By Nancy Volkers

Special To BioWorld Financial Watch

In April, the FDA approved several new drugs and biologics, including an accelerated approval for Agenerase (amprenavir), but denied approval to Scios Inc.'s Natrecor (nesiritide).

Natrecor is Scios' intravenous therapy for congestive heart failure (CHF); it was narrowly recommended for approval in January by an FDA advisory panel. The agency eventually decided, however, that it had reservations about a hypotensive side effect, and that Scios had not adequately characterized the activity of the drug.

"The hypotension occurred in about 10 percent of patients," said David Gryska, chief financial officer of Scios, which is headquartered in Mountain View, Calif. "We met with the FDA about three weeks ago, and now we're meeting with our investigators, as well as other experts in the field. We'll go ahead with a trial once we get all that information together. We believe that the process of better understanding the requirements and getting the clinical trial design ironed out will take at least a year."

Natrecor is a genetically engineered version of a naturally occurring peptide produced predominantly in the ventricles of the heart. The body secretes the peptide to combat fluid overload conditions such as CHF, a chronic, potentially life-threatening disorder with no cure.

Clinical studies in 721 patients, 505 of whom received Natrecor, showed a significant reduction in a measure of the blood pressure in the heart that, when elevated, results in fluid accumulation in the lungs.

If Natrecor is approved, it will be the first new therapy for CHF in a decade. The disease is the top cause of hospitalization in Americans ages 65 and older.

Vertex Pharmaceuticals Inc.'s Agenerase (amprenavir), the newest protease inhibitor, received an accelerated approval for use in combination with other anti-retrovirals to treat HIV infection.

Agenerase has been guided through clinical development by Glaxo Wellcome plc, of London, and will be co-promoted by the two companies. According to Cambridge, Mass.-based Vertex, the drug was designed using structure-based methods.

Glaxo Wellcome submitted the new drug application (NDA) for Agenerase in October 1998 via the FDA's accelerated approval route, which allows a company to file an NDA without a complete data set from clinical trials. The FDA established this track in 1991.

"[For accelerated approval products] the efficacy data are based on surrogate markers, not necessarily mortality or morbidity as you would have in the final data set," said Mary Faye Dark, product communications manager at Glaxo Wellcome's Research Triangle Park, N.C., office. "Full approval may take a year or two. The accelerated approval was based on 16-week data, so we'll just keep updating the FDA on the progress of the trials."

The companies got the approval based on an analysis of two studies. One compared Glaxo Wellcome's reverse transcriptase inhibitors, Retrovir and Epivir, against Retrovir, Epivir and Agenerase; the other study added Agenerase to any reverse transcriptase inhibitors.

Data from the first study showed that 88 percent of patients taking the triple therapy achieved viral load below the limit of detection, compared with 19 percent of patients taking Retrovir and Epivir alone. Agenerase's ability to sustain long-term suppression of HIV RNA or slow disease progression will be evaluated in the post-market setting in order for the drug to receive full approval.

Most protease inhibitors need to be taken three times a day, and some require the patient to fast before taking the drug. Agenerase, because of its long half-life, is taken only two times a day, and fasting is not necessary.

Natrecor was first cloned in 1989; Agenerase was created in 1993. For any product, it's a long and winding road. The FDA estimated that, on average, it takes 8.5 years to bring a new drug to market, including laboratory testing, animal testing and clinical trials, and that for every 100 compounds entering trials, only 20 will be marketed. The Pharmaceutical Research and Manufacturing Association estimated that only one in 5,000 compounds that enter preclinical testing actually reach pharmacy shelves.

The Tufts Center for the Study of Drug Development examined biotech approval rates and times to market from 1980-1994. In the early 1980s, biotech products received high approval rates in short time frames. However, as the industry matures, the approval rate is decreasing, and times to market are increasing.

The center found that by the late 1980s and early 1990s, success rates fell to levels similar to those of traditional new drugs. Kenneth Kaitin, director of the center, estimates that time from clinical development to market now stands at about 7.5 years for biotech products.

"Biologics have traditionally gone through [clinical phases] more quickly," Kaitin said, "possibly because [biotech companies are] dealing with products that the body is already familiar with, so toxicity issues are not as problematic. But all of the data we looked at suggest that the overall time [to market] for biologics is getting closer to traditional drugs. It's taking longer."

Kaitin theorized that the necessary increased time may have resulted from an influx of employees with experience in the pharmaceutical industry, where people are "used to doing more studies, sometimes doing a lot more than is necessary for a bare-bones approval," he said.

When the biotech industry was born, said Kaitin, "there were small biotech firms that had products ready to go to the FDA and they didn't have one person with experience with the FDA." As a result, many biotech companies mined pharmaceutical companies for employees who could provide such experience.

Kaitin's group also found that between 1980 and 1994, biological products tended to be discontinued later in clinical development than did traditional drugs.

To explain the difference, Kaitin again fingered the early biotech companies' lack of clinical development experience, as well as one of biotech's basic needs: money.

"A lot of [biotech] products are developed by small biopharmaceutical firms, which tend to have limited pipelines," Kaitin said. "There's a huge incentive to keep the products in development for long periods of time in hopes they'll pay off. Sometimes the hopes of the firm are riding on one product."

Kaitin said he's heard "horror stories" about products doing badly in early trials, but "they're held up, because if they fail there's no reason to fund the firm," he said. Also, he said, some companies keep products "artificially ventilated" while searching for alliances that would provide funding.

While the overall time to market might be increasing for biological products, the FDA has been streamlining the process of approving new products. From 1987 to 1997, the agency reduced the mean approval time from 29 months to 18 months, though it approved about 60 percent more NDAs in 1997 than in 1987.

Resources for streamlining have come from the 1992 Prescription Drug User Fee Act (PDUFA), which allows the FDA to collect fees from industry. In the first five years of the act, the FDA collected $327 million, enabling it to hire 600 additional reviewers and improve the drug approval process. During the next five-year period (1998-2002), companies will pay an estimated $600 million in user fees so the FDA can continue its progress in reducing approval times.

According to Nancy Smith, director of the office of training and communications for the FDA's Center for Drug Evaluation and Research, the fees are spent only on premarket review. PDUFA fees are waived for orphan drugs, and the fee for the first application from a new company also is waived, Smith said, "to try and help them get started."

By 2002, the FDA has agreed to review "standard" NDAs, applications for biologics, and efficacy supplements in an average of 10 months, down from the current average of 12 months.

The agency also agreed to establish an all-electronic filing system by the year 2002 for NDAs, investigational new drug (IND) applications, and other submissions.

Other FDA goals include:

* To encourage the provision of more information about how drugs should be used for children; six months of additional market exclusivity will be provided for studies of drugs for which the FDA believes pediatric information would be beneficial;

* To provide fast-track approval for drugs that meet unmet medical needs for patients with serious or life-threatening conditions;

* To provide expanded access to investigational drugs for patients with serious diseases and conditions;

* To maintain a public data bank on clinical trials for drugs in development to treat serious or life-threatening diseases;

* To allow data from one adequate and well-controlled clinical study, together with confirmatory evidence, to be at the agency's discretion sufficient to prove substantial evidence of effectiveness. Previously, two such studies were routinely required;

* To provide health-care economic information that, for example, compares the cost of a course of treatment for one drug with that of another;

* And to reduce the size and burden of IND applications.

The FDA's streamlining attempts are paying off. Between 1992 and 1997, the agency reduced by about 40 percent the time required to review new drug and biologic license applications. About 35 percent of NDAs filed in 1993 were approved within 18 months; by 1997, more than 60 percent were approved within that time frame. *