Box S1 Data and analysis Sample construction New molecular entities and novel biologics hereafter novel therapeutics approved by the US Food and Drug Administration (FDA) between January 1, 2005 and December 31, 2012, were identified using the publicly available Drugs@FDA database. Each novel therapeutic was classified as a small molecule or biologic, and into one of eight therapeutic areas. Using approval letters posted on the FDA website, we abstracted indications for which these novel therapeutics were first approved for use. Characterizing innovation To classify therapeutics according to their degree of innovation, we applied a scheme developed by FDA staff that has been used in its recent analyses of first-in-class therapeutics 1,2. Under this approach, the FDA identified first-in-class therapeutics by determining the first drug to be approved in each established pharmacologic class, a standardized designation used by the agency describing drugs mechanism of action. The remaining therapeutics that were not first-in-class were further classified according to their priority review status: those receiving such status were designated advance-in-class given that they were expected to potentially offer major advances in treatment 3, while those that did not receive a priority review were classified as addition-to-class. We used the FDA s classification to assign the degree of innovation for therapeutics in our sample where available, and in circumstances where an FDAassigned classification was unavailable, such as drugs approved in 2012, two reviewers (N.S.D. and N.D.S.) assigned a consensus classification by applying the FDA s methodology; for examples, see Table S1. Special regulatory pathways, review times and clinical trial evidence For each approved indication, we characterized the use of certain special regulatory pathways, regulatory review times and the pivotal trials that supported their approval using previously published methods 4,5 (for details, see Table S2). Although there are several special regulatory pathways available at present, our study focuses on priority review, which confers a goal regulatory review time of 6 months (as compared with 10 months for novel therapeutics without such status), and accelerated approval, which allows the FDA to grant approval on the basis of limited clinical trial evidence 6. We did not include orphan status because its primary benefit, an extended period of market exclusivity, occurs after approval and does not involve the development process or regulatory review. Since information about therapeutics receiving fast-track designation is not readily available on the FDA website and the most promising drugs receiving such status typically receive priority review or accelerated approval 7, we did not characterize therapeutics according to fast-track status. Finally, since the first approval of a drug with the breakthrough therapy designation occurred in 2013, after the end of our study period, we did not consider this special regulatory pathway. Statistical analysis Descriptive statistics were used to characterize therapeutics according to their degree of innovation (that is, first-in-class, advance-in-class, addition-to-class, as well as stratified by key characteristics, such as small molecule versus biologic and therapeutic area. A similar analysis was performed to characterize the use of special regulatory pathways (that is, priority review and accelerated approval) across therapeutics with differing degrees of innovation (for results, see article FIG. 1a). Chi-square and Fisher exact tests were used as appropriate to evaluate whether there were differences between the three groups of therapeutics. The number of review cycles, first and total review times were stratified by the degree of innovation, and medians compared using the Kruskal-Wallis test (for results, see article FIG. 1b and Table S3). Data describing the characteristics of pivotal trials were aggregated for each approved indication, and summarized using descriptive statistics at the indication-level (for results, see article FIG. 1c). Lastly, to reflect the possibility that multiple drug makers may simultaneously undertake development projects with the intention of producing a first-in-class therapeutic, we conducted a 1
sensitivity analysis in which any drug submitted to for regulatory review within three years of the submission date of the corresponding first-in-class therapeutic was considered to represent a first-in-class therapeutic (for details on category reassignment, see Table S4; for results of sensitivity analyses, see Tables S5, S6 and S7). All statistical tests were two-tailed and used a type I error rate of 0.05. Analyses were performed using Microsoft Excel 2013 (Microsoft Corporation; Redmond, WA) and JMP 9.0.0 (SAS Institute; Cary, NC). References 1. Miller, K. L. & Lanthier, M. Regulatory watch: Innovation in biologic new molecular entities: 1986-2014. Nat. Rev. Drug Discov. 14, 83 (2015). 2. Lanthier, M., Miller, K. L., Nardinelli, C. & Woodcock, J. An improved approach to measuring drug innovation finds steady rates of first-in-class pharmaceuticals, 1987 2011. Health Aff. 32, 1433 1439 (2013). 3. U.S. Food and Drug Administration (FDA). Priority review. FDA Website. http://www.fda.gov/forpatients/approvals/fast/ucm405405.htm. Accessed July 17, 2015. 4. Downing, N. S., Aminawung, J. A., Shah, N. D., Krumholz, H.M. & Ross, J. S. Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012. JAMA 311, 368 377 (2014). 5. Downing, N. S. et al. Regulatory Review of Novel Therapeutics Comparison of Three Regulatory Agencies. N. Engl. J. Med. 366, 2284 2293 (2012). 6. U.S. Food and Drug Administration (FDA). Accelerated approval. FDA Website. http://www.fda.gov/forpatients/approvals/fast/ucm405447.htm. Accessed July 17, 2015. 7. U.S. Food and Drug Administration (FDA). Fast track, breakthrough therapy, accelerated approval, priority review. FDA Website. http://www.fda.gov/forpatients/approvals/fast/default.htm. Accessed July 17, 2015. 2
Table S1 Examples of therapeutics of differing degrees of innovation Degree of Drug Drug class Indication Description innovation First-in-class Crizotinib ALK inhibitor Locally advanced or metastatic nonsmall cell lung cancer Advance-inclass Addition-toclass Denosumab Tipranavir Enzalutamide RANK Ligand inhibitor HIV protease inhibitor Androgren receptor blocker Treatment of osteoporosis HIV with evidence of viral replication among highly treatmentexperienced or have disease that is resistant to multiple protease inhibitors Castrationresistant metastatic prostate cancer First-in-class drug that inhibits a fusion protein that drives the subset of lung cancers involving a mutation in ALK First-in-class drug that inhibits osteoclast activity While protease inhibitors have long been a cornerstone of HIV therapy, tipranavir s development program emphasized patients with mutations associated with resistance to protease inhibitors, a population with a significant unmet medical need Earlier androgen receptor blockers (e.g., bicalutamide) are indicated for earlier stage prostate cancer, whereas enzalutamide showed promise when such therapies appear to have failed Pitavastatin Statin Hyperlipidemia Lovastatin was approved in 1987 and many popular statins, such as atorvastatin are now available as generics Asenapine Atypical antipsychotic Schizophrenia and bipolar I disorder Clozapine, the first atypical antipsychotic, was approved in 1989 and many members of the drug class are available as generics Source: Approval letters, drug labels and medical review documents available at Drugs@FDA (http://www.accessdata.fda.gov/scripts/cder/drugsatfda/) 3
Table S2 Definitions of approval characteristics Domain Approval characteristic Definition Special regulatory Priority review Application received a priority review pathways Accelerated approval Indication approved via accelerated approval pathway First review time The number of days between the date upon which the application was submitted and the date that the FDA made its first regulatory decision Regulatory review time Total review time The sum of the length of all regulatory review cycles. In the case of drugs approved after a single review, the first review time equals the total review time Total approval time The number of days between the date upon which the application was submitted and the approval date Number of pivotal trials Number of pivotal trials used to support the approval of Pivotal trial characteristics (indication-level) Randomized & doubleblinded At least one active comparator At least one clinical outcome or scale Total efficacy population Average trial length each indication All pivotal trials supporting the approval of the indication randomized patients between intervention and control arms and used a double-blinded design Indication approved on the basis of at least one clinical trial that used an active comparator Indication approved on the basis of at least one clinical trial that used a clinical outcome (e.g., overall survival) or a clinical scale (e.g., decrease of greater than 100 in Crohn s Disease Activity Index) as the primary endpoint. Note that failure to meet these criteria indicates that the indication was approved on the basis of surrogate outcomes (e.g., sustained virologic response) exclusively Sum of the intention-to-treat populations, defined as the number of patients receiving at least one dose of the study drug or comparator, across all pivotal trials supporting the approval of each indication Mean duration, defined as the length of time in weeks between the time when the first dose of the drug was administered and the time that the primary endpoint was measured, of pivotal trials supporting the approval of each indication 4
Table S3 First review, total review and total regulatory times for novel therapeutics approved by the FDA between 2005 and 2012 stratified by degree of innovation First-in-class (N = 70) (N = 42) Addition-to-class (N = 76) First review time, median (IQR) 274 (183-306) (182-270) 305 (302-395) Total review time, median (IQR) 291 (184-387) (182-275) 396 (304-576) Total regulatory time, median (IQR) 291 (184-391) (182-275) 396 (304-813) Note: IQR=Interquartile range 5
Table S4 Therapeutics that were reclassified as first-in-class in the sensitivity analysis Drug Established pharmacologic class Degree of innovation (under FDA approach) First-in-class approval Alvimopan Mecasermin Rinfabate Recombinant Sunitinib Peripherally acting µ-opioid Addition-to-class Methylnaltrexone receptor antagonist Insulin-like growth factor-1 Mecasermin Recombinant Kinase inhibitor (multi-kinase Sorafenib inhibitor; VEGFR and PDGFR) Eltrombopag Thrombopoiesis stimulating agent Romiplostim Everolimus Kinase inhibitor (mtor) Temsirolimus Saxagliptin Dipeptidyl peptidase 4 inhibitor Addition-to-class Sitagliptin Romidepsin Histone deacetylase inhibitor Addition-to-class Vorinostat Panitumumab Telaprevir Epidermal growth factor receptor antagonist Hepatitis C virus NS3/4A protease inhibitor Cetuximab Boceprevir 6
Table S5 The use of special regulatory pathways among therapeutics of differing degrees of innovation [sensitivity analysis] First-in-class (N = 79) (N = 36) Addition-to-class (N = 73) Priority review, no (%) 50 (63.3%) 36 (100.0%) 0 (0.0%) Accelerated approval, no (%) 8 (10.1%) 11 (30.6%) 3 (4.1%) 7
Table S6 Number of review cycles and regulatory review times stratified by degree of innovation [sensitivity analysis] First-in-class (N = 79) (N = 36) Addition-to-class (N = 73) Review cycles, no (%) One 62 (78.5%) More than one 17 (21.5%) 34 (94.4%) 2 (5.6%) 38 (52.1%) 35 (47.9%) First review time, median (IQR) 274 (183-307) (181-269) 305 (302-395) Among therapeutics with priority review only 186 (182-275) (181-269) n/a Among therapeutics with standard review only 306 (304-388) n/a 305 (302-395) Total review time, median (IQR) 183 (169-297) (181-272) 395 (304-574) Total regulatory time, median (IQR) 297 (183-391) (181-272) 396 (304-809) Note: IQR=Interquartile range 8
Table S7 Characteristics of development program, aggregated to the indication level, supporting approval of novel therapeutics stratified by degree of innovation [sensitivity analysis] First-in-class (N = 83) (N = 36) Addition-to-class (N = 82) Single pivotal trial, no (%) 29 (34.9%) 21 (58.3%) 24 (29.3%) Randomized and doubleblinded pivotal trials only, no (%) At least one pivotal trial using an active comparator, no (%) 60 (72.3%) 16 (19.3%) 21 (58.3%) 16 (44.4%) 62 (75.6%) 47 (57.3%) At least one pivotal trial measuring a clinical outcome or a scale, no (%) Combined efficacy population across all pivotal trials, median (IQR) Average pivotal trial length in weeks, median (IQR) 41 (49.4%) 623 (168-1503) 23.8 (8.9-28.1) 17 (47.2%) 715 (303-1201) 24.0 (12.0-52.0) 52 (63.4%) 1063 (347-1716) 12.0 (4.0-26.5) 9