1. Eastman, Peggy

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WHITE OAK, MARYLAND-The FDA's Oncologic Drugs Advisory Committee has affirmed the agency's firm position on the need for post-marketing studies to confirm clinical benefit in cancer drugs that receive accelerated approval.

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A company can face financial penalties if it does not use "due diligence" in completing confirmatory trials. Until recently, drugs that failed to confirm a clinical benefit were voluntarily withdrawn by the sponsor, but in December 2010 the FDA initiated withdrawal proceedings for bevacizumab for the treatment of HER-2 negative metastatic breast cancer-the first FDA-initiated withdrawal for an accelerated approval oncologic drug indication.


In an all-day meeting here on February 8, ODAC members reached consensus on the need for at least two well-controlled clinical trials conducted by drug sponsors to fulfill their accelerated-approval requirement to verify clinical benefit and receive full drug approval.


In oncology, the FDA has frequently approved drugs on the basis of a single well-controlled trial, but for drug approval in most other therapeutic areas two randomized trails are usually required, noted Richard Pazdur, MD, Director of FDA's Office of Oncology Drug Products, Office of New Drugs, Center for Drug Evaluation and Research.


He said that while the FDA remains committed to the accelerated-approval process to speed effective drugs to patients and believes this is a successful program, "we want to bring these accelerated-approval drugs into more focus" and make sure that confirmatory studies are carried out in a timely fashion.


"The ideal is always to do two," said ODAC Chair Wyndham Wilson, MD, PhD, Chief of NCI's Lymphoma Therapeutics Section.


Commented ODAC member Silvana Martino, DO, Director of the Breast Cancer Program at the Angeles Clinic and Research Institute in Santa Monica, California: "For me, to think of accepting anything less than two [trials] is ignorant."


Dr. Martino pointed out that sometimes even more trials have to be conducted-when studies yield conflicting results, for example.


"I think you're safer with two," agreed ODAC member Mikkael Sekeres, MD, MS, Director of the Leukemia Program at the Cleveland Clinic Taussig Cancer Institute, Chair of the Hematology/Oncology Pharmacy & Therapeutics Committee, and OT's Clinical Advisory Editor for Hematology/Oncology.


ODAC member/patient representative Musa Mayer, MS, added, "I don't want to get into the business of lowering the bar in the name of compassion."


Ultimate Responsibility for Completing a Confirmatory Trial Should Rest with Sponsor

ODAC members emphasized that confirmatory trials should be under way at the time a cancer drug receives accelerated approval, since more timely completion of accelerated-approval confirmatory trials could be enhanced if the confirmatory trial is ongoing.


This is the FDA's position, said Dr. Pazdur-"All we're really asking for is a drug-development plan that is well thought out."


And while the use of a cooperative group to conduct a confirmatory trial required for an accelerated-approval cancer drug could be useful (in patient accrual, for example), the committee agreed that such a trial should constitute only one of the confirmatory trials required for full drug approval.


Dr. Pazdur noted that while cooperative groups could certainly help a company gain patient accrual for post-marketing confirmatory studies on accelerated-approval cancer drugs, the aims of pharmaceutical manufacturers and cooperative groups are very different. A confirmatory trial for an accelerated-approval drug must be done in a timely manner, has penalties for non-completion, and has potentially very high public health implications.


"We can't be in a position of having responsibility for timeliness transferred to a third party," he said.


Role for Single-Arm Studies in Certain Situations

Finally, after an extensive discussion, committee members generally agreed that while single-arm trials have problems, they can be useful in oncology as part of an overall drug-development program in situations where the study population is very well defined and in rare cancers in which the response rate to the drug is very high.


"There's a role for single-arm studies in rare populations where there is an extraordinarily large drug effect," said Dr. Sekeres. He noted that as cancer is increasingly defined on a molecular basis, there will be smaller and smaller subpopulations, and a single-arm study might be appropriate for them.


Added Dr. Wilson: "You have small companies out there that may be developing targeted therapies; you don't want to squash them."


In EU, Yearly Renewal Needed

Guest speaker Hilde Boone, Pharm, MSc, European Medicines Agency (EMA) Liaison Official at the FDA In the European Union, noted that drugs that receive accelerated approval-termed conditional marketing authorization-from the EMA receive such approval only for one year. That authorization is renewable subject to an annual review.


Asked by Dr. Wilson if the yearly renewal requirement is a useful tool, Ms. Boone said yes. Dr. Pazdur said he approves of the concept of yearly review and would like to have an annual ODAC review of accelerated-approval drugs to see where they are in the process of confirmatory trials to show clinical benefit.


He noted that several companies have told the FDA that they really didn't want to come to such a review meeting and were going to consider withdrawing their candidate drugs. One problem: conducting a randomized confirmatory clinical trial when the drug has already demonstrated clinical benefit is problematic. However, post-marketing studies need not be carried out in the same population for which the drug was approved, according to FDA regulations.


Cetuximab, Tositumomab and Iodine I 131 Tositumomab; Clofarabine; Nelarabine; Panitumumab; & Imatinib

As a start on an annual review of accelerated-approval cancer drugs, ODAC members heard reviews during the morning session from officials representing sponsors of accelerated-approval indications for cetuximab; tositumomab and Iodine I 131 tositumomab; clofarabine; nelarabine; panitumumab; and imatinib mesylate.


Paul Eisenberg, MD, MPH, Amgen, Inc. Global Regulatory Affairs & Safety official, noted that a confirmatory trial on an accelerated-approval cancer drug can lead to challenges that ultimately could prove beneficial for patients. He cited panitumumab for chemorefractory metastatic colorectal cancer as an example.


"The discovery of KRAS as a biomarker changed the clinical landscape of metastatic colorectal cancer," said Dr. Eisenberg.


He noted that the lack of availability of a validated test kit for KRAS has been an obstacle, but that Amgen is now working with a test kit manufacturer to design a test that will identify this biomarker. Dr. Eisenberg said Amgen plans a trial to confirm clinical benefit in patients with wild-type KRAS, and said, "We would expect that full approval would be restricted to patients with wild-type KRAS."


In discussing post-marketing confirmatory trials for tositumomab and Iodine I 131 tositumomab for patients with varieties of non-Hodgkin's lymphoma who have not received rituximab, Thomas S. Lin, MD, PhD, Director of Clinical Development for GlaxoSmithKline Oncology, cited as a primary obstacle the collection of CT scans. He noted that some institutions do not have enough storage space to store physical scans, and so they destroy them. Privacy issues in having outside radiologists review scans are another problem, he said.


In presenting information on confirmatory trials on imatinib mesylate tablets for the adjuvant treatment of adult cancer patients following complete gross resection of Kit (CD117)-positive gastrointestinal stromal tumors (GIST), Laurie Letvak, MD, Vice President and Global Program Head at Novartis Pharmaceuticals Corp., cited several challenges the company has encountered.


She noted that multiple contracts and amendments with several legal entities involved in cooperative groups "can be a bit frustrating," and echoing Dr. Pazdur's comments, said the lesson is to collaborate early on in the process of doing post-marketing trials for accelerated-approval cancer drugs.


FDA Data on Accelerated-Approval Cancer Drugs


* In 2011, there are 49 new indications for 37 oncology products.


* Of these, 27 of 49 (55%) have had clinical benefit confirmed in post-marketing trials.


* Five of 49 (10.2%) have failed to confirm a benefit, and sponsors have or are in the process of withdrawing their indication after failing to complete their confirmatory trials.


* The proportion of indications failing to confirm a benefit has increased slightly since 2005, when it was 7.1%.


* Under accelerated approval, cancer drug indications have been made available to patients a median of 3.6 years before post-marketing verification of their clinical benefit.