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Abstract

Background: Advances in medicine, clinical trial design, and statistical methods affect product approvals. Over the last decade, there were many breakthroughs in the development of novel cancer therapies, including the wide application of biomarkers in drug development. Understanding trends and patterns of trial design and data submissions that lead to the approval of these novel agents assists oncologists, investigators, and regulatory personnel. Methods: All new molecular entity (NME) therapeutic oncological agents approved for the first time within the past 13 years (January 1, 1999 to December 31, 2011) were analyzed for product features, approved indications, regulatory metrics, and clinical trial design. Patterns and trends were reviewed. July 2005 marked the midpoint of this review, concurrent with the FDA establishing the Office of Oncology Drug Products (OODP). Regulatory metrics before and after the establishment of the OODP were compared and analyzed. The Fisher exact test was applied for statistical analyses. Results: A total of 47 new oncological approvals were identified, 2 to 7 approvals per year (median, 3.0), with 6.0-month median reviews. Comparing the pre- and post-OODP period, there was trending towards more approvals (4.3/year vs 2.9/year) along with more targeted agent approvals (50% vs 21%) in the post-OODP period, although these metrics did not reach statistical significance due to relatively small numbers and large variances. There were also numerically fewer orphan designations (36% vs 53%) and accelerated approvals (32% vs 37%) in the post-OODP period. Approvals were for small molecule targeted agents, 38% (frequently kinase inhibitors); monoclonal antibodies, 17%; conventional cytotoxics, 28%; hormonal agents, 13%; and miscellaneous agents, 4%. Two 2011 approvals were associated with companion diagnostics. First-line indications accounted for only 36%; 62% were parenterally administered. Multinational, multicenter, randomized phase II or III trials utilizing overall survival or progression-free survival endpoints were common pivotal trial features in solid tumors. Hematological malignancy trials involved multiple small, single-arm phase II studies measuring mainly response rate, commonly resulting in accelerated approval. Placebo controls (19%) and blinding (24%) were both seldom employed. Conclusions: Over the last 13 years, 55% of NME approvals were targeted agents or monoclonal antibodies, most not for first-line use. Most applications relied upon a single pivotal study for approval. Randomized trials supported most solid tumor approvals, whereas single-arm phase II studies supported (mostly accelerated) approvals in hematological malignancies. After establishment of the OODP, there were trends towards more approvals and less orphan designations.

Keywords

cancer drugs FDA approval NDA BLA trends biomarkers companion diagnostic targeted agents

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Emerging Trends in US Oncological Approvals: A 13-Year Review (1999-2011)

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