The main culprit in the NDA-review slowdown is pressure on FDA to implement FDAAA postmarketing safety requirements, which
is an enormous task for the agency and a growing burden on manufacturers. CDER's Safety First initiative aims to meet the
challenge by integrating drug-safety activities and establishing a broader approach to ensuring appropriate drug use throughout
the product life cycle.
The REMS program is the most visible new assignment. CDER has approved 63 new REMS in the past two years, 47 of which only
require pharmacists to hand Medication Guides to patients filling new prescriptions. Ten of the REMS have additional communication
plans that usually involve letters to healthcare professionals about product risks and how to prevent them, and six REMS include
Elements to Assure Safe Use, which may impose restrictions on prescribers or patients, limit drug distribution, or require
CDER's Office of Surveillance and Epidemiology has expanded its staff to assess REMS plans, among its other assignments, but
the backlog of REMS evaluations is growing, and more work is on the way as requests for periodic assessments emerge. The process
of devising, proposing, and negotiating a REMS with FDA is complex and time-consuming, as seen in the long-awaited draft guidance
on REMS content and format for drugs and biologics, which FDA issued on Sept. 30, 2009. Even a Medication Guide-only REMS
requires a manufacturer to explain why a moderate postmarketing strategy is sufficient to ensure safe product use, and to
allow FDA to determine that patient information or more detailed directions for use could prevent serious adverse events.
The need for a restricted REMS program, which requires considerable analysis to develop and implement, will be determined
based on the size of the patient population, the seriousness of the disease, the drug's benefits, the duration of treatment,
and the known adverse-event profile. The REMS rules for generic drugs are even more complex and will be addressed in further
The draft guidance describes how manufacturers should submit a REMS proposal to FDA to appropriately explain the risks addressed,
program goals and elements, materials involved, and how and when the plan will be implemented. A REMS supporting document
should provide a thorough explanation of the rationale for the program and give details about how the elements or tools in
the REMS are expected to mitigate risks without disrupting established drug distribution and dispensing systems.
An important REMS component 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 approved and adopted if goals
are not met or circumstances change. FDA also may unilaterally modify a REMS if new safety or effectiveness information emerges.
A major challenge for sponsors and for FDA is to determine how best to measure whether a REMS is effective. FDA suggests that
sponsors conduct surveys, collect prescriber information, or establish active systems to assess these programs. Although it's
fairly straightforward to verify that pieces of paper have been handed out as part of a Medication Guide distribution program,
it's much trickier to determine whether risk information influences prescribers' and patients' behavior. And manufacturers
cannot do much to compel practitioners to report adverse events or to limit inappropriate prescribing if physicians ignore
advisories and restrictions.
The pages of the detailed guidance on REMS submissions plainly show why FDA's review of these plans takes so much time. Manufacturers
report that information requests and negotiations with FDA on REMS can go on for months. If FDA determines late in the review
process that a product requires a more comprehensive REMS program than that initially expected by the sponsor, it's unlikely
that the application will be approved in one review cycle, explained John Jenkins, director of CDER's Office of New Drugs,
at the IOM workshop.
An important decision for manufacturers is whether it's better to propose a REMS voluntarily before filing an NDA, or to wait
and see whether FDA reviewers determine that such a program is necessary. No one wants to implement a REMS if it's not required,
because the process consumes considerable resources and elevates the risk associated with the product. But FDA seems to be
requiring REMS for most NMEs, and developing a REMS during the application review period will slow the approval process. More
drugmakers are talking about bringing up REMS issues at end-of-Phase-II meetings with FDA to avoid surprises later on.
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 that violate a REMS requirement face fines as high as $10 million and the possibility
that FDA will pull the product off the market.