FDA 1998 NME APPROVALS COULD FEATURE UP TO 10 NEW NEUROPHARM PRODUCTS; FDA APPROVES 39 NMEs IN 1997 IN AVERAGE OF 17 MONTHS, MAKING 92 NMEs IN TWO YEARS

FDA's 1998 new molecular entity approvals could feature up to 10 neuropharmacological drugs on top of the five NMEs approved in the neuropharm area in 1997.

Four neuropharm drugs are already "approvable" at FDA: Cephalon's Provigil (modafinil) for narcolepsy on Dec. 29; Hoechst Marion Roussel's Sabril (vigabatrin) for seizures on Nov. 25; Roche's Tasmar (tolcapone) for Parkinson's disease on June 5; and Abbott's Serlect (sertindole) for psychotic disorders, which has been approvable twice on Oct. 2, 1996 and June 16, 1997.

Two 5HT1 agonists for migraine could also be approved: Glaxo Wellcome's Amerge (naratriptan) was due in early December, but the user fee deadline was extended by FDA and the company. Merck's Maxalt (rizatriptan) for migraine has a user fee date in June.

Two cholinesterase inhibitors for Alzheimer's disease may reach the market in 1998: Novartis' Exelon (ENA-713) with a user fee deadline in April; and Bayer's metrifonate with a deadline in November, assuming a standard 12-month review. Forest's citalopram selective serotonin reuptake inhibitor for depression has a user fee deadline in May.

Following a user fee deadline extension, Cephalon resubmitted its NDA for Myotrophin (mecasermin) for amytrophic lateral sclerosis in November and is awaiting an FDA decision. An advisory committee found that a Myotrophin European trial did not support the efficacy of the company's North American trial. Janssen is adding analyses from a Phase III trial to its Prosynap (lubeluzole) NDA for neural protection in ischemic stroke. The company canceled an advisory committee meeting in mid-November to await results of the trial that was to have been completed by year-end.

FDA approved 39 new molecular entities in 1997. After 53 approvals in 1996, FDA has approved a total of 93 NMEs in the past two years, an unprecedented level.

Center for Drug Evaluation & Research Director Janet Woodcock had projected that the agency would clear 40 NMEs during 1997 in a presentation to the Pharmaceutical Research & Manufacturers Association at the start of the year ("The Pink Sheet" Feb. 17, 1997, T&G-1).

The agency's NME total for 1997 includes new molecular entity status for Fortovase, a new formulation of Roche's saquinavir (Invirase), as well as a separate NME designation for the I.V. formulation of Pfizer's Trovan.

The average total time for NME approvals declined from 20.5 months in 1996 to 17 months in 1997. The time to first action (approvable, not approvable or approval) by the agency averaged 11 months for all NMEs. FDA met all the user fee deadlines for the 1997 NMEs. In its user fee report to Congress, the agency said all applications it received and completed reviews for between Oct. 1, 1996 and Sept. 30, 1997 have been on time ("The Pink Sheet" Dec. 15, p. 7)

For the 10 priority applications approved in 1997, the average time to first action was 7.7 months and the average total approval time was 10.8 months, up from an average of 9.5 months for priority user fee applications in 1996. Standard approvals averaged 19.1 months from submission to approval, with FDA taking its first action in an average 12.1 months.

The five NMEs that received not approvable letters as the first agency action were approved in an average 33.4 months. There were three NMEs that were approvable twice that averaged 28.6 months for approval. The only literature-based NDA, for Bryan's Sclerosol (aerosol talc), became approvable twice before the company had to resubmit the application. The total approval time from the original application was 28.5 months, and 1.2 months from the resubmission.

FDA's shortest NME review time during the year was for Agouron's protease inhibitor Viracept, at 2.7 months. The longest total review was for Wyeth-Ayerst's low molecular weight heparin Normiflo, which overcame "not approvable" status, at 53.2 months.

As FDA continues to reduce review times, the agency is placing more emphasis on post-marketing surveillance. CDER is creating a separate office to manage postmarketing reports.

Two drugs approved in 1997 have already been the subject of "Dear Doctor" letters and public health advisories requiring labeling revisions. Warner-Lambert's Rezulin labeling was revised following reports of liver dysfunction and Roche's Posicor added warnings concerning concomitant use with some statins and heart warnings.

In 1997, FDA also oversaw the withdrawal of the weight-loss drugs Redux (dexfenfluramine) and Pondimin (fenfluramine) following the emergence of valvular heart disease in patients receiving the Wyeth-Ayerst products in the postapproval period. The agency also proposed the withdrawal of the antihistamine Seldane, and Hoechst Marion Roussel has announced that it intends to discontinue the product.