On February 8, 2011, the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voiced its support for tightening up the agency’s accelerated approval process for new cancer drugs. The agency has been criticized for failing to police the program, allowing drug companies that did not complete required post marketing studies to keep the drugs on the market for years.
ODAC must strike a difficult balance, ensuring patients’ expedited access to potentially life-saving medications, while keeping potentially toxic and untested treatments off the market.
Lee Newcomer, MD, United Health Group Senior Vice President for Oncology, supported the move. “The FDA’s first responsibility is determining safety and effectiveness,” he told Value-Based Cancer Care (VBCC). “They compromised on the standards to allow access to potentially important drugs, but they still have the obligation to ensure that the drugs did meet standards.”
Post marketing Issues The committee quizzed 4 drug companies that had not yet completed postmarketing trials on drugs approved for 6 different indications, and discussed the following common concerns:
“Water tends to seek its lowest level,” said Richard Pazdur, MD, FDA Director of Oncology Drug Products. “And we frequently find sponsors coming in and saying, ‘Dr Pazdur, what’s the fewest number of patients and the lowest response rate that you’ll take?’ That’s problematic for us.”
The accelerated approval program has expedited the availability of drugs that show early benefit on surrogate end points (eg, response rate and duration). The approval is conditioned on results of post marketing trials meeting a definitive end point.
In September 2009, a Government Accountability Office report criticized the FDA for allowing pharmaceutical companies to drag out post marketing trials. Failing to complete such trials is now a federal violation subject to financial penalties. Although the FDA has yet to issue such a fine, the pressure is growing for heightened scrutiny. The recent case of Avastin (bevacizumab) is one such example.
“While there’s no regulatory definition of due diligence related to the completion of post marketing clinical trial requirements,” said Paul Kluetz, MD, Medical Officer at the FDA Division of Drug Oncology Products, “most would agree that over 7 years of marketing, an unproved drug, with at least some level of toxicity, is suboptimal.” Barriers cited by drug companies include:
According to Dr Kluetz, 49 new indications for 37 oncology drug products have been approved since the program was expanded to oncology drugs in 1996. Of these drugs, 27 have completed required trials with a verified clinical benefit; in addition, companies have not been able to prove 5 indications.
Pro and Con Unlike the FDA’s accelerated approval process, the European “conditional approval” process must be renewed annually. By contrast, this ODAC meeting was its first since 2005 to review postmarketing requirements.
Silvana Martino, DO, Director, The Angeles Clinic Breast Cancer Program, strongly criticized the FDA. “I’m very disappointed that this process of approval has really become a screening process,” she said. “Everyone’s interested in ‘what is the least that we have to offer.’ I think that this committee and the FDA and others have allowed that to become the mood of science within the field of oncology...where we are willing to accept drugs with the most minimal evidence…. We’re dealing with drugs that have barely any activity.”
Acknowledging the need for change, Dr Kluetz nevertheless insisted that, “While accelerated approval allows for earlier marketing of promising drugs, it does come at the expense of increased uncertainty,” he said. “And while 10% of oncology indications approved under accelerated approval were unable to prove a benefit, this should not be thought of as a failure….The tradeoff is for earlier availability of promising agents for severe and life-threatening diseases.”
Jeff Allen, PhD, Executive Director of Friends of Cancer Research, supports the program and cautioned against an overreaction. “The accelerated approval process has historically shown to be an important tool to provide patients with timely access to highly beneficial treatments,” he told VBCC.
“The FDA should have the appropriate authority to ensure confirmatory trials are efficiently conducted. But there needs to remain a level of flexibility that allows the FDA and sponsors to develop the desired evidence in such trials. A blanket requirement for randomized controlled trials may not be the most appropriate approach in all cases,” said Dr Allen.
What Type of Postmarketing Trials? Single-Arm Trials Members of the panel agreed that single-arm studies should be limited, acknowledging that those could be useful in researching treatments for rare cancers. Of the cancer drugs approved under the accelerated approval program, 20 were based on randomized clinical trials and 29 on singlearm studies.
“There seems to be a real possibility in a lot of these situations for running a randomized trial,” said Ralph D’Agostino, PhD, Boston University Professor and Chair of Mathematics and Statistics. “And that should be the first item on the table.”
With increased focus on molecular therapies and subpopulations of patients, randomization may not always be possible. “I don’t think anyone would be interested in giving patients a drug that doesn’t work, but if an exceptional case comes along with truly outstanding results, there may be better approaches to sufficiently demon strate efficacy,” said Dr Allen.
Confirmatory Trials The ODAC members unanimously agreed that the FDA should require companies to complete 2 clinical trials to prove benefit after receiving accelerated approval. According to Dr Pazdur, oncology is alone in requiring only 1 trial.
“It’s a basic principle of science,” noted Dr Newcomer. “Any observation should be confirmed by an independent observer.”
Timing. Most ODAC members supported requiring that postmarketing trials be under way at the time of accelerated approval.
Cooperative groups. ODAC members voiced support for making it necessary for only 1 of 2 confirmatory trials to be conducted through cooperative groups. Pharmaceutical companies can not cede responsibility to cooperative groups, which carry out such studies for their own purposes.
There was concern over GlaxoSmith-Kline’s failure to fulfill postmarketing requirements in trials for Bexxar (tositumomab and iodine 131I tositumomab) therapy to treat relapsed and refractory low-grade follicular lymphoma. Two postmarketing commitments were delayed and 1 is ongoing. One of the trials set out to compare Bexxar and rituximab (Rituxan) and had trouble accruing sufficient patients, seeking FDA permission to shift to a study that is already being carried out by the Southwest Oncol ogy Group.
“We cannot be in a situation where a regulatory requirement is transferred to a third party,” said Dr Pazdur.
But some on the panel emphasized that cooperative groups had been successful, particularly in pediatrics. Dr Newcomer echoed the concern, cautioning against too much rigidity. “The key is doing a good study,” he said, “not the organizational structure under which it is accomplished.”
