The Office of Drug Safety's user fee proposal includes funding for the risk management "toolkit" collaboration between FDA and the Pharmaceutical Research & Manufacturers of America.

The toolkit effort to develop a systematic approach to risk management programs is included in FDA's Prescription Drug User Fee Act III proposals and "discussions are just beginning between CDER and PhRMA to determine what steps are necessary to advance this effort," the ¹ ODS fiscal 2001 annual report states.

"It is envisioned that this will be a multi-year initiative involving broad input from experts, stakeholders, advisory committees and other affected groups," FDA said.

The PhRMA/FDA "toolkit" group began meeting last fall. The goal is to develop "off the shelf" systems to be used consistently for all drugs that require risk management (² Also see "Pfizer “Toolkit” Proposal Focuses On Adverse Event Signals" - Pink Sheet, 17 December, 2001., p. 28).

ODS' PDUFA III proposal focuses on "(1) ensuring adequate resources for our current workload; (2) improved signal detection; (3) enhancing safety data analyses and feedback to industry; and (4) development and implementation of appropriate risk management/risk communication."

FDA hopes user fees can be collected to fund its initiative to supplement "the passive AERS system with a number of pilot projects for active surveillance." A CDER working group recently completed an active surveillance "white paper," the report notes. The document considers "how active surveillance could have impacted on the ultimate removal of a number of drugs over the past decade and suggestions for future pilot projects."

The agency has initiated pilot programs with the Department of Veterans Affairs and with Kaiser (see ³ Also see "FDA, Kaiser Discussing COX-2 Myocardial Infarction Study" - Pink Sheet, 21 January, 2002.).

ODS proposes user fees to evaluate methods to improve reporting of adverse events to the spontaneous reporting system. The PDUFA III proposal also seeks to upgrade "AERS to include an electronic inbox for medication error staff and to allow for more specific coding of medication errors," the report states.

"Specifically, the fields from the National Coordinating Council for Medication Error Reporting and Prevention Taxonomy of Medication Errors would be included in AERs," FDA said.

Finally, ODS wants user fees to fund the development of guidances and Manuals of Policy & Procedures on post-marketing safety update reports.

The report declares that there is "clear interest by both FDA and the pharmaceutical industry for post-marketing drug safety to be included in" PDUFA III.

FDA sought enhanced funding for post-marketing surveillance activities as part of the PDUFA II negotiation process in 1997, but industry did not agree.

In the current round of negotiations, payors are urging Congress to include Waxman/Hatch reforms in the user fee reauthorization process. In that environment, industry has more of an incentive to reach a speedy agreement with FDA on terms for a reauthorization (see ⁴ Also see "PDUFA III Or Waxman/Hatch II?: Payors Urge Fix For Generic “Loopholes”" - Pink Sheet, 21 January, 2002.).

FDA's Adverse Event Reporting System received 281,090 safety reports in fiscal year 2001 (through Sept. 24, 2001), the report shows.

"It is anticipated that the total number of reports in [calendar year] 2001 will be close to 271,000," FDA said. "If this trend holds, it will mark the second consecutive year in which the number of reports entered into AERs has slightly decreased."

One possible explanation for the decline in reported post-approval adverse events, FDA said, is "the decrease in the number of NMEs approved by the center since the high water mark in 1996."

FDA approved a record 53 new molecular entities in 1996. In 2001, FDA cleared 24, the lowest total since 1994 (⁵ Also see "FDA Drug Approval Time Edges Up To 18.5 Months In 2001" - Pink Sheet, 7 January, 2002., p. 12).

FDA suggests the decrease in reported AEs could also be due to the "aggressive...waiver program, relieving the industry from the requirement of submitting non-serious and labeled events."

The agency has encouraged industry to request a waiver for non-serious events that are included in labeling. ODS has been briefing Center for Drug Evaluation & Research staff about the waiver procedures and is developing a database on waiver information that will be accessible to the center's employees.

"By the end of FY 2001, over 60 firms had been granted this type of waiver for over 2,300 applications (NDAs and ANDAs)," the ODS report says. CDER issued a MaPP on its policy for handling industry requests to waive certain AE reporting requirements in November 1999.

The ODS annual report includes a list of the most often cited "suspect products" based on the number of post-marketing adverse event reports entered into AERs (see chart).

Merck's COX-2 inhibitor Vioxx had the highest number of AEs at nearly 7,000. Pharmacia/Pfizer's Celebrex , which was the first COX-2 inhibitor launched, had about 3,000 adverse event reports, the fifth highest total.

FDA generally expects more adverse event reports for recently launched products, particularly products with the rapid uptake of the COX-2 inhibitors.

Wyeth/Immunex' Enbrel had the second highest number of reports for the year, with 6,789. J&J/Centocor's competing rheumatoid arthritis agent Remicade was number 12 on the list, with 1,635.

The list includes two products that were withdrawn during the fiscal year: GlaxoSmithKline's Lotronex and Bayer's Baycol .

GSK pulled its irritable bowel syndrome therapy from the market in November 2000 after the company and FDA failed to agree on a risk management program (⁶ Also see "Glaxo Lotronex Withdrawal Follows Failed Risk Management Negotiations" - Pink Sheet, 4 December, 2000., p. 3).

FDA's Drug Safety & Risk Management Subcommittee and Gastrointestinal Drugs Advisory Committee are set to review the drug April 23, following GSK's December filing of supplemental safety data.

Bayer's cholesterol reduction drug was withdrawn in August 2001 due to reports of rhabdomyolysis (⁷ Also see "Baycol Withdrawal Gives Boost To Pravachol; Will Crestor NDA Be Affected?" - Pink Sheet, 13 August, 2001., p. 4).

With 2,641 safety reports received by AERs, Pfizer's Lipitor had 649 more reports than Baycol. Lipitor was also far more widely prescribed.

Celgene's Thalomid is among the top 20 drugs listed by FDA with 1,378 reports. The product is subject to restrictive distribution via patient and physician registries. The risk management program, which has been touted as a success, may be responsible for capturing a large percentage of AEs in patients taking the drug.

There were 3,605 post-marketing AE reports entered for Roche's Accutane , by far the most for any drug that has been on the market more than three years.

Accutane received another round of media and political attention for continued reports of pregnancies among users, and for claims that the drug may be linked to teen suicides (⁸ Also see "Roche Accutane Prescriber Registry Added To Pregnancy Prevention Program" - Pink Sheet, 5 November, 2001., p. 3).

FDA is in the process of implementing a new organizational structure for its post-marketing surveillance activities. ODS was formerly known as the Office of Postmarketing Drug Risk Assessment.

One challenge for the new structure, however, will be in finding a new director for ODS. Peter Honig, MD, is leaving FDA in February to join Merck.

FDA User Fee Proposal Calls For Funding Of Risk Management “Toolkit”

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