By Jennifer Van Brunt


The FDA seems to have taken to its mission of speeding new drugs to the market with a sort of missionary zeal. Since Congress passed the FDA Modernization Act of 1997 in mid-November, the FDA has truly taken some major steps toward fulfilling that agenda. It's obvious in almost every action the FDA has taken this year. For one thing, it's kept to the timetables set under the act — to the day.

Far from being the plodding behemoth of bureaucracy it once was, the new FDA has shifted into hyperdrive. There are more drugs — both biologic and chemical — waiting for the agency's actions than ever before, yet the FDA seems not to have been weighed down by the added burden. If anything, it's become more responsive than ever to petitioners' requests.

Speed Of Light

A look at some of the recent approvals and other actions taken by the FDA provides a snapshot of just how quickly the agency is responding.

Genentech Inc., of South San Francisco, completed its submission of a biologics license application (BLA) on Herceptin, its humanized monoclonal antibody for treating metastatic breast cancers that overexpress the HER-2 growth factor receptor, on May 4. The FDA already had granted the product fast-track status — on March 31 — and as such Genentech (NYSE:GNE) can now rightly expect it will get not only a priority review, but also a decision as to the product's approvability within six months — by Nov. 6.

Seattle-based Immunex Corp.'s recombinant soluble tumor necrosis factor receptor, Enbrel, also received a fast-track designation from the FDA in March, on the 17th. Immunex (NASDAQ:IMNX) then submitted its BLA on Enbrel, for treating active rheumatoid arthritis, on May 7. By June 22, exactly 45 days later, the FDA had accepted the BLA for review and assigned it priority review status — a decision it was required to make within that 45-day period.

Centocor Inc. submitted its BLA for Avakine — which the Malvern, Pa., company recently changed to its generic name, infliximab — on Dec. 30, 1997. The product, a chimeric monoclonal antibody to tumor necrosis factor alpha, is indicated for treating Crohn's disease. The FDA accepted Centocor's (NASDAQ:CNTO) BLA for filing and designated the application for priority review on Feb. 25, 1998. This was 57 days later, but that doesn't take into account the holidays. On May 28, three months later, the FDA's Gastrointestinal Drugs Advisory Committee voted unanimously that the product should be approved, and by June 30 Centocor had received a "complete review" letter from the agency. Once again, the FDA hit its six-month deadline right on time. Because infliximab was granted expedited review, the agency was required to make its decision by June 30. Since the only remaining issues concern final labeling, an agreement for a postmarketing clinical trial and the pre-approval inspection of the manufacturing facility, final marketing approval could come any day.

Keeping to the six-month deadlines does not yet appear to be an insurmountable hurdle, either. The FDA approved MedImmune Inc.'s (NASDAQ:MEDI) humanized monoclonal antibody for the prevention of respiratory syncytial virus infection in infants and children in that time frame, as well. MedImmune, located in Gaithersburg, Md., submitted its BLA on Synagis Dec. 19, 1997. It was awarded final marketing approval on June 19.

Even when faced with a product that was submitted before the 1997 Modernization Act, the FDA has kept from dragging its feet. For instance, the Orthopedic and Rehabilitation Devices Advisory Committee recommended the agency approve Gliatech Inc.'s Adcon-L on Dec. 12, 1997. On May 28, 1998, the product was cleared for marketing. Cleveland-based Gliatech (NASDAQ:GLIA) had submitted the premarket approval application (PMA) for the product, a semisynthetic carbohydrate polymer that acts like a barrier to prevent adhesions following back surgery, in December 1996; the FDA accepted the PMA for filing on Feb. 13, 1997, and granted it expedited review status in April 1997.

A Mind Of Its Own

If every company that receives a priority-review designation for its product could count on this degree of punctuality from the FDA, financial analysts and planners — among others — could remove a critical variable from the equation for revenues from product sales. But, of course, though it may stick to its rigorous timetable, the FDA does not smile on every product it sees. Nor does it always follow the advice of its expert advisory panels.

"The FDA is under no obligation to follow the advice of its advisory panels but usually does so." That stock phrase has appeared on every company-issued press release and virtually all newspaper articles concerning FDA advisory committee recommendations for decades.

Now it appears, however, the FDA is not just a rubber stamp for its various and sundry advisory panels of experts, but has taken some pains to demonstrate in spades it has a mind of its own.

Recently, several companies have been downright shocked by the FDA's penchant to exercise its prerogative. On June 11, the FDA overrode the opinion of its advisory panel and sent Advanced Tissue Sciences Inc. a nonapprovable letter for its wound-healing product Dermagraft. While acknowledging the tissue-engineered skin replacement product shows promise for the effective treatment of diabetic foot ulcers, the agency is requiring Advanced Tissue Sciences, of La Jolla, Calif., to conduct another trial. The company (NASDAQ:ATIS) had relied on a retrospective analysis of the pivotal trial; the data apparently were convincing enough for the General and Plastic Surgery Devices Advisory Committee to recommend approval on Jan. 29, 1998 — although the panel did add the caveat that the company and its U.K.-based partner, Smith & Nephew plc, should perform a postmarketing study. The FDA, however, has decided the data should be generated in a premarketing trial, a decision that will set back product approval by at least one year and probably longer.

On May 26, the agency sent DepoTech Inc. (NASDAQ:DEPO) a nonapprovable letter for its cancer drug DepoCyt. The agency informed the San Diego-based company and its corporate partner, Chiron Corp., located in Emeryville, Calif., that the clinical trials on DepoCyt had failed to prove decisively that the drug offers relief from neoplastic meningitis. The decision surprised both companies because they said they have surpassed the requirements put forth by the FDA in written agreements dating to October 1992. There was some warning, however. An FDA advisory panel cited similar deficiencies at its Dec. 18, 1997, meeting. The Oncologic Drugs Advisory Committee declined to recommend approval of DepoCyt, a sustained-release formulation of the chemotherapeutic drug cytarabine, when it found no evidence the drug works better than the current therapy (methotrexate). But since DepoTech supplied the FDA with further clinical trial data, as the agency requested in March, it gave the product three more months of review, until July 28. The FDA didn't need all that time, as it turns out.

And, of course, no one is sure what the agency has in mind for Myotrophin, Cephalon Inc.'s (NASDAQ:CEPH) drug for treating amyotrophic lateral sclerosis (ALS). The FDA canceled the Peripheral and Central Nervous System Drugs Advisory Committee meeting on April 6, just three days before the panel was to meet to consider — for the third time — the approvability of the drug. In canceling the meeting, the FDA cited the need to continue its review of the drug, which is a recombinant version of human insulin-like growth factor; under the Prescription Drug User Fee Act, it had until May 11 to do so. It met that deadline, but not in the way anyone would have predicted. The FDA issued a "potentially approvable" letter to Cephalon, of West Chester, Pa., and its partner, Chiron (NASDAQ:CHIR). This strange letter — which stated the agency will approve the product once it receives additional information from ongoing trials that demonstrate Myotrophin's effectiveness in treating ALS — has thrown the sponsoring companies, their shareholders, Wall Street analysts and patient advocacy groups into limbo. No one knows quite how to interpret the information and confusion reigns supreme.

While these companies may be bewildered by or even furious with the FDA's decisions, there's at least one company that's overjoyed. On the high end, the FDA also overrode its panel's recommendation regarding the approvable indications for Cor Therapeutics Inc.'s heart drug Integrilin. On April 2, the FDA informed South San Francisco-based Cor (NASDAQ:CORR) its drug was broadly approvable; the advisory committee had recommended a narrow therapeutic slot. On May 18, Integrilin got the FDA's final stamp of approval for treating acute coronary syndromes (unstable angina and non-Q-wave myocardial infarction) in patients who require only drug therapy, as well as in patients who are expected to undergo angioplasty.

Cor's joy may be tempered somewhat, however, by the competitors it now faces in the market — including Aggrastat, an antiplatelet drug developed by Merck & Co. Inc., of Whitehouse Station, N.J., which got the FDA's final nod only four days earlier, and Centocor's platelet inhibitor ReoPro, which was rewarded with an expanded label in November 1997.