By Jennifer Van Brunt


There's been a fundamental change at the FDA. It's taken a long time, and signs of it have been popping up every so often for several years. But the defining events occurred in early April.

First, the agency overrode the recommendation of its Cardiovascular and Renal Drugs Advisory Committee regarding the approvable indications for South San Francisco-based Cor Therapeutics Inc.'s (NASDAQ: CORR) heart drug Integrilin. The FDA's action was an exceptionally rare event. So, too, was the move it made the following week, when it canceled an advisory committee meeting to consider (for the third time) the approvability of West Chester, Pa.-based Cephalon Inc. (NASDAQ:CEPH) and Emeryville, Calif.-based Chiron Corp.'s (NASDAQ: CHIR) drug Myotrophin, for treating amyotrophic lateral sclerosis. 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 (PDUFA), it has until May 11 to do so.

These two events alone signal radical changes in the FDA's attitude. On top of that, the agency has taken a very active role in assisting and guiding DepoTech Corp. in efforts to get its cancer drug DepoCyt back on track. Last month, the two parties agreed that the San Diego-based company (NASDAQ:DEPO) could submit more trial data to back up its new drug application (NDA), which originally failed to win support from an advisory committee in December 1997. The FDA's Oncologic Drugs Advisory Committee voted against approval, saying the single Phase III trial was too small to support the NDA and had no evaluable endpoint. But now, the agency is willing to accept more clinical data to support the application; the review period has been extended by three months, to July 28, 1998.

As well, the FDA has assisted CollaGenex Pharmaceuticals Inc. in efforts to revitalize its stalled NDA for Periostat, a treatment for periodontitis. After discussions with the agency, the Newtown, Pa., firm (NASDAQ:CGPI) agreed in March to submit an amendment to its NDA, including data from a recently completed clinical trial that combines the drug (a subantibiotic dose of doxycycline) with the standard of care for the disease. The FDA suggested this action, which includes a revised claim for the drug and resets the regulatory clock by six months.

Another measure of the FDA's new attitude is the increasing number of potential new therapeutic products that have been assigned priority review and/or fast-track status. In March, South San Francisco-based Genentech Inc.'s (NYSE:GNE) humanized monoclonal antibody Herceptin for treating metastatic breast cancer was awarded fast-track status. And Seattle-based Immunex Corp.'s (NASDAQ:IMNX) Enbrel, a recombinant tumor necrosis factor receptor for treating severe rheumatoid arthritis, also got put in the fast lane. In early April, fast-track status was granted to Interneuron Pharmaceuticals Inc.'s (NASDAQ:IPIC) CerAxon (citicholine for treating ischemic stroke). The company is located in Lexington, Mass.

Reform Measures

Although these changes in the agency's approach to dealing with biotechnology companies — and their potential products — might appear to have sprung from nowhere, in reality they have been evolving slowly over the last 15 years, since biotech-derived drug applications first started showing up at the FDA. That evolution got a big push last year, however, as Congress hammered out the details of FDA reform.

After three years of bitter debate and haggling in both the House and the Senate, the final version of the FDA Modernization Act of 1997, which reauthorizes PDUFA, finally passed both chambers of Congress on a simple voice vote in mid-November of 1997 and then was signed into law by President Clinton around Thanksgiving.

The Modernization Act constitutes substantial FDA reform — it not only reauthorizes PDUFA for five more years, but provides for fast-track drug approval and codification of the biologics rewrite, among other items. By working together for so long on the issues of FDA reform, the biotech industry and the agency have come to new levels of understanding, as well; their relationship is much less adversarial than it once was. This is a new FDA: That's certainly been more than obvious over the last few months.

"It's clear that the FDA is trying to be helpful [to biotech companies]," explained Jim McCamant, editor of The Medical Technology Stock Letter, based in Berkeley, Calif. "One of the biggest changes is the willingness of the FDA to discuss freely and openly [with biotech companies] how to design and conduct clinical trials," he said. The FDA has been under increasing pressure over the last few years to get drugs onto the market, he continued, and Congress has helped to keep that pressure on. "[Former FDA Commissioner] David Kessler started to make the changes necessary to speed up drug approvals. That's when the agency instigated the six-month approval process for drugs to treat life-threatening diseases such as AIDS," McCamant said. "Congress kept the pressure on."

FDA reform bodes well for the biotech industry, whose financial health is forever intertwined with the stance the FDA takes toward regulating the flood of new therapeutic drugs, diagnostic products and medical devices that are pouring out of this sector.

When a drug fails to show efficacy in a late-stage clinical trial, the sponsoring company's stock almost inevitably takes a beating. As well, that company probably has used all its available cash just to get that far in the drug development process. It then finds itself stranded — with no product to show for its investment and very little hope of attaining the financing it needs to continue in a slightly altered direction. Investors abandon the stock before it drops any lower in value; of course, that's what it then proceeds to do.

It's a vicious circle. Yet if the FDA could provide the company with direction early in the clinical trial process — and tell that company what it expects from the results — then perhaps some of this misfortune could be avoided. When biotech-derived drug applications first started showing up at the FDA's door, they were unique and had no history or precedent. The agency has had to create a new vision of how to accurately and adequately regulate these products.