MONTREAL - Getting a drug from the early stages of development to the market is no mean feat, especially for small companies, but maintaining effective communication with the FDA can keep firms from getting lost on the regulatory pathway, said a panel of industry experts at the VentureForum East conference here.

On the final day of the meeting, attendees gathered in the ballroom at the Marriott Chateau Champlain hotel for a discussion, titled "Rules of Engagement: Best Practices for Working with the FDA," a topic of particular importance for small or foreign biotech firms.

From 1996 to 2006, the number of drugs approved by the FDA each year has dropped dramatically, a trend that has been reported widely throughout the sector and partly attributed to what panelist Thomas Garvey, of consulting firm Garvey Associates Inc., called the increasing "bureaucratization" of the agency.

Garvey, who previously served as supervisory medical officer in the FDA's Division of Cardio-Renal Drug Products, said firms used to be able to "pick up the phone" and talk directly to the drug reviewer to answer any questions. Now, however, there's a layer of formality to all FDA communications. Data have to be submitted in proper form, and meetings must be scheduled. "It's a very cumbersome way to communicate," he said, adding that company executives often "walk out [of those meetings] with a lot of other questions."

A study by consulting firm Booz Allen Hamilton, designed to understand which firms gained first-cycle approval for their drugs and why, reviewed 80 regulatory filings, 14 of which were biological license applications (BLAs) and the remainder were new drug applications (NDAs). Of those applications, half were approved on the first submission, about 25 were required to resubmit data or other information and the remaining applications still are pending, said Anna Pettersson, a senior associate at Booz Allen Hamilton in New York. And the "most important corollary" in the study for companies failing to get the agency's nod on the first round was ineffective communication, she added. "Companies were not responsive" or did not respond quickly enough to the FDA's request for additional information.

The Booz Allen Hamilton study also showed that U.S. firms typically have a greater likelihood of gaining a first-cycle approval compared to foreign companies, and that large and midsize biotechs generally are more successful than small firms. Naturally, having prior experience with the agency's machinations helps, but sometimes it's the financial constraints that hurt young firms.

Large companies - big pharma, as well as big biotechs such as Genentech Inc. and Amgen Inc. - can afford to conduct a range of studies, some of which might seem needless at the time, Garvey said, at least until the FDA starts asking for additional or clarifying data. Small firms, on the other hand, have "staked everything on one Phase III study" in their rush to regulatory filing.

That was the FDA's chief concern when it rejected in early 2005 an application for cancer drug Marqibo (vincristine sulfate liposomes injection) from Vancouver, British Columbia-based Inex Pharmaceuticals Corp. The NDA was based on data from a single-arm trial rather than a randomized Phase III study evaluating Marqibo in comparison to chemotherapy regimens in non-Hodgkin's lymphoma patients. At the time of the non-approvable letter, Inex maintained that the FDA previously had approved the protocols for the single-arm study and later changed its mind. (See BioWorld Today, Jan. 20, 2005.)

"It was obvious to me [that] there was a disregard for details of what the FDA was asking," said Ulrich Grau, president and CEO of Jersey City, N.J.-based Lux Biosciences Inc. "A diligent sponsor would not have let that happen."

Grau formerly served as the chief scientific officer for Enzon Pharmaceuticals Inc., which dropped its partnership with Inex two months after the Marqibo rejection. A year later, Inex licensed worldwide rights to Marqibo and two other cancer drugs to Hana Biosciences Inc., of South San Francisco, and Hana is gearing up for pivotal studies in acute lymphocytic leukemia and NHL.

One of the biggest mistakes companies can make is failing to ask enough questions, said Wilson Bryan, who served as a medical officer and team leader for the FDA's CDER and CBER before joining The Biologics Consulting Group as a senior clinical consultant. "And be sure those questions are clear," he added, "so that they generate discussion to clarify" the process.

Many small firms also are unaware that they can "push back" when dealing with the FDA, Bryan said, and try to negotiate and "come up with alternatives that might be acceptable" to the agency.

Meanwhile, as the organizer for the annual VentureForum meetings, the Biotechnology Industry Organization (BIO), continues to lobby for policy changes to improve the regulatory process, and is focusing efforts on several topics, such as the upcoming renewal of the Prescription Drug User Fee Act (PDUFA), patent reform and the approval pathway for biogenerics.

"This is, without a doubt, the most challenging advocacy agenda we've ever faced," BIO President and CEO Jim Greenwood told conference attendees Tuesday. There's "a lot of work to do."

BIO will bring together small biotechs and investors at two more meetings this year: the Mid-America VentureForum in Milwaukee, in September, and the BIO InvestorForum meeting in San Francisco a month later.