Efficacy, Safety, and Regulatory Approval of Food and Drug Administration–Designated Breakthrough and Nonbreakthrough Cancer M

JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT

Efﬁcacy, Safety, and Regulatory Approval of Food and Drug Administration–Designated Breakthrough and Nonbreakthrough Cancer Medicines Thomas J. Hwang, Jessica M. Franklin, Christopher T. Chen, Julie C. Lauffenburger, Bishal Gyawali, Aaron S. Kesselheim, and Jonathan J. Darrow

Author affiliations and support information (if applicable) appear at the end of this ABSTRACT article. Purpose Published at jco.org on April 24, 2018. The breakthrough therapy program was established in 2012 to expedite the development and Corresponding author: Aaron S. review of new medicines. We evaluated the times to approval, efficacy, and safety of breakthrough- Kesselheim, MD, JD, MPH, Program on designated versus non–breakthrough-designated cancer drugs approved by the US Food and Drug Regulation, Therapeutics, and Law (PORTAL), Division of Administration (FDA). Pharmacoepidemiology and Methods Pharmacoeconomics, Department of ’ We studied all new cancer drugs approved by the FDA between January 2012 and December 2017. Medicine, Brigham and Women s fi Hospital and Harvard Medical School, Regulatory and therapeutic characteristics (time to FDA approval, pivotal trial ef cacy end point, 1620 Tremont St, Suite 3030, Boston, MA novelty of mechanism of action) were compared between breakthrough-designated and non– 02120; e-mail: akesselheim@partners. breakthrough-designated cancer drugs. Random-effects meta-regression was used to assess the org. association between breakthrough therapy designation and hazard ratios for progression-free © 2018 by American Society of Clinical survival (PFS), response rates (RRs) for solid tumors, serious adverse events, and deaths not at- Oncology tributed to disease progression. 0732-183X/18/3699-1/$20.00 Results Between 2012 and 2017, the FDA approved 58 new cancer drugs, 25 (43%) of which received breakthrough therapy designation. The median time to first FDA approval was 5.2 years for breakthrough-designated drugs versus 7.1 years for non–breakthrough-designated drugs (difference, 1.9 years; P = .01). There were no statistically significant differences between breakthrough- designated and non–breakthrough-designated drugs in median PFS gains (8.6 v 4.0 months; P = .11), hazard ratios for PFS (0.43 v 0.51; P = .28), or RRs for solid tumors (37% v 39%; P = .74). Breakthrough therapy–designated drugs were not more likely to act via a novel mechanism of action (36% v 39%; P = 1.00). Rates of deaths (6% v 4%; P = .99) and serious adverse events (38% v 36%; P = 0.93) were also similar in breakthrough-designated and non–breakthrough-designated drugs. Conclusion Breakthrough-designated cancer drugs were associated with faster times to approval, but there was no evidence that these drugs provide improvements in safety or novelty; nor was there a statistically significant efficacy advantage when compared with non–breakthrough-designated drugs.

guidance from US Food and Drug Administra- INTRODUCTION tion (FDA) reviewers and senior managers to facilitate shorter drug development and are el- In July 2012, Congress established the breakthrough igible for rolling review of the marketing appli- therapy program to expedite the development and cation.2 These benefits seem to have contributed to review of new medicines (Appendix Table A1,online reduced development times.3 For example, pem- only). To qualify, a new medicine must be intended brolizumab received breakthrough therapy desig- ASSOCIATED CONTENT to treat a serious or life-threatening disease and, on nation in 2013 and was first approved by the FDA Appendix the basis of preliminary clinical evidence, have DOI: https://doi.org/10.1200/JCO. for the treatment of patients with unresectable or 2017.77.1592 the potential to offer substantial improvement metastatic melanoma in September 2014, approx- 1 fi DOI: https://doi.org/10.1200/JCO.2017. over existing treatment options. Sponsors of imately 3 years after the start of its rst-in-human 4 77.1592 breakthrough-designated products receive intensive clinical trial.

Cancer therapies represent 54% of the new breakthrough- ’ Table 1. Characteristics of New Cancer Drugs Approved by the US Food and designated drugs approved from the program s inception through Drug Administration, 2012 to 2017 December 2017 (25 of 46), compared with 26% of all new drugs Characteristic No. (%) approved by the FDA during this period (58 of 221).5 Despite the increasing frequency of breakthrough designations and approvals Cancer type Breast 6 (10) in oncology, the full implications of the breakthrough therapy Chronic lymphocytic leukemia 3 (5) program are not well understood. At the same time, physicians and Chronic myeloid leukemia 3 (5) patients have high expectations of products approved as break- Colorectal 3 (5) throughs. In two randomized survey studies, 94% of physicians and Multiple myeloma 6 (10) Non–small-cell lung cancer 6 (10) 92% of patients preferred a hypothetical cancer drug described as Ovarian 3 (5) being labeled by the FDA as a breakthrough over an equally effective Skin 8 (14) alternative without that moniker.6,7 Given the inconsistent health Other blood cancers 9 (16) 8-10 Other solid tumors 11 (19) gains delivered by new cancer drugs, recent initiatives, including Approval year work by ASCO’s Cancer Research Committee, have sought to more 2012 11 (19) clearly define clinically meaningful outcomes11,12 and promote 2013 8 (14) better understanding of the value of new medicines.13-16 2014 9 (16) 2015 14 (24) To understand the characteristics of drugs approved through this 2016 4 (7) new program, we evaluated the efficacy and safety of breakthrough and 2017 12 (21) nonbreakthrough cancer drugs. In addition, we compared the times Expedited program* to approval of breakthrough-designated versus non–breakthrough- None 3 (5) Priority review 46 (79) designated cancer drugs to characterize the relationship between Accelerated approval 26 (45) breakthrough designation and speed of drug development. Fast track designation 28 (48) Breakthrough therapy designation 25 (43) Orphan drug status Yes 42 (72) METHODS No 16 (28) Novel mechanism of action Sample Identification Yes 22 (38) We identified new cancer drugs approved by the FDA between No 36 (62) ’ January 1, 2012, and December 31, 2017, using the FDAs Drugs@FDA NOTE. Study cohort (N = 58). Sums may not total to 100% because of rounding. database. We focused on the first indication approved by the FDA, which *Drugs may qualify for more than one expedited program. represents the initial market availability of the drug for patients and clinicians. We linked approved products on our list with breakthrough therapy designation using the public lists of breakthrough therapy approvals published by the FDA’s Center for Drug Evaluation and Research.5 irinotecan, and oxaliplatin]-eligible patients with pancreatic cancer). We also collected the numbers of treated patients in the pivotal trial with any serious adverse event (as defined by the FDA) and deaths not related to Data Extraction progression of disease. Finally, two investigators (J.C.L. and T.J.H.) in- We extracted the dates of the Investigational New Drug (IND) ap- dependently assessed the novelty of the mechanisms of action, with a novel fi plication (marking the initiation of human trials) and rst FDA approval, mechanism of action defined as a pharmacologic target or biologic indication, mechanism of action, cancer type, treatment line (treatment pathway for which the FDA had not yet approved a therapeutic agent; ı na¨ve or experienced) and stage (advanced/metastatic or not), orphan disagreements were resolved by consensus. designation (which provides tax and market exclusivity incentives to manufacturers of rare disease drugs), and expedited program (priority review, accelerated approval, fast track, and/or breakthrough designation) Statistical Analysis for all drugs in our study cohort. The time to approval was calculated as the difference between the Using a prespecified protocol, we then extracted key information dates of IND and first FDA approval. We used Fisher’s exact test to compare from the FDA’s Summary, Medical, and Integrated Multi-Disciplinary the distributions of categorical variables (expedited program, novel Reviews relating to the primary efficacy outcomes for the main, or piv- mechanism of action, trial end point) and the nonparametric Kruskal- otal, clinical trials relied on by the FDA to support regulatory approval (for Wallis test to compare the median times to approval, OS and PFS gains (ie, all drugs, the trials designated as pivotal were indicated clearly in the FDA’s improvement in the experimental v control arms), and RRs (for drugs for review documents): overall survival (OS), progression-free survival (PFS), solid tumors) between breakthrough-designated and non–breakthrough- response rates (RRs), or other end points. For solid tumors, RRs were designated drugs. We fit multivariable Cox regression models, including all assessed as complete and partial responses according to Response Eval- studied variables regardless of statistical significance, to examine factors uation Criteria in Solid Tumors (RECIST), as summarized in the FDA associated with times to approval. To evaluate the association between documents. For controlled trials assessing OS or PFS, we evaluated whether breakthrough therapy designation and (1) hazard ratios (HRs), (2) RRs, the observed treatment effect was clinically meaningful. ASCO working (3) serious adverse events, and (4) deaths, we used random-effects meta- groups have defined meaningful clinical trial goals for four cancer types regression, which accounts for between- and within-study heterogeneity. (pancreatic, lung, breast, and colon), with targets for OS improvements For proportions (2, 3, and 4), CIs were calculated using the Wilson ranging from 2.5 to 6 months.11 Consistent with the authors of previ- method, and variances of pooled estimates were stabilized using the ous studies,17 we considered OS gains of $ 2.5 months and PFS gains Freeman-Tukey double arcsine transformation. of $ 3 months for all cancer types to be clinically meaningful, a generous In sensitivity analyses, we repeated our analysis excluding drugs definition given that the ASCO criteria for meaningfulness were higher in approved in 2012 and 2013, which may have been transition years as the certain cases (eg, . 4 months for FOLFIRINOX [leucovorin, fluorouracil, FDA implemented the breakthrough program. In a post hoc analysis, we

Downloaded from ascopubs.org by Journals Press Access on April 30, 2018 from 162.234.150.177 Copyright © 2018 American Society of Clinical Oncology. All rights reserved. FDA-Designated Breakthrough Cancer Drugs compared times to approval for drugs that received both breakthrough therapy designation and accelerated approval and drugs that received Table 2. Time to US Food and Drug Administration Approval of Cancer Drugs, accelerated approval but not breakthrough therapy designation. To account 2012 to 2017 for multiple testing, we used a modified Bonferroni correction known as Time from IND to Approval 18 the Simes procedure to test the null hypothesis of no differences between Characteristic No. (%) Years, Median (IQR) P breakthrough-designated and non–breakthrough-designated drugs across all significance tests on efficacy, novelty, and safety. Any expedited program Yes 55 (95) 6.8 (4.9-9.6) .25 Statistical analyses were performed using Stata version 12.0 (Stata- , fi No 3 (5) 8.3 (6.7-14.1) Corp). Two-tailed P values .05 were considered statistically signi cant. Expedited program* Institutional review board approval was not required because all the data All PR 46 (79) 6.4 (4.8-9.5) .32 were publicly available. All AA 26 (45) 5.5 (4.4-8.3) .05 All FT 28 (48) 6.5 (5.1-8.2) .18 All BTD 25 (43) 5.2 (4.2-8.3) .01 Accelerated approval* RESULTS AA and BTD 17 (29) 4.8 (3.9-7.3) .009 AA but no BTD 9 (16) 8.3 (6.2-10.2) Between 2012 and 2017, the FDA approved 58 new cancer drugs, Combinations of programs*† PR only 7 (12) 10.7 (6.6-19.6) .73 55 (95%) of which were expedited under at least one program (Table 1). FT only 5 (9) 6.8 (5.0-7.0) .30 Overall, 25 drugs (43%) received breakthrough therapy designation, PR, FT 9 (16) 6.1 (5.2-7.4) .17 whereas 26 (45%), 28 (48%), and 46 (79%) received accelerated PR, BTD 5 (9) 9.3 (4.6-14.1) .88 approval, fast track, and priority review, respectively. Orphan drug PR, AA, FT 3 (5) 5.1 (5.0-9.6) .28 PR, AA, BTD 11 (19) 4.8 (3.9-7.3) .05 designation was granted to 42 drugs (72%). The majority targeted PR, FT, BTD 3 (5) 6.1 (5.2-7.4) .51 solid tumors (37 [64%]) and were indicated for previously treated or PR, AA, FT, BTD 6 (10) 4.8 (2.7-8.1) .12 refractory disease (36 [62%]). Twenty-two drugs (38%) had novel Cancer type mechanisms of action. Excluding drugs approved in 2012 and 2013, Solid 37 (64) 6.8 (4.9-9.5) .52 Blood 21 (36) 7.0 (5.1-9.6) 23 (59%) received breakthrough therapy designation. Orphan drug status Yes 42 (72) 7.0 (4.8-9.5) .88 No 16 (28) 6.8 (5.3-10.4) Time to First Approval Novel mechanism of action Breakthrough-designated cancer drugs were first approved by Yes 22 (38) 7.0 (5.2-9.6) .46 the FDA a median of 5.2 years after IND, compared with 7.1 years No 36 (62) 6.9 (4.8-9.6) for non–breakthrough-designated drugs (difference, 1.9 years Abbreviations: AA, accelerated approval; BTD, breakthrough therapy designation; FT, fast track; IND, Investigational New Drug; IQR, interquartile range; PR, [27%]; P = .01; Table 2). Breakthrough-designated drugs were priority review. more likely to use accelerated approval (68% v 27%; P = .003) than *Drugs may qualify for more than one expedited program. P values for com- were non–breakthrough-designated drugs but were not signifi- parison with drugs receiving no expedited program. †Only combinations of expedited programs with more than two observations cantly more likely to use any other expedited program. Times to are presented. approval were also shorter among drugs with breakthrough designation and accelerated approval compared with those with accelerated approval but not breakthrough designation (4.8 v 8.3 drugs, although the difference between groups was not statisti- years; P = .009). In multivariable Cox regression models con- cally significant (8.6 v 4.0 months; P =.11).Therewasnodif- trolling for all expedited programs, orphan drug designation, and ferenceinmedianRRs(38%v 43%; P = .73) for drugs for solid drug, disease, and tumor characteristics, the interaction between tumors. Meta-regression analysis found no evidence across drugs breakthrough therapy designation and accelerated approval was the for an association between breakthrough therapy status and HR only significant predictor of times to approval (HR, 3.0; 95% CI, for PFS (0.43 [95% CI, 0.27 to 0.59] v 0.51 [95% CI, 0.40 to 0.63]; 1.4 to 6.4; P = .005; Fig 1). P =.28;Fig 2) or RR (37% [95% CI, 26% to 49%] v 39% [95% CI, 30% to 50%]; P = .74; Fig 3). Similar results were obtained when including trials where RR was not a primary end point (33% v Novelty, RRs, and Survival 35%; P = .78). Of the 58 drug approvals, eight (14%) were approved pri- The PFS gains for five of the six breakthrough-designated marily on the basis of OS, 19 (33%) primarily on the basis of PFS, drugs and nine of the 12 non–breakthrough-designated drugs two (3%) on the basis of both OS and PFS, one (2%) on the basis of met the benchmark for a clinically meaningful improvement (ie, invasive disease-free survival, and 28 (48%) on the basis of RRs. Of $ 3 months). Breakthrough-designated drugs were not more likely the 25 breakthrough-designated drugs, 16 (64%) were approved on to act via a novel mechanism of action (36% v 39%; P = 1.00). the basis of RRs, eight (32%) on the basis of PFS, and one (4%) on In sensitivity analyses, similar results were obtained excluding fi the basis of OS (Table 3). Signi cantly fewer drugs with versus drugs approved in 2012 (when the breakthrough therapy program without breakthrough therapy designation (4% v 27%) or was created) and 2013. accelerated approval (0% v 31%), but not priority review (17% v 17%) or fast track (25% v 10%), were approved on the basis of OS as a primary or co-primary end point. Safety Breakthrough-designated drugs were associated with nu- In the pivotal studies of the cancer drugs in our study cohort, merically greater PFS gains compared with non–breakthrough serious adverse events were reported in 2,586 of 6,857 treated jco.org © 2018 by American Society of Clinical Oncology 3

A B 1.0 1.0 BTD + AA Log-rank P = .04 Log-rank P = .01 BTD

0.8 0.8 No BTD AA, no BTD

0.6 0.6

0.4 0.4 First FDA Approval First FDA Approval 0.2 0.2 Cumulative Incidence Rate of Cumulative Incidence Rate of

- - 0246810 0246810 Time Since IND (years) Time Since IND (years)

Fig 1. Cumulative incidence curves of first US Food and Drug Administration (FDA) approval of new cancer drugs. (A) Cumulative incidence of FDA approval for cancer drugs with breakthrough therapy designation (blue curve) and non–breakthrough-designated drugs (gold curve). (B) Cumulative incidence of FDA approval for drugs with both breakthrough therapy designation and accelerated approval (AA; blue curve) and drugs with AA but not breakthrough designation (gold curve). BTD, breakthrough therapy designation; IND, investigational new drug application. patients receiving breakthrough-designated drugs (38%), compared of no differences between breakthrough-designated and non– with 4,347 of 11,933 patients (36%) receiving non–breakthrough- breakthrough-designated drugs. designated drugs (P = .93 for test for heterogeneity between sub- groups from random-effects meta-regression). The proportion of deaths was not significantly different between breakthrough- DISCUSSION designated and non–breakthrough-designated drugs (6% v 4%; P = .99 from random-effects meta-regression). In this analysis of cancer drugs approved by the FDA since the Combining all hypothesis tests conducted on efficacy, safety, breakthrough therapy program’s creation in 2012, we found that and novelty, the Simes procedure could not reject the null hypothesis breakthrough-designated cancer drugs were approved by the FDA

Table 3. Pivotal Trial End Points and Outcomes of US Food and Drug Administration–Designated Breakthrough Versus Nonbreakthrough Cancer Drugs, 2012 to 2017 Breakthrough-Designated Drugs Nonbreakthrough Drugs End Point or Outcome (n = 25) (n = 33) P Primary trial end point, No. (%) Response rate* 16 (64) 12 (36) .03 Progression-free survival† 8 (32) 11 (33) Invasive disease-free survival 0 (0) 1 (3) Overall survival‡ 1 (4) 9 (27) Efﬁcacy§ Response rate, % Median (IQR) 38 (24-54) 43 (34-47) .73 Pooled estimate (IQR)║ 37 (26-49) 39 (30-50) .74 Progression-free survival† Gain, months, median (IQR) 8.6 (4.5-11.9) 4.0 (3.0-6.0) .11 Pooled hazard ratio (IQR)║ 0.43 (0.27-0.59) 0.51 (0.40-0.63) .28 Clinically meaningful improvement, No. (%)¶ 5 (83) 9 (75) .99 Novelty Novel mechanism of action, No. (%) 9 (36) 13 (39) 1.00 Safety Serious adverse events, No. patients (%) 2,586 of 6,857 (38) 4,347 of 11,933 (36) .93║ Deaths not caused by progression, No. patients (%) 347 of 6,265 (6) 517 of 12,188 (4) .99║

NOTE. Sums may not total to 100% because of rounding. Abbreviation: IQR, interquartile range. *For solid tumors, assessed as complete and partial responses. †Median progression-free survival was not reached for the experimental group in the pivotal trials for three drugs at the time of Food and Drug Administration approval. ‡Includes two drugs approved on the basis of both overall survival and progression-free survival. §Evaluated for solid tumor response rate (n = 13), progression-free survival gain (n = 18), and hazard ratio (n = 21). ║From random-effects meta-regression. ¶On the basis of ASCO criteria of improvement in progression-free survival of $ 3 months.

Favors Experimental Favors Control  HR 95% CI Weight (%)

Lenvatinib (2015) 0.21 0.16 to 0.28 5.36 Cabozantinib (2012) 0.28 0.19 to 0.40 5.12 Dabrafenib (2013) 0.32 0.19 to 0.53 4.62 Trametinib (2013) 0.47 0.34 to 0.65 4.75 Cobimetinib (2015) 0.50 0.38 to 0.67 4.83 Trabectedin (2015) 0.55 0.44 to 0.70 4.95 Panobinostat (2015) 0.56 0.39 to 0.79 4.36 Dinutuximab (2015) 0.57 0.37 to 0.89 3.82 Afatinib (2013) 0.58 0.43 to 0.78 4.58 Pertuzumab (2012) 0.62 0.51 to 0.75 5.02 Ado-trastuzumab (2013) 0.65 0.55 to 0.77 5.08 Axitinib (2012) 0.67 0.54 to 0.81 4.91 Fig 2. Forest plot of hazard ratio (HR) for Ixazomib (2015) 0.74 0.59 to 0.94 4.58 progression-free survival for breakthrough- – Non-BTD subtotal 0.51 0.40 to 0.63 designated versus non breakthrough-designated cancer drugs. Weights are from random-effects analysis. BTD, breakthrough therapy designation.

Obinutuzumab (2013) 0.16 0.11 to 0.24 5.34 Idelalisib (2014) 0.18 0.10 to 0.31 5.12 Niraparib (2017) 0.26 0.17 to 0.41 5.02 Palbociclib (2015) 0.49 0.32 to 0.75 4.23 Abemaciclib (2017) 0.55 0.45 to 0.68 5.05 Ribociclib (2017) 0.56 0.43 to 0.72 4.83 Olaratumab (2016) 0.67 0.44 to 1.02 3.56 Elotuzumab (2015) 0.70 0.57 to 0.85 4.87 BTD subtotal 0.43 0.27 to 0.59 Between-group P = .28

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 nearly 2 years before (or 27% faster than) non–breakthrough- these surveys, may not be available for several years. Although designated drugs. Twenty-four of 25 breakthrough-designated can- some breakthrough approvals may eventually demonstrate cer drugs (96%) were approved on the basis of RRs or PFS. We found clinical benefit commensurate with their designations, it is also no statistically significant differences between breakthrough-designated possible that confirmatory studies for some costly drugs, in- and non–breakthrough-designated drugs in HRs for PFS, absolute PFS cluding those preferentially prescribed after their approval gains, RRs, or the proportions of drugs with clinically meaningful with breakthrough designation, will fail to fulfill the full extent improvements in PFS or that had a novel mechanism of action. of these drugs’ early promise. The eventual lack of evidence for Congress created the breakthrough therapy program in re- clinical benefitinconfirmatory studies—despite suggestive sponse to concerns that “major breakthroughs in drugs and other results from phase I and phase II trials—has been documented treatments for debilitating and terminal diseases… [were] not extensively,9,12,21-25 and approximately 70% of new cancer always getting to patients though the most efficient and safe drugs fail in late-stage trials because of concerns about efficacy, pathways.”19 Legislators hoped that this new program would en- safety, or both.26,27 For example, atezolizumab was approved sure that “lifesaving treatments will be more readily available for by the FDA in 2016 with breakthrough designation and patients.”20 Although breakthrough therapy designation was in- accelerated approval for patients with advanced urothelial deed associated with shorter times to approval, the study findings carcinoma on the basis of durable and improved objective RRs raise questions about the concordance between the available ev- compared with historical controls in a phase II trial of the idence of the efficacy and safety of breakthrough-designated drug.28 However, in a recent phase III study (IMvigor211) in medicines and the expectations that patients and physicians may patients with platinum-refractory advanced or metastatic hold for therapies described by the FDA as breakthroughs. In urothelial carcinoma, atezolizumab did not significantly im- a national survey of Board-certified internists and specialists, 64% prove OS compared with chemotherapy (11.1 v 10.6 months; of respondents believed an FDA-designated breakthrough drug HR, 0.87 [95% CI, 0.63 to 1.21]).29 Pricesforcancerdrugs would represent a major advance over currently approved treat- typically do not decline after their market introduction, even ments for its indication, and 77% presumed there was high-quality after negative trial results are announced.30 Indeed, in January evidence that the drug was more effective than approved treat- 2018, atezolizumab’s wholesale acquisition cost increased by ments.6 Similarly, in a survey of 597 American adults, 86% of 1.5% to $8,749 per 3-week treatment cycle. With rapidly in- respondents believed that a hypothetical lung cancer drug de- creasing cancer drug launch prices,31 access to high-quality scribed as a breakthrough was more effective than other drugs.7 information about the benefits and risks of new therapies is Rigorous evidence of clinical benefits sufficient to meet the important so that patients can make truly informed treatment expectations of patients and physicians, as demonstrated by decisions.32 jco.org © 2018 by American Society of Clinical Oncology 5

RR (%) 95 (%) CI Weight, %

Olaparib (2014) 31 24 to 40 7.78

Vismodegib (2012) 43 31 to 55 7.30

Sonidegib (2015) 47 35 to 59 7.34

Non-BTD subtotal 39 30 to 50

Atezolizumab (2016) 15 11 to 19 8.03

Durvalumab (2017) 17 12 to 23 7.89 Fig 3. Forest plot of response rates (RRs) for breakthrough-designated versus non– Pembrolizumab (2014) 24 16 to 34 7.52 breakthrough-designated cancer drugs. RRs indicate complete and partial responses for Nivolumab (2014) 32 24 to 40 7.72 drugs for solid tumors only. Weights are from random-effects analysis. CIs of RRs Avelumab (2017) 33 24 to 43 7.54 were estimated using the Wilson method, and variances were stabilized using the Freeman- Ceritinib (2014) 44 36 to 51 7.85 Tukey double arcsine transformation. BTD, breakthrough therapy designation. Alectinib (2015) 44 36 to 53 7.78

Rucaparib (2016) 54 44 to 63 7.65

Brigatinib (2017) 54 44 to 63 7.67

Osimertinib (2015) 61 54 to 67 7.93

BTD subtotal 37 26 to 49

Between-group P = .74

0% 20% 40% 60% 80% 100%

To strengthen the breakthrough therapy program, patients more general adoption by companies of best practices that could and clinicians, in collaboration with regulators and other stakeholders, safely expedite the development times of all drugs during the should have the opportunity to redefine the minimum level of collection of high-quality data about them. expected clinical benefit needed to qualify for the breakthrough This study has some limitations. First, because the break- designation, an effort that could follow the model set by ASCO’s through program was created only in 2012, follow-up on the Cancer Research Committee in developing benchmarks of clinically products in our analysis was limited. We studied the evidence meaningful outcomes.11 A higher and more transparent bar for available to patients and clinicians at the time of approval; breakthrough designation could ensure that the designation serves as however, risk-benefitprofiles may change as confirmatory studies a more reliable signal to patients in a manner that fulfills both are completed and other evidence is collected. Second, although legislative intent and patient expectations. More stringent criteria for our study included all new FDA-approved drugs, it was not breakthrough designation by the FDA may result in fewer products powered to detect marginal differences between breakthrough- receiving the designation and the associated intensive agency designated and non–breakthrough-designated products. Of guidance. As of December 2017, the FDA has granted 305 course, the breakthrough therapy program was not originally breakthrough therapy designations.33 Given the significant re- intended for drugs with marginal differences, nor is it currently source demands reported by the FDA34 in managing the program perceived to be applied to such drugs. Third, there are inherent compared with the standard approval process, an overly ex- challenges in assessing drugs on the basis of limited information, pansive use of the breakthrough designation could dramatically and greater attention to the lack of surrogate measures that are dilute its value to companies and patients. Limiting the number of well correlated with survival or other patient-important out- breakthrough designations could ensure that the benefits of this comes is needed. We did not consider alternative measures of novel program are devoted to developers of truly transformative clinical benefit that have been proposed, such as restricted mean therapies. Importantly, such a change would not preclude the survival time35 and milestone outcomes36; these measures may be development and approval of medicines with more modest relevant in some cases (eg, in the interpretation of recent im- benefits under the FDA’s other three expedited programs or the munotherapy trials37), but there is no consensus on their use.

Finally, as is the case with all observational studies, causal in- AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS ferences cannot be made, and additional unobserved predictors OF INTEREST may explain the association between breakthrough status and faster times to approval. Disclosures provided by the authors are available with this article at The breakthrough therapy designation was established in 2012 jco.org. to speed the development and approval of medicines representing transformative advances in clinical care. Early evidence with this program indicates that breakthrough-designated cancer medicines AUTHOR CONTRIBUTIONS were associated with faster times to approval than were non– breakthrough products. Although some therapies demonstrated Conception and design: Thomas J. Hwang, Bishal Gyawali, Aaron S. clinically meaningful benefits, to date there is little evidence that Kesselheim, Jonathan J. Darrow breakthrough-designated cancer medicines offer substantially Financial support: Aaron S. Kesselheim improved efficacy or safety or are more likely to act via a novel Administrative support: Aaron S. Kesselheim mechanism of action, as compared with non–breakthrough- Collection and assembly of data: Thomas J. Hwang designated drugs. Continued follow-up, rigorous confirmatory Data analysis and interpretation: Thomas J. Hwang, Jessica M. Franklin, Christopher T. Chen, Julie C. Lauffenburger, Bishal Gyawali, Aaron S. studies, and more robust and transparent criteria for breakthrough Kesselheim designation are needed for patients and clinicians to distinguish Manuscript writing: All authors true breakthroughs from those that are breakthroughs in name Final approval of manuscript: All authors only. Accountable for all aspects of the work: All authors

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Downloaded from ascopubs.org by Journals Press Access on April 30, 2018 from 162.234.150.177 Copyright © 2018 American Society of Clinical Oncology. All rights reserved. Hwang et al pink.pharmaintelligence.informa.com/PS079567/ survival time as an alternative to the hazard ratio. 37. Ben-Aharon O, Magnezi R, Leshno M, FDAs-Breakthrough-Bar-May-Be-Set-Too-Low-Jenkins- JAMA Oncol 3:1692-1696, 2017 et al: Association of immunotherapy with Says 36. Hellmann MD, Kris MG, Rudin CM: Medians durable survival as deﬁned by value frame- 35. Pak K, Uno H, Kim DH, et al: Interpretability of and milestones in describing the path to cancer works for cancer care. JAMA Oncol 4:326-332, cancer clinical trial results using restricted mean cures: Telling “tails”. JAMA Oncol 2:167-168, 2016 2018 Affiliations Thomas J. Hwang, Jessica M. Franklin, Julie C. Lauffenburger, Bishal Gyawali, Aaron S. Kesselheim, and Jonathan J. Darrow, Brigham and Women’s Hospital and Harvard Medical School; Christopher T. Chen, Dana-Farber Cancer Institute, Boston, MA; and Bishal Gyawali, Nagoya University Graduate School of Medicine, Nagoya, Japan. Support Supported by the Laura and John Arnold Foundation, with additional support from the Harvard Program in Therapeutic Science and the Engelberg Foundation (A.S.K.). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. nnn

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Efﬁcacy, Safety, and Regulatory Approval of Food and Drug Administration–Designated Breakthrough and Nonbreakthrough Cancer Medicines The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conﬂict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Thomas J. Hwang Julie C. Lauffenburger Other Relationship: Bain Capital Research Funding: AstraZeneca Jessica M. Franklin Bishal Gyawali Consulting or Advisory Role: Aetion, CHORDATA No relationship to disclose Research Funding: Merck (Inst), PCORI (Inst) Aaron S. Kesselheim Christopher T. Chen No relationship to disclose Employment: Vida Health (I) Leadership: Vida Health (I) Jonathan J. Darrow Stock or Other Ownership: Vida Health (I) No relationship to disclose Consulting or Advisory Role: Roche, WntRx

Appendix

Table A1. Summary of the FDA’s Expedited Programs Program Attribute Accelerated Approval Priority Review Fast Track Breakthrough Therapy Qualifying criteria Serious condition Yes Yes Yes Yes Benefit relative to available Meaningful advantage over Significant improvement in Potential to address Yes, substantial improvement on therapy available therapies safety or effectiveness unmet medical need a clinically significant end point over available therapies Evidence accepted to qualify for Surrogate end point reasonably New drug application or Nonclinical or clinical Preliminary clinical evidence program likely to predict clinical benefit supplement data Benefits Shorter FDA review time No Yes, 6 months (v standard No No 10 months) Rolling review of application No No Yes Yes Actions to expedite drug No No Yes Yes development More intensive guidance on No No No* Yes efficient drug development

NOTE. Drugs may qualify for more than one expedited program. Abbreviation: FDA, Food and Drug Administration. *The 1988 subpart E regulations also provided for early consultation and the involvement of senior FDA ofﬁcials.