FDA's oncology division is interested in revisiting the accelerated approval regulations as they apply to cancer treatments.

The oncology division is understood to believe that the definition is too limited. FDA currently grants accelerated approval to drugs that treat an unmet medical need or provide a benefit over available therapy in "serious or life-threatening" diseases.

FDA also is encouraging a change in the structure of clinical development for oncologic agents undergoing accelerated review.

Rather than relying on non-randomized Phase II trials, the agency is emphasizing interim analysis of a surrogate endpoint in a randomized trial.

"Although AA has been useful for approving many new anticancer drugs, there are disadvantages to drug development based on non-randomized Phase II trials in refractory populations," Oncology Drug Products Division Director Richard Pazdur, MD, Deputy Director Grant Williams, MD, and Medical Team Leader John Johnson, MD, suggest in a paper to be submitted to an oncology journal.

"An alternative to a non-randomized trial is to base AA approval on interim analysis of a surrogate endpoint in a randomized trial, with the ultimate clinical benefit assessed by completing the trial," the FDAers said.

Sanofi-Synthelabo's Eloxatin (oxaliplatin) was approved based on an interim analysis of response rate and time to progression in a three-arm, randomized trial (¹ Also see "Sanofi Eloxatin First-Line Colorectal Cancer Data Will Be Submitted By 2003" - Pink Sheet, 19 August, 2002. p. 5).

FDA is discouraging use of non-randomized trials because they provide limited information on safety and actual patient use. "The drug is often used in a wider population than the one studied" in Phase II trials, the authors observed. Moreover, "the small Phase II studies provide only limited safety data."

The FDAers noted that early trials for the accelerated approval of AIDS therapies were randomized controlled trials.

"These early AAs used a different model of drug approval than that commonly used in oncology." Accelerated approval "was based on an interim analysis of a surrogate endpoint evaluated in a randomized controlled trial. Subsequent proof of clinical benefit and regular drug approval were usually based on final analyses of the same trial."

"In contrast, AA in oncology has usually relied on response rate as the surrogate endpoint, usually determined in non-randomized trials with limited patient numbers. Clinical benefit has been demonstrated in randomized trials after drug approval, usually in patients with less refractory tumors," the FDAers added.

The oncology regulators expressed concern that sponsors have difficulty in conducting confirmatory randomized trials for drugs that are available commercially.

"Once the drug is available, it may be difficult to initiate the required confirmatory [randomized controlled trial] in the population for which the drug is approved."

Except for Pharmacia's colorectal cancer agent Camptosar (irinotecan) and Aventis' breast cancer drug Taxotere (docetaxel), "there are no other drug applications where a new drug was initially given AA as a single agent based on tumor response rate and was subsequently evaluated as a single agent in a [randomized controlled trial] for effect on survival in the same population," the FDAers noted.

At its recent meeting, FDA's Oncologic Drugs Advisory Committee questioned whether patients would participate in a randomized confirmatory trial for AstraZeneca's Iressa (gefitinib) if the drug were widely available either commercially or via expanded access (² Also see "Iressa Cross-Over Study Could Show Clinical Benefit, AZ Says; ODAC Is Wary" - Pink Sheet, 30 September, 2002., p. 13).

The oncology division granted 11 accelerated approvals through Jan. 1, 2002, nine of which were based on tumor response in single-arm Phase II trials in refractory cancer.

The division is encouraging greater use of time to progression rather than tumor response as a surrogate endpoint for agents undergoing accelerated review (see ³ [A#00640420005] ).

FDA May Revisit Accelerated Approval For Oncology Products

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