final questions to odac

Final questions to ODAC, from the FDA website:


FOOD AND DRUG ADMINISTRATION
Center for Drug Evaluation and Research
Oncologic Drugs Advisory Committee
QUESTIONS
March 22, 2010
Page 1 of 2
NDA 022-374
OMAPRO (omacetaxine mepesuccinate) for injection
APPLICANT: ChemGenex Pharmaceuticals
PROPOSED INDICATION: for the treatment of adults with chronic myeloid leukemia (CML) bearing a genetic alteration known as the Bcr-Abl T315I mutation, and who have failed prior therapy with the drug imatinib
The efficacy claim for this NDA is based on the findings from a single, incomplete, single-arm trial in 66 patients with CML who had failure on or intolerance of imatinib and who had the T315I Bcr-Abl mutation. The primary efficacy endpoints for chronic phase patients were major cytogenetic response (complete cytogenetic response + partial cytogenetic response) and complete hematologic response. The primary efficacy endpoints for accelerated phase and blast phase patients were major cytogenetic response and major hematologic response (including complete hematologic response, no evidence of leukemia and return to chronic phase). An independent Data Monitoring Committee adjudicated all responses for the primary efficacy analysis.
FDAs review found that for the chronic phase cohort of 40 patients, the major cytogenetic response rate was 15% (including 10% complete cytogenetic response + 5% partial cytogenetic response) with a median response duration of 7.7 months. The accelerated phase cohort of 16 patients had a 6% major cytogenetic response rate and a 31% complete hematologic response with a median response duration of 5.1 months. There were no responders in the blast phase cohort. The toxicity profile was similar to that of a conventional chemotherapeutic agent, with hematologic toxicities such as neutropenia, thrombocytopenia and anemia occurring most frequently. Additionally, 20% of patients had cardiac-related adverse events, the majority of which were arrhythmias. Laboratory abnormalities included 49% with hyperglycemia and 36% with hyperbilirubinemia.
Major issues with this application are listed below:
1.
A single, small and incomplete efficacy study (CML-202) is submitted to support this application
Study CML-202 planned to enroll 100 patients; however, the NDA submission only included the efficacy and safety data from 66 patients. The Applicant continued to enroll 31 additional patients after the data cut-off for these 66 patients with a current enrollment of 97 patients. Thus, data from approximately one-third of the patients enrolled on this efficacy trial are missing from the current submission. FDA believes that any efficacy claims for the accelerated and blast phase cohorts are insufficiently demonstrated due to small sample sizes.
2.
One-third of CML-202 patients submitted to the FDA are ineligible per protocol-defined criteria
Thirty-five percent of CML-202 patients did not have a confirmation of their Bcr-Abl T315I mutation status by the central laboratories at the time of enrollment, a required study entry criterion. The regulations governing the contents of an NDA submission, 21 CFR314.126, state that for a trial to be considered adequate and well controlled, The method of selection of subjects provides adequate assurance that they have the disease or condition being studied. The applicant did not meet this criterion.
3.
Assays with different performance characteristics were used at the two central laboratories to detect the T315I mutation
The Applicant used two different assays at the two central laboratories for the confirmation of T315I mutation status prior to patient enrollment. There were no bridging studies performed to support assumptions about the similarity of the enrolled patient population tested at each site.
Performance characteristics of an assay should be known prior to widespread use of the assay and drug use based on this assay. These characteristics include sensitivity, specificity, limit of detection and reproducibility of the test and its ability to identify eligible patients. Information for the assays to detect the T315I mutation has not been submitted to FDAs Center for Devices and Radiological Health (CDRH).
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. 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.
4.
Low response rates observed in the efficacy study
Due to the single-arm trial design and lack of historical control to compare the efficacy results, the clinical meaningfulness of the observed low response rates is unclear.
5.
Safety concerns regarding the overfilled vial size
The Applicant has presented an overfilled vial size that contains more than twice the average dose of omacetaxine used in the efficacy and safety studies (CML-202 and CML-203). FDA has concerns about the potential for overdose as well as the environmental impact of drug disposal.
Question to ODAC (VOTE):
A well characterized in vitro diagnostic test is defined as a test for which analytical performance characteristics (e.g., sensitivity, specificity, limit of detection, reproducibility) have been adequately demonstrated and shown to support clinical use. This information has not been provided to the FDA at this time. Two different in vitro tests were used in trial CML-202. The comparability of these tests is unknown. Furthermore, 23 of the 66 patients (including 5 of 11 responders) did not have central laboratory confirmation of the mutation at enrollment at either site.
Should a well characterized in vitro diagnostic to identify patients with the T315I mutation be required and reviewed by the FDA and correlated to clinical trial results prior to approval of omacetaxine for the proposed indication?