WASHINGTON _ Officials at the FDA's Center for BiologicsEvaluation and Research (CBER) are worried about the significantdecline in product license applications (PLAs) seen in the last twoyears and have contracted a research firm to study the matter. CBERDeputy Director Michael Beatrice told a packed audience at theBioEast '95 conference here Monday that the center received 10PLAs in 1993, eight in 1994 and only one so far in 1995. (CBER'sfiscal year runs from Oct. 1 through Sept. 30.)

"We don't know all the reasons why the number of applications isn'thigher than it is. It's very disturbing," said CBER Director KathrynZoon. "The trend [of declining numbers of PLAs] is unique to CBERwhich shows that the complexities and economic variables facing thebiologics community are different than those we see in the traditionaldrug industry."

Beatrice said CBER analysts have concluded the dearth of PLAs isnot due to the fees imposed upon companies by the PrescriptionDrug User Fee Act of 1992. "It's not difficult to get waivers andexemptions if you're a small company," he said. "We don't think it'sthe fees." An analysis of Investigational New Drug applications(IND) at CBER suggested that product failures may be responsible,rather than unintended harmful effects of the user fee program.

"This question is so significant that we have initiated a marketforecast analysis," said Beatrice. "We will actually have a contractorgoing out and talking to the industry to see what's happening,whether this [PLA decline] is due to forces from their side or ourside. And if it's from our side, we will do something to try andcorrect it."

The FDA's hired analytical guns may need look no further than thepages of BioWorld Today for a partial explanation of the recentdecline in PLAs. As reported here, 1994 was a banner year for INDsthat derailed just before reaching the PLA (or, in some cases, thefinal PLA supplement) stage.

Even a partial list of products that failed to show statisticallysignificant efficacy in a Phase III trial in 1994 is depressingly long. Itincludes: Biogen Inc.'s Hirulog (an anti-coagulant for angioplastypatients), Celtrix Pharmaceuticals Inc.'s BetaKine (for treatment ofmacular holes _ the clinical results were "inconclusive"), GensiaInc.'s Arasine (for myocardial infarctions during bypass surgery),ProCyte Corp.'s Iamin gel (for diabetic plantar ulcers), TeliosPharmaceuticals Inc.'s Argidene gel (also for diabetic plantar ulcers),Ribi ImmunoChem Research Inc.'s Melacine (for advancedmalignant melanoma), Synergen Inc.'s Antril (for severe sepsis),Regeneron Pharmaceuticals Inc.'s ciliary neurotrophic factor (foramyotrophic lateral sclerosis), and Chiron Corp.'s T-88 (for Gram-negative sepsis).

Last year was also the first full year of implementation of the UserFee Act (the program's clock began ticking in mid-1993) and FDAofficials have crowed about meeting its new, more stringent reviewtime deadlines. Agency statistics suggest that application backlogshave been reduced almost to nil.

Yet the User Fee Act was designed, in part, to help the agency dealmore efficiently with an expected onslaught of applications.Ironically, the marked decline in PLA activity could make itrelatively easy for CBER to meet the legislation's mandateddeadlines. Backlog reductions could represent a somewhat hollowvictory if CBER doesn't get any new PLAs. "Obviously, we can't acton applications unless they come in," said Zoon.

The ever-lightening PLA workload for CBER has meant that, underthe terms of the User Fee Act, the center gets less money to hire newstaff. Last year, Zoon said, CBER got funds for roughly 30 full-timeequivalent (FTE) positions while the Center for Drug Evaluation andResearch (CDER) got about 70 FTEs. (CDER's workload hasremained steady over the last two years.)

Beatrice noted that PLAs at CBER actually represent twosignificantly complex documents, the PLA and the EstablishmentLicense Application (ELA), which must be filed simultaneously.Thus, in 1994 CBER received eight PLAs and eight ELAs, whichmeant there were really 16 lengthy, complex documents to review.(CDER does not require ELAs.) In addition to PLAs and ELAs,CBER staff must review manufacturing supplements (which are onthe rise) and PLA supplements, among other things. "It's just thenew PLAs that are not coming in," Beatrice told BioWorld.

Zoon said that there will be an increase in PLAs, although "it won'tbe as great as we had originally projected." Past failures were due, inpart, to inexperience and to the fact that biotechnology companies"searched for diseases for the molecules they had discovered," sheadded.

"Now, we're getting smarter and the industry is getting smarter as tohow to really plan and go for clinical indications," she toldBioWorld. "Certain types of approaches, such as replacement factorsor factors with very targeted activity, have an increased probabilityof success."

Industry representatives who suspect that CBER policies may be asignificant part of the declining PLA problem will get a chance toshare their thoughts at an FDA meeting on Jan. 26 in Rockville, Md.The FDA plans to rewrite its General Biologics Regulations and islooking for industry participation during a four-hour public meeting,scheduled to take place between 1:30 and 5:30 pm in the agency'sParklawn building.

BioEast '95, co-sponsored by the International Society for theAdvancement of Biotechnology and Genetic Engineering News,continues here through Jan. 12. About 2,200 people had pre-registered to attend. n

-- Lisa Piercey Washington Editor

(c) 1997 American Health Consultants. All rights reserved.

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