NDA Submissions Are Shrinking In Size But Increasing In Complexity - Peck

Clinical dossiers are decreasing in size, but new product submissions overall are becoming more complex, Georgetown Center for Drug Development Science Director Carl Peck, MD, told the Drug Information Association annual meeting.

"The clinical dossier has been decreasing, especially in the domain of the number of clinical trials as a size metric," Peck observed. At the same time, intersecting "scientific objectives, medical imperatives and pharmacoeconomic realities" make development programs "increasingly complex," he continued.

Industry has stepped up the intensity of drug development programs, incorporating more efficient and scientifically rigorous standards, Peck noted. In particular, pharmaceutical companies are conducting more randomized double-blind trials, and initiating them earlier in the development cycle, he said.

"Consider the cohort of protease inhibitors. Clinical development times from first in human to NDA submission ranged from five years for the innovator to a little over two years for the Agouron product [Viracept (nelfinavir)]," Peck observed.

"There were about 25 trials in each one of these programs, or a little over 1,000 subjects. Interestingly, the clinical trials in these were dominated by randomized double-blind dose-response types of trials; highly informative trials that led to a small number of Phase III confirmatory trials," Peck recounted, adding that he has "seen this pattern emerge in a number of other product areas."

In another study, CDDS evaluated two small molecules and a biologic in advanced development and found that the sponsors were conducting less than 25 trials in each program, with a greater emphasis on well conducted Phase I and Phase II trials.

A number of these were randomized and double blinded, so researchers "understand the drug action and get the dose right with a smaller effort in Phase III," Peck stated. Between the mid-1980's and mid-1990's, CDDS data indicate an average of 70 or more clinical trials for each program.

A new CMR International survey on recent submissions and current strategies concurs with Peck's analysis of dossier trends. CMR Research Associate Carolyn Hynes, PhD, commented at the meeting that the upward trend for clinical dossiers observed in the late 1980's and early 1990's "is perhaps being reversed," given the falling number of clinical trials.

CMR polled fourteen leading pharmaceutical companies. The average number of trials among the 21 dossiers evaluated decreased from 45 in 1995-1996 to 20 in 1998-1999. The number of subjects evaluated, however, remained consistent with over 400 subjects in Phase I trials, 600 in Phase II and 3,000 in Phase III.

Most companies surveyed reported that over the last five years, they have worked towards "conducting fewer and more successful clinical trials, focusing on both the speed of individual trials and also the speed of the transition between the phases of clinical development," Hynes said.

Peck also commented that fewer recent studies are failed or flawed than those CDDS evaluated in the mid-1990s. This could be attributable to greater efficiency and improved management, he added.

Lilly VP-Clinical Research & Regulatory Affairs Timothy Franson, MD, observed that the trend toward eliminating candidates earlier in development as well as the industry's movement toward narrowing the therapeutic areas in which a company works is contributing to the shrinking size of the dossier.

Hynes commented that the companies surveyed indicated that "the structure of the dossier, and not its actual size, is really of paramount importance."

Companies reported, however, that "the four most important factors having a major impact on the size of the clinical dossier" are 1) suitability for global submission; 2) an increase in regulatory requirements; 3) conducting trials for special populations; and 4) pressure to differentiate products.

"I think there is a consensus growing that...the number of clinical trials per clinical dossier may be decreasing, but that the complexity is on the rise and I think we should expect that to continue," Peck declared.

"Personally, I am not very apologetic or concerned about that," he added. "Our theory is that advances in drug development science, regulation and R&D management will be the solution to dealing with this complexity and to managing the number of clinical trials and the size of these clinical dossiers."