Andrew L. Pecora, MD

Editor-in-Chief

Chief Innovations Officer, Professor, and Vice President of Cancer Services

John Theurer Cancer Center at Hackensack University Medical Center

Much has been made of the difficulties companies, investigators, and patient advocates have in providing access to novel therapies. These difficulties are due, in part, to the complexities of the regulatory approval process. There are clear examples of where the regulatory approval process has slowed the approval of potentially life-extending medications (eg, Provenge). Largely, delays have been due to questions regarding efficacy or safety. However, until recently, drug approvals have languished when the usual standards by which efficacy is measured were not achieved despite a clear benefit to patients. This has changed in a positive direction with the recent approval of the JAK inhibitor ruxolitinib, for treatment of myelofibrosis.

JAK1 and JAK2 enzymes regulate blood production, and at times when these enzymes are aberrant, as in myelofibrosis, there is uncontrolled hematopoiesis leading to splenomegaly. In addition to the discomfort caused by splenomegaly, other and more troubling symptoms can occur, including fatigue, fever, night sweats, pruritis, and bone pain. Evolving cachexia, deterioration in blood counts, and ultimate organ failure and death follow after years of suffering. Agents such as thalidomide and, more recently, lenalidomide have been used in conjunction with hydroxyurea to control blood counts and lessen splenomegaly. But efficacy of these agents has been mixed and short term. With the discovery that a mutation of JAK2 was present in some patients with myelofibrosis, the new agent ruxolitinib was tested in clinical trials. Ruxolitinib was found to have a biologic effect in most patients with myelofibrosis, regardless of the JAK2 mutation, but a question arose: Was the effect, although clinically meaningful, adequate for regulatory approval?

Two phase II trials (COMFORT I and II) presented at the 2011 ASCO meeting had unusual endpoints for a cancer drug. Nevertheless, these endpoints were clinically meaningful for patients with myelofibrosis. The studies demonstrated a ≥35% reduction in spleen size and, equally important, significant symptom alleviation. Symptom alleviation as part of a registration endpoint of efficacy of a cancer drug was somewhat surprising to the industry. The decision to include symptom alleviation as an endpoint arose from pre-agreed specifications negotiated with the FDA using a myelofibrosis symptom assessment form that was developed through a collaboration between the FDA and industry. Nearly all patients had a reduction in spleen size, and 42% met criteria for a 35% reduction. Moreover, 46% of patients had at least a 50% decrease in total symptom score. The drug was largely nontoxic and showed evidence, although not extensive, that drug administration may lead to longer survival.

The debate will continue about how we can and should accelerate drug approval in the United States. Regardless, this is a specific example where industry and the FDA collaborated to create criteria that went beyond the traditional efficacy metric and resulted in a clinically meaningful drug approval.