FDA Rules Hamper Novel Ovarian Cancer Drugs

Anita T. Shaffer @Shaffer1
Published: Tuesday, Jan 07, 2014
Dr. J. Tate Thigpen

J. Tate Thigpen, MD

The FDA’s rules for approving new drugs for the treatment of women with ovarian cancer pose frustrating problems for researchers developing novel agents and for clinicians seeking to improve outcomes for their patients, according to leading oncologists.

Those sentiments surfaced in interviews during the 9th International Symposium on Ovarian Cancer and Gynecologic Malignancies,® a one-day meeting that Physicians’ Education Resource, LLC (PER®) hosted October 5 in Philadelphia, where various strategies for treating patients and novel therapies under study were discussed.

Although there are several promising new agents in the pipeline, experts fear that a new drug for advanced ovarian cancer will not gain approval in the United States unless the FDA accepts evidence of progression-free survival (PFS) as a primary outcome measure in clinical trials, rather than the “gold standard” of overall survival (OS).

The multiple lines of therapy that patients with recurrent ovarian cancer receive make it difficult to obtain a clear comparison of the OS impact of a novel therapy versus a standard treatment, said J. Tate Thigpen, MD, director of the Division of Medical Oncology at the University of Mississippi School of Medicine in Jackson, one of the course directors of the conference.

“In our studies, we cannot control for what the patient gets after the patient progresses on the study therapy,” said Thigpen. “The patient essentially comes off study and is followed for survival. You start introducing then, at random if you will, additional lines of treatment. In the case of ovarian cancer, that may go up to as many as eight or 10 lines of therapy.”

Thigpen, who has played a leadership role in the Gynecologic Oncology Group (GOG), has long been a proponent of considering PFS as an acceptable endpoint for clinical trials in ovarian cancer, particularly for first-line therapy in advanced disease and in recurrent/persistent disease.1,2 He contended that large trials have confirmed that PFS provides clinical benefit to patients and is a surrogate for OS.1

If the FDA does not recognize PFS as a valid endpoint in ovarian cancer trials, new drug approvals for the disease will remain stalled while patients continue to be treated upon recurrence primarily with cytotoxic agents. “It is going to be very difficult to get a new drug approved, or to get the pharmaceutical industry to invest in evaluating new drugs in ovarian cancer, if they know that the odds of their being able to get the drug approved based on an overall survival endpoint is just by chance alone,” said Thigpen.

PFS Definitions Disputed

In recent years, the use of PFS (and time-to-progression [TTP]) as a primary endpoint in phase III randomized clinical trials has increased dramatically, from 0% in 1975-1984 to 26% in 2005-2007, according to an analysis of four eras of reports concerning breast, colorectal, and non-small cell lung cancers published in the Journal of Clinical Oncology.3 And, the FDA has been willing to approve oncology drugs based on PFS, with 23% of new drug approval indications from 2005-2007 and 29% of approvals from 2000-2010 based on trials with PFS or TTP endpoints.3

In ovarian cancer, the question of how to assess PFS in patients emerged as a major point of contention when the FDA convened a workshop on clinical trial endpoints for the malignancy in 2006.1

The optimal use of CA-125 values to evaluate whether a patient’s disease has progressed and how such assay results should be incorporated into clinical trials were disputed. In addition, some panelists believed that PFS assessments are susceptible to bias because of their timing during the course of a trial. “The point that the FDA makes is they do not believe that progression-free survival can be assessed accurately in ovarian cancer, because it is an intra-abdominal disease process,” said Thigpen in the interview. “We believe that the literature shows that PFS can be measured consistently in ovarian cancer and is the optimal endpoint for ovarian cancer.”

Issues concerning the FDA’s views on PFS as a clinical trial endpoint go beyond ovarian cancer, noted Maurie Markman, MD, senior vice president for Clinical Affairs and national director for Medical Oncology at Cancer Treatment Centers of America, who also served as a symposium director.

“Progression-free survival in a phase III randomized trial or well-designed randomized phase II trial with adequate differences in hazard ratios should be unequivocally acceptable for approval of an agent within weeks of the data being reported,” said Markman.

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