procedures to make the review process more efficient, but many reviews go beyond the first review cycle timeframe, or more.

Jill Wechsler

In fact, the US 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, Peter Honig, Merck's executive vice president, noted that first cycle approval trends are down and that user fee approval dates are "routinely missed" because of increased scrutiny of safety issues. The FDA is "clearly struggling" with postmarket safety demands, he said, suggesting that "drug lag" may be rearing up once more as European regulators approve some new drugs for market faster than in the US.

The review slowdown is having a noticeable impact on drugs and biologics granted priority review status by the agency, a designation traditionally reserved for highly innovative therapies. In the past, about 70% of priority review applications gained first-cycle approval, but this proportion dropped to 50% in 2008, according to a report from Parexel Consulting (available at User fee approval targets are 10 months for new drug applications (NDAs) and biologics license applications (BLAs), and six months for priority applications. It's particularly difficult for reviewers to improve on the six-month review goal.

The good news is that manufacturers are submitting more NDAs and that the approval numbers are going up. Parexel cites 147 NDAs pending at the FDA at the beginning of this year, a notable increase from the 86 under review a year earlier.



The REMS program is the most visible new assignment. CDER has approved 63 new REMS in the last two years: 47 require only distribution of medication guides for pharmacists to give patients; 10 have additional communication plans involving healthcare professionals; and six REMS include elements to ensure safe use (ETASU), which limit distribution or require special monitoring.

The process of devising, proposing and negotiating a REMS with the FDA is complex and time-consuming, as revealed in the draft guidance on REMS content and format for drugs and biologics, issued Sept. 30 (available at Even MedGuide-only programs require a manufacturer to explain why such a moderate strategy is sufficient to ensure safe product use; more restrictive REMS programs are much more complex to implement. The guidance describes how manufacturers must submit a REMS proposal to the FDA to explain risks addressed, program goals, materials involved, and how and when the plan will be implemented. A REMS supporting document should provide a thorough explanation of program rationale and more detail on how the REMS elements and tools will mitigate risks.

An important part of the REMS proposal is a timetable for assessing the program after 18 months, three years, and seven years, or more often if warranted. The policy spells out detailed procedures for modifying a REMS after it is adopted if goals are not met or circumstances change. The FDA also may unilaterally modify a REMS if new safety or effectiveness information emerges. Assessments assume that sponsors and the FDA can 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.

The details in the guidance for submitting a REMS to the FDA indicate why vetting these proposals as part of the application review process takes so much time. Manufacturers thus have to decide whether it's better to propose a REMS voluntarily before filing an NDA or BLA, or to wait and see if FDA reviewers determine that such a program is needed. No one wants to implement a REMS if it's not necessary, but the FDA seems to be requiring REMS for most NMEs, and developing a REMS during the review period will slow the approval process.

Whatever tack a company takes, it's important to get the details of a REMS right and to establish reasonable and practical goals and timetables. Manufacturers face hefty fines for violating a REMS requirement (up to $10 million) and the possibility of the FDA pulling the product off the market.


REMS assessments include updated information on postapproval studies or clinical trials undertaken by the sponsor, including the status of the study, expected completion date, and whether any difficulties have been encountered in meeting set goals. This information also is provided in annual reports on postapproval studies, as required by FDAAA in an effort to address complaints that pharmaceutical companies have failed to complete agreed-on postmarketing studies in a timely manner. Congress authorized the FDA to require postapproval studies to achieve specific objectives and to levy fines on companies that miss agreed-on deadlines.

Consequently, FDA reviewers now have to determine the scope and timing of postmarketing studies as part of the application review process. Instead of merely vetting study proposals from manufacturers, agency staffers have to examine what scientific data can best assess known and unknown serious risks and set appropriate timeframes for completion of postmarket studies and trials.

This greater scrutiny of postmarketing studies seems to be having a notable effect. The FDA's latest annual report on the program showed considerable progress by manufacturers in achieving "on schedule" status for fulfilling postmarketing study obligations. About 20% of studies are ongoing (started on schedule) or submitted to the 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.

FDAAA also authorizes the FDA to require additional postmarket 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, another task that taps agency resources.


Woodcock hopes that CDER's 21st century review process will deal with these new challenges by better managing the application review process. The aim is to compress application review times upfront to provide more leeway at the end of the review period and address safety issues and resolve internal and external disputes. This is a considerable challenge, though, because the average NDA consists of 10 gigabytes of material, a massive amount of information for reviewers to digest.

CDER conducted a pilot program last year that reviewed 17 applications for NMEs under the system and plans to extend the streamlined approach to most NMEs and new BLAs this year and to all applications and supplements by 2012. The new process involves meeting in advance with manufacturers to identify key issues, such as whether an advisory committee meeting will be needed and potential postmarket safety requirements. There are earlier internal deadlines for establishing multi-disciplinary review teams, for identifying application deficiencies, and for reviewing product labeling to meet approval decision timeframes. These efforts may get the FDA on track with review deadlines, but changes have to support more stringent assessment of biomedical safety issues and ensure safe use throughout the product lifecycle.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634,