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FDA APPROVES 15 OF 21 NEW MOLECULAR ENTITIES IN DECEMBER; COMMISSIONER YOUNG SAYS APPROVALS WILL BE MORE EVENLY DISTRIBUTED IN COMING YEARS

Executive Summary

FDA continued a trend established several years ago by pushing through 15 of the 21 new molecular entities (NMEs) approved in 1987 during December. The last-minute wave of approvals has become somewhat of a tradition at FDA. However, the ratio of approvals occurring in the last month of the year in 1987 significantly outpaced the ratio of prior years. In the last five years, the closest FDA has come to 1987's December clearance rate of 71% was in December 1985 when it approved just over half (16 of 30) of that year's NME approvals. December drug approvals accounted for 10 of 20 NMEs in 1986, eight of 22 in 1984, two of 14 in 1983, and six of 28 in 1982. Following the wave of late December approvals, FDA Commissioner Young announced that a number of approvals will be granted in early 1988 and that approvals in subsequent years will be more evenly distributed throughout the year. "You will see a substantial number of approvals in the next quarter," Young said. Among the likely coming NME approvals in Lilly's Axid (nizatidine), which reached the approvable stage in December ("The Pink Sheet" Dec. 21, T&G-1). Young stated that "procedures have been put in place to reduce the applications approved, [or] evaluated, at the end of the year." To accomplish a more even flow of reviews, Young explained, "the divisions and the offices are working with Dr. Peck to have analysis, on a periodic basis, of the entire portfolio of what's out there. We have to do this, and we are working with the division directors and the office for that reason -- to avoid the last minute rush whenever possible." Young said he is concerned about the distribution of approvals "for two reasons: First, on a good management basis we should be having things coming evenly distributed. . . Secondly, I believe that it sets a tone that we can look to and give thoughtful analysis to applications throughout the year and bring companies in to answer questions in a less hurried fashion." While FDA has been criticized in the past for rushing approvals at the end of the year (for example, Merital, Suprol and Wellbutrin, which were all withdrawn from the market after adverse drug reaction problems), 1987's December drugs appear to be relatively "safe" approvals. A number of the late approvals are for "me-too" products with unlikely widespread usage; three products may not even be marketed, and three are topical products, which tend to have fewer safety problems. Lilly's Levatol (penbutolol), approved Dec. 31, will enter the already crowded antihypertensive market, if introduced at all. Lilly has said that it is "continuing to assess the marketing strategy" for the once-a-day, noncardioselective beta blocker. Cefmax, TAP's I.V. antibiotic for lower respiratory tract and urinary tract infections, may not be introduced either, according to Abbott. The Abbott/Takeda joint venture product was approved Dec. 30 as a "C" drug (little or no therapeutic gain). The launch of Sterling's I.V. milrinone, approved Dec. 31 as a "C" drug, also does not appear to be imminent. The company declined to comment on marketing plans for the product, which is indicated for short-term therapy of congestive heart failure. Sterling faces a difficult marketing strategy with I.V. milrinone. If launched, milrinone is likely to cannibalize sales of Sterling's Inocor (amrinone) I.V., the only other inotropic congestive heart failure product to be approved by FDA. Sterling may wait for approval of the oral form of milrinone; FDA's Cardio-Renal Drugs Advisory Committee recommended approval of the oral product, Corotrope, as a last resort treatment at its Dec. 7 meeting ("The Pink Sheet" Dec. 14, p. 7). The December rush caught at least two companies by surprise. Delayed launches are planned for Roche's NSAID Rimadyl (carprofen) and Beecham's topical ointment for impetigo, Bactroban. Approved as "C" drugs on Dec. 31, spring launches have been announced for both products. FDA approved two other nonsystemic products on Dec. 31: Alcon's Iopidine (aplonidine HCl), an ophthalmic solution indicated "to control or prevent postsurgical elevations in intraocular pressure that occur in patients after argon laser trabeculoplasty or argon laser iridotomy"; and Ortho's Terazol 7 (terconazole) cream, indicated "for the local treatment of vulvovaginal candidiasis (moniliasis)." Both products were approved as "C" drugs. Alcon said it plans to launch Iopidine "in the next month or two." Marketing plans for Terazol 7 have not yet been finalized, according to Ortho. The FDA commissioner noted that the reviews of Merital and Suprol, although completed in December, were not rushed and that more lengthy review times would probably not have exposed the adverse reactions seen after the drugs were marketed. "I do not think the Merital [situation] would have occurred any differently," Young said. "It just surprises me beyond end to call a seven year drug evaluation rushed." Suprol, Young said, was an example of the post-marketing surveillance system "working beautifully." He asserted that "the only way that we will not have drugs removed [from the market] after they're approved is to have 20-year reviews." With the 15 December approvals, FDA managed to exceed by one the 20 NMEs it cleared in 1986. The 21 approvals, however, fall short of FDA's record year in 1985 when it approved 30 NMEs. During the five years prior to 1987, FDA approved an average of 23 NMEs each year. The average approval time, from date of submission to date of approval, was slightly less in 1987 than in either 1986 or 1985. On average, NME applications were approved in 31 months in 1987, compared to 34 months in 1986 and 32 months in 1985. The two approvals rated as "A" drugs by FDA -- signifying an important therapeutic gain -- were cleared in an average of 6.5 months. Merck's cholesterol reduction agent, Mevacor (lovastatin), aproved Aug. 31, was cleared in nine months ("The Pink Sheet" Sept. 7, p. 3). Burroughs Wellcome's Retrovir (zidovudine or AZT), which carries the "AA" classification slated for all AIDS therapies, was approved March 19 after a four month review ("The Pink Sheet" March 23, p. 3). In a Jan. 7 "Talk Paper," FDA cited the quick reviews of Mevacor and Retrovir, but disregarded its fastest review of the year -- Alcon's lopidine. The eye pressure drug, which carries a "B" rating for a modest therapeutic gain, was approved only three months after the NDA was submitted. The five "B" drugs cleared during the year were approved in an average of 28 months each, while the 14 "C" drugs were approved in an average of 31 months. Although the approval times for the 1987 crop of approvals appear to follow FDA's policy of clearing products with therapeutic advantages more quickly, the total time to approval does not necessarily correlate with FDA's review time. The NDA for Bactroban, for example, was submitted 45 months before the product was approved. However, FDA did not actively review the NDA for the entire 45-month period. According to FDA's most recent New Drug Evaluation Statistical Report, the Bactroban NDA was considered not approvable in October 1986 and then subsequently resubmitted. Beecham noted that it did not expect to receive the Bactroban approval in 1987 in explaining the reason for the product's delayed market introduction. Approvals in 1986 followed the same general pattern of quicker clearances for "A" and "B" drugs (17 months and 33 months, respectively), than for "C" drugs, which were cleared in an average of 37 months. "A" approvals in 1985, however, took four months longer on average to clear than "B" drugs, which were approved in 29 months. The three "A" drugs (Wyeth's Cordarone [amiodarone], Genentech's Protropin [somatrem], and Viratek's Virazole [ribavirin]) took more than two years each and averaged 33 months. Two of the "C" approvals, Lederle's Novantrone and Rorer's Parathar, carry orphan drug designations. Novantrone (mitoxantrone) was approved Dec. 23 for acute nonlymphocytic leukemia ("The Pink Sheet" Jan. 4, p. 9). Also approved Dec. 23, Parathar (teriparatide acetate) is indicated as a diagnostic agent to "distinguish between hypoparathyroidism and pseudohypoparathyroidism" in patients with evidence of hypocalcemia. Rorer plans to launch Parathar in March. The product was approved 2-1/2 years after the NDA was submitted. FDA's approval letter to the firm notes that "a condition of this approval is that a post-marketing study to define the pharmacokinetics of the drug will be conducted." In addition to Parathar and Novantrone, two other products were approved as orphan drugs: Retrovir and Kendall McGaw's Ucephan. Approved Dec. 23 after a 27 month review, Ucephan (sodium benzoate and sodium phenylacetate) is a "B" drug indicated as adjunctive therapy for the prevention and treatment of hyperammonemia in chronic management of urea cycle enzymopathies. Lilly, Merck, Roche, and Abbott topped the 1987 approval list with two drugs each. Had final labeling issues been resolved for the H[2] antagonist Axid by the end of the year, Lilly would have been the biggest beneficiary of the year-end approvals with three products. In addition to Levatol, Lilly received clearance to market the antidepressant Prozac (fluoxetine). Prozac was approved Dec. 29 after a 4-1/2 year review ("The Pink Sheet" Jan. 4, p. 3). Among the firms with two product approvals, Merck obtained the quickest reviews. The nine month review of the firm's Mevacor was followed by a 20 month review for Prinivil (lisinopril). The ACE inhibitor for hypertension, which will be comarketed by Stuart under the brand name Zestril, was approved Dec. 30 as a "C" drug ("The Pink Sheet" Jan. 4, p. 4). In addition to Rimadyl, Roche obtained approval for its lipid soluble brain imaging agent Spectamine (iofetamine HCl). The agent, approved Dec. 24 after a 34 month review, will be marketed by Roche's diagnostics subsidiary Medi-Physics. Abbott's two approvals include the antibiotic Cefmax, developed via the firm's joint venture with Takeda, and Hytrin (terazosin), the first electronic NDA to clear the agency. Hytrin, approved Aug. 7, is comarketed with Burroughs Wellcome. FDA also cleared a number of important biologic drugs during the year. Besides the much anticipated approval of Genentech's Activase (TPA or alteplase) in November, Connaught had two significant vaccine approvals: ProHIBIT, the first haemophilus b conjugate vaccine, which was approved Jan. 11 ("The Pink Sheet" Jan. 4, p. 5); and an enhanced potency inactivated polio virus vaccine, approved Nov. 20 ("The Pink Sheet" Dec. 21, T&G-1). Chart omitted.
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