HEALTH POLICY Full-length article is available online at ascopubs.org Clinical Benefit and Expedited Approval of original contributions Cancer Drugs in the United States, European Union, Switzerland, Japan, Canada, and Australia Thomas J. Hwang, MD1,2; Aaron S. Kesselheim, MD, JD, MPH2; Ariadna Tibau, MD3; ChangWon C. Lee, AB2; and Kerstin N. Vokinger, MD, PhD, JD2,4 QUESTION ASKED: What are regulatory review times, WHAT WE FOUND: There were 128 drugs that received delays in the approval process, and the association initial approval in at least one of the six included ju- between review times and clinical benefit for new risdictions. Most drugs approved by the FDA (91%) cancer medicines in the United States, European and Health Canada (59%) qualified for at least one Union, Switzerland, Japan, Canada, and Australia? expedited program within those jurisdictions, com- SUMMARY ANSWER: Most new cancer therapies were pared with 46% of EMA approvals and 18% of PMDA first approved by the US Food and Drug Administration approvals. The FDA was the first regulator to approve (FDA), and delays in submission of regulatory appli- 102 (80%) drugs. Delays in submission accounted for cations accounted for between 20% and 84% of the a median of 20.2% (EMA) to 83.8% (PMDA) of the time to subsequent approval. There was no evidence time to subsequent approval. of an association between high clinical benefit and BIAS, CONFOUNDING FACTORS, REAL-LIFE IMPLICATIONS: faster regulatory review. Consistent with prior studies, regulatory review time was WHAT WE DID: We studied new cancer drugs approved defined as the total time between drug application by the FDA (United States), European Medicines submission and date of approval, and may include time Agency (EMA; European Union), Swissmedic (Switzer- that is not directly within regulators’ control. In addition, land), Pharmaceuticals and Medical Devices Agency clinical benefit was assessed on the basis of the data (PMDA; Japan), Health Canada (Canada), and Thera- available at approval, since this represents the data used peutic Goods Administration (Australia) from January to justify inclusion in expedited programs. Assessments 2007 to May 2020 using publicly available registers of of clinical benefit could change as more evidence be- drug approvals available for each regulatory agency. We comes available after approval. Delays in regulatory extracted all applicable expedited programs, regulatory submission account for a substantial fraction of delays in review times, and, for drugs first approved by the FDA, approving new cancer drugs in other countries. Review times to subsequent regulatory approval. We assessed times were fastest in the United States, mainly because clinical benefit using validated and widely used value virtually all cancer drugs approved by the FDA qualified frameworks: the European Society for Medical Oncology for one or more expedited programs. Drugs with high Magnitude of Clinical Benefit Scale and the ASCO’s clinical benefit should be prioritized for faster regulatory Cancer Research Committee targets. review and availability globally. ASSOCIATED CONTENT CORRESPONDING AUTHOR Appendix Thomas J. Hwang, MD, Cancer Innovation and Regulation Author affiliations Initiative, Lank Center for Genitourinary Cancer, Dana-Farber and disclosures are Cancer Institute and Division of Urological Surgery, Brigham and available with the Women's Hospital, 45 Francis St, Boston, MA 02115; complete article at e-mail: thomas_hwang@dfci.harvard.edu. ascopubs.org/ journal/op. Accepted on May 19, 2022 and published at ascopubs.org/journal/ op on June 22, 2022: Full-length article available online at DOI https://doi.org/10. 1200/OP.21.00909 676 Volume 18, Issue 9 HEALTH POLICY Clinical Benefit and Expedited Approval of original contributions Cancer Drugs in the United States, European Union, Switzerland, Japan, Canada, and Australia Thomas J. Hwang, MD1,2; Aaron S. Kesselheim, MD, JD, MPH2; Ariadna Tibau, MD3; ChangWon C. Lee, AB2; and Kerstin N. Vokinger, MD, PhD, JD2,4 abstract PURPOSE Regulatory agencies have sought to speed up the review of new cancer medicines and reduce delays in approval between countries. We examined trends in regulatory review times and association with clinical benefit for new cancer medicines in six jurisdictions: United States (Food and Drug Administration [FDA]), European Union (European Medicines Agency [EMA]), Switzerland (Swissmedic), Japan (Pharmaceuticals and Medical Devices Agency [PMDA]), Canada (Health Canada), and Australia (Therapeutic Goods Administration). METHODS We studied all new cancer drugs approved in the six aforementioned jurisdictions from 2007 to 2020. We extracted all applicable expedited programs, total regulatory review times, and, for drugs first approved by the FDA, times to subsequent regulatory approval. Clinical benefit was assessed using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale value framework and ASCO-Cancer Research Committee’s targets. Nonparametric Kruskal-Wallis test was used to compare total review times for high versus low clinical benefit drugs. RESULTS One hundred and twenty eight drugs received initial approval in at least one of the six included jurisdictions. Most drugs approved by the FDA (91%) and Health Canada (59%) qualified for at least one expedited program within those jurisdictions, compared with 46% of EMA approvals and 18% of PMDA ap- provals. The FDA was the first regulator to approve 102 (80%) drugs. Delays in submission accounted for a median of 20.2% (EMA) to 83.8% (PMDA) of the time to subsequent approval. There was no association between high clinical benefit and shorter total review times. CONCLUSION Most new cancer therapies were approved first by the FDA, and delays in submission of regulatory applications accounted for substantial delays in approving cancer drugs in other countries. Regulators should prioritize faster review for drugs with high clinical benefit. JCO Oncol Pract 18:e1522-e1532. © 2022 by American Society of Clinical Oncology Creative Commons Attribution Non-Commercial No Derivatives 4.0 License INTRODUCTION Nevertheless, regulatory agencies continue to face Regulatory agencies around the world have increas- pressure to accelerate new drug approvals4-6 and re- ingly sought to speed up the development and ap- duce delays in approval when drugs are approved first proval of new medicines. Notably, since 2012, in a comparable country.7 In 2019, the FDA announced regulators in the United States (Food and Drug Ad- plans (Project Orbis) for concurrent submission and Author affiliations ministration [FDA]), Europe (European Medicines review of oncology products with regulators in Canada and support and Australia; this initiative was expanded in 2020 to information (if Agency [EMA]), Japan (Pharmaceuticals and Medical Devices Agency [PMDA]), Switzerland (Swissmedic), include Switzerland and Singapore.8 In October 2020, applicable) appear at the end of this and Australia (Therapeutic Goods Administration the United Kingdom announced plans to join a con- article. [TGA]) have established new expedited programs. sortium of drug regulatory agencies to jointly review Accepted on May 19, These expedited programs, as well as existing regu- certain new medicines with its exit from the European 2022 and published at latory pathways, are frequently used to facilitate the Union (EU).9 Ideally, both international initiatives and ascopubs.org/journal/ op on June 22, 2022: approval of cancer therapies.1,2 For example, in 2019, individual regulators’ expedited programs would prior- DOI https://doi.org/10. all cancer drugs approved by the FDA qualified for at itize cancer therapies providing clinically meaningful 1200/OP.21.00909 least one expedited program.3 benefits. Widely used value frameworks include the e1522 Volume 18, Issue 9 Clinical Benefit and Expedited Approval of Cancer Drugs European Society for Medical Oncology (ESMO)-Magnitude approval of the included drugs. For solid tumor drugs, clinical of Clinical Benefit Scale (MCBS)10 and the ASCO’s Cancer benefit was assessed using the ESMO-MCBS version 1.1 Research Committee (ASCO-CRC) targets.11 scale10 and targets for clinically meaningful benefit developed Given substantial changes in the regulatory landscape in by working groups of ASCO-CRC (limited to randomized recent years, we aimed to assess trends in total regulatory controlled trials).11 Consistent with prior studies1,12-16 as well review times for new cancer medicines in six jurisdictions: as developers of these frameworks,17 high clinical benefit was United States (FDA), EU (EMA), Switzerland (Swissmedic), defined as ESMO-MCBS scores of 4-5 (in palliative settings) Japan (PMDA), Canada (Health Canada), and Australia or A-B (in adjuvant or neoadjuvant therapy settings), and (TGA). We also evaluated the association between clinical overall survival gains . 2.5 months or progression-free benefit and times to approval and use of expedited programs. survival gain . 3 months.11,18 Statistical Analysis METHODS For jurisdictions with available data (all except Swissmedic), We identified new cancer drugs approved by the FDA we calculated total regulatory review times, defined as the (United States), EMA (EU), Swissmedic (Switzerland), PMDA time from submission to regulatory approval. We assessed (Japan), Health Canada (Canada), and TGA (Australia) from differences in total review times and submission dates be- January 2007 to May 2020 using publicly available registers tween jurisdictions. For drugs first approved by the FDA, we of drug approvals available for each regulatory agency. The evaluated times to subsequent regulatory approval by one of study period was chosen to include key expedited programs the other included regulators and the proportion of these that have been established by regulators, including EMA’s times accounted for by later submission to other regulators conditional marketing authorization in 2006 and the FDA’s (ie, delays in submission of regulatory applications). breakthrough therapy designation in 2012. For each drug, To evaluate the association between regulatory review we used the ingredient (generic) name to determine whether times and clinical benefit, we used the nonparametric it had been approved by any of the other regulators. We Kruskal-Wallis test to compare total review times for high included drugs for solid tumors and hematologic malig- versus low benefit drugs. We then fit separate Cox re- nancies, and focused on the first approved indication, which gression models to assess the association between clinical corresponds to initial market availability of these therapies. benefit and times to subsequent regulatory approval for Data Extraction drugs first approved by the FDA. To assess the regulatory characteristics of the included Statistical analyses were performed using Stata version drug approvals, for each drug, we extracted the dates of 12.0 (Stata Corp, College Station, TX). Two-tailed regulatory application submission and approval, indication, P values , .05 were considered statistically significant. cancer type, and expedited program. Dates of regulatory Institutional review board approval was not required be- approval were available from all six regulators; dates of cause all data were publicly available. regulatory application submission were available for the FDA, EMA, PMDA, and Health Canada for the entire study RESULTS period and for TGA after 2014, but not for Swissmedic. Between January 2007 and May 2020, 128 cancer drugs Information on expedited program and approval type received initial regulatory approval in at least one of the six (Appendix Table A1, online only) were publicly available included jurisdictions (Table 1, Appendix Table A2, online from FDA (priority review, accelerated approval fast track, only). Seventy-seven (60%) of the 128 included drugs were breakthrough therapy designation, and real-time oncology approved for solid tumors. As of May 2020, 58 (45%) drugs review pilot), EMA (accelerated assessment, conditional were approved by all six regulators; 26 (20%) were ap- marketing authorization, and priority medicines scheme), proved in only one jurisdiction. The FDA approved 117 PMDA (priority review, conditional approval, and sakigake (91%) drugs, the EMA 94 (73%), Swissmedic 84 (66%), designation), Swissmedic (temporary authorization), Health PMDA 75 (59%), Health Canada 88 (69%), and the TGA Canada (priority review and Notice of Compliance with 84 (66%). The FDA was the first regulator to approve 102 Conditions), and TGA (priority review and provisional ap- (80%) drugs, compared with 10 (8%) drugs approved first proval). Among these, the expedited programs with shorter by EMA, three (2%) by Swissmedic, 11 (9%) by PMDA, and targets for regulatory review times were FDA’s priority review two (2%) by TGA; no drugs were first approved by Health (6 months), EMA’s accelerated assessment (150 days), Canada. PMDA’s priority review (9 months) and sakigake (6 months), Health Canada’s priority review (180 days), and TGA’s pri- Regulatory Review and Expedited Programs ority review (150 days). All data for the study period were Overall, most cancer drugs approved by the FDA (91%) updated in December 2021. and Health Canada (59%) qualified for at least one ex- We reviewed regulatory review dossiers or, if unavailable, pedited program within those jurisdictions (Table 2). By product labeling for data on the pivotal trials supporting contrast, only 46% of EMA approvals and 18% of PMDA JCO Oncology Practice e1523 Hwang et al TABLE 1. Characteristics of New Cancer Drugs Approved by the FDA, 9.7 months (95% CI, 7.9 to 11.7), 15.7 months (95% CI, EMA, Swissmedic, PMDA, Health Canada, and TGA, January 2007- 13.6 to 18.0) for Swissmedic, 37.4 months for PMDA (95% May 2020 CI, 31.2 to 42.7), 12.2 months for Health Canada (95% CI, Study Cohort (N 5 128) No. (%) 10.2 to 15.7), and 17.1 months for TGA (95% CI, 13.7 to Cancer type 21.8; Fig 1). Solid tumors 77 (60) Delays in submission accounted for a median of 20.2% Hematologic malignancies 51 (40) (interquartile range [IQR], 4.3%-32.9%) of the time to Initial approval year subsequent approval by EMA, 44.2% (IQR, 29.7%-77.9%) 2007-2009 16 (13) of time to approval by TGA, 60.9% (IQR, 44.9%-81.4%) of time to approval by Health Canada, and 83.8% of time to 2010-2012 24 (19) approval by PMDA (IQR, 65.8%-96.4%). 2013-2015 31 (24) 2016-2018 38 (30) Association With Clinical Benefit 2019-2020 19 (15) Sixteen of 74 (22%) solid tumor drugs were rated as high Approval jurisdiction clinical benefit as assessed with ESMO-MCBS. Drugs con- sidered high clinical benefit according to ESMO-MCBS were FDA 117 (91) associated with shorter total regulatory review times for EMA 94 (73) Health Canada (–1.90 months; 95% CI, –0.18 to Swissmedic 84 (66) –3.61 months; P 5 .03). However, there was no association PMDA 75 (59) between clinical benefit and total review times for FDA Health Canada 88 (69) (P 5 .90), EMA (P 5 .32), PMDA (P 5 .83), and TGA (P 5 .57). TGA 84 (66) No. of approved jurisdictions In Cox regression models for each jurisdiction, high-benefit drugs were associated with decreased times to subsequent 1 26 (20) approval by EMA (6.0 v 10.4 months; hazard ratio, 2.61; 2 10 (8) 95% CI, 1.32 to 5.17; P 5 .006) and Swissmedic (6.7 v 3 6 (5) 15.9 months; hazard ratio, 2.18; 95% CI, 1.12 to 4.23; 4 11 (9) P 5 .02; Fig 2, Appendix Table A3, online only). The as- 5 17 (13) sociation between clinical benefit and time to subsequent approval was not significant for PMDA (18.7 v 31.7 months; 6 58 (45) P 5 .21), Health Canada (6.9 v 10.8 months; P 5 .05), and First regulatory approval TGA (8.8 v 17.0 months; P 5 .09). FDA 102 (80) Only 38 drugs could be assessed with ASCO-CRC (ran- EMA 10 (8) domized controlled trials), of which 28 (74%) were catego- Swissmedic 3 (2) rized as providing high clinical benefit. No expedited PMDA 11 (9) programs were associated with high clinical benefit according Health Canada 0 (0) to ASCO-CRC. There was no association between clinical benefit according to ASCO-CRC and total review times or time TGA 2 (2) to subsequent approval by any regulatory agency. NOTE. Sums may not total to 100% because of rounding. Abbreviations: EMA, European Medicines Agency; FDA, US Food DISCUSSION and Drug Administration; PMDA, Pharmaceuticals and Medical Devices Agency; TGA, Therapeutic Goods Administration. In this analysis of regulatory review times and clinical benefit for cancer drugs approved by six major regulatory agencies since 2007, we found that most new cancer therapies were approvals qualified for an expedited program within those approved first by the FDA and qualified for one of FDA’s jurisdictions. Most (82%) cancer drugs approved by the expedited programs. For drugs approved first by the FDA, the FDA received priority review, compared with 17% of EMA median time to subsequent approval ranged from 9.7 months approvals (accelerated assessment), 16% of PMDA ap- for Europe (EMA) to 37.4 months for Japan (PMDA). Delays provals (priority review and sakigake), 28% of Health in submission of regulatory applications accounted for 20% Canada approvals, and 12% of TGA approvals (after cre- (EMA), 44% (TGA), 61% (Health Canada), and 84% (PMDA) ation of the program in July 2017). of these times to subsequent approval. Time to Subsequent Regulatory Approval Our findings that delays in regulatory submission to reg- As of May 2020, among the 102 drugs first approved by ulators other than the FDA and EMA account for a sub- FDA, the median time to subsequent approval by EMA was stantial fraction of delays in approving new cancer drugs in e1524 © 2022 by American Society of Clinical Oncology Volume 18, Issue 9 Clinical Benefit and Expedited Approval of Cancer Drugs TABLE 2. Expedited Programs and Total Regulatory Review Times by Jurisdictiona 1.0 Median Regulatory Review Characteristic No. (%) Time, Months (IQR) FDA 0.8 Cumulative Incidence None 11 (9) 10.0 (9.7-11.9) Priority review 96 (82) 6.1 (5.0-7.9) 0.6 Accelerated approval 43 (37) 6.0 (4.9-8.0) Fast track 51 (44) 6.9 (5.0-9.1) Breakthrough therapy designation 43 (37) 6.2 (4.8-7.8) 0.4 Real-time oncology review pilot 1 (1) NA EMA PMDA EMA HC 0.2 None 61 (64) 14.4 (13.4-16.5) Swiss TGA Accelerated assessment 16 (17) 9.7 (9.0-10.8) Conditional marketing authorization 19 (20) 14.9 (11.7-16.8) 0 12 24 36 48 60 72 84 96 108 120 132 144 Priority medicines scheme 3 (3) 12.8 (9.6-12.9) Time Since Initial FDA Approval (months) PMDA None 61 (82) 10.0 (8.8-11.0) FIG 1. Time to subsequent regulatory approval for cancer drugs in Priority review 10 (14) 10.5 (7.8-11.7) other countries first approved by the FDA. EMA, European Medicines Conditional approval 1 (1) NA Agency (European Union); FDA, US Food and Drug Administration; HC, Health Canada (Canada); PMDA, Pharmaceuticals and Medical Sakigake 2 (3) 6.0 (NA) Devices Agency (Japan); Swiss, Swissmedic; TGA, Therapeutic Goods Health Canada Administration (Australia). None 35 (41) 11.5 (11.4-13.3) Priority review 24 (28) 7.3 (7.0-8.3) epidermal growth factor receptor 2–positive breast cancer, NOC/c 30 (35) 9.7 (9.1-13.0) was the first new drug approved through Project Orbis21: TGAa FDA approval was granted in April 2020, with subsequent approval by Swissmedic issued in 19 days (May 2020) and None 79 (94) 11.5 (9.9-12.5) by Health Canada in 49 days (June 2020). Priority review 3 (4) 6.2 (3.9-7.3) In addition to international regulatory collaboration, regula- Provisional approval 2 (2) 12.0 (NA) tory agencies have established expedited programs, which NOTE. Regulatory review times were not available from Swissmedic. Sums may have resulted in shorter regulatory review times for qualifying not total to 100% because of rounding. products. We found that the application of these expedited EMA, European Medicines Agency; FDA, Food and Drug Administration; IQR, programs varied between countries. Although the FDA interquartile range; NA, not available; NOC/c, notice of compliance with conditions; granted priority review to 82% of cancer drugs, only 12%- PMDA, Pharmaceuticals and Medical Devices Agency; TGA, Therapeutic Goods 28% of drugs approved by EMA, PMDA, Health Canada, or Administration. TGA qualified for faster regulatory review through compa- a Expedited programs for TGA came into effect from 2017. rable programs. We also found little evidence that expedited programs successfully prioritized drugs with high clinical those countries provide support for coordinating joint benefit, including notably the breakthrough therapy program submission and review of new drug applications. Such in the United States. These findings may reflect uncertainty initiatives are currently underway. In 2018, Australia, or lack of systematic definition of the level of benefit expected Canada, Switzerland, and Singapore announced plans to for drugs qualifying for faster clinical development or reg- jointly review and approve new medicines through a New ulatory review. Aligning reviews with health technology as- Chemical Entities Work Sharing Initiative.19 The first sessment agencies, such as in Canada and in the EU, and products approved by this consortium were cancer ther- using a validated value framework, such as ESMO’s MCBS, apies, namely, apalutamide (prostate cancer), abemaciclib may help raise the bar for expedited programs in general so (breast cancer), and niraparib (ovarian, fallopian tube, or that regulators can deploy limited time and resources most peritoneal cancers). In 2019, Switzerland established a efficiently. Strengthening the standards for expedited pro- pathway for temporary approval of drugs already approved grams is also important for patients and clinicians, given the in comparable countries20; this pathway was used to ac- signaling effect that such programs may have,22 the need for celerate the availability of larotrectinib (tumors with NTRK patient-relevant outcomes data to guide treatment decisions, gene fusion) and cemiplimab (cutaneous squamous cell and the possible safety risks associated with drugs approved carcinoma). In 2020, tucatinib, indicated for human through expedited programs in general.23-25 JCO Oncology Practice e1525 Hwang et al ACumulative Incidence B Cumulative Incidence 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 12 24 36 48 60 72 84 96 108 120 0 12 24 36 48 60 72 84 96 108 120 Time Since Initial FDA Approval (months) Time Since Initial FDA Approval (months) C D Cumulative Incidence Cumulative Incidence 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 12 24 36 48 60 72 84 96 108 120 0 12 24 36 48 60 72 84 96 108 120 Time Since Initial FDA Approval (months) Time Since Initial FDA Approval (months) E Cumulative Incidence 1.0 0.8 0.6 0.4 0.2 0 12 24 36 48 60 72 84 96 108 120 Time Since Initial FDA Approval (months) FIG 2. Association between time to subsequent regulatory approval and clinical benefit according to ESMO-MCBS: (A) EMA, (B) Swissmedic, (C) PMDA, (D) Health Canada, and (E) TGA. High clinical benefit is shown in blue; low clinical benefit is shown in red. EMA, European Medicines Agency; ESMO-MCBS, European Society for Medical Oncology Magnitude of Clinical Benefit Scale; FDA, US Food and Drug Administration; PMDA, Pharmaceuticals and Medical Devices Agency; TGA, Therapeutic Goods Administration. This study has limitations. First, we focused on approved the manufacturer submits updated data or application products and assessed differences in regulatory review times amendments, responds to questions from the regulator, or between jurisdictions. Some variation in times to approval corrects other components of the overall application (eg, may be accounted for by factors other than application manufacturing issues)—which may not be directly within the submission or regulatory review alone. For example, man- regulator’s control. Finally, clinical benefit was assessed on ufacturers may need to conduct additional trials enrolling the basis of the data available at approval, since this rep- local participants. Second, there were limited data for several resents the data used to justify inclusion in expedited pro- expedited programs, such as PMDA’s sakigake program and grams. It is possible that assessments of clinical benefit could TGA’s priority review, which were only recently established. change as more evidence becomes available after approval. Third, consistent with prior studies,26-29 total regulatory review time was defined as the total time between drug In conclusion, this study found substantial variation in application submission and date of approval. This period regulatory review times for cancer drugs by major regulatory includes time elapsed (including regulatory clock-stops) as agencies around the world. Review times were fastest in the e1526 © 2022 by American Society of Clinical Oncology Volume 18, Issue 9 Clinical Benefit and Expedited Approval of Cancer Drugs United States, mainly because virtually all cancer drugs subsequent approval. Although some drugs with expe- approved by the FDA qualified for one or more expedited dited approval provided substantial clinical benefit, reg- programs. For regulators other than the FDA and EMA, ulators could use value frameworks such as ESMO-MCBS delays in submission of regulatory applications by man- to better prioritize faster review for drugs with high clinical ufacturers accounted for a significant portion of the time to benefit. AFFILIATIONS Institute for Health Policy. Dr. Kesselheim and Mr. Lee were additionally 1 Cancer Innovation and Regulation Initiative, Lank Center for supported by Arnold Ventures. Genitourinary Cancer, Dana-Farber Cancer Institute and Division of Urological Surgery, Brigham and Women's Hospital, Boston, MA AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF 2 Program on Regulation, Therapeutics, and Law (PORTAL), Division of INTEREST Pharmacoepidemiology and Pharmacoeconomics, Department of Disclosures provided by the authors are available with this article at DOI Medicine, Brigham and Women’s Hospital and Harvard Medical School, https://doi.org/10.1200/OP.21.00909. Boston, MA 3 Department of Oncology, Hospital de la Santa Creu i Sant Pau, Institut d’Investigació Biomèdica Sant Pau and Universitat Autònoma de AUTHOR CONTRIBUTIONS Barcelona, Barcelona, Spain Conception and design: Thomas J. Hwang, Aaron S. Kesselheim, 4 Institute of Law, University of Zurich, Zurich, Switzerland Kerstin N. Vokinger Financial support: Thomas J. Hwang, Aaron S. Kesselheim, Kerstin N. Vokinger CORRESPONDING AUTHOR Administrative support: Thomas J. Hwang, Kerstin N. Vokinger Thomas J. Hwang, MD, Cancer Innovation and Regulation Initiative, Lank Provision of study materials or patients: Ariadna Tibau Center for Genitourinary Cancer, Dana-Farber Cancer Institute and Division Collection and assembly of data: Thomas J. Hwang, Ariadna Tibau, of Urological Surgery, Brigham and Women's Hospital, 45 Francis St, ChangWon C. Lee Boston, MA 02115; e-mail: thomas_hwang@dfci.harvard.edu. Data analysis and interpretation: All authors Manuscript writing: All authors Final approval of manuscript: All authors Accountable for all aspects of the work: All authors SUPPORT Supported by the Swiss Cancer Research Foundation, Swiss National Science Foundation (PCEGP1_194607), and Kaiser Permanente REFERENCES 1. Hwang TJ, Franklin JM, Chen CT, et al: Efficacy, safety, and regulatory approval of Food and Drug Administration-designated breakthrough and non- breakthrough cancer medicines. J Clin Oncol 36:1805-1812, 2018 2. 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US Food and Drug Administration: CDER Approval Times for Priority and Standard NDAs and BLAs, 2016. https://www.fda.gov/media/102796/download n n n e1528 © 2022 by American Society of Clinical Oncology Volume 18, Issue 9 Clinical Benefit and Expedited Approval of Cancer Drugs AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Clinical Benefit and Expedited Approval of Cancer Drugs in the United States, European Union, Switzerland, Japan, Canada, and Australia The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 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/op/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Aaron S. Kesselheim Ariadna Tibau Expert Testimony: Blank Rome Honoraria: Novartis, Lilly No other potential conflicts of interest were reported. JCO Oncology Practice e1529 Hwang et al APPENDIX TABLE A1. List of Key Expedited Programs and Approval Pathways Regulatory Agency Year Qualifying Criteria FDA (United States) Priority review 1992 Drug that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness Accelerated approval 1992 Drug that treats a serious condition; and generally provides a meaningful advantage over available therapies; and demonstrates an effect on a surrogate end point that is reasonably likely to predict clinical benefit or on a clinical end point that can be measured earlier than IMM that is reasonably likely to predict an effect on IMM or other clinical benefit (ie, an intermediate clinical end point) Fast track 1997 Drug that is intended to treat a serious condition and nonclinical or clinical data demonstrate the potential to address unmet medical need Breakthrough therapy 2012 Drug that is intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate designation substantial improvement on a clinically significant end point(s) over available therapies Real-time oncology review 2018 Drug that is likely to demonstrate substantial improvements over available therapy; straightforward study design; and end pilot program points that can be easily interpreted, including overall survival or progression-free survival EMA (EU) Accelerated assessment 2006 Drug is expected to be of major interest for public health and therapeutic innovation Conditional marketing 2006 Drug is aimed at treating, preventing, or diagnosing seriously debilitating or life-threatening diseases and the following criteria authorization are met: risk-benefit balance of the medicinal product is positive; it is likely that the applicant will be in a position to provide the comprehensive clinical data; unmet medical needs will be fulfilled; and the benefit to public health of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required PRIME 2016 Fulfill criteria for accelerated assessment; and may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options PMDA (Japan) Priority review 1993 Drug intended to treat a serious disease; and no standard therapy exists or substantial improvement compared with existing products in efficacy, safety, or quality of life Sakigake designation 2015 Innovative medical product intended to treat a serious disease; prominent effectiveness expected on nonclinical and early- phase clinical studies; and intent to develop and file new drug application first in Japan or simultaneously with other countries Conditional approval 2017 Fulfill criteria for priority review; and confirmatory clinical trials are time-consuming or impracticable because of reasons such as a small subject population Fast track procedure 1998 Drug indicated for treatment or prevention of severe, disabling or life-threatening disease; treatment using currently authorized medicinal products is either unavailable or unsatisfactory; and a high therapeutic benefit is expected Temporary authorization 2019 Drug indicated for life-threatening or debilitating diseases if compatible with the protection of health; its use is expected to (Article 9 TPA) have a major therapeutic benefit; and no authorized, alternative, or equivalent medicinal product is available in Switzerland Health Canada (Canada) Priority review 1996 Drug intended for treatment, prevention, or diagnosis of serious, life-threatening or severely debilitating illnesses or conditions where there is no existing drug on the Canadian market with the same profile or where the new product represents a significant improvement in the benefit/risk profile over existing products NOC/c 1998 Eligibility for priority review; and promising clinical effectiveness in clinical trials through surrogate or clinical end point that is reasonably likely to predict clinical benefit; must also be of high quality and possess an acceptable benefit/risk profile TGA (Australia) Priority review 2017 Drug is indicated for treatment, prevention or diagnosis of a life-threatening or seriously debilitating condition; compared against registered therapeutic goods; and substantial evidence demonstrating that the medicine provides a major therapeutic advance Provisional approval 2018 Drug is indicated for treatment, prevention, or diagnosis of a life-threatening or seriously debilitating condition; compared against registered therapeutic goods; preliminary clinical data demonstrating that the medicine is likely to provide a major therapeutic advance; and evidence of a plan to submit comprehensive clinical data NOTE. Swissmedic additionally has a prior notification procedure and pathway for approval of products already approved in a country with comparable medicinal product control (Article 13 TPA). Abbreviations: EMA, European Medicines Agency; EU, European Union; FDA, US Food and Drug Administration; IMM, irreversible morbidity or mortality; NOC/c, Notice of Compliance with Conditions; PMDA, Pharmaceuticals and Medical Devices Agency; PRIME, Priority Medicines scheme; TGA, Therapeutic Goods Administration; TPA, Therapeutic Products Act. e1530 © 2022 by American Society of Clinical Oncology Volume 18, Issue 9 Clinical Benefit and Expedited Approval of Cancer Drugs TABLE A2. List of Cancer Drugs Approved by FDA, EMA, Swissmedic, TABLE A2. List of Cancer Drugs Approved by FDA, EMA, Swissmedic, PMDA, Health Canada, and TGA, 2007-May 2020 PMDA, Health Canada, and TGA, 2007-May 2020 (continued) Health Health Drug FDA EMA PMDA Canada Swissmedic TGA Drug FDA EMA PMDA Canada Swissmedic TGA Lapatinib C C C C C C Ado-trastuzumab C C C C C C Temsirolimus C C C C C C emtansine Ixabepilone C C Radium-223 C C C C C C Nilotinib C C C C C C Trametinib C C C C C C Trabectedin C C C C C Dabrafenib C C C C C C Tegafur/ C C Afatinib C C C C C C gimeracil/ Obinutuzumab C C C C C C oteracil Ibrutinib C C C C C C Bendamustine C C C C C Ramucirumab C C C C C C Plerixafor C C C C C C Ceritinib C C C C C C Degarelix C C C C C C Belinostat C Everolimus C C C C C C Idelalisib C C C C C Pralatrexate C C C C C Pembrolizumab C C C C C C Pazopanib C C C C C C Blinatumomab C C C C C C Ofatumumab C C C C C C Olaparib C C C C C C Romidepsin C C C C Nivolumab C C C C C C Vinflunine C C Trifluridine/tipiracil C C C C C C Miriplatin C Alectinib C C C C C C Mifamurtide C C Nintedanib C C Cabazitaxel C C C C C C Palbociclib C C C C C C Eribulin C C C C C C Lenvatinib C C C C C C Sipuleucel-T C C Panobinostat C C C C C Ipilimumab C C C C C C Dinutuximab C C C Vandetanib C C C C C C Sonidegib C C C C Abiraterone C C C C C C Cobimetinib C C C C C Vemurafenib C C C C C C Osimertinib C C C C C C Brentuximab C C C C C C Daratumumab C C C C C C Crizotinib C C C C C C Ixazomib C C C C C C Ruxolitinib C C C C C C Necitumumab C C C C Axitinib C C C C C C Elotuzumab C C C C C C Vismodegib C C C C C Talimogene C C C C Pertuzumab C C C C C C laherparepvec Carfilzomib C C C C C C Venetoclax C C C C C C Ziv-aflibercept C C C C C C Atezolizumab C C C C C C Enzalutamide C C C C C C Olaratumab C C C C Bosutinib C C C C C C Rucaparib C C Regorafenib C C C C C C Ribociclib C C C C C Omacetaxine C Avelumab C C C C C C Cabozantinib C C C C C C Niraparib C C C C C Ponatinib C C C C C C Brigatinib C C C C Mogamulizumab C C C Midostaurin C C C C C Pixantrone C Durvalumab C C C C C C Pomalidomide C C C C C C Neratinib C C C C C (continued in next column) (continued on following page) JCO Oncology Practice e1531 Hwang et al TABLE A2. List of Cancer Drugs Approved by FDA, EMA, Swissmedic, TABLE A2. List of Cancer Drugs Approved by FDA, EMA, Swissmedic, PMDA, Health Canada, and TGA, 2007-May 2020 (continued) PMDA, Health Canada, and TGA, 2007-May 2020 (continued) Health Health Drug FDA EMA PMDA Canada Swissmedic TGA Drug FDA EMA PMDA Canada Swissmedic TGA Enasidenib C C C Isatuximab C C C C Inotuzumab C C C C C C Selumetinib C Copanlisib C Tucatinib C C Abemaciclib C C C C C C Pemigatinib C Acalabrutinib C C C Sacituzumab C govitecan Lutetium Lu177 C C C C Tisagenlecleucel C C C C C C Abbreviations: EMA, European Medicines Agency; FDA, US Food Padeliporfin C and Drug Administration; PMDA, Pharmaceuticals and Medical Devices Agency; TGA, Therapeutic Goods Administration. Axicabtagene C C C C C ciloleucel Tivozanib C Forodesine C Apalutamide C C C C C C TABLE A3. Cox Regressions of Clinical Benefit and Time to Binimetinib C C C C C Subsequent Approval Encorafenib C C C C C C Regulatory Agency HR (95% CI) P Ivosidenib C EMA 2.61 (1.32 to 5.17) .006 Moxetumomab C Swissmedic 2.18 (1.12 to 4.23) .02 Duvelisib C PMDA 1.57 (0.77 to 3.17) .21 Dacomitinib C C C C C Health Canada 1.94 (0.98 to 3.81) .05 Cemiplimab C C C C TGA 1.80 (0.92 to 3.52) .09 Talazoparib C C C C C Abbreviations: EMA, European Medicines Agency; FDA, US Food Lorlatinib C C C C C C and Drug Administration; HR, hazard ratio; PMDA, Pharmaceuticals Glasdegib C C and Medical Devices Agency; TGA, Therapeutic Goods Administration. Larotrectinib C C C C Gilteritinib C C C C C Calaspargase C Tagraxofusp C Plitidepsin C Erdafitinib C C Alpelisib C C C C Polatuzumab C C C Selinexor C Darolutamide C C C C C Pexidartinib C Entrectinib C C C Fedratinib C Zanubrutinib C Enfortumab C Fam-trastuzumab C C Quizartinib C Avapritinib C Tazemetostat C (continued in next column) e1532 © 2022 by American Society of Clinical Oncology Volume 18, Issue 9