The US Food and Drug Administration’s use of regular approval for cancer drugs based on single-arm studies: implications for subsequent evidence generation
Authors: E.P. DeLoughery, V. Prasad
Journal: Annals of Oncology (2018)

Recently the US Food & Drug Administration (FDA) granted regular approval to dabrafenib–trametinib (Tafinlar® and Mekinist®; Novartis Pharmaceuticals Inc., Basel, Switzerland) for patients with BRAF V600E mutation in metastatic non-small-cell lung cancer (NSCLC). The approval was made on the basis of a 63% response rate (RR) in a single-arm study. Dabrafenib–trametinib is the second recent regular approval in NSCLC made based on RR—a 50% or greater shrinkage in tumor on serial computed tomography scans. It follows crizotinib (Xalkori; Pfizer Inc., NY, New York) used for patients with ROS1 proto-oncogene receptor tyrosine kinase (ROS1) rearranged metastatic NSCLC [1.Kazandjian D. Blumenthal G.M. Luo L. et al.Benefit-risk summary of crizotinib for the treatment of patients with ROS1 alteration-positive, metastatic non-small cell lung cancer.Oncologist. 2016; 21: 974-980Crossref PubMed Scopus (56) Google Scholar]. In both cases, what is notable is not that the FDA demonstrated flexibility in making highly active and promising drugs quickly available on the basis of small, single-arm data, but that the agency granted full or regular—not accelerated—marketing authorization for these drugs. Regular approval omits the need for further post-marketing efficacy testing requirements (though not further safety commitments). Here, we summarize the FDA's use of regular approval on the basis of single-arm data, describing potential unintended consequences. Currently, there are two forms of marketing authorization granted by the US FDA: accelerated and regular approval. Accelerated approval is given to agents that are expected to provide significant benefit over existing therapies for serious conditions [2.Naci H. Wouters O.J. Gupta R. Ioannidis J.P.A. Timing and characteristics of cumulative evidence available on novel therapeutic agents receiving Food and Drug Administration accelerated approval.Milbank Q. 2017; 95: 261-290Crossref PubMed Scopus (27) Google Scholar] based on their improvement in surrogate markers of disease considered 'reasonably likely' to predict clinical benefit. However, continued approval is contingent on the completion of post-marketing efficacy studies, which provide clearer estimates of the magnitude of benefit on clinical end points. If such studies are not carried out, or if they are negative, the FDA may revoke marketing authorization—as occurred with bevacizumab in breast cancer. In contrast, regular approval is made for drugs with improvement in overall survival, quality or life, or an established surrogate for these end points [3.Johnson J.R. Williams G. Pazdur R. End points and United States Food and Drug administration approval of oncology drugs.J Clin Oncol. 2003; 21: 1404-1411Crossref PubMed Scopus (402) Google Scholar]. In such cases, drugs can only be removed from the market for unanticipated safety concerns, and the FDA does not mandate post-marketing trials to confirm efficacy. In recent years the FDA has utilized regular approval based on the RR from single-arm studies. In Table 1, we list cancer drugs that received regular approval based on RR since 2008. We believe granting regular approval based on surrogate end points in single-arm trials raises four concerns for public policy.Table 1Oncology drugs approved based on relative responseYearDrugIndication2017Dabrafenib/trametinib combinationMetastatic NSCLC with BRAF V600E mutation2016CrizotinibMetastatic ROS1-positive NSCLCVenetoclaxCLL with 17p deletion2015IbrutinibWaldenstrom's macroglobulinemiaSonidegibLocally advanced basal cell carcinoma, recurrent post-surgeryTalimogene laherparepvecUnresectable recurrent cutaneous, subcutaneous, and nodal melanoma lesions2014OlaparibDeleterious or suspected deleterious germ-line BRCA mutated advanced ovarian cancer previously treated with more than three lines of chemotherapy2013LenalidomideRelapsed or progressive after two prior therapies (including bortezomib) mantle cell lymphomaDenosumabUnresectable giant cell tumor of bone2012VismodegibAdults with metastatic basal cell carcinoma or locally advanced recurrent basal cell carcinoma following surgeryBosutinibChronic, accelerated, or blast phase Philadelphia chromosome positive CML in resistant or intolerant adults2009RomidepsinCutaneous T-cell lymphoma after at least one prior systemic therapy2008Bendamustine hydrochlorideIndolent B-cell non-Hodgkin's lymphoma that progressed within or during 6 months of treatment with rituximabNSCLC, non-small-cell lung cancer; CLL, chronic lymphocytic leukaemia; CML, chronic myeloid leukaemia. Open table in a new tab NSCLC, non-small-cell lung cancer; CLL, chronic lymphocytic leukaemia; CML, chronic myeloid leukaemia. In order to grant BRAF and ROS1 inhibitors regular approval, the FDA must consider RR in untreated metastatic NSCLC as an established surrogate end point. To make this claim, a surrogate validation study must be conducted. Using all randomized trials carried out in that indication, a validation study asks whether a change in the surrogate correlates with a change in survival or quality of life. Guidance from the German Institute for Quality and Efficiency in Health Care advocates for the 95% confidence interval of correlation coefficient to be >0.85 for a surrogate to be considered strong and suitable for regulatory purposes. Before designating RR as an established surrogate, the FDA carried out exactly such an analysis in NSCLC. The FDA concluded that 'there was no association between overall survival and objective response rate (R(2) = 0.09; 95% confidence interval, 0–0.33)' [4.Blumenthal G.M. Karuri S.W. Zhang H. et al.Overall response rate, progression-free survival, and overall survival with targeted and standard therapies in advanced non–small-cell lung cancer: US Food and Drug Administration trial-level and patient-level analyses.J Clin Oncol. 2015; 33: 1008-1014Crossref PubMed Scopus (150) Google Scholar]. Thus, there is concern that the FDA's own analysis and interpretation does not justify RR in this setting as an established end point. In several other examples in Table 1, the empirical evidence supporting these surrogates is limited or weak [5.Kim C. Prasad V. Strength of validation for surrogate end points used in the US Food and Drug Administration's approval of oncology drugs.Mayo Clinic Proc. 2016; 91: 713-725Abstract Full Text Full Text PDF Scopus (82) Google Scholar]. Some may contend that randomized trials for some of these indications may be impossible due to the rarity of molecular subgroups. Yet, though both ROS1 and BRAF represent rare mutations in a common cancer, researchers estimate that, given the 1.5 million new cases of lung cancer annually, tens of thousands of cases globally may be due to such drivers [6.Shaw A.T. Ou S.-H.I. Bang Y.-J. et al.Crizotinib in ROS1-rearranged non–small-cell lung cancer.N Engl J Med. 2014; 371: 1963-1971Crossref PubMed Scopus (1412) Google Scholar]. Although it is appealing to believe that drugs with very high RRs must confer large benefits to patients regarding survival, quality of life, or both, empirical evidence suggests caution is warranted. In an evaluation of 181 studies, Zia et al. found RRs in phase II trials were on average 12.9% larger than RRs in randomized trials for the same therapies [7.Zia M.I. Siu L.L. Pond G.R. Chen E.X. Comparison of outcomes of phase II studies and subsequent randomized control studies using identical chemotherapeutic regimens.J Clin Oncol. 2005; 23: 6982-6991Crossref PubMed Scopus (116) Google Scholar]. Furthermore, even drugs with very high (>60%) RRs have revealed unanticipated surprises in randomized testing. Iodine 131 Tositumumab (Bexaar; Corixa Corp., Seattle, Washington) was approved on the basis of a RR of 63% in follicular lymphoma [8.Prasad V. The withdrawal of drugs for commercial reasons: the incomplete story of tositumomab.JAMA Intern Med. 2014; 174: 1887-1888Crossref PubMed Scopus (26) Google Scholar]. After a decade of being on the market, the drug failed to show it could improve outcomes in two randomized trials, and the manufacturer voluntarily withdrew it from market [8.Prasad V. The withdrawal of drugs for commercial reasons: the incomplete story of tositumomab.JAMA Intern Med. 2014; 174: 1887-1888Crossref PubMed Scopus (26) Google Scholar]. Thus, a high RR is not guarantee of benefit and does not eliminate equipoise around new drugs. In NSCLC, randomized trials of crizotinib for EML4-ALK rearranged cancers have also yielded surprising results. Randomized trials with crossover to crizotinib have shown that though the drug improves progression-free survival, it does not improve overall survival. Because of crossover, one interpretation is that one can defer administration of this agent to the second line without any clear loss of survival benefit. This fact may be informative to many other countries that seek to prioritize interventions. A high RR does not provide information regarding how a drug compares against alternatives. For a patient with BRAF V600 mutation positive NSCLC, is it better to administer the combination of dabrafenib–trametinib, single-agent pembrolizumab (for tumors with Programmed death-ligand 1 (PDL-1) staining >50%), chemotherapy (with BRAF inhibition deferred to second line), or chemotherapy with pembrolizumab? All of these options are FDA approved or widely in use, but the regular approval for dabrafenib–trametinib means it is unlikely to be tested against these alternatives, and choosing remains guesswork. Although the US FDA is not tasked with ensuring comparative effectiveness, the agency is tasked with ensuring that novel agents improve outcomes beyond the standard-of-care therapy or offer greater convenience or reduced toxicity. Even this bar is uncertain for single-arm regular approvals in the front-line setting of NSCLC. Many nations struggle with the high price of cancer drugs, and desperately rely upon randomized studies to make accurate estimates of the cost to attain 1 quality adjusted life year. Approval based on single-arm, uncontrolled data essentially deprives agencies of rigorous estimates of benefit—forcing cost-effectiveness analyses to be made based on models. Prior work has suggested that for cancer drugs benefits postulated through modeling are larger than benefits directly measured, suggesting that models may be inaccurate, likely due to favorable but unrealistic assumptions [9.Prasad V. Overestimating the benefit of cancer drugs.JAMA Oncol. 2017; 3: 1737-1738Crossref PubMed Scopus (8) Google Scholar]. While the US FDA is not tasked with ensuring cost-effectiveness, the use of regular approval will make performing cost-effectiveness more challenging for third parties. In several specific settings, the US FDA has designated RR as an established surrogate and used it to justify regular approval. This decision waives post-marketing randomized trials to further evaluate efficacy and leads to considerable uncertainty for policy makers. While granting regular approval based on surrogate end points may appear to achieve the goal of making promising oncology drugs available sooner, it does so at the price of evidence. Once a manufacturer obtains FDA approval for an indication, there is less incentive to continue testing the drug [2.Naci H. Wouters O.J. Gupta R. Ioannidis J.P.A. Timing and characteristics of cumulative evidence available on novel therapeutic agents receiving Food and Drug Administration accelerated approval.Milbank Q. 2017; 95: 261-290Crossref PubMed Scopus (27) Google Scholar]. Indeed, there is a disincentive, as favorable results will not lead to any further benefits for the manufacturer, while unfavorable results may lead to loss of market share. We believe that the accelerated approval pathway remains the preferred track for cancer drugs with high RRs, and regular approval should be reserved only for validated surrogate end points.