FDA on CLL Drug Approval and Expanded Access


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The ASCO Post article, “Ibrutinib CLL Trial: Where is the Equipoise?” published in May 2013, inaccurately conveyed that the Food and Drug Administration (FDA) requires an improvement in overall survival for chronic lymphocytic leukemia (CLL) drug approval and opposes allowing crossover in the RESONATE trial. To the contrary, the FDA recognizes the needs of patients with cancer and encourages drug companies to provide earlier patient access to promising therapies.

The FDA understands the challenges of showing an overall survival improvement in CLL, given the long natural history of the disease and availability of multiple therapies. Therefore, while we may request drug companies to collect overall survival data to ensure there is no detrimental effect on overall survival and to observe any potential improvement, an improvement in overall survival is not necessary for approval in CLL.

Recent FDA approvals for a CLL indication (bendamustine [Treanda] and rituximab [Rituxan]) were based on improvements in progression-free survival together with a favorable benefit-risk profile. Crossover at the time of disease progression is acceptable to the FDA in these settings since the interpretation of progression-free survival would not be confounded by crossover. The 2013 approvals of dabrafenib (Tafinlar) and trametinib (Mekinist) in metastatic melanoma and the supplemental approval of erlotinib (Tarceva) in non–small cell lung cancer are additional examples of approvals based on progression-free survival where crossover was allowed at the time of progression.

Expanded Access

Patients with cancer frequently have exhausted currently approved drugs and are willing to try investigational drugs that have not been approved by the FDA. In 1987, the FDA formally established rules that allow patients with serious or immediately life-threatening diseases access to investigational drugs outside of clinical trials for treatment use. This process is called expanded access. In 2009, the FDA revised its expanded access regulations by clarifying and broadening these rules for both single-patient and larger-population access to investigational drugs.

The FDA has encouraged drug companies to allow earlier patient access to promising therapies, such as ibrutinib, through the use of expanded access. However, drug companies must agree to provide these drugs to patients. The FDA cannot require a drug company to provide access to an investigational drug. In the past, FDA oncologists have agreed with patients and their physicians that an investigational drug could be used, only to find later that a company is unwilling to provide the drug.

We recommend that drug companies, including those with drugs that have received a breakthrough therapy designation, provide clear and timely guidance on plans for expanded access, including specifying if and when access programs will be available after encouraging results are publicly announced. For companies that are unable or have decided not to offer expanded access programs, we recommend they publicly provide the rationale for the decision.

Coordination With ASCO

The FDA has coordinated educational efforts with ASCO to inform health-care professionals and patients about expanded access programs. This includes providing information regarding appropriate patients for these programs and procedures to obtain expanded access to investigational drugs. These resources are available on the FDA and ASCO websites.

As a next step, we recommend that ASCO develop a policy on the timely disclosure of information on expanded access programs when promising results are made public at ASCO meetings or in publications. This will provide clarity and transparency to patients and practicing oncologists. ■

—R. Angelo de Claro, MD,  Edvardas Kaminskas, MD,
Ann Farrell, MD, and Richard Pazdur, MD
Office of Hematology and Oncology Products
Center for Drug Evaluation and Research
U.S. Food and Drug Administration


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