Htadock R&D Briefing

Review of HTA outcomes and timelines in Australia, Canada and Europe 2014-2018

Figure 1: First HTA recommendations: comparisons across key jurisdictions 2017 and 2018 Positive Restriction Negative Multiple © CIRS, R&D Briefing 73

Australia Canada England France N=43 N=44 N=52 N=49

4% 8% 12% 14% 44% 38% 54% 54% 47% 82% 41%

Germany Poland Scotland Sweden N=53 N=37 N=41 N=39 2% 5% 14% 19% 32% 33% 42% 45% 43%

43% 49% 62% 11%

Contents Summary 1 Overview of new drug recommendations 2 Synchronisation of regulatory and HTA recommendations 3 38 NASs appraised by seven key jurisdictions in 2014-2018 4 Focus on US Breakthrough Designation 5 Features of Australia 6 Features of Canada 7 Features of Europe 8 Overview of reimbursement outcomes 9 Methodology and definitions 10

R&D BRIEFING 73 SUMMARY Introduction Timely recommendation for drug reimbursement by health technology assessment (HTA) agencies is critical to ensure that patient access to medicines of therapeutic value is not delayed. As part of an ongoing study to monitor regulatory and HTA performance, CIRS has been collecting data on new active substances (NASs) appraised between 2014 and 2018 by eight health technology assessment (HTA) agencies, analysing synchronisation between the regulatory decision and first HTA recommendation in timing and outcome. Recommendations were collected from the Australian Pharmaceutical Benefits Advisory Committee (PBAC), Canadian Agency for Drugs and Technologies in Health (CADTH; both Common Drug Review [CDR] and pan-Canadian Oncology Drug Review [pCODR]), English National Institute for Health and Care Excellence (NICE), French Haute Autorité de Santé (HAS), German Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), Polish Agencja Oceny Technologii Medycznych i Taryfikacji (AOTMiT), Scottish Medicines Consortium (SMC) and Swedish Tandvårds- & läkemedelsförmånsverket (TLV), for NASs approved 2012-2018 by the respective jurisdictional regulatory agencies, the Australian Therapeutic Goods Administration (TGA), Health Canada and European Medicines Association (EMA). Using a methodology outlined on page 10, the HTA recommendations in this report have been classified as positive, positive with restrictions or negative. Figure 27 illustrates how the specific recommendations by the eight HTA systems are captured within this trichotomous categorisation. In cases in which more than one HTA dossier was submitted by a company for the same drug based on different sub-indications within an approved regulatory label and the final HTA outcome for these individual sub-indications differed, the outcome was classified as multiple.

Observations

• Overall, more than 50% of NASs In Australia, more than 70% of NASs were reimbursed approved by regulatory agencies after receiving a positive or positive with restrictions received a positive or positive with first recommendation. restrictions first recommendation by HTA agencies across all of the studied Of 85 drug submissions in Australia from 2015-2018, 64 were jurisdictions between 2017-2018. reimbursed. In the last two years, the proportion of products with a Sweden and England had the highest one-cycle review with a positive/ positive with restriction proportion of positive/positive with recommendation increased from 52% in 2015-2016 to 77% in 2017- restrictions recommendations for 2018. Multiple review cycles can increase the time to the final NASs appraised by HTA agencies. reimbursement decision. The difference between the one-cycle and multiple-cycle review for median time taken from HTA submission to • Of all studied HTA agencies, Australia reimbursement decision was 380 days between 2015-2016 and 212 had the highest percentage of and days between 2017-2018. greatest increase in products recommended within one year of In Canada, the HC/CADTH parallel process reduced regulatory approval (94% in 2018). the time from regulatory approval to HTA • Australia had the shortest median recommendation. time between regulatory approval and In 2014-2018, approximately half of the NASs submitted for HTA HTA recommendation (19 days) in recommendation underwent the Health Canada/ CADTH parallel 2014-2018, followed by Germany (129 review process. The parallel review process was a success in reducing days). the time taken to reach the first HTA recommendation. The reduction • CIRS analysed NASs rolled out to in median time taken from regulatory approval to HTA seven jurisdictions, excluding Poland, recommendation using the parallel process (152 days) was shorter and identified 38 NASs that received a than the sequential process (361 days). recommendation by all HTA agencies during the period of 2014-2018. In Europe, the lag between EMA approval and HTA Interestingly, NAS approval by US FDA recommendations varied across the European via Breakthrough Designation did not jurisdictions, from 129 median days in Germany to translate to quicker time from 521 median days in Poland. regulatory approval to HTA recommendation nor an increase in In the studied European jurisdictions, the time from EMA approval to proportion of positive or positive with HTA recommendation was generally longer for those NASs receiving a restrictions HTA recommendations. negative HTA outcome. Among 40 commonly appraised NASs approved by EMA, accelerated products generally had the fastest median time from regulatory approval to HTA recommendation.

R&D Briefing 73 July 2019, © Centre for Innovation in Regulatory Science, Ltd. 1 OVERVIEW OF NEW DRUG RECOMMENDATIONS Figure 2: First HTA recommendation comparison across key jurisdictions by year of HTA recommendation Between 2014-2018 Positive Restriction Negative Multiple 100% 1 1 1 1 1 1 1 2 3 2 2 2 3 2 2 5 4 3 4 5 2 3 3 4 2 5 5 10 4 7 5 8 10 80% 3 9 9 1011 10 7 14 14 12 8 14 11 6 6 14 13 13 14 13 8 60% 13 3 14 11 17 11 15 7 12 8 17 5 6 19 7 8 10 40% 1 13 19 3 1 13 24 27 18 12 4 1112 16 16 12 8 12 20% 1110 10 11 11 11 9 8 6 9 9 8 4 7 6 5 8 7 4 5 4

Proportionrecommended ofNASs 2 2 1 2 0% 1 1 1 1

Australia Canada England France Germany Poland Scotland Sweden N= Number of NASs © CIRS, R&D Briefing 73 In 2017 and 2018, Sweden and England had the highest proportion (95% and 92%) of positive/positive with restrictions recommendations for NASs appraised by HTA agencies (Figure 1). Germany appraised the highest number of NASs in 2017-2018 (53 NASs), while Poland appraised the fewest (37 NASs) (Figure 1). The biggest difference in the number of HTA recommendations between 2017 and 2018 was seen in Scotland, with an increase of 56%. The year-on-year variation in the number of recommendations is due to a number of reasons, including the number of regulatory approvals, the company submission strategy and the review time by the HTA agencies. More than 60% of NASs approved by relevant regulatory agencies received a positive or positive with restrictions recommendation by HTA agencies in all of the studied jurisdictions in 2018. In particular, Poland showed the greatest increase in proportion of NASs appraised receiving a positive or positive with restrictions recommendation, from 28% in 2017 to 84% in 2018. There were no negative recommendations for products appraised by TLV in 2018 (Figure 2). Australia had the fastest median rollout time from regulatory submission to HTA recommendation in 2018 (373 days), followed by Canada (518 days). Lower timing variation was also seen in these two countries in 2018 compared with 2017, which indicated an improved consistency (Figure 3). The median rollout time was shortened in 2018 in most jurisdictions compared with 2017, while England showed an increased review time over the past four years. The biggest improvement in the rollout time was seen in Poland, with a decrease of 143 median days from 2017 to 2018. However, it still took the longest time for products to roll out in Poland compared with other jurisdictions. Figure 3: Rollout time from regulatory submission to HTA recommendation by year of HTA recommendation Median, Box : 25th and 75th percentiles, Overall median (1744) 1400

821 1200 1188 581 803 1045 1000 743 706 687 467 700 709 692 800 658 971 597 362 585 909 757 535 857 600 674 Time, Time, days 712 774 685 609 590 694 679 572 571 400 648 521 542 538 587 518 404 383 373 200 © CIRS, R&D Briefing 73 0 3

Australia Canada England France Germany Poland Scotland Sweden (75th percentile of regulatory submission to HTA recommendation for Poland in 2017)

R&D Briefing 73 July 2019, © Centre for Innovation in Regulatory Science, Ltd. 2 SYNCHRONISATION OF REGULATORY AND HTA RECOMMENDATIONS Figure 4: Proportion of first HTA recommendation NASs made within one year of regulatory approval Australia- PBAC Canada- CADTH England- NICE France- HAS Germany - IQWIG Poland - AOTM Scotland- SMC Sweden- TLV 100% 94% 90% 80% 84% 76% 67% 60% 58%

40% 26% 20%

© CIRS, R&D Briefing 73 0% © CIRS, R&D Briefing 73 within within of year one regulatory approval 2014 2015 2016 2017 2018 Proportion Proportion of recommendations HTA made Year of HTA recommendation Of all HTA agencies, PBAC had the highest percentage of and greatest increase in NASs recommendations made within one year of regulatory approval: from 72% in 2017 to 94% in 2018 (Figure 4). On average, IQWiG appraised the most NASs within one year of regulatory approval (89% across 2014-2018), while PBAC appraised the most NASs within one year of regulatory approval in 2018. The breakdown of rollout time is shown in Figure 5. A longer median time from regulatory approval to HTA recommendation in 2018 compared with 2017 was seen in France, Germany and Sweden; this can be attributed to both company submission strategy and HTA review time. The parallel review mechanism in Australia and Canada has shortened the time from regulatory approval to HTA submission (Figure 6). Figure 5: Breakdown of rollout time in key jurisdictions 2014-2018 2014 397 26 Australia 2015 380 15 2016 351 32 2017 360 126 Regulatory authority review time 2018 364 17 Regulatory approval to HTA 2014 356 266 recommendation (national level) Canada 2015 391 251 2016 348 175 2017 356 182 2018 338 162 2014 458 397 England 2015 409 314 2016 443 341 2017 402 386 2018 444 288 2014 462 230 France 2015 417 228 2016 418 202 2017 421 194 2018 407 246 2014 415 135 Germany 2015 437 139 2016 406 129 2017 388 116 2018 446 124 2014 449 479 Poland 2015 394 444 2016 427 524 2017 422 802 2018 388 603 2014 438 141 Scotland 2015 418 257 2016 369 203 2017 419 293 2018 430 259 2014 446 241 Sweden 2015 415 184 2016 406 159 © CIRS, R&D Briefing 73 2017 406 217 2018 423 241 Median time, days 0 200 400 600 800 1000 1200

Figure 6: Breakdown of rollout time in jurisdictions where HTA submission date is provided 2014-2018* Regulatory authority review time HTA submission to HTA recommendation (national level)

Australia (111) 370 © CIRS, R&D Briefing 73 122

Canada (124) 351 * Only jurisdictions with HTA 207 submission dates available Germany (131) 419 in the public domain were 88 included in this figure.

Poland (91) 415 79 Median time, days 0 200 400 600 800 1000

R&D Briefing 73 July 2019, © Centre for Innovation in Regulatory Science, Ltd. 3 38 NASS APPRAISED BY ALL SEVEN JURISDICTIONS IN 2014-2018

Figure 7: First HTA recommendation comparison across all jurisdictions for 38 common NASs Positive Restriction Negative Multiple n = Date order of the HTA recommendations FDA Breakthrough Designation

Country AUS CAN ENG FRA GER SCO SWE France had the highest proportion of positive ombitasivr; paritaprevir; recommendations for 38 NASs appraised by all seven 6 5 7 2 3 4 1 ritonavir HTA agencies (58%), with Canada showed the lowest simeprevir 2 1 7 6 4 3 5 proportion (3%).

glecaprevir / pibrentasvir 4 6 7 5 3 2 1 CIRS analysed NASs rolled out to seven jurisdictions, excluding Poland, and identified 38 NASs that had been ixekizumab 1 4 6 3 7 5 2 approved between 2012 and 2018 and that had also

secukinumab 1 6 4 7 5 2 3 received an HTA recommendation between 2014 and 2018 by all seven HTA agencies. Figure 7 shows a traffic ledipasvir; sofosbuvir 5 6 7 4 3 1 2 light system to compare the different HTA outcome

sarilumab 7 1 2 5 3 6 4 across jurisdictions in 2014-2018, reflecting the diverse perception on the value of these NASs across the daclatasvir 5 6 7 4 2 1 3 agencies. The recommendation dates for each product

tofacitinib citrate 1 2 6 5 4 7 3 were compared across all seven agencies and the order of first HTA decisions was ranked accordingly. venetoclax 4 6 5 2 1 3 7 In England and France, the majority of NAS received a sofosbuvir / velpatasvir 6 5 7 4 3 2 1 positive/ positive with restrictions recommendation (95% and 92% respectively). In comparison, in Australia and empagliflozin 1 7 6 5 3 2 4 Germany the first HTA recommendation were mostly ceritinib 7 4 6 2 1 3 5 negative (61% and 45% of the NASs review respectively). NASs were mostly likely to receive a restrictive alectinib hydrochloride 2 1 7 5 3 6 4 recommendation in Canada (76% of the 38 products). In midostaurin 1 2 6 6 3 5 4 this cohort, none of the NASs had the same first HTA recommendation but 7 NASs received positive/ positive eliglustat tartrate 2 6 5 3 1 7 4 with restrictions outcome from all seven jurisdictions. sacubitril / valsartan 2 3 6 7 4 1 5

5 2 7 4 1 6 3 ibrutinib Germany provided the highest number of migalastat hydrochloride 6 7 5 4 1 2 3 recommendations as the first country of appraisal (34%), followed by Australia (26%). idelalisib 4 6 7 5 1 2 3 In England, the majority of NASs (66%) received a NICE elbasvir + grazoprevir 2 1 5 4 7 6 3 decision as the 6th or 7th country among all jurisdictions;

ribociclib succinate 1 7 3 5 2 6 4 none of the 38 products received a first HTA decision in France. vedolizumab 1 7 6 4 2 5 3

3 1 7 4 2 6 5 palbociclib Australia had the shortest median time from first world- evolocumab 1 5 7 3 2 6 4 wide regulatory submission to jurisdictional HTA recommendation although it had the largest median 2 7 6 5 3 1 4 nintedanib regulatory submission gap of 97 days (Figure 8). lenvatinib 4 5 7 2 1 6 2

4 5 7 3 1 2 6 Figure 8: Breakdown of rollout time (days) across all sofosbuvir jurisdictions for 38 common NASs mepolizumab 1 5 7 6 2 3 4 Regulatory submission gap © CIRS, R&D Briefing 73 osimertinib mesylate 7 5 3 2 1 4 6 Regulatory authority review time Regulatory approval to HTA recommendation guselkumab 4 2 6 7 3 5 1 Australia 97 367 17 7 5 3 2 1 4 6 alirocumab Canada 49 350 161 trifluridine/tipiracil hydrochloride 5 7 1 3 4 6 2 England 366 311 France lumacaftor 2 6 5 4 1 3 7 366 202 Germany 366 123 apremilast 1 5 6 7 3 2 4 Scotland 366 173 daratumumab 4 2 7 5 1 3 6 Sweden 366 158 6 7 5 2 4 3 1 olaparib 0 100 200 300 400 500 600 700 Median time, days dupilumab 5 3 6 4 1 7 2

R&D Briefing 73 July 2019, © Centre for Innovation in Regulatory Science, Ltd. 4 FOCUS ON BREAKTHROUGH DESIGNATION OF 38 COMMON NASS

Figure 9: Breakdown of rollout time by US Breakthrough Figure 10: Time taken from regulatory approval to HTA Designation (BTD) for 38 common NASs recommendation by US Breakthrough Designation (BTD) Regulatory authority review time Median Box : 25th and 75th percentiles Regulatory approval to HTA recommendation (national level) 450 Australia Standard 382 50 © CIRS, R&D Briefing 73 BTD 350 14 400

350 Canada Standard 379 162 314 BTD 284 160 300 307 218

250 England Standard 384 307 201 162 212 BTD 351 314 200 153 Time, days Time, 143 175 150 France Standard 384 201 160 BTD 351 212 100 171 50 106 50 Germany Standard 384 143 BTD 351 106 0 14 © CIRS, R&D Briefing 73 Median time (days) -50

Scotland Standard 384 175

BTD BTD BTD BTD BTD BTD

BTD 351 171 BTD

Standard Standard Standard Standard Standard Standard Standard Sweden Standard 384 153 Australia Canada England France Germany Scotland Sweden BTD 351 218 Median time, days 0 200 400 600 Number of standard = 19; Number of BTD = 19 Number of standard = 19; Number of BTD = 19 50% of the common NASs had been approved by US FDA via Breakthrough Designation (BTD). In an effort to expedite the approval of drugs treating serious illnesses or addressing unmet medical need, breakthrough therapy designation (BTD) has been used by the FDA. The BTD designation has resulted in a shorter timeline in both development (IND to submission) and FDA approval (CIRS R&D Briefing 70). The FDA approval status was explored for 38 common NASs in terms of the BTD; 19 products among the common NASs were approved via BTD, reflecting the innovativeness of these products. The NASs approved by FDA BTD process had shortened regulatory review time across all jurisdictions (Figure 9). NASs with BTD had a faster regulatory review time in each jurisdiction as compared with non-BTD; this was in line with the expedited approach by FDA. However, it did not translate to quicker post-regulatory processes in all jurisdictions. The time taken from regulatory approval to HTA recommendation was shorter in Australia, Canada, Germany and Scotland. In general, there were more variations in time from regulatory approval to HTA recommendation for the 19 BTD NASs, except in Germany and Scotland. (Figure 10).

Figure 11: First HTA recommendation comparison by US Breakthrough Designation (n=38) © CIRS, R&D Briefing 73 Positive Restriction Negative Multiple 100% 1 1 1 1 1 1 3 1 2 3 5 2 80% 7 6 9 8 11 9 7 7 12 11 60% 10 12 40% 1 16 13 4 6 11 12 9 10 10 20% 7 7 7 6 5 6

Proportion Proportion of NASs recommended 4

0% 1

BTD BTD BTD BTD BTD BTD BTD

Standard Standard Standard Standard Standard Standard Standard

Australia Canada England France Germany Scotland Sweden Number of standard = 19; Number of BTD = 19 BTDs do not lead to an increase in proportion of positive/positive with restrictions compared with non-BTDs (Figure 11). The proportion of NASs receiving a positive/positive with restriction recommendation between BTD products and non-BTD products were similar across all jurisdictions. BTD products had faster timeline from regulatory submission to HTA recommendation; however, this was mainly driven by the shorter regulatory review time.

R&D Briefing 73 July 2019, © Centre for Innovation in Regulatory Science, Ltd. 5 FEATURES OF AUSTRALIA

Figure 12: Time taken from regulatory approval to HTA submission according to company size in 2014-2018 Median, Box : 25th and 75th percentiles 600 Review type of products appraised by Sequential Parallel PBAC between 2014 and 2018 (n=111) 500

400

300 Sequential 32% Time, Time, days 200 207 Parallel 100 120 106 68%

0 -124 -100 -124 -130 © CIRS, R&D Briefing 73 -200 © CIRS, R&D Briefing 73 Overall Top Non-top Overall Top Non-top sequential company company parallel company company Top company is defined as having R&D (36) (23) (13) (75) (46) (29) budget >3 billion USD in 2017. N= Number of NASs Companies have taken advantage of the parallel review mechanism in Australia, with 68% products undergoing this process and saving approximately 4 months from PBAC submission to TGA approval (Figure 12). Median submission to PBAC was 124 days prior to TGA approval for products that went through parallel review, compared with a 120-day delay in HTA submission with sequential review. Size of the company was assessed and used to stratify the trend of review process, showing no difference in preference for review process between top companies and non-top companies: 67% of top companies submitted products through parallel review, compared with 69% non-top companies. More than 70% of products were reimbursed in Australia in 2015-2018 (Figure 13). However, 36% appraised by PBAC took more than one Figure 13: Proportion of products that cycle to receive the reimbursement decision (Figure 14) in this cohort. received reimbursement in Australia In Australia, a negative PBAC recommendation will lead to non- reimbursable decisions. When the first HTA recommendation does not support a reimbursement decision, companies can re-submit an 9, 21% 2015-2016 application with an improved dossier. Consequently, a number of review cycles may take place until a positive/positive with restriction 33, recommendation is achieved to support reimbursement. The proportion 79% of products with one-cycle review increased in 2017-2018 (77%), Not reimbursable compared with 2015-2016 (52%). Multiple review cycles may increase Reimbursable the time to receive the final reimbursement decision (732 median days in 2015-2016 and 535 median days in 2017-2018, Figure 15). In the last two years, the difference in time taken from HTA submission to 12, 28% reimbursement decision between one-cycle and multiple cycle review 2017-2018 decreased by a median of 168 days compared with 2015-2016. The decrease 31, 72% in re-submissions and improvement in time to reimbursement is in line with the commitment by the Department of Health and Medicines Australia since © CIRS, R&D Briefing 73 late 2017 under clause 10 of the Strategic Agreement to streamline medicines listing processes, including a target of 50% reduction in the number of resubmissions to the PBAC and reduction in time from PBAC recommendation to listing by an average of two months. Figure 14: Number of cycles to first positive/ positive Figure 15: Breakdown of rollout time for with restrictions HTA recommendation in 2015-2018 reimbursable drugs in Australia in 2015-2018 © CIRS, R&D Briefing 73 Regulatory authority review time 1 cycle 2 cycles 3 or more cycles HTA submission to reimbursement decision 362

1 cycle 352

2016 - 2015-2016 17 9 7 374 >1 cycle 2015 732 364

1 cycle 323 2018

2017-2018 24 5 2 - 351 © CIRS, R&D Briefing 73 2017 >1 cycle 535 0% 20% 40% 60% 80% 100% 0 200 400 600 800 1000 Proportion of NASs recommended Median time, days

R&D Briefing 73 July 2019, © Centre for Innovation in Regulatory Science, Ltd. 6 FEATURES OF CANADA

Compared with 2015-2016, alimentary & metabolism Figure 16: Time from regulatory approval to HTA products appraised in 2017-2018 took a shorter time from recommendation by therapeutic area Median Box: 25th and 75th percentiles regulatory approval to HTA recommendation (Figure 16). Overall median 2015-2018 for each therapy area Alimentary Anti- The top four therapeutic groups from the 105 NASs Cardiovascular Anti-cancer & immunomodulators & metabolism infectives 600 assessed by CADTH in 2015-2018 were anti-cancer & Overall ATC L: ATC L: 343 ATC L CDR pCODR immunomodulators (42%), alimentary & metabolism 500

(22%), anti-infectives (10%) and cardiovascular (6%). 400 224 146 Looking at the overall median time taken from regulatory 233 199 300 181 approval to HTA recommendation, anti-infectives were 188 193 121160 fastest, followed by anti-cancer & immunomodulators and 200 168 cardiovascular NASs (Figure 16). In addition, all four anti- Time, days 100 152 © CIRS, R&D Briefing 73 infectives products appraised in 2017-2018 received a 0 positive CADTH recommendation (Figure 17).

In 2015-2018, 32 anti-cancer & immunomodulators were

2017-2018 (1) 2017-2018 (7) 2015-2016 (4) 2017-2018 (8) 2015-2016 (4) 2017-2018

submitted under the pan-Canadian Oncology Drug Review (5) 2015-2016

2017-2018 (10) 2017-2018 (27) 2015-2016 (17) 2017-2018 (19) 2015-2016 (13) 2017-2018 (pCODR), which evaluates oncology drugs and makes (13) 2015-2016 recommendations and guides the drug funding Figure 17: HTA outcome by therapeutic area © CIRS, R&D Briefing 73 Positive Restriction Negative recommendations of provinces. Established in 2010, 100% pCODR enables all provinces and cancer agencies to take a 1 1 3 4 6 single approach to cancer drug evaluation; pCODR moved 80% to CADTH in 2014. In 2015-2016, anti-cancer & 60% 6 immunomodulators that underwent the pCODR evaluation 9 1 4 40% 4 20 13 were faster from regulatory approval to HTA 8 recommendation than those that underwent the CDR 20% 1 review process; however, in 2017-2018, pCODR timelines 0% 1 1 1

were slightly longer than those for CDR (Figure 16). Proportion of recommended NASs

Alimentary & Cardiovascular Anti-infectives Anti-cancer & The Health Canada/CADTH parallel process shortened the metabolism immunomodulators overall time taken from regulatory approval to HTA Figure 18: Breakdown of rollout time by type of sequence recommendation (Figure 18). Regulatory authority review time HTA submission to HTA recommendation (national level) The Health Canada/CADTH parallel review process, which allows for a submission to CADTH within 90 days before the Sequential 361 © CIRS, R&D Briefing 73

date of anticipated Notice of Compliance (NOC) from (33) 211

2016 - Health Canada, has been available for companies since Parallel 351

2012. However, on 2 April 2018, CADTH submission criteria 2015 (28) 202 were changed to within 180 days before the anticipated NOC from Health Canada. In 2015-2018, 51% of the NASs Sequential 350

submitted for HTA recommendation underwent the Health (18) 195

2018 - Canada/CADTH parallel review process. In the last two-year 349 cohort, an increased proportion of NASs were submitted Parallel 2017 (26) 190 through the parallel process: 46% in 2015-2016 to 59% in 0 200 400 600 800 2017-2018. Assessed in two-year cohorts, products that N= Number of NASs Median time, days underwent the parallel review process in 2015-2016 and in Figure 19: Time taken from regulatory approval to HTA 2017-2018 had faster regulatory and HTA review times. In recommendation by review type 2017-2018, the median time taken from regulatory Sequential Regulatory authority review time Parallel approval to HTA recommendation for the parallel process HTA submission to HTA recommendation (national level) was a median 220 days faster that the sequential process. © CIRS, R&D Briefing 73 CDR (42) 354 40% 60%

A higher proportion of NASs submitted to the Health 213 2016 Canada/CADTH parallel process underwent pCODR review - pCODR (19) 348 35% compared with CDR review (Figure 19). Thus, the rollout 65%

2015 193 time from regulatory submission to HTA recommendation for NASs submitted for pCODR review was shorter than CDR (31) 356 42%

those submitted for CDR review. In 2017-2018, NASs 193 58% 2018 submitted to pCODR had a faster time to HTA - recommendation than CDR, which was mainly driven by pCODR (13) 270 38% 62% shorter review time by Health Canada. 2017 199 0 200 400 600 800 N= Number of NASs Median time, days

R&D Briefing 73 July 2019, © Centre for Innovation in Regulatory Science, Ltd. 7 FEATURES OF EUROPE

Figure 20: Time taken from regulatory approval to HTA recommendation by HTA outcome Positive Restriction Negative 1600 Time taken from regulatory approval 1400 to HTA recommendation includes • Company submission strategy 1200 • Company time for pre-submission 1000 preparation • HTA agency review time 800

600

400 Median time, time, days Median 200 © CIRS, R&D Briefing 73

2014 2015 2016 2017 2018 2014 2015 2016 2017 2018 2014 2015 2016 2017 2018 2014 2015 2016 2017 2018 2014 2015 2016 2017 2018 2014 2015 2016 2017 2018 England France Germany Poland Scotland Sweden * NASs with multiple outcome were excluded from the analysis due to low numbers Generally, NASs that received a negative recommendation took longer to receive that HTA recommendation from the time of EMA approval. However, the median time from regulatory approval to HTA recommendation in 2018 shortened in England, France and Scotland for all HTA outcomes (Figure 20). Despite the fact that new drugs were approved at the centralised level, Figure 20 shows divergent timing from regulatory approval to HTA recommendation across the jurisdictions. The shortest time from regulatory approval to HTA recommendation for NASs that received a positive recommendation occurred in Germany, at a median of 113 days in 2014-2018. Figure 21: Breakdown of rollout time (days) by EMA approval type for 40 common NASs 40 NASs approved by EMA have been Regulatory authority review time appraised by all six EMA jurisdictions, of Regulatory approval to HTA recommendation (national level) which 21 were anti-cancer products and 9 England Standard 394 297 were anti-infectives. Acc only 258 314 Cond only 468 476 Acc+Cond 248 465 Among the 40 commonly appraised NASs, Standard 394 213 © CIRS, R&D Briefing 73 France Acc only 258 112 eight were approved as accelerated approval Cond only 468 235 Acc+Cond 248 392 by EMA, four were conditional approvals and Standard 394 143 two were accelerated and conditional Germany Acc only 258 102 Cond only 468 154 approvals. Accelerated products had the Acc+Cond 248 116 fastest median time from regulatory approval Standard 394 502 Poland Acc only 258 264 Cond only 468 524 to HTA decision in all jurisdictions except Acc+Cond 248 635 England. In particular, in Poland, the median Standard 394 172 Acc only 258 87 time was nearly half of the standard approvals. Scotland Cond only 468 268 Acc+Cond 248 275 (Figure 21). In general, anti-infective NASs Standard 394 179 showed the fastest median time from Acc only 258 87 Sweden Cond only 468 263 regulatory approval to HTA recommendation Acc+Cond 248 579 and the highest proportion of positive or 0 200 400 600 800 1000 Median time, days positive with restrictions HTA Number of Standard = 26; Number of Accelerated = 8; Number of Cond only = 4; Number of Acc+Cond = 2 recommendation (Figure 22 and 23).

Figure 22: Time taken from regulatory approval to HTA Figure 23: First HTA recommendation comparison for 40 recommendation by therapeutic area in for 40 common NASs common NASs by therapeutic area © CIRS, R&D Briefing 73 Median, Box : 25th and 75th percentiles Positive Restriction Negative Multiple England France Germany Poland Scotland Sweden 1200 England France Germany Poland Scotland Sweden Number of Anti-cancer = 21; Number of Anti-infectives = 9; Others = 10 100% 1 1 1 1 1000 1 1 1 1 2 3 2 © CIRS, R&D Briefing 73 3 6 3 80% 4 4 7 11 5 800 4 4 14 6 12 690 60% 6 8 600 5 9 366 5 40% 7 314 5 Time, Time, days 400 479 14 6 222 5 12 4 5 190282 5 5 136 148 20% 5 9 Proportion recommended Proportion of NASs 8 200 290 3 3 3 213 228 214 79 5 2 2 1 103 166

0 107 93 0%

Others Others Others Others Others Others

Anti-cancer Anti-cancer Anti-cancer Anti-cancer Anti-cancer Anti-cancer

Anti-infectives Anti-infectives Anti-infectives Anti-infectives Anti-infectives Anti-infectives

Anti-cancer Anti-cancer Anti-cancer Anti-cancer Anti-cancer

Anti-cancer 9

Anti-infectives Anti-infectives Anti-infectives Anti-infectives Anti-infectives Anti-infectives

Figure 24: Comparison of the regulatory and reimbursement system across targeted jurisdictions

Australia TGA PBAC PBS list Pharmaceutical Benefits Scheme + 79 NASs

England EMA NICE Implementation of NICE guidance + 91 NASs

France EMA HAS Publication in Journal Officiel + 93 NASs

Germany EMA IQWiG G-BA decision +/- 85 NASs

Sweden EMA TLV TLV decision +/- 96 NASs

+ List of reimbursable drugs available HTA recommendation vs reimbursement +/- List of reimbursable and non-reimbursable drugs available outcome HTA recommendations are used by payers to support reimbursement decisions. In this report, the database was extended beyond HTA information to collect reimbursement outcome decisions and dates. Figure 24 illustrates the key agencies involved in the regulatory and reimbursement systems and the connection between the HTA recommendation and reimbursement outcome. Data were collected only on reimbursable drugs in this cohort up to May 2019 to explore the availability of new medicines in these jurisdictions. Figure 25: Breakdown of rollout time for reimbursable drugs with HTA recommendation in 2014-2018 Regulatory authority review time Regulatory approval to first HTA recommendation First HTA recommendation to reimbursement decision Australia (79) 368 16 261 © CIRS, R&D Briefing 73

England (91) 423 338 91

France (93) 409 201 259

Germany (85) 408 116 86

Sweden (96) 420 214 1

N= Number of NASs 0 200 400 600 800 1000 Median time, days France took the longest time to receive a Figure 26: Rollout time from first HTA recommendation to reimbursement reimbursement decision for new medicines, Median, Box : 25th and 75th percentiles approximately 1.5 years after EMA approval (Figure 25). N= Number of NASs Median, Box : 25th and 75th percentiles 500 © CIRS, R&D Briefing 73 Reimbursement decision dates reflect the availability of 450 new medicines. Germany showed the quickest time from 400 regulatory approval to reimbursement decision (median, 350 206 days). The variation between time from first HTA 300 261 259 recommendation to reimbursement decision shows the 250 diversity of reimbursement systems (Figure 26). In 200

Time, Time, days Sweden, reimbursement was granted immediately after 150 91 86 TLV recommendation. In England, drugs must be 100 reimbursed within 3 months of a NICE recommendation 50 1 by law and 30 days for NASs on the Early Access to 0 Medicines Scheme (EAMS) and fast track appraisal. In Australia England France Germany Sweden Germany, according to The Act on the Reform of the (79) (91) (93) (85) (96) Market for Medical Products (AMNOG), G-BA needs to make a decision 3 months after an IQWiG recommendation.

R&D Briefing 73 July 2019, © Centre for Innovation in Regulatory Science, Ltd. 9 METHODOLOGY The data on individual NASs appraised by HTA agencies in 2014-2018 were collected using public domain data derived from the agencies’ official websites. Only the first recommendation based on the first assessment reports were considered. HTA agencies provide recommendations/ advice on the medicines that can be reimbursed by the healthcare systems. In Australia, England, Scotland and Sweden, HTA recommendations not to list are binding. However, in Canada, France, Germany and Poland, a relevant decision-making body such as the Ministry of Health makes the final reimbursement decision. PBAC can defer a recommendation pending the provision of specific additional information that would be relevant and important to its recommendation. The HTA recommendations in this report have been classified into the following categories: positive, positive with restrictions and negative. Figure 27 illustrates how the specific recommendations by the eight HTA systems fall into this trichotomous categorisation. There are a number of cases that reflected the different HTA approaches based on the regulatory approved label; these are illustrated in Figure 28. Scenario 1: For France and Germany, the HTA agencies’ assessment of the added therapeutic benefit rating for a product may be for a sub-indication of the approved regulatory label, with possible different assessment outcomes for each sub- indication. The final HTA outcome for these cases was classified in this study as positive with restrictions. Scenario 2: In the case in which more than one HTA dossier was submitted by companies for the same drug based on different sub-indications of an approved regulatory label and obtained different first HTA recommendations, the final HTA outcome was classified as multiple. In this study, this occurrence was observed in Australia, Germany and Scotland.

Figure 27: Trichotomous categories of HTA recommendations

Figure 28: Special cases of HTA recommendations Scenario 1 – HTA recommendations were based on assessments of sub-indication of approved regulatory label

Recommendation for sub-indication 1 NAS regulatory One HTA submission with Company submission to HTA agency HTA recommendation sub-indication 2 approval one HTA assessment sub-indication 3 sub-indication 4

Scenario 2 – HTA recommendations were multiple as companies submitted dossier based on sub-indications of approved regulatory label

HTA submission for sub- Recommendation for assessment indication 1 of sub-indication 1 NAS regulatory Company submission to HTA agency HTA recommendation approval HTA submission for sub- Recommendation for assessment indication 2 of sub-indication 2

R&D Briefing 73 July 2019, © Centre for Innovation in Regulatory Science, Ltd. 10 DEFINITIONS Anti-cancer drugs molecular structure, nature of source material or In this Briefing, anti-cancer drugs refers to anti- manufacturing process and which will require cancer and immunomodulators (ATC code L). clinical investigation. • A radiopharmaceutical substance that is a Exclusion criteria radionuclide or a ligand not previously available Applications that are excluded from the study as a medicinal product; alternatively, the coupling • Vaccines mechanism linking the molecule and the • Any other application, where new clinical data radionuclide has not been previously available. were submitted Parallel review • Generic applications Pharmaceutical companies submit evidence to the • Those applications where a completely new regulatory agency that prove the efficacy, safety, dossier was submitted from a new company for quality of the product. However, during the the same indications as already approved for regulatory review process, companies submit another company dossiers to HTA bodies so that the two review • Applications for a new or additional name, or a steps can occur in parallel. Following the regulatory change of name, for an existing compound (i.e. approval, HTA recommendation will be provided to a ‘cloned’ application) companies for drug reimbursement. This sequence is available in Australia and Canada. In this report, First assessment report a drug is identified as parallel if HTA The first assessment report is the earliest recommendation is earlier than regulatory assessment available. Note that for some drugs; approval. for example, those with the same INN, strength and presentation, are listed more than one time. US Breakthrough Designation The reasons may be twofold – consideration of the An FDA process designed to expedite the drug in more than one indication or re-assessment development and review of drugs that may of the drug by the agency. demonstrate substantial improvement over available therapy. Health technology assessment (HTA) Reimbursement date For the purpose of this project, HTA refers to the assessment and appraisal of pharmaceuticals prior Publication date of reimbursement decision. to reimbursement. The HTA process includes Regulatory submission gap clinical assessment, economic assessment and an appraisal that results in either a coverage Date of submission at the first regulatory agency to recommendation or recommendation. the date of regulatory submission to the target agency. HTA review time Time (calendar days) calculated from the date of Regulatory review time submission to the date of recommendation by the Time (calendar days) calculated from the date of HTA agency; Note: The HTA recommendation submission to the date of approval by the agency; refers to the recommendation at national level. this time includes agency and company time. Note: The EMA approval time includes the EU New active substance (NAS) Commission time. A chemical, biological, biotechnology or radiopharmaceutical substance that has not been Rollout time previously available for therapeutic use in humans Date of submission at the regulatory agency to the and is destined to be made available as a date of HTA recommendation at the target ‘prescription-only medicine’, to be used for the jurisdiction (calendar days). cure, alleviation, treatment, prevention or in vivo Sequential review diagnosis of diseases in humans; the term NAS Regulatory review is conducted first to determine also includes: the benefit-risk profile of a new medicine, followed • An isomer, mixture of isomers, a complex or by the HTA review to assess the value of the derivative or salt of a chemical substance medicine for a reimbursement decision. The previously available as a medicinal product but regulatory-HTA sequence is seen at a national differing in properties with regard to safety and level in many countries, and also at a super- efficacy from that substance previously available national level in Europe where a centralised as a medicinal product, but differing in molecular regulatory decision made by the European structure, nature of source material or Medicines Agency is followed by jurisdictional HTA manufacturing process and which will require recommendations by member states. clinical investigation. • A biological or biotech substance previously available as a medicinal product, but differing in

Report prepared by

Tina Wang, MSc, HTA Programme Manager Jesmine Cai, PhD, Senior Analyst Neil McAuslane, PhD, Director Jamie Munro, PhD, Executive Director

Please cite this report as:

Wang T, Cai J, McAuslane N, Munro J. 2019. R&D Briefing 73: Review of HTA outcomes and timelines in Australia, Canada and Europe 2014 -2018. Centre for Innovation in Regulatory Science. London, UK.

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