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Cancer Therapeutic Clinical Trials Supporting FDA Approval and Compendia Inclusion

Evidentiary standards for new or supplementary cancer therapeutic indication approvals by the FDA are consistent with off-label indication inclusions on Medicare-referenced compendia.
Published Online: Jul 28,2017
Kevin W. Su, MD; Cary P. Gross, MD; Nicholas S. Downing, MD; Kerin B. Adelson, MD; and Joseph S. Ross, MD, MHS

Objectives: To characterize clinical trials supporting FDA approval of new cancer therapeutics and of supplementary indications and off-label indication inclusions on DRUGDEX, a Medicare-referenced compendium, each of which can guarantee reimbursement by Medicare.

Methods: Cross-sectional study using publicly available documents for cancer therapeutics initially approved by the FDA from 2005-2012. Trials supporting approval were identified, characterizing randomization, blinding, comparator, end point, number of patients, and duration.

Results: Between 2005-2012, FDA approved 37 new cancer therapeutics for 39 indications, based on 50 supportive trials. These therapeutics subsequently received 21 FDA supplementary indication approvals and 16 DRUGDEX off-label indication inclusions, based on 22 and 37 supportive trials, respectively. Of 109 total trials, 53.2% (95% CI, 43.9%-62.3%), 28.4% (95% CI, 20.8%-37.5%), and 53.2% (95% CI, 43.9%-62.3%) were randomized, double-blinded, and used a comparator, respectively. There was a median of 383 (interquartile range, 178 to 623) patients among aggregated supportive trials, whereas 38.2% (95% CI, 28.1%-50.6%), 69.7% (95% CI, 58.7%-78.9%), and 18.4% (95% CI, 11.3%-28.6%) were supported by at least 1 trial that lasted ≥6 months, used a comparator group, or used overall survival as a primary end point, respectively. There were few substantive differences in the aggregated clinical trial evidence supporting FDA new drug and supplementary indication approvals and DRUGDEX off-label indication inclusions.

Conclusions: The evidence supporting DRUGDEX off-label indications was similar to that used for FDA approval of new and supplementary cancer therapeutic indications, all of which had limitations for informing clinical decision making.

                                                                                           Am J Pharm Benefits. 2017;9(4):122-130

Understanding the evidence supporting new drug and supplementary indication approvals by the FDA is important for cancer care. Because many cancer patients face life-threatening disease for which there is not necessarily an effective treatment, anecdotal evidence can exert a strong influence on clinical decisions,1 making rigorous and objective evaluation by the FDA essential. The FDA approves the use of cancer therapeutics for specific medical indications only when “adequate and well-controlled investigations” can demonstrate the therapeutic’s safety and efficacy.2 Although physicians can use therapeutics “off-label”—that is, for an indication not specifically approved by the FDA—FDA approval guarantees an indication’s reimbursement by CMS.3 Reimbursement, in turn, may influence how cancer therapeutics are used in an era of increasingly expensive cancer treatment.4,5

For cancer therapeutics, there are 2 ways by which pharmaceutical manufacturers can ensure reimbursement for indications beyond those initially approved by the FDA. First, manufacturers can apply to the FDA for a second (or third, and so on) “supplementary indication” by providing supportive clinical evidence of a therapeutic’s efficacy and safety when used for the new indication. Second, manufacturers can seek the inclusion of off-label indications on Medicare-referenced compendia, which are comprehensive drug guides that list off-label indications deemed appropriate based on expert review of biomedical literature. The Omnibus Budget Reconciliation Act of 1993 required that CMS reimburse off-label cancer therapeutic use endorsed by these compendia.6 Because some private insurers are required to follow the same compendia per state legislation,7,8 inclusion of an off-label indication on compendia can secure coverage without FDA indication approval.

Concerns have been raised regarding the quality of clinical evidence supporting the FDA approval of new cancer therapeutics,5,9 particularly the reliance on surrogate markers of disease as opposed to clinical outcomes.10,11 One prior study found that new drug and supplementary indication approvals for cancer drugs were supported by trials focused on clinical outcomes with similar frequency, but that trials supporting supplementary indication approvals more frequently used active comparators (ie, compared the new therapeutic with an available therapeutic alternative).12 However, no studies have comprehensively assessed the quality of evidence supporting the inclusion of off-label indications on compendia for cancer therapeutics, even though a 2009 review by the Agency of Healthcare Research and Quality raised concerns regarding whether compendia used consistent standards and methodologies.13 Our objective was to characterize and compare the clinical trials supporting new drug and supplementary indication approvals by the FDA and off-label indication inclusion on DRUGDEX, a Medicare-referenced compendium, focusing on trial number, size, design, duration, and end points. We used DRUGDEX, the compendium managed by Micromedex, because all of its supporting documentation is publicly available, it may list the greatest number of off-label indications among Medicare-referenced compendia,13 and its classification of indications as on-label versus off-label facilitated comparison with the FDA approval process.