By Lisa Seachrist

Washington Editor

WASHINGTON * Efforts to reform the FDA and speed the drug approval process have been fast and furious in recent years. Once again, reform attempts will be a major issue for this new Congress.

However, tie ups at the FDA remain only one aspect of the increasing time it takes to develop drugs; new evidence points to the amount of time companies spend on clinical trials. Concerns over this increase in drug development time have spawned consulting companies that promise to speed the process.

"We have our system in place at one major pharmaceutical company where we have consulted one product and are designing trials for three more," said Camilla Olsen, vice president of marketing and founder of Pharsight Corp., of Palo Alto, Calif., a clinical trial consulting firm that features computer assisted clinical trial design. "You can't afford to have a Phase III clinical trial produce ambiguous results."

Consultants like Pharsight are making inroads with big pharmaceutical companies; however, success with smaller biotech firms seems less likely.

"In big pharma, it is a lot more difficult to manage the projects and they may need organizational and design help," said Alison Taunton-Rigby, CEO and president of Aquila Biopharmaceuticals Inc., of Worcester, Mass. "Biotechs are small enough and are working on a limited number of projects that the extra layer is unnecessary."

A recent study by Tufts University Center for the Study of Drug Development documented that the time it takes the FDA to approve drugs has been dropping. During the time period 1990 to 1993, the agency took an average 2.7 years to approve a new drug. The FDA trimmed a year from that average by 1994-1995.

However, the Tufts study also noted that during the same period of time, companies increased the time spent on clinical trials from 5.5 years to 7.2 years. Everything from FDA requiring larger pivotal clinical trials to the complexity of proving new drugs to be more efficacious than existing drugs has been blamed for the increase.

To get a handle on these expanding clinical trials, Pharsight surveyed 16 clinical directors in big pharma and found 79 percent had difficulty designing clinical trial objectives. Twenty four percent claimed that they lacked the time to adequately design clinical trials and 19 percent pointed to difficulty in recruiting patients.

"Companies must develop their Phase III protocols a year in advance when they have incomplete Phase II results," Olsen said. "As a result, they can design trials that may not provide clear answers."

Even so, Peggy Phillips, senior vice president of pharmaceutical development at Immunex Corp., in Seattle, said she finds it hard to believe that 79 percent of the clinical directors interviewed had difficulty designing clinical endpoints.

"If someone wants to take a product into the clinic they better have good preclinical and Phase II data to know what they are looking for," Phillips said.

Phillips did note, however, that the "movable goal post"* changes in ideal endpoints from trial design to FDA approval * can be an issue. Trial recruitment also seems to be a universal problem for both big pharma and biotech. With high profile diseases like breast cancer and AIDS, most patients willing to participate in clinical studies are already on study protocols and often these patients are unwilling to be on a placebo arm of the study.

A New Industry Spawned

"If I had breast cancer, I would flatly refuse not to be on the drug," Taunton-Rigby said.

As pharmaceutical companies have become concerned about the length of time to drug development, consulting firms have begun to come up with methods to expedite the process. Pharsight, for one, offers consulting in conjunction with a computer-assisted trial design (CATD) program that Olsen said helps companies design appropriate clinical trials.

"We are experts in thinking through how drugs interact with human physiology and using 'what if' scenarios for contingency planning," Olsen said.

The program allows companies to complete a series of 'what if' scenarios to design trials that have the power to clearly demonstrate efficacy. For example, Olsen notes that if patients are likely to have a high non-compliance rate, the program can predict the necessary size of the trial. And, the program can model what happens if the companies decide on different endpoints.

"With CATD, companies can look at the issues around doing the study in special populations like the elderly and children," Olsen said. "Our system fits in with the activities already going on in drug development, but it allows you to examine thousands of scenarios very quickly."

Nevertheless, Taunton-Rigby scoffs at the idea that a computer program can design clinical trials. "As illogical as it sounds, designing clinical trials is a combination of both art, science, and judgment," she said. "I laugh at the idea of a computer program. A computer program is only as good as your assumptions, so you come back to the human designing the trial."

Pharsight isn't alone in drug development consulting, Franklin Quest Consulting Group, of Salt Lake City, also has a system. The company maintains several industry practices substantially slow the process. For one, too much time was spent getting the final new drug application (NDA) approved by various layers of management and those reviews often don't improve the document. In addition to the review process, companies often file documents that don't follow a logical development of ideas.

"The beauty of the system is that it is very commonsensical * that is what makes it work," said Mason Stout, a scientific consultant with Franklin Quest."

Franklin Quest has detailed in two white papers a system which establishes drug development teams including everyone who will work on or sign off on the NDA. Their method requires that companies create a prototype NDA which will be continually updated to anticipate questions reviewers may have.

However, Phillips and Taunton-Rigby question the real value of these consulting firms, especially for the biotech industry where the vast majority are small companies that typically have no products on the market. They both cite fostering a collegial relationship with the FDA as the most important thing a biotech company can do when developing a drug.

"FDA tries very hard to do a good job," said Taunton-Rigby. "You want to make that job as easy as possible and you don't want to throw them any surprises." *