Here is a good review of the ODAC meeting...ODAC Votes to Send...

Here is a good review of the ODAC meeting...


ODAC Votes to Send Omacetaxine Back to Drawing Board for Companion Diagnostic Test
Eastman, Peggy
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GAITHERSBURG, MD?The Oncologic Drugs Advisory Committee to the US Food and Drug Administration voted 7 to 1 to require the sponsor of omacetaxine for a subset of refractory chronic myeloid leukemia (CML) patients to submit a validated in vitro companion diagnostic test to the agency before approval of the drug. Omacetaxine mepesuccinate, a new molecular entity and first in its class of cephalotaxines, is intended for injection to treat the small subset of adult CML patients who have the Bcr-Abl T315I mutation and have not responded to prior therapy with imatinib.

ODAC members were not asked to vote on the safety and efficacy of omacetaxine; rather they were asked to vote on whether the company, ChemGenex Pharmaceuticals Ltd., should submit to the FDA a well-characterized in vitro diagnostic test for the mutation and correlate it with clinical trial data before approval of omacetaxine. While testing for this mutation is widely available, there is no one standardized uniform assay.
The new drug application (NDA) for omacetaxine has implications that go beyond the drug itself: It is an example of a drug that must be coupled with a validated diagnostic test. ?We're going to see this more and more: a molecularly defined subset of patients, so it's critical that we require a good molecularly defined assay,? said ODAC Chair S. Gail Eckhardt, MD, Professor and Division Head of Medical Oncology at the University of Colorado.

Pazdur: Lack of Uniform In Vitro Diagnostic Test Creates Uncertainty about Patient Selection
Richard Pazdur, MD, Director of FDA's Office of Oncology Drug Products, agreed. ?We're getting increasing applications with in vitro diagnostics,? he said, so he emphasized that close attention has to be paid to the accuracy and validity of the diagnostic test used to select the subset of patients who might benefit most from the drug in question.
?The lack of having a uniform in vitro diagnostic test creates uncertainty about patient selection both in this trial and, more importantly, in a post-approval setting,? he said. ?If a patient does not harbor the T315I mutation but is falsely identified as having such a mutation by these un-reviewed assay methods, the patient may not receive more effective, less toxic therapy, such as dasatinib or nilotinib. Conversely, patients with a false-negative test result would receive an ineffective therapy.?
He added that the agency has to have a strong degree of confidence in the homogeneity of the subpopulation for whom the drug is intended.
ODAC member William Kelly, DO, Associate Professor of Medicine and Surgery at Yale University, said, ?This is the era of personalized medicine: the right treatment for the right patient at the right time.? Thus, he emphasized, diagnosing the right patients for cancer treatment is becoming even more important as specific subpopulations of cancer patents are identified.
An Institute of Medicine (IOM) workshop summary report, ?Policy Issues in the Development of Personalized Medicine in Oncology,? emphasized that a predictive diagnostic test for a drug should have analytic validity (accuracy in detecting the specific entity it was designed to detect); clinical validity (accuracy for a specific clinical purpose, such as predicting response to treatment); and clinical utility (usefulness in clinical decision making and improving patient outcomes).


Company News Briefing
In a news briefing for reporters held after the ODAC vote, ChemGenex Chief Medical Officer Adam Craig, MB, BS, PhD, said his company, which has offices outside Melbourne, Australia, and in Menlo Park, CA, is in discussion with the FDA about a validated diagnostic assay for omacetaxine and was set to have a meeting with the agency in April.
Asked why the company did not submit a validated companion diagnostic assay with its NDA for omacetaxine, Dr. Craig said, ?Our point was, mutation testing is readily available.? He said there are multiple assay methods for detection of the Bcr-Abl T315I mutation, and they are already being widely performed in the community on patients who have failed to respond to imatinib.
Dr. Craig added that he was pleased with ODAC members' reception to the drug and their interest in a treatment for CML patients with an unmet need. ?Overall the safety and efficacy of the drug has been endorsed today?.Our task now is to validate our samples against an assay,? he said.


FDA: Multiple Concerns
Dr. Pazdur said the FDA had multiple concerns about the incomplete, single-arm trial of 66 patients that ChemGenex submitted with its NDA, including the small number of study subjects. The company had planned to enroll 100 patients, but data on just 66 were submitted with the NDA. ChemGenex continued to enroll 31 additional patients after the data cut-off, but these data were not included in the NDA.
Also troubling, said Dr. Pazdur, is that 35% of CML patients in the study did not have a central laboratory confirmation of their Bcr-Abl T315I mutation status at the time of enrollment?a required study entry criterion. In addition, he said, the agency had concerns about low response rates in the efficacy study, rates which Dr. Pazdur said ?cannot be considered to be robust.?
He added that the FDA has real concerns about the drug's overfilled vial size, which contains more than twice the average dose of omacetaxine used in the safety and efficacy studies. ChemGenex has developed the drug in 5-mg vials for single-dose use by the patient at home, but the average dose used in the study was 2.4 mg. Not only is there an overdose potential, said Dr. Pazdur, but there could be a harmful environmental impact of unused drug disposal.


Ellin Berman: Why She Voted No, That Test Should Not Be Required
ODAC temporary voting member Ellin Berman, MD, Attending Physician on the Leukemia Service in the Division of Hematologic Oncology at Memorial Sloan-Kettering Cancer Center, cast the only ?no? vote on whether ChemGenex should be required to submit a validated diagnostic test before approval of its NDA for omacetaxine.
?I think the drug should be approved based on what we heard today,? she said. ?The likelihood of having a standardized test for T315I is, I believe, years in coming.?
Pointing out that there is very little to offer patients with this mutation, she said, ?Patients are going to be harmed by this [vote]. I believe the drug should be licensed now?.I feel comfortable that this is a resistant population. It's a step forward. It gives us something to use with these patients.?


Patient Representatives
Several CML patient representatives spoke during the public part of the ODAC meeting. Susan Carrow, a CML patient with the T315I mutation who has been treated with multiple drugs for CML and has been on a clinical trial of omacetaxine, said, ?Although there are so few of us, we need all the help we can get. Please, let's get this approved now.? Gerald Cox, who also has the T315I mutation and is on a clinical trial of omacetaxine, said, ?I feel better today than at any time since I was diagnosed with CML.?
Dr. Pazdur said he is well aware of cancer patients' need to have access to new drugs as soon as possible, but he emphasized several times during the day-long ODAC meeting that FDA approval is not the only means of access to a new drug. ?We realize patients want access,? he said. ?An approval is the best access to a drug, but it is not, not the only access to a drug.?
In October 2009, FDA's final regulations on expanded access to investigational drugs went into effect, he noted. These regulations are intended to improve access to investigational drugs for patients with serious or life-threatening diseases and who have no satisfactory alternative therapies. They apply to individual patients, including in emergencies, intermediate-size patient populations and larger populations under a treatment protocol or treatment IND. The new FDA expanded access regulations allow drug sponsors to recover certain costs for making investigational drugs available.