Debating Drug Approval Decisions

U.S. Food and Drug Administration (FDA) regulators often face difficult decisions about whether a cancer drug should receive marketing approval. They send hard-to-judge candidates to the Oncologic Drugs Advisory Committee (ODAC), and the doctors who have chaired the committee over the past decade discussed some of their toughest calls at an April 7 session during the AACR Annual Meeting 2013 in Washington, DC.

When a package of information about a specific drug arrives, it's clear that approval will need very careful thought, commented current chair Mikkael Sekeres, MD, an oncologist at the Cleveland Clinic in Cleveland, OH. “I read through it and say, I still don't know how I'm going to vote.”

The committee's drug discussions parallel risk/benefit considerations in the clinic, where “doctors often have conflicting feelings,” said Wyndham Wilson, MD, PhD, head of lymphoma therapeutics at the National Cancer Institute's Center for Cancer Research, and a former ODA chair. “The real conflict is that you have so few good drugs.”

“It is to the benefit of the patient that we can speak and disagree,” declared Maha Hussain, MD, associate director for clinical research at the University of Michigan Comprehensive Cancer Center in Ann Arbor, and also a former ODA chair.

Some of ODAC's sharpest disagreements centered on the 2008 FDA accelerated approval of Avastin (bevacizumab; Genentech) for use with paclitaxel in metastatic breast cancer, based on improvements in progression-free survival. The approval was made after a 5-to-4 ODAC vote against it, and withdrawn in December 2011 after a storm of controversy.

“What were you thinking when the FDA approved Avastin?” Hussain asked Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, who chaired the session.

Hussain noted that Avastin had not shown overall survival or quality-of-life benefits and upped the risk of serious side effects. “To me, the obligation is to do no harm,” she emphasized.

However, long after Avastin's indication was withdrawn, “a lot of patients and physicians today remain convinced that Avastin was a wonderful drug,” noted Silvana Martino, DO, director of the breast cancer program at The Angeles Clinic in Los Angeles, CA, and another former ODA chair.

“I probably would have voted yes,” added Wilson, who was not on ODAC at the time. “A number of patients said they rose out of a semi-stupor in bed and had quality of life back.” He added that during his time on the committee, he became more likely to give a drug the benefit of the doubt.

“Avastin was not a clear-cut decision by any means,” said Pazdur. The situation became much clearer after follow-up studies failed to demonstrate improvement in overall survival or quality of life. “We asked the firm to take the drug off the market, and the entire process evolved because it was reluctant to do so,” he said, acknowledging that it is unusual for drug approval to be pulled for a combination of safety concerns and lack of efficacy.

ODAC's discussion about using erythropoiesis-stimulating agents to combat chemotherapy-induced anemia was more straightforward, said S. Gail Eckhardt, MD, head of medical oncology at the University of Colorado Denver Health Sciences Center, and also a former ODA chair.

After trials showed the drugs shortened survival in patients with breast cancer or head and neck cancers, the FDA took ODAC's advice and required labeling changes on several Amgen drugs, restricting their use after chemotherapy.

The restrictions were controversial and followed protests from patients during an ODAC public hearing. However, “there was a disconnect between what the drug was advertised for and what the drug was approved for,” Eckhardt said. “It was given to patients who were told that they would have more energy, where actually they were having less survival.”

Overall, ODAC's findings “are advisory decisions, but they are taken very seriously by the FDA,” Pazdur emphasized. “We're not so interested in the vote per se; we're interested in the principles discussed.”