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APPROVAL TIME FOR 1989 NEW MOLECULAR ENTITIES IS UNDER THREE YEARS; DECEMBER APPROVAL RUSH IS STILL FACT OF LIFE AT FDA, BUT IS LESS PRONOUNCED IN 1989

Executive Summary

FDA's 23 NDA approvals in 1989 for new molecular entities on average took 33 months, or about 2-3/4 years, from submission to final approval. The 1989 approval time average is on par with FDA's performance most years in the past decade, except 1984, when the average approval time was 39 months, and 1982 and 1983 , when approval averages were less than 30 months (see chart). [EDITORS' NOTE: 1989 approval times are calculated by "The Pink Sheet" from dates of submission, as reported by FDA or sponsors, to dates of approval. Averages for prior years are taken from FDA statistical reports, which also rely on date of original submission to date of final approval. Neither calculation takes into account periods of time when the applications were not under active review.] During the 1980s, FDA approved a total of 217 NMEs (an average of 21.7 per year). The mean approval time for the 1980-1989 NMEs was 32.3 months. Long approval times for many of the 1989 drugs were the result of FDA requests for additional data. Approval of Wyeth-Ayerst's injectable analgesic Dalgan (dezocine), for example, took over six years, three of which were spent conducting and analyzing new studies. The five-year approval time for Somerset Pharmaceuticals' orphan drug Eldepryl (selegiline) was similarly affected by FDA's request for further studies. Two-and-a-half years of that time were spent doing additional development work requested by FDA. The five year approval time for the Parkinson's drug (as calculated by FDA) does not include a year-and-a-half period when rights to the NDA were not yet held by Somerset. Approved in June, the Eldepryl NDA was reviewed in under two-and-one-half years from its resubmission in February 1987. The time spent doing additional studies is not always included in FDA's calculation of approval time. With Sandoz' Clozaril (clozapine), for example, FDA uses Sept. 1, 1987 as the official date of NDA submission. The firm originally submitted its application in 1983, but FDA asked for further studies and the company resubmitted a new application in 1987. The quickest approval times were for Ciba-Geigy's Anafranil (clomipramine), cleared in six months, Bristol-Myers' Paraplatin (carboplatin), cleared in nine months, and Medco Research's Adenocard (adenosine), approved in 10 months. Anafranil, the first drug approved for obesessive compulsive disorder, carries FDA's "1A" designation (representing a drug with important therapeutic gain). Paraplatin, indicated for recurrent ovarian cancer, and Adenocard, which is indicated for paroxysmal supraventricular tachycardia, were both rated "1B" (representing a modest therapeutic gain) by the agency. FDA approved four other drugs in less than two years -- two "1B" drugs -- Schering's Eulexin (flutamide) for prostate cancer and Merck's Losec (omeprazole), for gastroesophageal reflux disease, erosive esophagitis, and Zollinger-Ellison syndrome -- and two "1C" drugs -- Bausch & Lomb's ophthalmic beta blocker Betamet (metipranolol HCl) and Wyeth-Ayerst's injectable cephalosporin, cefpiramide. Because of the quick approval times for Paraplatin, Adenocard, Eulexin and Losec, the "1B" rated drugs in FDA's class of 1989 approvals were reviewed faster than the "1A" and "1AA" rated drugs. The six "1B" drugs were approved in an average of 24 months, compared to 25 months for the four "1A" and "1AA" drugs (FDA's high priority designation for AIDS drugs), and 40 months for the 13 "1C" drugs. The only "1AA" drug approved in 1989, Syntex' Cytovene (ganciclovir), cleared the agency in two-and-a-half years. The somewhat lengthy approval time for an AIDS-related therapy was criticized by AIDS activists. However, in granting the approval, FDA noted that the ganciclovir review had been delayed by a lack of well-controlled trials. The drug, which is indicated for cytomegalovirus retinitis in immune compromised patients, was made available under a compassionate use IND beginning in 1984 and under a Treatment IND in November 1988. In winning approval, Syntex agreed to conduct a number of post-marketing studies ("The Pink Sheet" July 3, p. 4). Cytovene is one of three Treatment IND drugs approved by the agency in 1989. Anafranil and Eldepryl were made available under Treatment INDs in August 1988 and June 1988, respectively. The average time between Treatment IND availability and final marketing approval for the three drugs was 12 months. Four companies obtained approvals for more than one new molecular entity in 1989: Lilly, Syntex, ICI and Wyeth-Ayerst. Lilly has had the two-NME approval distinction for three years in a row now, with approvals in 1987 for the antihypertensive Levatol (penbutolol), which was licensed to Reed and Carnrick, and the antidpressant Prozac (fluoxetine), and approvals in 1988 for the Parkinson's therapy Permax (pergolide mesylate) and the ulcer drug Axid (nizatidine). This year, Lilly obtained approval for the antihypertensive Pindac (pinacidil), on Dec. 28, and the anti-arrhythmic Decabid (indecainide), on Dec. 29. Lilly says it has not yet finalized launch plans for either of the late-December approvals. ICI's two 1989 drug approvals include the anesthetic Diprivan (propofol), approved Oct. 2, and the prostate cancer therapy Zoladex (goserelin acetate), approved Dec. 29 (see story, p. 9). Diprivan, an anesthetic for induction and maintenance of anesthesia, appeared to be languishing at the agency after a reorganization of the drug review divisions. Approval was then expedited with the first and only, to date, combination "NDA Day"/advisory committee review in late August ("The Pink Sheet"Sept. 4, p. 3). Syntex, in addition to Cytovene, received approval for the injectable non-narcotic analgesic Toradol (ketorolac). Toradol, which was reviewed in an "NDA Day" in July after an April advisory committee review, is the first analgesic to use a new labeling format that may become standard for all analgesics. The labeling replaces the traditional indications for use in mild, moderate or severe pain with a more general "pain" indication, and then describes clinical use of the drug ("The Pink Sheet" Dec. 4, p. 7). Wyeth-Ayerst's injectable analgesic Dalgan (dezocine), approved one month later on Dec. 29, uses a similar labeling format. Wyeth-Ayerst has not yet announced marketing plans for either Dalgan or the Jan. 31-approved "1C" antibiotic cefpiramide. The company eventually may outlicense the drug. FDA followed its usual pattern of late-year approvals, clearing 10 of the 23 NMEs in December. The percentage of December approvals (43%), however, is declining from recent years (see chart, p. 3). In the four preceding years, December approvals have ranged between 50%, in 1986, and 71%, in 1987, when the agency approved 15 of 21 NMEs in the final month of the year. In the early 1980s, NME approvals were dispersed much more evenly throughout the year. In total, FDA approved 87 NDAs during the year (including the 23 NMEs), 265 generic drug applications, and 113 biologics. The generic drug group, affected by the investigations into fraud and corruption, approved less than half its 1988 record of 573 ANDAs and 111 generic antibiotics. The agency also cleared over 1,300 supplements. Among some of the significant supplemental approvals were expanded labeling for Warner-Lambert's Lopid in January for reducing the risk of coronary heart disease; a liquid version of Burroughs Wellcome's AIDS therapy Retrovir; and an OTC version of Schering's clotrimazole, Lotrimin AF, which marked the first time FDA has allowed simultaneous prescription and OTC marketing of a product in the same strength and dosage form. FDA also approved several new ibuprofen products, including Whitehall's CoAdvil, an ibuprofen/pseudoephedrine combo product, and two liquid ibuprofens for children -- Whitehall's Childrens Advil and McNeil's Pedia Profen.

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