Htadock R&D Briefing

Review of HTA outcomes and timelines in Australia, Canada and Europe 2015-2019

Figure 1: First HTA recommendations: comparisons across key jurisdictions in 2019 Positive Restriction Negative Multiple © CIRS, R&D Briefing 78 Australia Canada England France N=13 N=26 N=22 N=32 5% 22% 31% 36% 41% 69% 59% 46% 54% 37%

Germany Poland Scotland Sweden N=26 N=19 N=21 N=14 5% 11% 21% 31% 21% 19% 36% 54% 43% 33% 15% 68% 43%

Contents Summary 2 Overview of new drug recommendations 3 Synchronisation of regulatory and HTA recommendations 4 37 NASs appraised by seven jurisdictions in 2015-2019 5 Focus on Orphan Designation 6 Focus on ATMPs 7 Features of Australia 8 Features of Canada 9 Features of Europe 10 Overview of HTA implementation 12 Methodology and definitions 13

R&D BRIEFING 78 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 2015 and 2019 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 2012-2019 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 13, the HTA recommendations in this report have been classified as positive, positive with restrictions or negative. Figure 32 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

• In 2019, 46% to 95% of NASs approved In Australia, more than 60% of NASs were listed in the by regulatory agencies received a PBS list in 2015-2019 after receiving a positive or positive or positive with restrictions positive with restrictions first recommendation. first recommendation by HTA agencies across all of the studied jurisdictions. Of 103 drugs with PBAC recommendations in Australia from 2015- England had the highest proportion of 2019, 63 were listed in the PBS list. Of those drugs in the PBS list, 38% positive/positive with restrictions took more than one cycle to receive a positive/ positive with recommendations for NASs appraised restrictions PBAC recommendation. by HTA agencies.

• Of all studied HTA agencies, Germany had the highest proportion of In Canada, the HC/CADTH parallel process reduced products recommended within one the time from regulatory approval to HTA year of regulatory approval (92% in recommendation. 2019). Approximately half of the NASs submitted for HTA recommendation underwent the Health Canada/ CADTH parallel review process. The • Australia had the shortest median parallel review process was a success in reducing the time taken to time between regulatory approval and reach the first HTA recommendation. In 2018-2019, the median time HTA recommendation (24 days) in taken from regulatory approval to HTA recommendation was reduced 2015-2019, followed by Germany (132 by using the parallel process (144 days), compared to the sequential days). process (426 days).

• CIRS analysed NASs rolled out to seven jurisdictions, excluding Poland due to variation, and identified 37 In Europe, the lag between EMA approval and HTA NASs that received a recommendation recommendations varied across the European by all HTA agencies during the period jurisdictions, from 132 median days in Germany to of 2015-2019. Germany provided the 538 median days in Poland. highest number of recommendations as the first country of appraisal (30%), In the studied European jurisdictions, the time from EMA approval to followed by Australia (24%). England HTA recommendation was generally longer for those NASs that and Scotland had the highest received a negative HTA outcome. Among 39 commonly appraised congruence (73%) of first HTA NASs approved by EMA, drugs with accelerated regulatory approval recommendations. generally had the fastest median time from regulatory approval to HTA recommendation.

R&D Briefing 78 July 2020, © Centre for Innovation in Regulatory Science, Ltd. 2 OVERVIEW OF NEW DRUG RECOMMENDATIONS

Figure 2: First HTA recommendation comparison across key jurisdictions by year of HTA recommendation Between 2015-2019 Positive Restriction Negative Multiple 100% 1 1 1 1 1 1 1 2 2 2 2 2 2 3 3 3 3 2 2 5 4 4 5 7 3 10 8 10 4 7 5 4 8 80% 10 1011 6 10 7 14 14 8 1411 12 13 13 13 8 4 13 8 60% 10 1915 1312 14 7 11 17 13 7 6 12 8 17 5 6 19 8 1 19 40% 3 4 1 24 18 27 12 13 7 16 18 12 8 12 20% 10 10 9 13 11 9 6 7 8 11 8 4 9 8 5 8 9 8 5 8 4 5 6 4 4

Proportionrecommended ofNASs 2 2 2 0% 1 1 1

Australia Canada England France Germany Poland Scotland Sweden N= Number of NASs © CIRS, R&D Briefing 78 In 2019, England had the highest proportion (95%) of positive/positive with restrictions recommendations for NASs appraised by HTA agencies (Figure 1). Within this cohort, France appraised the highest number of NASs in 2019 (32 NASs), while Australia appraised the fewest (13 NASs) (Figure 1). In 2019, three Australian PBAC recommendations obtained TGA approval in 2020 and were outside of the criteria of this briefing. 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 45% 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 2019 (Figure 2). Over these five years, Australia and Poland had a gradual increase in the proportion of positive or positive with restrictions recommendations (increase from 42% in 2015 to 54% in Australia and increase from 11% in 2015 to 89% in Poland). Australia had the fastest median rollout time from regulatory submission to first HTA recommendation in 2019 (408 days), followed by Canada (556 days). There were less variation in rollout time in these two countries in 2019 compared with 2018, which indicated an improved consistency (Figure 3). The median rollout time has been relatively constant in 2015-2019 across all jurisdictions with the exception of England and Poland, which showed a decrease of 83 and 103 median days respectively from 2018 to 2019. In Poland, a decrease in 246 median days was observed over the last 3 years, from 1188 days in 2016 to 942 days in 2019. 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 th th Median 25 and 75 percentiles, Overall median (1744) 1400

762 1200 673 857 971 723 1000 774 694 743 706 467 609 679 674 700 800 609 1188 1045 571 521 538 942 350 803 600 383 709 Time, Time, days 821 687 692 665 658 581 590 572 597 585 535 400 556 518 408 362 200 © CIRS, R&D Briefing 78 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 78 July 2020, © Centre for Innovation in Regulatory Science, Ltd. 3 SYNCHRONISATION OF REGULATORY AND HTA RECOMMENDATIONS

Figure 4: Breakdown of rollout time across all jurisdictions in 2015-2019 2015 380 15 Australia 2016 351 32 2017 360 126 Regulatory authority review time 2018 364 17 2019 346 25 Regulatory approval to HTA 2015 391 251 recommendation (national level) Canada 2016 348 175 2017 356 182 2018 338 162 2019 344 207 Time taken from regulatory approval 2015 409 314 to HTA recommendation includes England 2016 441 341 2017 402 386 • Company submission strategy 2018 444 288 • Company time for pre-submission 2019 415 321 preparation 2015 417 228 France 2016 418 202 • HTA agency review time 2017 421 194 2018 407 246 2019 436 276 2015 437 139 Germany 2016 406 129 2017 388 116 2018 450 142 2019 435 140 2015 394 444 2016 427 524 Poland 2017 422 802 2018 388 603 2019 419 564 2015 418 257 2016 369 203 Scotland 2017 419 293 2018 430 259 2019 417 257 Median time, days 2015 415 184 2016 406 159 Sweden 2017 406 217 2018 423 241 © CIRS, R&D Briefing 78 2019 433 222 0 200 400 600 800 1000 1200 Median time, days

Australia had the shortest median time between regulatory approval and HTA recommendation of 24 days in 2015- 2019 (Figure 4). PBAC had the shortest overall median time between regulatory approval and HTA recommendation, suggesting the proactive approach within Australia to move toward synchronising the timing of HTA and regulatory recommendation is achieving its purpose. The time taken from regulatory approval to HTA recommendation can be attributed to company submission strategy, company time for pre-submission preparation and HTA agency review time. Among these eight jurisdictions, HTA submission dates are only provided in Australia, Canada, England, Germany and Poland (Figure 5). The parallel review mechanism in Australia and Canada has shortened the time from regulatory approval to HTA submission. In Germany, companies can set their drug prices freely at market entry but they must submit a HTA dossier to G-BA (Federal Joint Committee, Gemeinsamer Bundesausschuss) who then request IQWiG to assess the added therapeutic benefit of the drug over the appropriated comparator within 3 months. Although Poland had a shorter HTA appraisal time (80 days), it took a longer time for the product to reach patients due to the gap between regulatory approval and HTA submission. Figure 5: Breakdown of rollout time in jurisdictions where HTA submission date is provided 2015-2019*

Australia (103) 364 © CIRS, R&D Briefing 78 122 Regulatory authority review time Canada (131) 349 203 HTA submission to HTA recommendation (national level) England (105) 423 267

Germany (137) 423 89 * Only jurisdictions with HTA Poland (97) 414 submission dates available in the public 80 domain were included in this figure. 0 200 400 600 800 1000 Median time, days

R&D Briefing 78 July 2020, © Centre for Innovation in Regulatory Science, Ltd. 4 37 NASS APPRAISED BY SEVEN JURISDICTIONS IN 2015-2019 France had the highest proportion of positive recommendations Figure 6: First HTA recommendation comparison for 37 common NASs across seven jurisdictions for 37 NASs appraised by all seven HTA agencies (51%), with Positive Restriction Negative Multiple Canada showed the lowest proportion (3%). n = Date order of the first HTA recommendation CIRS analysed NASs rolled out to seven jurisdictions, excluding Country AUS CAN ENG FRA GER SCO SWE Poland due to variation, and identified 37 NASs that had been approved between 2012 and 2019 and that had also received a first abemaciclib 4 7 3 1 2 5 6 HTA recommendation between 2015 and 2019 by all seven HTA 2 1 7 5 3 6 4 alectinib hydrochloride agencies. Figure 6 shows a traffic light system to compare the alirocumab 7 5 3 2 1 4 6 different HTA outcome across jurisdictions in 2015-2019, reflecting apremilast 1 5 6 7 3 2 4 the diverse perception on the value of these NASs across the baricitinib 6 7 5 2 3 4 1 agencies. The recommendation dates for each product were compared across all seven agencies and the order of first HTA benralizumab 1 4 6 5 2 7 3 recommendation was ranked accordingly. brigatinib 7 5 2 6 3 4 1 In England and France, the majority of NAS received a positive/ ceritinib 7 4 6 2 1 3 5 positive with restrictions recommendation (95% and 92% 4 2 7 5 1 3 6 daratumumab respectively). In comparison, in Australia and Germany the first HTA dupilumab 5 3 6 4 1 7 2 recommendation were mostly negative (54% and 46% of the NASs elbasvir + grazoprevir 2 1 5 4 7 6 3 review respectively). NASs were mostly likely to receive a restrictive eliglustat tartrate 2 6 5 3 1 7 4 recommendation in Canada (73% of the 37 products). In this cohort, none of the NASs had the same first HTA recommendation but 7 1 5 7 3 2 6 4 evolocumab NASs received positive/ positive with restrictions outcome from all glecaprevir / pibrentasvir 4 6 7 5 3 2 1 seven jurisdictions. 4 2 6 7 3 5 1 guselkumab Germany provided the highest number of recommendations as the ibrutinib 5 2 7 4 1 6 3 first country of appraisal (30%), followed by Australia (24%) ixekizumab 1 4 6 3 7 5 2 (Figure 7). ledipasvir; sofosbuvir 5 6 7 4 3 1 2 In England, 57% of the NASs received a NICE recommendation as the th th lenvatinib 4 5 7 2 1 6 3 6 or 7 country among all jurisdictions (Figure 7). England and lumacaftor 2 6 5 4 1 3 7 Scotland had the highest congruence (73%) of first HTA recommendations, where identical HTA outcomes were provided 1 5 7 6 2 3 4 mepolizumab based on the trichotomous categories of HTA recommendation midostaurin 1 2 6 6 3 5 4 (Figure 8). 6 7 5 4 1 2 3 migalastat hydrochloride Germany had the shortest median time (523 days) from first nintedanib 2 7 6 5 3 1 4 world-wide regulatory submission to jurisdictional HTA olaparib 6 7 5 2 4 3 1 recommendation, followed by Australia (578 days) (Figure 9). ombitasivr; paritaprevir; ritonavir 6 5 7 2 3 4 1 Figure 8: Congruence of first HTA recommendations osimertinib mesylate 7 5 3 2 1 4 6 for 37 common NASs across seven jurisdictions AUS CAN ENG FRA GER SCO palbociclib 3 1 7 4 2 6 5 CAN 19% 1 7 3 5 2 6 4 ribociclib succinate ENG 22% 57% risankizumab 3 1 4 7 5 6 2 FRA 30% 32% 35% sacubitril / valsartan 2 3 6 7 4 1 5 GER 22% 32% 24% 41% SCO 27% 51% 73% 43% 35% sarilumab 7 1 2 5 3 6 4 SWE 19% 54% 57% 49% 38% 57% secukinumab 1 6 4 7 5 2 3 ≥ 50% and <75% congruence 75% congruence sofosbuvir / velpatasvir 6 5 7 4 3 2 1 tofacitinib citrate 1 2 6 5 4 7 3 Figure 9: Breakdown of rollout time (days) across 7 jurisdictions trifluridine/tipiracil for 37 common NASs in 2015-2019 5 7 1 3 4 6 2 hydrochloride Regulatory submission gap © CIRS, R&D Briefing 78 Regulatory authority review time venetoclax 4 6 5 2 1 3 7 Regulatory approval to HTA recommendation Australia 127 362 14 Figure 7: First agency to obtain HTA recommendation Canada 65 349 162 for 37 common NASs across seven jurisdictions England Australia 379 272 Canada France 379 198 19% England 24% Germany 379 128 France 8% Scotland 13% Germany 379 184 3% Scotland Sweden 379 154 30% 3% Sweden 0 100 200 300 400 500 600 700 © CIRS, R&D Briefing 78 Median time, days

R&D Briefing 78 July 2020, © Centre for Innovation in Regulatory Science, Ltd. 5 FOCUS ON ORPHAN DESIGNATION

Figure 10: Breakdown of rollout time by regulatory Figure 11: First HTA recommendation comparison across key orphan designation in 2015-2019 jurisdictions by regulatory orphan designation in 2015-2019

Regulatory authority review time Positive Restriction Negative Multiple © CIRS, R&D Briefing 78 Regulatory approval to HTA recommendation (national level) Australia England France Germany Poland Scotland Sweden 100% 1 2 3 AUS Standard (76) 365 7 © CIRS, R&D Briefing 78 4 5 3 4 8 Orphan (27) 12 1 350 166 5 13 10 ENG Standard (67) 417 273 80% 26 17 Orphan (48) 428 445 37

18 22 FRA Standard (87) 417 226 33 54 7 27 11 38 Orphan (60) 444 238 60% 38 32 GER Standard (82) 420 134 2 Orphan (55) 441 119 51 40% Standard (63) 29 POL 414 470 recommended Proportion of NASs Orphan (34) 416 734 38 13 37 41 20 SCO Standard (71) 20% 10 414 253 17 23 Orphan (41) 410 260Median time (days) 9 21 23 21

SWE Standard (63) 418 182 8 3 2 Orphan (25) 423 553 0%

0 200 400 600 800 1000 1200

Orphan Orphan Orphan Orphan Orphan Orphan Orphan

Standard Standard Standard Standard Standard Standard Median time, days Standard

The regulatory orphan designation lengthened the overall time to HTA recommendation (Figure 10) but did not have a considerable effect on the type of HTA recommendation in all jurisdictions except Germany (Figure 11). In an effort to expedite the approval of drugs treating serious illness or addressing unmet medical need, orphan designations has been used in several regulatory agencies (TGA in Australia and EMA in Europe). The effects of regulatory orphan designation was explored in terms of time to first HTA recommendation and HTA outcome. NAS with regulatory orphan designation had a longer time post-regulatory process (time from regulatory approval to HTA recommendation) in all jurisdictions except Germany (Figure 10). Interestingly, there is little time difference in regulatory approval between standard and orphan drugs, indicating that the increase in overall time was driven post-regulatory. The time taken from regulatory approval to HTA recommendation includes company strategy and HTA review time. In addition, the regulatory orphan designation do not have a considerable effect on HTA recommendation with the exception of Germany (Figure 11). In this briefing, IQWiG recommendations for orphan drugs are considered as positive as additional therapeutic benefit is considered to be proved at marketing authorisation. The assessment of orphan drugs are conducted by G-BA and the assessment report outcome was out of scope of this briefing. Figure 12: Proportion of regulatory orphan designations The list of HTA orphan/rare disease-related pathways across all with HTA orphan/rare disease-related Pathways jurisdictions are elaborated in the Appendix (HTA orphan/rare disease-related pathway, Figure 34). Standard HTA pathways © CIRS, R&D Briefing 78 HTA orphan/ rare disease-related pathways Not all NAS that received a regulatory orphan designation

Australia (27) England (48) undergo a HTA orphan/rare disease-related pathway (Figure 12). In Germany and Scotland, the majority of the NAS that received a 11, regulatory orphan designation underwent a HTA orphan/ rare disease-related pathway (93% and 85% respectively) while in 12, 23% Australia and England, less than half of the NAS that received a 44% 15, regulatory orphan designation went on to a HTA orphan/ rare 56% 37, 77% disease-related pathway. In England and Germany, all the NAS that underwent a HTA orphan/ rare disease-related pathway received a regulatory Germany (55) Scotland (41) orphan designation. In these countries, the EMA orphan 4, designation criteria is used in the HTA orphan/ rare disease- 6, 7% related pathways (Figure 34). However, in Australia and Scotland, 15% a fewer proportion of NAS that underwent a HTA orphan/ rare disease-related pathway received a regulatory orphan designation (55% and 69% respectively). In Australia, the HTA orphan/ rare 51, 35, disease-related pathways identified do not apply to only orphan 93% 85% drugs and thus, there is less congruence in the orphan-related criteria between regulatory and HTA.

R&D Briefing 78 July 2020, © Centre for Innovation in Regulatory Science, Ltd. 6 FOCUS ON ATMP Advanced therapy medical products (ATMPs) have the potential to address high unmet medical need but their complexity and novelty present challenges to patient access. Ten ATMPs were approved in Australia, Canada and Europe in 2015-2019. Data on the regulatory and HTA landscape of ATMPs were collected up to June 2020 (Figure 13). Figure 13: Regulatory and HTA landscape of ATMPs

Regulatory HTA © CIRS, R&D Briefing 78

EMA Brand EMA Regulatory Type EMA FRP approval AUS CAN ENG FRA GER SCO SWE POL Name Orphan approval year

Alofisel Y 2018 Orphan Cell therapies Zalmoxis Conditional Y 2016

Imlygic N 2015 AUS (2015) PAS HE

AUS (2018), Ultra- Kymriah PRIME Y 2018 MAA MEA HE CAN (2018) Orphan; PAS

Luxturna Y 2018 HST; PAS HE Gene therapies Strimvelis Y 2016 HST

AUS (2020), Ultra- HE Yescarta PRIME Y 2018 2020 MAA MEA CAN (2019) Orphan; PAS (2020) PRIME, MEA Zynteglo Y 2019 2020 Accelerated (2020)

Tissue- Holoclar Conditional Y 2015 AUS (2015) PAS based therapies Spherox N 2017

First HTA recommendations: Positive Restriction Negative Different HTA committee PAS: Patient Access Schemes; MAA: Managed Access Agreement; HST: Highly-Specialised Technologies; HE: Health Economic Assessments ATMPs can be assessed through a different HTA assessment procedure (e.g. medical devices), undergo a HTA-related orphan drug pathway and be provided Managed Entry Agreements (MEAs) to address its uncertainty. HTA agencies have various ways of dealing with this uncertainty (Figure 13), in terms of: 1) HTA assessment procedure. ATMPs may be assessed as a health technology by a different HTA committee in Australia (Medical Services Advisory Committee, MSAC) and Canada (Health Technology Expert Review Panel, HTERP). In Sweden, health economic assessments (HE) are conducted for ATMPs and TLV is investigating the payment models for ATMP. 2) Orphan drug pathways. 80% of ATMPs with EMA approval are classified as orphan drugs and HTA orphan/ rare disease- related pathways can be applied to these ATMPs. In Scotland, all 3 ATMPs assessed were considered for a PACE meeting. 3) Managed Entry Agreements (MEAs). Financial MEAs through Patient Access Schemes (PAS) in NICE and SMC and performance-based MEA such as Managed Access Agreement (MAA) in NICE can be used. Kymriah is the first ATMP to receive a HTA recommendation in all key jurisdictions excluding Poland and Sweden, followed by Yescarta. The time from regulatory approval to HTA recommendation across these jurisdictions for Kymriah is relatively similar (117 median days), with France and Germany having the fastest time to HTA recommendation (Figure 14). Yescarta took a longer time to HTA recommendation and more variation in time between the jurisdictions is observed. Figure 14: Breakdown of rollout time (days) across key jurisdictions for Kymriah and Yescarta Regulatory rollout time Regulatory approval to HTA recommendation (HTA outcome) Regulatory submission gap Regulatory authority review time Positive Restriction Negative Australia 159 253 111 Kymriah Australia TGA information unavailable Yescarta

Canada 99 208 132 Canada 359 205 183

England 293 121 England 390 153

France 293 112 France 390 104 Median time (days) Germany 293 113 Germany 390 159 © CIRS, R&D Briefing 78 © CIRS, R&D Briefing 78 Scotland 293 142 Scotland 390 141 238 0 100 200 300 400 500 600 700 800 0 100 200 300 400 500 600 700 800 Median time, days © CIRS, R&D Briefing 78 Median time, days

R&D Briefing 78 July 2020, © Centre for Innovation in Regulatory Science, Ltd. 7 FEATURES OF AUSTRALIA

Figure 15: Breakdown of rollout time by type of sequence Companies have taken advantage of the parallel in 2015-2019 Regulatory authority review time review mechanism in Australia, with 65% products HTA submission to HTA recommendation (national level) undergoing this process and submitted to PBAC approximately 4 months before TGA approval (Figure Sequential 367 © CIRS, R&D Briefing 78 (36) 15). 122 Under the TGA/PBAC parallel process, the TGA Parallel 362 delegate’s overview is informative to PBAC (67) 122 consideration to appraise a drug and companies can submit the regulatory delegate overview up to a week 0 200 400 600 800 prior to the PBAC meeting. Median submission to PBAC Median time, days (N)= Number of NASs was 138 days prior to TGA approval for products that went through parallel review, compared with a 110-day Figure 16: Number of cycles to first positive/ positive with delay in HTA submission with sequential review. restrictions HTA recommendation in PBS list in 2015-2019 In PBS list 61% of drugs with PBAC recommendations in 2015- Positive PBAC recommendation 2019 were listed in the PBS list in Australia, of which 1 cycle 2 cycles 3 or more cycles but not in PBS list yet Not in PBS list 38% appraised by PBAC took more than one cycle to 21% be listed in the PBS in this cohort (Figure 16). 2015 10 5 4 79% PBAC makes HTA recommendations for listing of 22% medicines on the Pharmaceutical Benefits Scheme (PBS) 2016 7 4 3 78% list that are non-binding and require Ministerial approval. For pharmaceuticals with a projected annual 4% 2017 10 4 4 24% cost of less than AUD$20 million, the Minister of Health 72% (or a delegate) is the decision maker for listing new 17% drugs onto the PBS. For pharmaceuticals with a 2018 9 39% 44% projected annual cost of greater than AUD$20 million, Cabinet consideration is required. These decisions 23% 18% 2019 3 follow the completion of negotiations with the sponsor 59% by officers from the Australian Government 0% 20% 40% 60% 80% 100% Department of Health based on the advice from PBAC. Proportion of NASs recommended © CIRS, R&D Briefing 78 In Australia, drugs cannot be listed on the PBS without a Figure 17: Breakdown of rollout time for PBS-listed PBAC recommendation to do so. When the first HTA drugs in Australia in 2015-2019 recommendation does not support listing, companies can re-submit an application with an improved dossier. Regulatory authority review time Consequently, a number of review cycles may take HTA submission to HTA implementation place until a positive/positive with restriction recommendation is achieved to support listing. The 2015 1 cycle (10) 368 367 proportion of drugs that had a regulatory approval, HTA recommendation and was listed with one-cycle review >1 cycle (9) 382 747 was higher in 2018-2019 (all 12 products in PBS list) compared with 2015-2017 (53%). However, the 2016 1 cycle (7) 350 352 proportion of drugs not listed in the PBS list was higher in 2018-2019 compared to previous years as drugs may >1 cycle (7) 352 535 not be listed yet or have not gone through a re- submission. Multiple review cycles increase the time 2017 1 cycle (10) 362 321 from HTA submission to HTA implementation/ publication in the PBS list (732 median days in 2015- >1 cycle (8) 353 672 2017, Figure 17). The Department of Health and Medicines Australia have been working since 2017 to 2018 1 cycle (9) 364 323 deliver on commitments under clause 10 of the >1 cycle (0) Strategic Agreement to streamline medicines listing processes, including a target of 50% reduction in the number of resubmissions to the PBAC and reduction in 2019 1 cycle (3) 378 381 time from PBAC recommendation to listing by an >1 cycle (0) average of two months. © CIRS, R&D Briefing 78

0 200 400 600 800 1000 (N)= Number of NASs Median time, days

R&D Briefing 78 July 2020, © Centre for Innovation in Regulatory Science, Ltd. 8 FEATURES OF CANADA

In 2016-2019, anti-infectives took the shortest time from Figure 18: Time from regulatory approval to HTA regulatory approval to HTA recommendation (Figure 18). recommendation by therapeutic area Median 25th and 75th percentiles The top four therapeutic groups from the 96 NASs assessed Overall median 2016-2019 for each therapy area Alimentary Anti- Nervous by CADTH in 2016-2019 were anti-cancer & Anti-cancer & immunomodulators & metabolism infectives system 500 immunomodulators (40%), alimentary & metabolism Overall ATC L: ATC L: (21%), anti-infectives (10%) and nervous system (5%). ATC L CDR pCODR 400 301 Looking at the overall median time taken from regulatory 300 132 approval to HTA recommendation, anti-infectives were 157 181 144 262 175 fastest, followed by anti-cancer & immunomodulators 200 221 Time, Time, days 99 105 (Figure 18). In addition, all anti-infectives and nervous 100 160 system products appraised in 2016-2019 received a 117 © CIRS, R&D Briefing 78 positive or positive with restrictions CADTH 0 recommendation (Figure 19).

In 2016-2019, 21 anti-cancer & immunomodulators were

2018-2019 (6) 2018-2019 (2) 2016-2017 (3) 2018-2019 (3) 2016-2017 (4) 2018-2019

submitted under the pan-Canadian Oncology Drug Review (4) 2016-2017

2018-2019 (10) 2018-2019 (16) 2016-2017 (22) 2018-2019 (13) 2016-2017 (18) 2018-2019 (pCODR), which evaluates oncology drugs and makes (10) 2016-2017 recommendations and guides the drug funding Figure 19: HTA outcome by therapeutic area Positive Restriction Negative © CIRS, R&D Briefing 78 recommendations of provinces. Established in 2010, 100% pCODR enables all provinces and cancer agencies to take a 3 5 5 single approach to cancer drug evaluation; pCODR moved 80% to CADTH in 2014. In 2018-2019, anti-cancer & 60% 3 9 immunomodulators that underwent the pCODR evaluation 6 2 3 40% were faster from regulatory approval to HTA 7 10 17 recommendation than in 2016-2017. In general, pCODR 20% 1 timelines were longer than those that underwent CDR 0% 1 1

(Figure 18). Proportion of recommended NASs

The Health Canada/CADTH parallel process shortened the Alimentary & Anti-infectives Nervous system Anti-cancer & overall time taken from regulatory approval to HTA metabolism immunomodulators recommendation (Figure 20). Figure 20: Breakdown of rollout time by type of sequence The Health Canada/CADTH parallel review process, which Regulatory authority review time allows for a submission to CADTH within 90 days before the HTA submission to HTA recommendation (national level) date of anticipated Notice of Compliance (NOC) from Sequential 361 © CIRS, R&D Briefing 78

Health Canada, has been available for companies since (21) 193 2017 2012. However, on 2 April 2018, CADTH submission criteria - Parallel 340

were changed to within 180 days before the anticipated 2016 (26) 193 NOC from Health Canada. In 2016-2019, 58% of the NASs submitted for HTA recommendation underwent the Health Sequential 329

Canada/CADTH parallel review process. In the last two-year (19) 195

2019 - cohort, an increased proportion of NASs were submitted 346 through the parallel process: 55% in 2016-2017 to 61% in Parallel 2018 (30) 230 2018-2019. Assessed in two-year cohorts, products that 0 200 400 600 800 underwent the parallel review process in 2018-2019, had (N)= Number of NASs Median time, days faster regulatory review time and time from regulatory Figure 21: Time taken from regulatory approval to HTA approval to HTA submission (24 median days) than in 2016- recommendation by review type 2017. In 2018-2019, the median time taken from Regulatory authority review time Sequential regulatory approval to HTA recommendation for the HTA submission to HTA recommendation (national level) Parallel parallel process was a median 282 days faster that the CDR (34) sequential process. 359

190 47% 53% 2017

A higher proportion of NASs submitted to the Health - pCODR (13) 322 38% Canada/CADTH parallel process underwent pCODR review 62% compared with CDR review (Figure 21). Thus, the rollout 2016 202 time from regulatory submission to HTA recommendation CDR (30) 347 43% 57%

for NASs submitted for pCODR review was shorter than 213 2019 those submitted for CDR review. In 2018-2019, NASs -

32% submitted to pCODR had a faster time to HTA pCODR (19) 284 68% recommendation than CDR, which was mainly driven by 2018 224 shorter review time by Health Canada. 0 200 400 600 (N)= Number of NASs Median time, days © CIRS, R&D Briefing 78

R&D Briefing 78 July 2020, © Centre for Innovation in Regulatory Science, Ltd. 9 FEATURES OF EUROPE

Figure 22: 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, days time, Median 200 © CIRS, R&D Briefing 78

2016 2015 2016 2017 2018 2019 2015 2016 2017 2018 2019 2015 2017 2018 2019 2015 2016 2017 2018 2019 2015 2016 2017 2018 2019 2015 2016 2017 2018 2019 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 (Figure 22). Despite the fact that new drugs were approved at the centralised level, Figure 22 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 132 days in 2015-2019.

Figure 23: Breakdown of rollout time (days) by EMA approval type for 39 common NASs In 2015-2019, 39 NASs approved by EMA Regulatory authority review time have been appraised by all six EMA Regulatory approval to HTA recommendation (national level) jurisdictions, of which 23 were anti-cancer England Standard 394 251 © CIRS, R&D Briefing 78 Acc only 254 259 products and 6 were anti-infectives. Cond only 478 476 Acc+Cond 248 465 Among the 39 commonly appraised NASs, Standard 394 210 France Acc only 254 106 six were approved as accelerated approval Cond only 478 193 Acc+Cond 248 392 by EMA, four were conditional approvals and Standard 394 129 two were accelerated and conditional Germany Acc only 254 103 Cond only 478 154 approvals. Accelerated products had the Acc+Cond 248 116 fastest median time from regulatory Standard 394 470 Poland Acc only 254 195 approval to HTA recommendation in all Cond only 478 733 Acc+Cond 248 635 jurisdictions. In particular, in Poland, the Standard 394 175 median time was nearly half of the standard Acc only 254 87 Scotland Cond only 478 360 approvals. (Figure 23). In general, anti- Acc+Cond 248 275 infective NASs showed the fastest median Standard 394 154 Acc only 254 75 time from regulatory approval to HTA Sweden Cond only 478 391 Acc+Cond 248 579 recommendation and the highest proportion 0 200 400 600 800 1000 1200 of positive or positive with restrictions HTA Median time, days Number of Standard = 27; Number of Accelerated = 6; Number of Cond only = 4; Number of Acc+Cond = 2 recommendation (Figure 24 and 25).

Figure 24: Time taken from regulatory approval to HTA Figure 25: First HTA recommendation comparison for 39 recommendation by therapeutic area in for 39 common NASs common NASs by therapeutic area th th Median 25 and 75 percentiles Positive Restriction Negative Multiple England France Germany Poland Scotland Sweden 1200 England France Germany Poland Scotland Sweden Number of Anti-cancer = 23; Number of Anti-infectives = 6; Others = 10 © CIRS, R&D Briefing 78 100% 1 1 1 1000 1 1 1 1 2 2 2 2 3 2 3 3 80% 4 3 12 11 800 270 11 4 11 4 13 690 60% 6 9 600 4 6 4 223 267 40% 5 8 5 Time, Time, days 400 472 4 4 4 4 259 222 6 156 11 5 20% 10 9 9 128 137 2 200 307 3 6 3 3 207 203 71 4 195 1 103 recommendedNASs of Proportion

0 97 103 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

Anti-infectives Anti-infectives Anti-infectives Anti-infectives Anti-infectives Anti-infectives © CIRS, R&D Briefing 78

R&D Briefing 78 July 2020, © Centre for Innovation in Regulatory Science, Ltd. 10 FEATURES OF ENGLAND

Figure 26: Breakdown of rollout time in England

EMA approval time 418 © CIRS, R&D Briefing 78

Overall (115) Completion of final scoping to NICE Submission 56 NICE Submission to Recommendation 267

Median time, days 100 200 300 400 500 600 700 800

Anti-cancer and EMA approval time 441 immunomodulators Completion of final scoping to NICE Submission (70) 56 NICE Submission to Recommendation 264

Median time, days 100 200 300 400 500 600 700 800 Others (45) EMA approval time 385 Completion of final scoping to NICE Submission 56 NICE Submission to Recommendation 326

(N)= Number of NASs Median time, days 100 200 300 400 500 600 700 800

In England, before NICE appraisal process, scoping occurs 46 median days before EMA approval in 2015-2019. In England, not all NASs undergo the NICE appraisal process. Scopes are first developed before marketing authorisation is achieved. In 2015-2019, the completion of final scoping occurs 46 median days before EMA approval (Figure 26). After the scoping process, the appraisal topic is referred to NICE for development by the Department of Health. In 2015-2019, the time taken from NICE submission to HTA recommendation was 267 median days. Anti-cancer and immunomodulators take 25 median days earlier for time from EMA approval to completion of final scoping than other NASs. The time from NICE submission to HTA recommendation is also faster for anti-cancer and immunomodulators (264 median days) as compared to other NASs (326 median days, Figure 26).

Figure 27: Type of NICE recommendations (n=115) Figure 28: Breakdown of NICE recommendations by funding agreements © CIRS, R&D Briefing 78 NHS funding (71) Cancer drug fund (44) 4% Patient access scheme 16% 30% Managed Access Agreement 55% 18% 48% Agreement with Commercial Medicines Unit 3% 66% Simple discount 8% 7% 17% Standard Patient access scheme Managed Access Agreement 5% 2% Managed Access Agreement Patient access scheme 11% Agreement with Commercial Medicines Unit N/A N/A Simple discount Standard 10% © CIRS, R&D Briefing 78 N/A The majority of NICE recommendations (79% of 115 NASs) were provided through funding agreements in 2015-2019. In England, drugs can be provided through various funding agreements: Simple discounting; Agreement with Commercial Medicines Unit; Patient Access Scheme (PAS) and; Managed Access Agreement (MAA). PAS allow patients to have a technology when NICE’s assessment of value, on the current evidence base, is unlikely to support the list price and can be introduced through simple discounting or complex schemes. MAA allows earlier access to drugs while further evidence is collected to address clinical uncertainty. Of the 115 NAS that received a NICE recommendation in 2015-2019, the majority were funded through the PAS (55%), followed by MAA (17%, Figure 27). The Cancer Drug Fund (CDF) was established by the government in 2011 as a temporary solution to support clinicians and their patients to gain access to cancer drugs not routinely available on the NHS. Drugs receiving a positive NICE recommendation were funded by routine baseline commissioning budgets within 90 days of NICE final guidance. On 29 July 2016, the new CDF was introduced, providing earlier access to promising new treatments through MAA and interim funding. Interim funding ends 90 days after positive final guidance is published, at which point funding will be switched to baseline commissioning budgets. 58% of 75 anti-cancer and immunomodulators that received a HTA recommendation in 2015-2019 were funded through the CDF. Of the 44 CDF drugs, 66% were funded by baseline funding through PAS, 7% by CDF through MAA, and 11% by new CDF through MAA (Figure 28).

Figure 29: Comparison of the regulatory and HTA implementation across targeted jurisdictions HTA implementation up to May 2020 that received HTA recommendation in 2015-2019 Australia PBS list Pharmaceutical TGA PBAC Benefits Scheme + 63 NASs

England EMA NICE Implementation of NICE + guidance 102 NASs France EMA HAS Publication in Journal Officiel + 93 NASs Germany EMA IQWiG G-BA decision +/- 137 NASs Sweden EMA TLV TLV decision +/- 82 NASs + HTA recommendation vs List of positive HTA implementation outcome available implementation outcome Same +/- List of positive and negative HTA implementation outcome available © CIRS, R&D Briefing 78 Different HTA recommendations are used by payers to support reimbursement decisions. In this report, the database was extended beyond HTA information to collect HTA implementation outcome and dates. Figure 29 illustrates the key agencies involved in the regulatory approval all the way through to the implementation of HTA. Data were collected only on HTA implementation in this cohort up to May 2020 to explore the availability of new medicines in these jurisdictions. In Germany, if G-BA decides that the new pharmaceutical does not have any additional benefit over the appropriate comparator, it will be included in the reference price system within six months of market launch. If a pharmaceutical without additional benefit cannot be allocated to a reference price group, a reimbursement price will also be agreed on. The annual treatment costs must not exceed those of the appropriate comparator. Figure 30: Breakdown of rollout time for implemented drugs with HTA recommendation in 2015-2019

Regulatory authority review time Pos/Res = Positive/ Positive with Restrictions Regulatory approval to first HTA recommendation Neg = Negative First HTA recommendation to HTA implementation (N)= Number of NASs Australia Pos/Res (39) 364 14 201 © CIRS, R&D Briefing 78 Neg (24) 360 13 611 Time taken from first negative England Pos/Res (99) 417 321 90 HTA recommendation to HTA Neg (3) 433 597 671 implementation includes • Re-submission to positive France Pos/Res (92) 409 211 308 HTA recommendation Neg (1) 295 210 650 • HTA agency review • HTA implementation Germany Pos/Res (80) 422 119 86 decision-making Neg (57) 428 140 85 Sweden Pos/Res (79) 418 189 1 Neg (3) 394 159 612 0 200 400 600 800 1000 1200 1400 1600 1800 Median time, days France took the longest time to receive a HTA Figure 31: Rollout time from first HTA recommendation implementation for new medicines, 308 median days to implementation after first HTA recommendation (Figure 30). Pos/Res = Positive/ Positive with Restrictions Median, Neg = Negative th th Median, Box : 25 and 75 percentilesth th (N)= Number of NASs 25 and 75 percentiles HTA implementation dates reflect the availability of new © CIRS, R&D Briefing 78 medicines. Germany showed the quickest time from Australia England France Germany Sweden 800 regulatory approval to HTA implementation (median, 218 671 650 days). The variation between time from first HTA 700 611 612 recommendation to HTA implementation shows the 600 diversity in implementing HTAs (Figure 31). In Sweden, HTA 500 was implemented immediately after TLV recommendation. In England, drugs must be implemented within 3 months of 400 308 a NICE recommendation by law and 30 days for NASs on the

Time, Time, days 300 201 Early Access to Medicines Scheme (EAMS) and fast track 200 90 86 85 appraisal. Drugs in the CDF can be available before the

100 1 publication of guidance through MAA. In Germany, 0 according to The Act on the Reform of the Market for Pos/Res Neg Pos/Res Neg Pos/Res Neg Pos/Res Neg Pos/Res Neg Medical Products (AMNOG), G-BA needs to make a decision (39) (24) (99) (3) (92) (1) (80) (57) (79) (3) 3 months after an IQWiG recommendation.

R&D Briefing 78 July 2020, © Centre for Innovation in Regulatory Science, Ltd. 12 METHODOLOGY The data on individual NASs appraised by HTA agencies in 2015-2019 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 implemented by the healthcare systems. In Australia, England, Scotland and Sweden, HTA recommendations not to implement 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 32 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 33. 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 32: Trichotomous categories of HTA recommendations

Figure 33: 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

Anti-cancer drugs • A biological or biotech substance previously In this Briefing, anti-cancer drugs refers to anti-cancer available as a medicinal product, but differing in and immunomodulators (ATC code L). molecular structure, nature of source material or manufacturing process and which will require Exclusion criteria clinical investigation. Applications that are excluded from the study: • A radiopharmaceutical substance that is a • Vaccines radionuclide or a ligand not previously available as a • Any other application, where new clinical data medicinal product. Alternatively, the coupling were submitted mechanism linking the molecule and the • Generic applications radionuclide has not been previously available. • Those applications where a completely new dossier Parallel review was submitted from a new company for the same Pharmaceutical companies submit evidence to the indications as already approved for another regulatory agency that prove the efficacy, safety, company quality of the product. However, during the regulatory • Applications for a new or additional name, or a review process, companies submit dossiers to HTA change of name, for an existing compound (i.e. a bodies so that the two review steps can occur in ‘cloned’ application) parallel. Following the regulatory approval, HTA recommendation will be provided to companies for First assessment report drug reimbursement. This sequence is available in The first assessment report is the earliest assessment Australia and Canada. In this report, a drug is identified available. Note that for some drugs; for example, those as parallel if HTA recommendation is earlier than with the same INN, strength and presentation, are regulatory approval. listed more than one time. The reasons may be twofold – consideration of the drug in more than one indication HTA implementation date or re-assessment of the drug by the agency. Publication date of HTA implementation.

Health technology assessment (HTA) Regulatory submission gap For the purpose of this project, HTA refers to the Date of submission at the first regulatory agency to the assessment and appraisal of pharmaceuticals prior to date of regulatory submission to the target agency. reimbursement. The HTA process includes clinical assessment, economic assessment and an appraisal Regulatory review time that results in either a coverage recommendation or Time (calendar days) calculated from the date of recommendation. submission to the date of approval by the agency; this time includes agency and company time. Note: The HTA review time EMA approval time includes the EU Commission time. Time (calendar days) calculated from the date of submission to the date of recommendation by the HTA Rollout time agency. Note: The HTA recommendation refers to the Date of submission at the regulatory agency to the date recommendation at national level. of HTA recommendation at the target jurisdiction (calendar days). Managed entry agreements (MEAs) Sequential review Arrangements between companies and HTA agencies that allow early access of new drugs while managing Regulatory review is conducted first to determine the uncertainty around their financial impact or benefit-risk profile of a new medicine, followed by the performance. HTA review to assess the value of the medicine for a reimbursement decision. The regulatory-HTA sequence New active substance (NAS) is seen at a national level in many countries, and also at A chemical, biological, biotechnology or a super-national level in Europe where a centralised radiopharmaceutical substance that has not been regulatory decision made by the European Medicines previously available for therapeutic use in humans and Agency is followed by jurisdictional HTA is destined to be made available as a ‘prescription-only recommendations by member states. medicine’, to be used for the cure, alleviation, treatment, prevention or in vivo diagnosis of diseases in humans; the term NAS also includes: • An isomer, mixture of isomers, a complex or derivative or salt of a chemical substance previously available as a medicinal product but differing in properties with regard to safety and efficacy from that substance previously available.

R&D Briefing 78 July 2020, © Centre for Innovation in Regulatory Science, Ltd. 14 HTA ORPHAN/RARE DISEASE-RELATED PATHWAYS Figure 34: HTA orphan/ rare disease-related pathways Country HTA Orphan/ Rare Disease-Related Pathways Australia Rule of rescue: A principle that favours listing of medicines with the following circumstances applied concurrently: • No alternative exists in Australia to treat patients with the specific circumstances of the medical condition meeting the criteria of the restriction. • The medical condition defined by the requested restriction is severe, progressive and expected to lead to premature death. • The medical condition defined by the requested restriction applies to only a very small number of patients. • The proposed medicine provides a worthwhile clinical improvement sufficient to qualify as a rescue from the medical condition. Life Saving Drugs Program (LSDP): LSDP provides fully subsidised access for eligible patients to expensive and life saving drugs for life threatening and rare diseases. The LSDP is separate to the PBS. All LSDP medicines have been considered by PBAC but not recommended for the PBS due in part to the high cost of the medicine. Highly specialised drugs: The Highly Specialised Drugs (HSD) Program provides access to specialised Pharmaceutical Benefits Scheme (PBS) medicines for the treatment of chronic conditions which, because of their clinical use and other special features, have restrictions on where they can be prescribed and supplied. Canada There is no separate CADTH review process but in March 2016, the standard HTA recommendation Framework was revised to make special consideration drugs for rare diseases. Note: The regulatory agency in Canada (Health Canada) do not currently have an orphan policy. England Highly specialised technologies (HST): A separate review process for very rare conditions. These evaluations have a higher cost-effectiveness threshold than technology appraisals. Following changes introduced in April 2017, NICE set a maximum additional QALY threshold of £300,000 for highly specialised treatments, under which they will automatically be approved for routine commissioning. This is ten times higher than the standard NICE threshold of £30,000 for non-specialised treatments. France There is no separate HAS review process but France offers early access of innovative drugs, including orphan drugs, through the Temporary Licensing System (ATU). Germany For orphan drugs, additional therapeutic benefit is considered to be proven at marketing authorisation as long as the annual SHI expenditure for the entire population is below EUR 50 million. IQWiG only assesses information provided by the companies on patient costs and patient numbers. The IQWiG recommendations for orphan drugs are categorized as “positive” within this briefing. Once the EUR 50 million threshold is exceeded, companies are required to submit data on additional therapeutic benefit and orphan drugs are evaluated and prices renegotiated in the same manner as for all other drugs. The assessment of orphan drugs are conducted by G-BA, and the approach for evidence appraisal is similar to the non-orphan assessed by IQWiG. However, the orphan assessment report only determines the extent of additional benefit, and the categories ‘no additional benefit’ or ‘less benefit’ are not applicable. Under the GSAV law implemented in July 2019, additional real-world evidence can be requested by G-BA at the initial assessment for drugs with conditional approval and all orphan drugs. Poland There is no separate AOTMiT process but there are ongoing plans to introduce a separate procedure for rare and ultra-rare diseases such as the introduction of multi-criteria decision analysis (MCDA) method (Polityka Lekowa Państwa 2018–2022). Scotland Orphan medicine: A medicine with European Medicines Agency (EMA) designated orphan status (conditions affecting fewer than 2,500 people in a population of 5 million) or a medicine to treat an equivalent size of population irrespective of whether it has orphan status. Ultra-orphan medicine: To be considered as an ultra-orphan medicine all criteria listed should be met: • the condition has a prevalence of 1 in 50,000 or less in Scotland, • the medicine has an EMA orphan designation for the condition and this is maintained at time of marketing authorisation, • the condition is chronic and severely disabling, and • the condition requires highly specialised management. Submissions for medicines that are validated as ultra-orphan according to this definition will be assessed by SMC and will then be available to prescribers for a period of up to three years while further clinical effectiveness data are gathered. After this period the company will be asked to provide an updated submission for reassessment and SMC will make a decision on routine use of the medicine in NHS Scotland. For medicines used at end of life and for very rare conditions, companies may ask for the medicine to be considered at a Patient and Clinician Engagement (PACE) meeting. This additional step allows SMC to hear more evidence from patient groups and clinicians on the added value of a medicine which may not always be captured in the company’s submission. The output from a PACE meeting is a major factor in SMC decision making. Companies can also submit or improve a Patient Access Scheme (PAS), which can help to improve the value for money of the medicine. Sweden There is no separate review process in Sweden but TLV can consider a higher cost-effectiveness threshold based on unmet need, severity of condition, and limited budget impact due to small populations.

Report prepared by

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

Please cite this report as:

Cai J, Wang T, McAuslane N, Munro J. 2020. R&D Briefing 78: Review of HTA outcomes and timelines in Australia, Canada and Europe 2015 -2019. Centre for Innovation in Regulatory Science. London, UK.

About CIRS

The Centre for Innovation in Regulatory Science (CIRS) is a neutral, independently managed UK-based subsidiary company, forming part of the Clarivate Analytics group. CIRS’ mission is to maintain a leadership role in identifying and applying scientific principles for the purpose of advancing regulatory and HTA policies and processes. CIRS provides an international forum for industry, regulators, HTA and other healthcare stakeholders to meet, debate and develop regulatory and reimbursement policy through the innovative application of regulatory science and to facilitate access to medical products through these activities. This is CIRS’ purpose. CIRS is operated solely for the promotion of its purpose. The organisation has its own dedicated management and advisory boards, and its funding is derived from membership dues, related activities, special projects and grants.

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