The Comparison of Review Processes of Hematological Malignancy Drugs Between the Pmda and the FDA

Both the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan and the US Food and Drug Administration (FDA) review drug applications for market approval. In 1992, the FDA instituted accelerated approval (AA) regulations based on surrogate endpoints including response rate, and it allows distribution of drugs for serious diseases before granting regular approval (RA) based on confirmed clinical benefit including improved survival. The PMDA has not adopted such regulations. Differences in the total review time and the approval date of drug applications between regulatory agencies of some countries have recently attracted considerable attention. (N Engl J Med. 2012; 366:2284-93) Few studies have examined the differences in review process, however, from the point of view of AA regulations and primary endpoints in pivotal trials.

38 indications of 28 hematologic anticancer drugs approved in Japan after the year of 2000 were studied in order to analyze the influence of the differences in regulations and primary endpoints in registration trials between the PMDA and the FDA. Information concerning regulatory decisions made by the PMDA and the FDA was obtained from publicly accessible data including the PMDA's review reports, the FDA's review reports, the Drugs@FDA website, and articles written by the FDA. (J Natl Cancer Inst. 2010; 102:230-43, J Natl Cancer Inst. 2011; 103:636-44, and so on).

Thirteen indications have not been approved by the FDA. One indication (rituximab for CD20-positive aggressive B-cell non-Hodgkin's lymphoma) was approved by the PMDA earlier than the FDA. Three indications were approved by the PMDA with clinical data of off-label drug use but not trials in Japan after RA without AA by the FDA, and the median of delay was 64 months. Ten indications were approved by the PMDA with trials in Japan after RA without AA by the FDA, and the median of delay was 52 months. Eleven indications were approved by the PMDA with trials in Japan after AA by the FDA, and the median of delay was 24 months. Of these, AA converted to RA in one indication (bortezomib for relapsed or refractory multiple myeloma) before the PMDA's approval in Japan, and in four indications after the PMDA's approval.

All trials in Japan were carried out aiming for response rate or safety data, but not survival, and these included only two comparative trials. Both of these trials were international trials of nilotinib or dasatinib for newly diagnosed chronic myeloid leukemia compared with imatinib. These indications of the drugs were approved by the PMDA later than AA by the FDA by 6 and 8 months, respectively.

Next, the targeted population and the primary endpoints of the comparative clinical trials conducted for the FDA's approval of these indications were examined. In most of these comparative trials, patients with newly diagnosed hematological malignancies were targeted and progression-free survival or time to progression was investigated as the primary endpoint. It should be noted that there were no comparative trials in which improved time-to-event endpoints led to RA by the FDA for patients with relapsed/refractory disease other than multiple myeloma. Moreover, overall survival has been adopted as the primary endpoint in none of these trials although improved overall survival which was not adopted as the primary endpoint has been shown in some trials for multiple myeloma.

Japanese registration trials of hematological malignancy drugs have frequently been conducted aiming for response rate or safety data after foreign pivotal trials were completed. Whether the FDA grants AA or RA, therefore, it is important to participate in appropriate international trials for timely approval in Japan. Moreover, from the global point of view, it is desirable that improved overall survival is demonstrated in comparative trials for patients with relapsed/refractory disease before market approval of new hematological malignancy drugs as well as solid malignancy drugs.

Off Label Use: I will tell that the PMDA approved a few indications with Japanese clinical data of off-label drug use.