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www.aacrjournals.org Clin Cancer Res; 19(14) July 15, 2013 3731
Oncology Approvals
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- 1. CCR Perspectives in Drug Approval Use of Multiple Endpoints and Approval Paths Depicts a Decade of FDA Oncology Drug Approvals Michael B. Shea, Samantha A. Roberts, Jessica C. Walrath, Jeff D. Allen, and Ellen V. Sigal Abstract This study explores the historic use of different endpoints to support regular and accelerated approval of cancer drugs between 2002 and 2012. In the past 10 years, two thirds of oncology regular approvals were based on endpoints other than overall survival. More than three quarters of accelerated approvals were based on response rates. The accelerated approval program has been heavily used over this time period, with one third of all approved oncology indications receiving accelerated approval. At times, critics have characterized the agency as rigid and unpredictable. This research describes the degree of regulatory flexibility that U.S. Food and Drug Administration and drug sponsors have used over the past decade in the development of new treatments for cancer. Clin Cancer Res; 19(14); 3722–31. Ó2013 AACR. Introduction Drug development is a long and costly process, typically requiring up to 15 years and more than $1 billion to shepherd a drug through initial discovery, clinical testing, and regulatory approval (1). Despite advances in basic research, the pharmaceutical industry is widely considered to be in an innovation crisis; although research and devel- opment costs have increased drastically, the rate of new drug output has remained relatively constant since the 1950s (2). This crisis has been attributed to many factors, including the exhaustion of "easy" drug targets, overuse of molecular screening strategies for drug discovery, increased attention to high-risk, targeted therapeutics, and, in partic- ular, an overcautious U.S. Food and Drug Administration (FDA; refs. 3–5). A 2011 report released by the National Venture Capital Association’s Medical Innovation and Competitiveness Coalition, Vital Signs: The Threat to Invest- ment in U.S. Medical Innovation and the Imperative of FDA Reform, described a significant decrease in investment in biopharmaceutical and medical device companies by U.S. venture capitalists and cited FDA regulatory rigidity and unpredictability as the key drivers for this decrease (6). While the impact of the regulatory environment on drug development is important in every therapeutic area, it is especially so for cancer, the second leading cause of death in the United States. Although recent studies have found that the FDA reviews new oncology drug applications relatively quickly, concerns remain about the long timelines in oncol- ogy drug development, in part due to the high hurdles required to meet regulatory approval (7–9). Some have voiced concern that the FDA is increasingly requiring spon- sors to conduct large, randomized trials that measure over- all survival (OS) benefit to be granted regular approval (10). Others have questioned the willingness of the FDA to consider novel anticancer medicines for accelerated approv- al (11). Many of these concerns have stemmed from recent high- profile events, such as the FDA-initiated withdrawal of the breast cancer indication for bevacizumab in November 2011 (12). Bevacizumab originally received accelerated approval for first-line treatment of metastatic breast cancer in 2008 based on the results of a small randomized trial (E2100) in which bevacizumab combined with paclitaxel showed a 5.5-month improvement in progression-free sur- vival (PFS) compared with paclitaxel alone (13). In two large randomized confirmatory trials (AVADO and RIB- BON-1), bevacizumab failed to show an OS benefit (14). Furthermore, these trials were unable to reproduce the originally observed effect on PFS. The AVADO trial, in which patients were randomized to docetaxel combined with either bevacizumab or placebo, showed only a 0.8- month improvement in PFS. The RIBBON-1 trial examined bevacizumab in combination with two different chemo- therapy backbones: capecitabine or anthracycline/taxane. In the capecitabine cohort, bevacizumab showed a 2.9- month improvement in PFS, while in the anthracycline/ taxane cohort, only a 1.2-month improvement in PFS was observed. The magnitude of these PFS results was not considered clinically meaningful by the FDA, particularly in light of the drug’s adverse effects, and ultimately the breast cancer indication was withdrawn (15). However, because a statistically significant, if not clinically significant, improvement in PFS was observed in these trials, this withdrawal prompted worries that the FDA would no longer accept drugs without a survival benefit (16). Another controversial event occurred in February 2011, when the FDA convened its Oncologic Drugs Advisory Authors' Affiliation: Friends of Cancer Research, Washington, District of Columbia Corresponding Author: Samantha A. Roberts, Friends of Cancer Research, 1800 M Street NW, Suite 1050 South, Washington DC 20036. Phone: 202-944-6717; Fax: 202-944-6704; E-mail: sroberts@focr.org doi: 10.1158/1078-0432.CCR-13-0316 Ó2013 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 19(14) July 15, 20133722 on March 30, 2016. © 2013 American Association for Cancer Research.clincancerres.aacrjournals.orgDownloaded from Published OnlineFirst May 10, 2013; DOI: 10.1158/1078-0432.CCR-13-0316
- 2. Committee (ODAC) to discuss possible changes to the accelerated approval pathway. The meeting focused on two key issues: the use of single-arm trials to support accelerated approval and requirements for confirmatory trials (17). FDA officials expressed their concerns that too many spon- sors were pursuing accelerated approval through single-arm trials, the results of which can be difficult to interpret, as well as their concerns that sponsors were not completing con- firmatory trials with due diligence (17). In a publication later that year, FDA officials noted that the majority of accelerated approvals were pursued in heavily pretreated patient populations, which may not be representative of the cancer type being studied (18). These incidents raised skepticism about the future use of accelerated approval in oncology. To investigate whether the FDA approval process has in fact become more demanding in recent years, we have reviewed a decade of FDA oncology approvals from 2002 to 2012. This study examines the endpoints accepted for regular and accelerated approval and the FDA’s utilization of the accelerated approval program. Materials and Methods Study data Information was collected about all initial and supple- mental oncology drug approvals from January 1, 2002, to December 31, 2012. We collected data for antineoplastic agents only; drugs for supportive or palliative care were not included. Supplemental approvals for new dosing regimens were also not included; dataare limited to approvals for new indications. All data presented were collected from publicly available documents stored on the CDER database Drugs@FDA (19). Drug labels were viewed to identify clinical trial information including trial size, trial type (randomized or single-arm), and primary efficacy end- points. Press releases published by the Office of Hematol- ogy and Oncology Products (OHOP) were used to confirm information collected on Drugs@FDA (20). Approval dates and types Several supplemental indications included in the data were preceded by initial approvals granted before January 1, 2002. These pre-2002 approvals were not included in our analysis because they did not fall into the specified date range of this study. In some cases, a new molecular entity received approval for two indications simultaneously. For example, on January 26, 2006, sunitinib was approved for both gastrointestinal stromal tumors (GIST) and advanced renal cell carcinoma (RCC), and on August 19, 2011, brentuximab vedotin was approved for both Hodgkin lym- phoma and systemic anaplastic large-cell lymphoma (21, 22). In these cases, both indications were considered initial approvals due to the fact that they share the status as the first approved indication of a particular drug. In some cases, multiple supplemental indications were granted approval in the same approval letter. These indications were consid- ered separate, even if data from the same study were used to approve the indications. For example, on October 19, 2006, imatinib was approved for five indications, all based on findings from one open-label, phase II study (23). Approvals were classified as either "first-line" or "second- line or later." Adjuvant therapies were viewed as first-line if they were part of a regimen that was the first treatment option following cancer diagnosis. For example, the December 19, 2008, approval of imatinib for treatment of adult patients following complete gross resection of cKit- positive GIST was considered part of the first therapeutic regimen for that disease (24). Endpoint classification The majority of drug labels name a commonly used endpoint such as OS, PFS, response rate (RR), time to progression (TTP), or disease-free survival (DFS). Some labels specify less common endpoints that could reason- ably be categorized with one of those just mentioned. For example, the label for bosutinib, approved September 4,2012, cites "rate of major cytogenetic response" and "rate of complete hematologic response" as primary endpoints (25). These were categorized as RRs. Many efficacy studies involve multiple or coprimary endpoints. To identify the primary outcome measure of each study, we erred on the side of the most rigorous endpoint recorded on each label: (i) if OS and an inter- mediate endpoint such as PFS or RR were listed as coprimary endpoints, we classified OS as the basis for approval; (ii) if PFS and RR were listed as coprimary endpoints, we classified PFS as the basis for approval because its measurement necessitates a controlled trial; and (iii) if PFS and TTP were listed as coprimary end- points, we classified PFS as the basis for approval because PFS does not involve censoring and is considered by the FDA to be preferable to TTP (26). Results Approval statistics Between January 1, 2002, and December 31, 2012, the FDA granted approval to 65 oncology products for 127 indications (Table 1). Fifty-four of these products were either new molecular entities or new biologic products. The remaining 11 products were initially approved before 2002 but were approved for supplemental indications between 2002 and 2012. During this time period, the agency granted accelerated approval to 30 oncology pro- ducts for 42 new indications and regular approval to 49 products for 85 new indications. Of the indications granted accelerated approval, 18 were converted to reg- ular approval following confirmatory trials, 2 were revoked after failing to confirm clinical benefit, 1 was released from its postmarketing commitment, and 22 have yet to complete confirmatory trials. Endpoint utilization We examined the endpoints used as the basis of accel- erated and regular approval in the past decade. We found that OS was the most frequently used endpoint Oncology Approvals www.aacrjournals.org Clin Cancer Res; 19(14) July 15, 2013 3723 on March 30, 2016. © 2013 American Association for Cancer Research.clincancerres.aacrjournals.orgDownloaded from Published OnlineFirst May 10, 2013; DOI: 10.1158/1078-0432.CCR-13-0316
- 3. Table 1. FDA oncology drug approvals (January 2002–December 2012) Product Approval date Approval typea Indication(s) Primary endpoint AA? Single-arm vs. randomized trial Trial size Imatinibb 2/1/2002 S First-line GIST RR Yes Randomized 74 12/20/2002 S First-line Phþ CML PFS Yes Randomized 1,106 5/20/2003 S Second-line pediatric Phþ CML RR Yes Extrapolated from 2 single-arm studies 39 9/27/2006 S First-line pediatric Phþ CML RR Yes Single-arm 51 10/19/2006 S Dermafibrosarcoma protuberans RR No Single-arm 12 10/19/2006 S Myelodysplastic syndrome RR No Single-arm 7 10/19/2006 S Adult Phþ ALL RR No Single-arm 48 10/19/2006 S Adult aggressive systemic mastocytosis RR No Single-arm 5 10/19/2006 S Hypereosinophilic syndrome RR No Single-arm 14 12/19/2008 S Adjuvant therapy for GIST DFS Yes Randomized 713 Ibritumomab 2/19/2002 I Relapsed follicular lymphoma RR Yes Randomized 143 9/3/2009 S First-line NHL PFS No Randomized 414 Fulvestrant 4/25/2002 I Second-line breast cancer TTP No 2 Randomized 400; 451 Oxaliplatin 8/9/2002 I Second-line metastatic CRC RR Yes Randomized 463 1/9/2004 S First-line advanced CRC OS No Randomized 531 11/4/2004 S Adjuvant stage III CRC DFS No Randomized 2,246 Anastrozoleb 9/5/2002 S Adjuvant HERþ breast cancer DFS Yes Randomized 9,366 Docetaxelb 11/27/2002 S NSCLC combination therapy OS No Randomized 1,218 5/19/2004 S Metastatic prostate cancer OS No Randomized 1,006 8/18/2004 S Adjuvant node þ breast cancer DFS No Randomized 1,491 3/22/2006 S Gastric cancer OS No Randomized 457 10/17/2006 S Inoperable SCCHN PFS No Randomized 358 9/28/2007 S Induction treatment of SCCHN OS No Randomized 501 Gefitinib 5/5/2003 Ic Third-line NSCLC RR Yes Single-arm 142 Bortezomib 5/13/2003 I Third-line multiple myeloma RR Yes Single-arm 202 3/25/2005 S Second-line multiple myeloma OS No Randomized 669 12/8/2006 S Second-line mantle cell lymphoma RR No Single-arm 155 6/20/2008 S First-line multiple myeloma TTP No Randomized 682 Tositumomab 6/27/2003 Ic Relapsed NHL RR No 2 Single-arm 40; 60 12/22/2004 S Refractory low-grade lymphoma RR Yes Single-arm 60 Pemetrexed 2/4/2004 I Malignant pleural mesothelioma OS No Randomized 456 8/19/2004 Sc Second-line NSCLC RR Yes Randomized 571 9/26/2008 S First-line NSCLC combination therapy RR Yes Randomized 1,725 7/2/2009 S Maintenance NSCLC OS No Randomized 663 (Continued on the following page) Shea et al. Clin Cancer Res; 19(14) July 15, 2013 Clinical Cancer Research3724 on March 30, 2016. © 2013 American Association for Cancer Research.clincancerres.aacrjournals.orgDownloaded from Published OnlineFirst May 10, 2013; DOI: 10.1158/1078-0432.CCR-13-0316
- 4. Table 1. FDA oncology drug approvals (January 2002–December 2012) (Cont'd ) Product Approval date Approval typea Indication(s) Primary endpoint AA? Single-arm vs. randomized trial Trial size Cetuximab 2/12/2004 I Single agent for second- line CRC RR Yes 1 Randomized, 1 Single-arm 329; 57 2/12/2004 I Second-line CRC combination therapy RR Yes 1 Randomized, 1 Single-arm 329; 138 3/1/2006 S SCCHN combination therapy OS No Randomized 424 3/1/2006 S Second-line SCCHN as single agent RR No Single-arm 103 11/7/2011 S First-line SCCHN combination therapy OS No Randomized 442 7/6/2012 S First-line mCRC OS No 3 Randomized 1,217; 453; 315 Bevacizumab 2/26/2004 I First-line mCRC OS No Randomized 813 6/20/2006 S Second-line mCRC OS No Randomized 829 10/11/2006 S First-line NSCLC OS No Randomized 878 2/22/2008 Sd First-line HER2À breast cancer PFS Yes Randomized 712 5/5/2009 Sc Glioblastoma RR Yes 2 Single-arm 85; 56 7/31/2009 S Metastatic RCC PFS No Randomized 649 Gemcitabineb 5/19/2004 S First-line metastatic breast cancer combination therapy TTP No Randomized 529 7/14/2006 Sd Second-line ovarian cancer combination therapy PFS No Randomized 356 Azacitidine 5/19/2004 I Myelodysplastic syndrome RR No 1 Randomized, 2 Single-arm 191; 120 Letrozoleb 10/29/2004 S Extended adjuvant breast cancer DFS Yes Randomized 5,187 12/28/2005 S Adjuvant breast cancer DFS Yes Randomized 8,000þ Erlotinib 11/18/2004 I Second-line NSCLC OS No Randomized 731 11/2/2005 Sc Metastatic pancreatic cancer OS No Randomized 569 4/16/2010 Sd Maintenance therapy for NSCLC OS No Randomized 889 Clofarabine 12/28/2004 Ic Relapsed pediatric ALL RR Yes Single-arm 49 Paclitaxel 1/7/2005 I Second-line breast cancer RR No Randomized 460 10/11/2012 S First-line locally advanced NSCLC RR No Randomized 1,052 Nelarabine 10/28/2005 Ic T-cell ALL or T-cell lymphoblastic lymphoma RR Yes 2 Single-arm 39; 28 Sorafenib 12/20/2005 I Advanced RCC PFS No Randomized 769 11/16/2007 S Hepatocellular carcinoma OS No Randomized 602 Lenalidomide 12/27/2005 Ic Myelodysplastic syndromes RR No Single-arm 148 6/29/2006 S Second-line multiple myeloma TTP No 2 Randomized 341; 351 Pegaspargaseb 7/24/2006 S First-line ALL DR No Randomized 118 Topotecanb 6/14/2006 S Carcinoma of the cervix OS No Randomized 293 Rituximabb 2/10/2006 S Diffuse large B-cell, CD20þ , NHL OS No 3 Randomized 632; 399; 823 9/29/2006 S NHL combination therapy PFS No Randomized 322 9/29/2006 S NHL following chemotherapy PFS No Randomized 322 2/18/2010 S First-line CLL combination therapy PFS No 2 Randomized 817; 522 1/28/2011 S Maintenance therapy for NHL PFS No Randomized 1,018 (Continued on the following page) Oncology Approvals www.aacrjournals.org Clin Cancer Res; 19(14) July 15, 2013 3725 on March 30, 2016. © 2013 American Association for Cancer Research.clincancerres.aacrjournals.orgDownloaded from Published OnlineFirst May 10, 2013; DOI: 10.1158/1078-0432.CCR-13-0316
- 5. Table 1. FDA oncology drug approvals (January 2002–December 2012) (Cont'd ) Product Approval date Approval typea Indication(s) Primary endpoint AA? Single-arm vs. randomized trial Trial size Thalidomideb 5/26/2006 S Multiple myeloma ORR Yes Randomized 207 Trastuzumabb 11/16/2006 S Adjuvant nodeþ breast cancer DFS No 2 Randomized (Total) 3,752 10/20/2010 S Adenocarcinoma OS No Randomized 594 Vorinostat 1/6/2006 I Third-line CTCL RR No Single-arm 74 Sunitinib 1/26/2006 I Second-line GIST TTP No Randomized 312 1/26/2006 I Advanced RCC RR Yes Randomized 750 5/20/2011 Sc Advanced pNET tumors PFS No Randomized 171 Decitabine 5/2/2006 I Myelodysplastic syndromes RR No Randomized 170 Dasatinib 6/28/2006 Ic Second-line CML RR Yes 3 Single-arm 186; 107; 74 6/28/2006 Ic Second-line Phþ ALL RR No Single-arm 78 10/28/2010 S First-line Phþ CML RR Yes Randomized 519 Panitumumab 9/27/2006 I Second-line CRC PFS Yes Randomized 463 Lapatinib 3/13/2007 I Second-line HER2þ metastatic breast cancer combination therapy TTP No Randomized 399 1/29/2010 S First-line HER2þ metastatic breast cancer combination therapy PFS Yes Randomized 1,286 Doxorubicinb 5/17/2007 S Multiple myeloma combination therapy TTP No Randomized 646 Temsirolumus 5/30/2007 I Advanced RCC OS No Randomized 626 Ixabepilone 10/16/2007 I Second-line metastatic breast cancer combination therapy PFS No Randomized 752 10/16/2007 S Second-line breast cancer monotherapy RR No Single-arm 126 Nilotinib 10/29/2007 I Second-line Phþ CML RR Yes Single-arm 105 6/17/2010 S Newly diagnosed Phþ CML RR Yes Randomized 846 Bendamustine 3/20/2008 I Second-line CLL PFS No Randomized 301 10/31/2008 S Indolent B-cell NHL RR No Single-arm 100 Fludarabine 12/18/2008 I Second-line B-cell CLL RR Yes Single-arm 78 Degarelix 12/24/2008 I Advanced prostate cancer DR No Randomized 620 Everolimus 3/30/2009 I Second-line advanced RCC PFS No Randomized 416 10/29/2010 S SEGA with tuberous sclerosis RR Yes Single-arm 28 5/5/2011 Sc pNET tumors PFS No Randomized 410 4/26/2012 S Renal angiomyolipoma with tuberous sclerosis RR Yes Randomized 118 7/20/2012 S HER2þ breast cancer PFS No Randomized 724 Romidepsin 9/5/2009 Ic Second-line CTCL RR No 2 Single-arm 96; 71 6/16/2011 S PTCL RR Yes Single-arm 130 Eribulin 11/15/2010 I Third-line metastatic breast cancer OS No Randomized 762 Pralatrexate 9/24/2009 Ic Relapsed or refractory PTCL RR Yes Single-arm 115 Pazopanib 10/19/2009 Ic Advanced RCC PFS No Randomized 435 4/26/2012 Sc Second-line soft-tissue sarcoma PFS No Randomized 369 Ofatumumab 10/26/2009 Ic Refractory CLL RR Yes Single-arm 154 Cabazitaxel 6/17/2010 I Second-line prostate cancer OS No Randomized 755 (Continued on the following page) Shea et al. Clin Cancer Res; 19(14) July 15, 2013 Clinical Cancer Research3726 on March 30, 2016. © 2013 American Association for Cancer Research.clincancerres.aacrjournals.orgDownloaded from Published OnlineFirst May 10, 2013; DOI: 10.1158/1078-0432.CCR-13-0316
- 6. for regular approval, serving as the basis for 36% (31/85 indications) of regular approvals. However, 64% (54/85 indications) of regular approvals between 2002 and 2012 were approved on the basis of endpoints other than OS. Of the 54 indications that were granted regular approval on the basis of endpoints other than OS, 28 indications were based on improvements in time to event endpoints (PFS or TTP). We found that 14 of these 28 approvals were reported as not statistically significant OS results at the time of approval. For some drugs, such as sorafenib for RCC (2005), statistically significant OS findings were not reported at the time of approval, but subsequent follow- up analyses did achieve significant OS results after post– cross-over placebo survival data were censored (27). For other drugs, such as abiraterone for prostate cancer (2012), favorable but not statistically significant OS results were reported. For the remaining 14 non–survival-based indi- cations, survival data were not reported at the time of Table 1. FDA oncology drug approvals (January 2002–December 2012) (Cont'd ) Product Approval date Approval typea Indication(s) Primary endpoint AA? Single-arm vs. randomized trial Trial size Ipilimumab 3/25/2011 I Melanoma OS No Randomized 676 Peginterferon alfa-2bb 3/29/2011 Sc Melanoma DFS No Randomized 1,256 Vandetanib 4/6/2011 Ie Medullary thyroid cancer PFS No Randomized 331 Abiraterone 4/28/2011 I Second-line prostate cancer OS No Randomized 1,195 12/10/2012 S Metastatic prostate cancer PFS No Randomized 1,088 Vemurafenib 8/17/2011 I Melanoma with BRAF mutation OS No Randomized 675 Brentuximab 8/19/2011 Ic Third-line Hodgkin lymphoma RR Yes Single-arm 102 8/19/2011 Ic Second-line ALCL RR Yes Single-arm 58 Crizotinib 8/26/2011 I NSCLC ALKþ RR Yes 2 Single-arm 136; 119 Asparaginase 11/18/2011 I ALL combination therapy DR No Single-arm 58 Axitinib 1/27/2012 Ic Second-line RCC PFS No Randomized 723 Vismodegib 1/30/2012 I Metastatic basal cell carcinoma RR No Single-arm 104 Pertuzumab 6/8/2012 I HER2þ metastatic breast cancer PFS No Randomized 808 Carfilzomib 7/20/2012 Ic Relapsed multiple myeloma RR Yes Single-arm 266 Ziv-aflibercept 8/3/2012 I Second-line mCRC OS No Randomized 1,226 Vincristine sulfate 8/9/2012 Ic Third-line adult PhÀ ALL CR Yes Single-arm 65 Enzalutamide 8/31/2012 I Castration-resistant prostate cancer OS No Randomized 1,199 Bosutinib 9/4/2012 I Second-line Phþ CML RR No Single-arm 546 Regorafenib 9/27/2012 I Refractory mCRC OS No Randomized 760 Omacetaxine mepesuccinate 10/26/2012 If Third-line CML RR Yes 2 Single-arm 73; 35 Cabozantinib 11/29/2012 I Medullary thyroid cancer PFS No Randomized 330 Ponatinib 12/14/2012 I Second-line chronic, accelerated, or blast-phase CML RR Yes Single-arm 449 Abbreviations: AA, accelerated approval; ALCL, anaplastic large-cell lymphoma; ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelocytic leukemia; CRC, colorectal cancer; CTCL, cutaneous T-cell lymphoma; DR, durable response; NHL, non–Hodgkin lymphoma; NSCLC, non–small cell lung cancer; Ph, Philadelphia chromosome; pNET, pancreatic neuroendocrine tumors; PTCL, peripheral T-cell lymphoma; SCCHN, squamous cell carcinoma of the head and neck; SEGA, subependymal giant cell astrocytoma. a I, initial approval; S, supplemental approval. b Initial approval granted before January 1, 2002. c ODAC recommended approval. d ODAC did not recommend approval. e ODAC convened to discuss postmarketing safety studies. f ODAC did not recommend approval, and the drug was subsequently approved under a different new drug application. Oncology Approvals www.aacrjournals.org Clin Cancer Res; 19(14) July 15, 2013 3727 on March 30, 2016. © 2013 American Association for Cancer Research.clincancerres.aacrjournals.orgDownloaded from Published OnlineFirst May 10, 2013; DOI: 10.1158/1078-0432.CCR-13-0316
- 7. approval, either because the data were not mature or because the data were not measured. For example, ixabe- pilone for second-line metastatic breast cancer (2007) did not report OS results at the time of approval, but an analysis of OS was planned once a predetermined number of patients had died (28). For indications granted accelerated approval, we found that 79% (33/42) were approved on the basis of RRs. While the majority of confirmatory trials for products granted accelerated approval have not yet been complet- ed, 18 of the 42 indications granted accelerated approval between 2002 and 2012 have been converted to regular approval. Thirty-nine percent of these conversions were based on OS. The remaining 61% were based on PFS, DFS, or RR. Use of OS over time The number of indications approved based on OS has increased in recent years; however, that increase has been accompanied by an increase in total regular approvals. As a percentage of approvals per year, OS indications have not increased. In 2010, 80% of regular approvals were based on OS; in 2011 and 2012, OS indications were reduced to 40% and 38%, respectively (Fig. 1A). We did not detect a trend indicating that approvals based on overall survival, relative to total yearly approvals, have increased. Accelerated approval over time We examined the number of accelerated approvals and regular approvals in oncology from 2002 to 2012 (Fig. 1B). All other endpoints Overall survival A B 10 15 20 25 30 5 0 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Numberofindications Year of approval Number of regular approvals Number of accelerated approvals 10 15 20 25 35 30 5 0 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Numberofindications Year of approval © 2013 American Association for Cancer Research Figure 1. Approval trends between 2002 and 2012. A, the use of OS to support regular approval is compared with all other endpoints supporting regular approval. B, the number of accelerated approvals is compared with the number of regular approvals per year. Shea et al. Clin Cancer Res; 19(14) July 15, 2013 Clinical Cancer Research3728 on March 30, 2016. © 2013 American Association for Cancer Research.clincancerres.aacrjournals.orgDownloaded from Published OnlineFirst May 10, 2013; DOI: 10.1158/1078-0432.CCR-13-0316
- 8. These numbers include both initial and supplemental indi- cations. We did not detect any trend indicating a decrease in accelerated approvals in oncology. Although there is vari- ation from year to year, the absolute number of accelerated approvals has remained relatively constant in this time period. There is a slight decrease in the percentage of accelerated approvals per year following the 2007 reautho- rization of the Prescription Drug User Fee Act, but this difference is not statistically significant (43% per year, 2002–2007, vs. 38% per year, 2008–2012) and is likely reflective of a slight increase in the number of regular approvals in this time period. Accelerated approval by line of therapy We found a noticeable pattern in the way the acceler- ated approval pathway has been used in the past decade: All but one (21/22) of the new drugs entering the market that received accelerated approval were indicated for second-line or later therapy (Fig. 2). In contrast, 70% (14/20) of supplemental indications were for first-line disease. Discussion Our research indicates that the FDA has exercised considerable flexibility in the approval of oncology drugs over the past decade. We found that the accelerated approval program has been used consistently in this time period, showing that sponsors’ interest in the program and the FDA’s willingness to grant accelerated approvals have not waned. Indeed, in 2012, the FDA granted accel- erated approval to five oncology drugs, matching its second-highest single-year total in the past 10 years. We also found that extension of OS, while still considered the gold standard by the FDA, is by no means required for approval in oncology. Even the conversion of accelerated approval to regular approval has frequently taken place without demonstration of an improvement in OS. Our research is consistent with a 2003 study conducted by the FDA, which found that 68% of drugs were approved on the basis of endpoints other than survival (29), as well as with a 2011 study that showed the FDA’s flexibility in approving orphan drugs (30). It is reasonable to expect that as our understanding of cancer improves, new cancer therapies may be more likely to significantly extend and improve survival and perhaps should be held to higher standards than cancer therapies of the past. However, problems remain with measuring OS (31). First, measuring an OS benefit requires large numbers of patients and can take several years, delaying access to new drugs for very sick patients who lack effective options. Second, clinical trials often permit con- trol-arm patients to cross over to the investigational agent after disease progression, confounding analysis of the impact of the investigational agent on survival. Third, as improved therapies become the standard of care, showing a survival benefit compared with these therapies becomes increasingly difficult. Our research shows that the FDA understands these limitations and is willing to accept notable improvements in intermediate endpoints in place of a demonstrated OS benefit. In fact, as experience is gained with an intermediate endpoint in a specific dis- ease, the FDA may become more willing to accept that endpoint as the basis for full approval in that disease. For example, PFS is now routinely accepted as the basis for full approval in RCC (18). This study has some limitations. First, our data do not include drugs that were submitted for approval but were rejected by the FDA. Unfortunately, information about failed submissions is not made public by the FDA. With- out knowledge of drugs that failed to obtain approval, we can assert only what the FDA deems acceptable and not what it deems unacceptable. Second, because of the con- fidentiality of prenew drug application meetings between sponsors and the FDA, we cannot determine the motiva- tions of sponsors when designing drug development pro- grams. For example, sponsors may choose to design a clinical trial to measure an OS benefit not because the FDA has required it, but because they wish the drug to be more competitive with other drugs already on the market, or because an OS benefit is needed to secure reimbursement in Europe. Third, it may be too soon to make a judgment about the ramifications of the February 2011 ODAC on the approval of drugs based on single-arm trials. For example, any drugs granted accelerated approval after February 2011 that enjoyed Special Protocol Assess- ments (SPA) would have been exempt from any new FDA expectations. SPAs are agreements between the FDA and trial sponsors regarding the protocol design, size, and endpoints of a particular trial. Our research revealed that, of the eight drugs granted accelerated approval between February 2011 ODAC and the end of 2012, two 0 First-line Initial indications Numberofindications Supplemental indications First-line Second-line or later Second-line or later 5 10 15 20 25 Perspectives in Drug Approval © 2013 American Association for Cancer Research Figure 2. The use of accelerated approval in first-line treatment settings is compared with use of accelerated approval in pretreated settings for initial and supplemental indications from 2002 to 2012. Oncology Approvals www.aacrjournals.org Clin Cancer Res; 19(14) July 15, 2013 3729 on March 30, 2016. © 2013 American Association for Cancer Research.clincancerres.aacrjournals.orgDownloaded from Published OnlineFirst May 10, 2013; DOI: 10.1158/1078-0432.CCR-13-0316
- 9. (romidepsin for peripheral T-cell lymphoma and brentux- imab vedotin for Hodgkin lymphoma) were approved under SPAs. Both were approved on the basis of the results of single-arm trials using RR as an endpoint. However, five of the six remaining drugs were also approved on the basis of single-arm trials without predetermined trial designs, suggesting that the FDA has continued, of its own accord, to grant accelerated approvals based on single-arm trials. A major trend in our data is that 95% of accelerated approvals for new oncology drugs were indicated for disease that has failed to respond to other therapeutic options or progressed after prior treatment. The high incidence of pretreated disease among accelerated approvals is, in part, an unintended consequence of the requirement that a drug must show improvement over available therapy to be considered for accelerated approv- al. Sponsors seeking accelerated approval in early disease settings must show superiority over existing therapies, whereas those seeking accelerated approval in late-line disease settings must show only that they provide a therapy where none exists. Sponsors seeking accelerated approval in late-line disease settings are thus able to conduct single-arm trials using historical controls that measure RR as an intermediate endpoint (18, 26). Although the FDA has expressed concern about the ten- dency to pursue accelerated approval in pretreated or refractory disease, our research shows that the agency continues to grant accelerated approval in these settings, perhaps because it recognizes the significant unmet need in these patient populations, as well as the barriers to conducting randomized trials in earlier settings. Although 95% of drugs first entering the market that receive accelerated approval are indicated for late-stage disease, 70% of supplemental accelerated approvals are approved in the first-line setting. A major risk in grant- ing accelerated approval to a new agent is that there is a limited safety database. This risk is at least somewhat mitigated when the drug is already in use in some disease setting, which may help to explain why supplemental accelerated approvals are more likely to be in first-line settings. Furthermore, sponsors often seek to expand the label of a drug by studying its use in an entirely different disease than the original indication, and in some cases these supplemental approvals are in very rare diseases with no effective therapies. In other cases, these supple- mental approvals represent label expansions to earlier settings of the originally indicated disease. The FDA encourages sponsors to conduct confirmatory trials in earlier settings of a disease than that for which accelerated approval was granted. In some cases, this leads to full approval in both settings, while in others, approval in the earlier setting is accelerated. For example, the confirma- tory studies for the 2003 accelerated approval of imatinib for second-line chronic myelocytic leukemia (CML) were conducted in patients with CML who had not received prior therapy. Those studies led to the accelerated approv- al of imatinib for first-line CML in 2006 (18). While the finding that the vast majority of new drugs obtain accelerated approval through studies in pretreated patients is not surprising, it is concerning and is not beneficial for patients, drug sponsors, or regulators. The intent of the accelerated approval program is to expedite patient access to improved therapies for very serious diseases. This program, as it is currently being used in oncology, is not providing expedited access to new and potentially beneficial therapies for patients who have not already been heavily pretreated. These patients, still rel- atively healthy, may stand to benefit the most from novel therapies. Furthermore, by pursuing accelerated approval in heavily pretreated patients, sponsors decrease the pool of eligible patients that may participate in a clinical trial, thus increasing the challenge of accrual. Finally, trials in refractory patient populations often yield marginal results, making regulatory review difficult. Finding ways to promote the use of accelerated approval in earlier- disease settings should be a priority for all stakeholders. In a recent article, Wilson and colleagues propose a revised approach to accelerated approval to accomplish this goal (32). In their proposal, the authors argue for a mechanistic-based approach to defining what constitutes "available therapy" in any given disease setting and for a more structured approach to accelerated approval. If such a proposal were to be adopted, this might enable spon- sors of truly novel therapeutics to pursue accelerated approval in earlier patient populations. Our research shows that recent criticism of the FDA’s regulatory policy in oncology has been overstated. Approval trends over the past decade reveal that the agency has widely accepted the use of intermediate end- points in the place of overall survival, consistently grant- ed accelerated approvals, and, despite its outspoken resistance to single-arm trials in refractory populations, continued to grant accelerated approval to late-line therapies. The findings presented here indicate that the recent FDA statements about the accelerated approval pathway should not be taken to signal a more restrictive stance but rather as a call for rethinking drug develop- ment strategies. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. Authors' Contributions Conception and design: S.A. Roberts, J. Allen, E.V. Sigal Development of methodology: M.B. Shea, S.A. Roberts, J. Allen Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): M.B. Shea Analysis and interpretation of data (e.g., statistical analysis, biosta- tistics, computational analysis): M.B. Shea, S.A. Roberts, J. Allen Writing, review, and/or revision of the manuscript: MB. Shea, S.A. Roberts, J. Allen Administrative, technical, or material support (i.e., reporting or orga- nizing data, constructing databases): M.B. Shea Study supervision: J. Allen, E.V. Sigal Received February 1, 2013; revised April 11, 2013; accepted April 30, 2013; published OnlineFirst May 10, 2013. Shea et al. Clin Cancer Res; 19(14) July 15, 2013 Clinical Cancer Research3730 on March 30, 2016. © 2013 American Association for Cancer Research.clincancerres.aacrjournals.orgDownloaded from Published OnlineFirst May 10, 2013; DOI: 10.1158/1078-0432.CCR-13-0316
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- 11. 2013;19:3722-3731. Published OnlineFirst May 10, 2013.Clin Cancer Res Michael B. Shea, Samantha A. Roberts, Jessica C. Walrath, et al. FDA Oncology Drug Approvals Use of Multiple Endpoints and Approval Paths Depicts a Decade of Updated version 10.1158/1078-0432.CCR-13-0316doi: Access the most recent version of this article at: Cited articles http://clincancerres.aacrjournals.org/content/19/14/3722.full.html#ref-list-1 This article cites 16 articles, 7 of which you can access for free at: Citing articles http://clincancerres.aacrjournals.org/content/19/14/3722.full.html#related-urls This article has been cited by 1 HighWire-hosted articles. Access the articles at: E-mail alerts related to this article or journal.Sign up to receive free email-alerts Subscriptions Reprints and .pubs@aacr.org To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at Permissions .permissions@aacr.org To request permission to re-use all or part of this article, contact the AACR Publications Department at on March 30, 2016. © 2013 American Association for Cancer Research.clincancerres.aacrjournals.orgDownloaded from Published OnlineFirst May 10, 2013; DOI: 10.1158/1078-0432.CCR-13-0316