Safety and Risk Assessment Gain Importance

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Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-03-01-2002,

FDA is revising policies to ensure that clinical studies generate sufficient data to ensure the safe use of new medical products.

Risk management is in the spotlight at the Food and Drug Administration as the agency seeks to gain more control over the way therapies are used in medical practice. The agency is reorganizing its staff and developing new policies to improve processes for evaluating risk factors in new drug candidates and to improve processes for tracking and evaluating adverse events once a product is on the market. These developments are generating calls from some experts for longer and larger studies to capture adequate safety information and are prompting sponsors to consider risk management in product development programs.

In recent months, FDA has taken action to enhance its ability to manage postmarketing safety issues. The most visible initiative involves establishing a new Office of Pharmacoepidemiology and Statistical Science (OPSS) in the Center for Drug Evaluation and Research (CDER). The main component of this new super office is the renamed Office of Drug Safety (ODS; formerly the Office of Post-Marketing Drug Risk Assessment, or OPDRA). Both OPDRA and CDERs Office of Biostatistics were shifted to OPSS from CDERs Office of Review Management.

Related to these changes, ORM was renamed the Office of New Drugs (OND) to reflect its increased focus on the review and approval of new drug applications and supplements. That office will work closely with the new drug safety office to evaluate risk concerns during the review process. OND is headed by John Jenkins, who was selected as director in December. CDER is developing internal policies for such issues as tradename reviews, post-marketing safety issues, evaluation of risk management programs, and medication guides to coordinate activities by the review divisions and ODS. ODS now manages its expanded functions through three divisions.

Division of Drug Risk Evaluation (DDRE). Julie Beitz heads a group of more than 40 people who work with CDER medical reviewers to identify and evaluate the context of safety reports as part of the new drug review process. The group prepares materials for FDA advisory committees and participates in CDER preapproval safety conferences. The staff includes 10 epidemiologists to review protocols for Phase 4 studies and to advise on postapproval risk management strategies, such as patient registries and restricted distribution programs. After the approval of a new drug, the staff reviews adverse event reports to detect and assess safety signals and evaluates patient databases and published literature to estimate the public health impact of risk issues.

Medication Errors and Technical Support (METS). Jerry Phillips is acting director of METS, and also serves as ODS associate director. The METS staff analyzes medication errors involving marketed drugs and reviews all proprietary names and labeling prior to approval to reduce the potential for confusion that can lead to medication errors.Surveillance, Research, and Communication Support (SRCS). Under Anne Trontell, this new unit will handle data resources, risk communication, and outcomes research related to drug safety risk management programs. It assumes management of FDAs MedWatch program, previously run out of a CDER staff office, and activities formerly handled by CDERs Division of Drug Marketing, Advertising, and Communications (DDMAC). These include development of Med Guides, patient package inserts, and pharmacy information surveys. SRCS provides international regulatory liaison for postmarketing safety issues and manages FDA use of drug safety and epidemiologic data resources, including CDERs Adverse Event Reporting System (AERS), drug-use data from IMS Health, and access to insurance and health plan databases.

New leadership
Heading up OPSS is Paul Seligman, who came to FDA from the Department of Energy in July. Seligman was deputy assistant secretary for health studies at DOE, where he was involved with epidemiology and surveillance programs related to radiology and nuclear weapons. He reports to CDER deputy director Steven Galson, another newcomer who was brought into FDA (in April 2001) to oversee expansion of drug safety activities. Formerly with the Environmental Protection Agency, Galson has been serving as CDERs acting director during director Janet Woodcocks temporary assignment to the FDA commissioners office to develop the agencys counter-bioterrorism plan.

One unanticipated task for Galson and Seligman will be to appoint a new director for ODS following the departure of Peter Honig, former head of OPDRA and briefly of the new drug safety office. Honig left FDA last month to direct a new risk management office at Merck, a move reflecting the companys interest in emphasizing product safety and risk management strategies as part of its product development programs. As vice president of risk management, Honig reports to Merck executive vice president of clinical sciences and product development, Douglas Greene.

Experts weigh in
CDER will gain added advice on drug safety issues from a new advisory panel on Drug Safety and Risk Management. Because of federal government restrictions on establishing new advisory committees, the new panel is a subcommittee of CDERs Advisory Committee for Pharmaceutical Science. Patient safety expert Peter Gross, MD (chairman, Department of Internal Medicine, Hackensack University), chairs the patient subcommittee that will provide FDA with input on methods of risk assessment, management, and communications.

Among the experts in risk communications, clinical trial methodology, biometrics, and pharmacoepidemiology on the 10-person panel are Michael Cohen, RPh, MS, DSc (president, Institute for Safe Medication Practices), and Curt D. Furburg, MD, PhD (Department of Public Health Sciences, Wake Forest University). In a journal article analyzing the review and withdrawal of Bayers Baycol (cerivastatin) last year, Furberg noted that large, long-term clinical trials often are needed to evaluate drugs prescribed for chronic use. He has raised questions about the use of surrogate endpoints, such as lipid markers, in approving lipid-lowering agents and about long-term risks related to calcium channel blockers.


At its first meeting, set for 23 April, the new subcommittee is slated to review safety concerns related to GlaxoSmithKlines irritable bowel syndrome therapy, Lotronex (alosetron). Glaxo pulled that new product off the market in November 2000 because of serious adverse events and an inability to reach agreement with FDA on a risk management program. At the April meeting, Glaxo is expected to present safety data derived from Phase 4 studies underway at the time of withdrawal. The session also will provide an opportunity to evaluate FDA risk management proposals and safety strategies available to sponsors.

New policies and proposals
In addition to expanding agency structure for overseeing medical safety and risk issues, FDA is working on a number of policies and programs to enhance the safe use of drugs and to reduce medication errors. For example, CDER epidemiologists are weighing new techniques and modeling methods for analyzing clinical trial safety databases. FDA also is developing proposals and guidances to reduce confusion related to drug trade names, labeling, and packaging.

A lead initiative involves revision of the content and format of professional labeling for drugs and biologics, which has been in the works for several years. Manufacturers have been concerned that the agencys proposal to revise drug labeling will make prescribing information much longer, requiring costly changes in manufacturing and packaging operations. An added fear is that the proposal to include important prescribing information in a highlights section would open manufacturers to liability charges. FDA officials believe that the new format will make it much easier for practitioners to gain important prescribing information and to ensure the safe use of medicines. To soften the impact on industry, the agency may apply the new requirements initially to new products and permit manufacturers to phase in changes for previously approved drugs over time.

More collaboration
Mercks move to hire FDAs Honig as vice president of risk management reflects increased interest among manufacturers in giving drug safety issues more prominence. Officials at FDA and PhRMA (Pharmaceutical Research and Manufacturers of America) have formed a risk management tool kit committee to reach consensus on new approaches to drug safety problems. Agency officials have complained that FDAs limited regulatory authority allows it only to revise product labeling, require a manufacturer to send letters about safety concerns to health professionalsor require withdrawal of a medicine from the market.

CDER officials recognize that the current tools often are not very effective in bringing about changes in prescribing or patient use of certain therapies, but they often are reluctant to ban distribution of an effective therapy. To provide more options, ODS plans to develop a more systematic approach to selecting methods for managing risk and assessing the effectiveness of those methods. The ultimate aim is to develop certain off-the-shelf systems that can be applied to all drugs that require risk management.

These issues will be part of continuing discussions about the scope and focus of the next phase of the Prescription Drug User Fee Act, PDUFA III, which is set for reauthorization by the end of September. CDER would like to have a portion of user fee revenues available to support expansion of adverse event reporting systems, for development of additional guidance documents on safety reforms, and for devising new risk management approaches. Industry is wary of expanding user fees to cover more FDA activities, but may consider added payments to support certain postapproval programs.

CDER plans to issue a white paper on risk management later this year. It will define the problem and describe approaches for addressing risk and future objectives. The agency also has been developing an extensive proposed rule on postmarketing drug risk surveillance, which also may appear later this year. All these initiatives affect the testing and marketing of new drugs and put safety issues in the forefront of product development and distribution.