EU To Revise Oncologics Guidelines To Increase Cancer Product Approvals

The European Committee on Proprietary Medicinal Products is considering revisions to its guidelines for oncologic products that would help accelerate the development and approval of anticancer agents.

"Within the CPMP we are in the process...of reviewing the current guidelines," CPMP member and French Medicines Agency Registration and Clinical Studies Department Director Eric Abadie, MD, told the Drug Information Association annual meeting June 12.

The committee is scheduled to meet at the European Medicines Evaluation Agency in London on June 27-29, and plans to discuss clinical endpoints and choice of control groups in clinical trials of oncologic agents, Abadie said.

One reason for the re-evaluation is the discrepancy in oncologic approval rates between FDA and the EU, EMEA Sector for New Chemical Substances Deputy Head Anthony Humphreys said.

Out of 11 products with a negative review outcome in the centralized EU system in 1999 (not including products reviewed through the mutual recognition procedure), six were approved in the U.S., Humphreys said. He noted that "the highest area of divergence is in the oncology area."

The "CPMP has decided to review their position on the anticancer guideline, to...contact a lot of the interested parties and reassess their position on that," Humphreys said. "But the jury is still out on that process. It's starting off now in the second quarter and will continue on through the end of this year."

Out of 49 applications reviewed in the EU in 1998, "20 applications out of 49 were actually pulled before they got to a final decision," Humphreys said. "We got a bit alarmed at what appeared to be a rather sudden rise."

EMEA studied "how many of these negative outcomes in the EU centralized system were actually authorized in the U.S." Humphreys said. "Although that peak in 1998 was somewhat worrying for us, we were somewhat reassured that there were only five of those decisions where we actually differed with the FDA."

After discovering a more striking difference between European and U.S. drug evaluation in 1999, EMEA performed an analysis of the most common concerns that emerged in EU reviews of products approved in the U.S. but not in Europe.

"The top five concerns with respect to clinical efficacy that emerged were" study design (cited in 81% of the divergent reviews), regimen justification (63%), robustness of pivotal data (54%), endpoints (45%), and pharmacodynamics/pharmacokinetics (45%), Humphreys reported.

In the analysis "what we're looking for is, is there any room for any improvement in any therapeutic areas?" Humphreys said. "I've mentioned the fact that we're going to look at the anticancer area again."

In addition, "we want to look at the outcome in terms of predictors and the timing of the events. We also want to look at the distribution of concerns across the therapeutic areas. Because obviously they're not all in common. We also want to see is there a relationship between factors. Are concerns over study design also linked with something else? So we're trying to analyze the data set to see what potential factors could be linked."

"We would hope that we're going to be able to do a comparison more in-depth between ourselves and FDA," including products approved through the mutual recognition procedure in Europe, Humphreys commented. "The possibility of doing that should be improved in the very near future."

FDA Office of Review Management Deputy Director Murray Lumpkin, MD, will begin a sabbatical at EMEA shortly, and plans to review differences in EU and FDA reviews of new molecular entities submitted in 1998 (¹ (Also see "FDA And EMEA To Compare Regulatory Approaches Used In 1998 NME Cohort" - Pink Sheet, 5 Jun, 2000.)).

Humphreys said that EMEA is considering making information on "the negative decisions and companies withdrawing products before they get to a negative decision" available to the public. "We are attempting to publish them in a somewhat generic form, but obviously there's a lot of sensitivity about that process."

Bristol-Myers Squibb VP- Regulatory Science and Outcome Research Claude Nicaise, MD, pointed to the different regulatory approval mechanisms and clinical developments requirements in the U.S. and Europe as an obstacle to timely oncologic drug development.

"The industry challenge is actually to deal with the differences between the U.S. and European regulatory requirements," Nicaise said. "The mechanisms to bring new drugs faster to the market need to be appropriately evaluated and probably some of the difference that still exist between U.S. and Europe needs to be challenged and revisited in the future."

"One important difference is the [EU] requirement for comparative data even in refractory disease and in fairly late stage of disease," Nicaise said.

The "problem of comparative trials in this situation where there is no validated treatment...at the very late stage of the disease" is one question that will be discussed by the CPMP when reviewing the guidelines, the French Medicines Agency's Abadie told DIA.

Nicaise pointed out that although the U.S. and EU each have mechanisms for speeding up the development or review process for certain drug products (such as accelerated approval and priority review in the U.S. and documentation of application in extraordinary circumstances in the EU), the requirements differ across the two systems; the U.S. system allows for quicker, more flexible development.

Specifically, "surrogate markers, and especially tumor response, are more often used in the U.S. in the accelerated approval than in Europe," Nicaise said.

In addition, "the need for randomized trials is more important in Europe than in the U.S. in terms of the accelerated approval."

Nicaise pointed to Bristol's development of the anti-cancer agent Taxol as an example. "The approval of Taxol for second line ovarian cancer...in the United States was achieved by a number of Phase II noncomparative trials demonstrating an acceptable response rata and an acceptable benefit in those populations," he noted. "However it required randomized trials in Europe, prior to its final approval."

Nicaise also said that although the EU offers accelerated evaluation, the process is "infrequently used." Humphreys noted that no product has qualified for accelerated evaluation in the EU since the program's inception. "We must have raised the hurdle very, very high," he commented.