Journal of Population Therapeutics & Clinical Pharmacology

Original Research DOI: 10.15586/jptcp.v27i1.658

Alignment of health technology assessments and price negotiations for new drugs for rare disorders in Canada: Does it lead to improved patient access? Nigel S. B. Rawson1,2,3 1Eastlake Research Group, Oakville, ON, Canada 2Canadian Health Policy Institute, Toronto, ON, Canada 3Fraser Institute, Vancouver, BC, Canada

Corresponding author: [email protected]

Submitted: 27 November 2019. Accepted: 24 January 2020. Published: 13 February 2020.

ABSTRACT A previous assessment of submissions for rare disorder drugs made to the Canadian Agency for Drugs and Technologies in Health (CADTH) found that, from 2012, all positive recommendations included criteria advocating a price reduction. Since 2016, CADTH and the pan-Canadian Pharmaceutical Alliance (pCPA), which conducts drug price negotiations with manufacturers for all public drug programs, have aligned their processes. This analysis examined drugs for rare and ultra-rare disorders (DRDs and DURDs)—prevalence of ≤20 to >2 and ≤2 per 100,000, respectively—with a completed pCPA negotiation or no negotiation between 2014 and 2018, together with their reimbursement recommendations and listings in public drug programs. A positive recommendation led to a successful price negotiation for 81.8% and 78.6% of the DRD and DURD submissions and a negative recommendation to no negotiation for 100.0% and 66.7%. Less than half the recommendations for DURDs reported before 2016 mentioned the need for a substantial price reduction, but this increased to 80% in those reported from 2016 onwards. A successful price negotiation led to listing in the majority of the public drug programs and a negative recommendation usually led to no listing. The CADTH- pCPA alignment is working for the governments who own and fund public drug programs but has yet to lead to coverage for all appropriate patients in all provinces. There is still a way to go to ensure that patients with unmet needs can access high-cost innovative medicines that alleviate suffering, prevent premature death, and/ or significantly improve their quality of life. Keywords: rare diseases, orphan drugs, health technology assessment, price negotiations, formulary listing, Canada

J Popul Ther Clin Pharmacol Vol 27(1):e48–e64; 13 February 2020. This article is distributed under the terms of the Creative Commons Attribution-Non Commercial 4.0 International License. ©2020 Nigel S. B. Rawson.

e48 Alignment of health technology assessments and price negotiations in Canada

Health technology assessment of new pre- of intent that implies the drug will be listed in scription medicines is performed for all Canadian any subsequent Product Licensing Agreement provincial and territorial public drug programs with an agreed price and listing criteria. (except those in Quebec) by the Canadian Agency Agreement terms are confidential. for Drugs and Technologies in Health (CADTH) Public drug plans are not mandated to list a through two processes: the pan-Canadian medicine that has been successfully negotiated Oncology Drug Review (pCODR) for cancer with the pCPA. Consequently, a listing agreement drugs and the Common Drug Review (CDR) for is not guaranteed in all participating plans. Using all other drugs. At around 80%,1 the pCODR the basis of the terms in the letter of intent, man- positive reimbursement recommendation rate is ufacturers must negotiate individual Product significantly higher than the CDR rate of Licensing Agreements with each participating 50–55%.2–4 Positive recommendations from both jurisdiction. Information on how the public drug processes are commonly qualified with clinical plans make funding decisions is not generally criteria and/or a need for a price reduction. available. Negative recommendations are frequently based A previous evaluation of submissions for on the opinion that a drug’s efficacy evidence is rare disorder drugs made to the CDR between inadequate2,5 despite having been assessed by 2004 and February 3, 20165 found that, as the Health Canada’s regulatory review as acceptable. prevalence of the drug’s indication decreased, CADTH does not publicly acknowledge having a the positive reimbursement recommendation cost-effectiveness threshold for assessing drugs, rate also decreased, while an increase occurred but evidence exists to suggest that $50,000 per in the proportion of recommendation reports in quality-adjusted life year is used, although not which attention was drawn to the drug’s cost or consistently applied.2 the need for a price reduction. However, a The pan-Canadian Pharmaceutical Alliance change took place around 2012 in how high- (pCPA) is the federal, provincial, and territorial cost rare disorder drugs are dealt with by the governments’ organization that negotiates prices CDR. Before 2012, high cost was a factor in of new and existing medicines with pharmaceu- 85% of the negative reimbursement recommen- tical manufacturers.6 The pCPA’s objectives dations for rare disorder drugs, whereas between include achieving consistent and lower drug 2012 and February 2016, no rare disorder drug costs for participating jurisdictions and improv- with a negative recommendation had its cost ing consistency of coverage criteria among par- noted in the CDR report, but 100% of the rare ticipating jurisdictions. The pCPA has been disorder drugs with a positive recommendation criticized for its lack of transparency,7,8 but in included criteria advocating a price reduction or May 2018 it published guidelines that describe drawing attention to less expensive alternative the four phases of its method.9 Following a therapies. health technology assessment recommendation, Since 2016, CADTH and the pCPA have the pCPA considers whether a price negotiation aligned their processes. Ensuring a negative reim- will be opened with the manufacturer. For med- bursement recommendation results in no price icines for which a negotiation is begun, each negotiation and a positive recommendation sets government drug plan must declare whether it up factors for inclusion in the price negotiation intends to join the negotiation. If an agreement appears to be part of this alignment. Insufficient is reached between the lead negotiating province recommendations were available in the post-2015 and the manufacturer, both parties sign a letter period in the previous work to assess the impact

e49 Alignment of health technology assessments and price negotiations in Canada of the CADTH-pCPA alignment on the out- ≤20 to >2 per 100,000 population—labeled drugs comes of price negotiations and listing in public for rare disorders (DRDs)—and those for indica- drug programs. tions with a prevalence of ≤2 per 100,000 popula- The objective of this analysis was to examine tion—labeled drugs for ultra-rare disorders reimbursement recommendations for rare disor- (DURDs). der drugs, results of the price negotiations, and Reimbursement recommendation reports for listings in public drug programs for rare disorder non-oncology drugs in the pCPA list were identi- drugs that had completed negotiations or for fied from the CDR’s website.13 Provincial formu- which the pCPA decided not to negotiate between laries, special benefit lists and bulletins and the 2014 and 2018. Since much effort has been put federal Non-Insured Health Benefits formulary into aligning the processes, it is critical to assess available at the end of September 2019 were whether the system is working. reviewed to assess how many drugs are listed in these public programs. Coverage criteria, where METHODS available, were evaluated for consistency between The monthly lists of active negotiations, com- the CDR’s recommendation and the public pleted negotiations with or without an agree- programs. ment, and medications for which no negotiation Since the positive rate of reimbursement rec- has been undertaken published by the pCPA on ommendation for oncology drugs has been shown its website between January 2014 and December to be considerably higher than that for non- 2018 were used to identify appropriate medicines. oncology drugs,2–4 a similar evaluation of pCPA January 2014 was the starting point because negotiations and pCODR recommendations14 for pCPA outcomes are only available from this oncology DURDs was performed for a compari- date.10 If multiple negotiations had occurred for son with the CDR recommendations. Information the same product and indication, the most recent on listing in public drug plans (except for the outcome was recorded, but if a drug had more Quebec and federal plans) was obtained from than one negotiation for different diagnoses, each provincial funding summaries available from the one was included. pCODR website. Coverage in the Quebec and Only drugs for indications with a prevalence federal plans was obtained from the relevant of ≤20 per 100,000 population were included in websites. this evaluation. Prevalence figures were obtained from the Orphanet website11 or up-to-date publi- RESULTS cations when Orphanet provided a wide range or Two of the drugs in the evaluation were for no data. Health Canada has proposed a preva- cystic fibrosis patients with specific gene muta- lence of <1 per 2,000 individuals to define a rare tions. Cystic fibrosis has an overall prevalence of disorder,12 but health conditions cover a wide ≤10 to >2 per 100,000. The combination product spectrum from extremely common disorders of lumacaftor and ivacaftor indicated for patients through uncommon to rare and ultra-rare ones, with homozygous F508del mutation, which con- and there is no consistent agreement on when a stitutes about 50% of cystic fibrosis cases in disorder is considered to be rare. For this evalua- Canada,15 was considered to be a DRD. Ivacaftor, tion, a prevalence of ≤20 per 100,000 was chosen on the other hand, was included as a DURD to ensure that unquestionably rare or ultra-rare because it is indicated for G551D, R117H, and disorders were the focus. The drugs were divided other gating mutations, which have a prevalence into those for indications with a prevalence of of ≤2 per 100,000.15

e50 Alignment of health technology assessments and price negotiations in Canada

Fifteen pCPA price negotiations for non-on- outcome are unknown. In addition, elosulfase cology DRDs completed with or without success alfa for mucopolysaccharidosis IVA originally or for which none was begun between 2014 and received a negative recommendation from the 2018 were identified (Table 1). These concerned CDR and the pCPA decided not to negotiate, but 14 drugs of which six (42.9%) were indicated for a following a re-evaluation by the CDR, the drug genetic disorder. Nine price negotiations were received a positive recommendation and was suc- successfully completed, and all these drugs had a cessfully negotiated with the pCPA. One of the positive CDR reimbursement recommendation. reasons for the change in recommendation was Two unsuccessful negotiations were for maciten- that mucopolysaccharidosis IVA is “a life-threat- tan and riociguat, which had both received a pos- ening, seriously debilitating disease that is chronic itive reimbursement recommendation. Overall, in nature, and no alternative enzyme treatments nine (81.8%) of the 11 DRDs with a positive are available.”16 reimbursement recommendation had a successful Three (42.9%) of the seven reimbursement rec- price negotiation; all DRDs with a positive recommendations for DURDs reported before 2016 ommendation reported after 2015 were success- were negative and two of the three had no pCPA fully negotiated. Each of the four DRDs for negotiation or an unsuccessful one. The CDR which the pCPA decided not to negotiate had a assessments for the four DURDs with positive negative reimbursement recommendation. Four recommendations reported before 2016 all men- (57.1%) of the seven CDR recommendations tioned the need for a price reduction, but none reported after 2015 included a specific suggested had a specific target. In contrast, all 10 reimburse- price reduction to attain an incremental cost ratio ment recommendations for DURDs reported of $50,000 or to bring the drug’s price into line after 2015 were positive, and eight (80.0%) CDR with a comparable drug. Based on the list prices reports included the need for a substantial price provided in the CDR reports, the estimated daily reduction, with seven having a reduction of cost of all but one DRD was under $500. 60–97% specified. The DURDs were generally Seventeen pCPA negotiations concerned 13 more costly than the DRDs; of those with a list DURDs of which 12 (92.3%) are indicated for price provided in the CDR report, almost 80% genetic disorders (Table 2). Multiple price negoti- had an estimated daily cost of $500 or more. ations related to ivacaftor, which had three posi- Eight pCPA price negotiations for seven tive reimbursement recommendations, but only oncology DURDs completed with or without the pCPA negotiation for the G551D mutation success or for which none was begun between was successfully completed (the pCPA decided 2014 and 2018 were identified Table( 3). Only two not to negotiate for the other indications), and submissions (25.0%) received a negative recom- nitisinone for tyrosinemia type 1, for which three mendation for which there was no price negotia- products from different companies were all suc- tion. The other six submissions (75.0%) received cessfully negotiated with the pCPA. For two a “fund conditional on cost-effectiveness drugs (asfotase alfa for hypophosphatasia and improvement” recommendation (a statement taliglucerase alfa for Gaucher’s disease), the most commonly used by the pCODR) and had a suc- recent price negotiation outcome was successful cessful price negotiation. completion, but a previous negotiation for asfo- Tables 4–6 show the percentage of public drug tase alfa had resulted in no agreement and the programs listing the non-oncology DRDs and pCPA had originally decided not to negotiate for DURDs and the oncology DURDs by the end of taliglucerase alfa. Reasons for the change in September 2019, respectively. A successful price

e51 Alignment of health technology assessments and price negotiations in Canada a Most recent recent Most outcome Completed Completed No negotiation No No negotiation No No agreement No Completed Completed No agreement No No negotiation No No negotiation No Completed Price negotiation Price Year 2015 2015 2015 2015 2015 2016 2016 2017 2016 2016 2017

Cost comment Not cost-effective cost-effective Not substantial without reduction price Price reduction to to reduction Price improve cost-effectiveness – Cost-effectiveness Cost-effectiveness uncertain Price reduction reduction Price required Substantial price price Substantial reduction Must not exceed cost exceed cost not Must pirfenidone of More expensive than than expensive More drugs comparable – 98% price reduction reduction 98% price cost incremental for $50,000 of ratio – Outcome LwC LwC DNR DNR LwC LwC LwC LwC DNR DNR LwC Reimbursement recommendation Reimbursement Year 2014 2014 2015 2015 2015 2015 2015 2015 2016 2016 2016 b <$500 <$500 <$500 <$500 <$500 <$500 <$500 <$500 <$500 Redacted Estimated Estimated daily cost $500–$999 c c c c Clinical indication Pulmonary arterial IV class hypertension, Dravet syndrome Dravet Cushing’s disease Cushing’s Subependymal giant cell giant Subependymal with associated astrocytoma complex sclerosis tuberous Pulmonary arterial III II and classes hypertension, Idiopathic pulmonary fibrosis pulmonary Idiopathic Idiopathic pulmonary fibrosis pulmonary Idiopathic Pulmonary arterial I, II & III classes hypertension, Autosomal dominant polycystic dominant Autosomal kidney disease Cystic fibrosis, homozygous homozygous fibrosis, Cystic mutation F508del Urea cycle disorders Urea

. Reimbursement Recommendation and Price Negotiation Outcome for Non-Oncology Drugs for Rare Disorders Rare Drugs for Non-Oncology Outcome for and Price Negotiation Recommendation . Reimbursement 1 Generic name name) (brand Riociguat (Adempas) Riociguat Stiripentol (Diacomit) Stiripentol Pasireotide (Signifor) Pasireotide Everolimus (Afinitor) Everolimus Macitentan Macitentan (Opsumit) Pirfenidone (Esbriet) Pirfenidone Nintedanib (Ofev) Nintedanib Riociguat (Adempas) Riociguat Tolvaptan (Jinarc) Tolvaptan Lumacaftor/ivacaftor Lumacaftor/ivacaftor (Orkambi) Sodium phenylbutyrate Sodium phenylbutyrate (Pheburane) TABLE

e52 Alignment of health technology assessments and price negotiations in Canada Completed Completed Completed Completed 2017 2017 2018 2018 >42% price >42% price for reduction cost incremental $50,000 of ratio Price is 46% higher is Price comparable than drug >60% price >60% price for reduction cost incremental $50,000 of ratio Price reduction Price Genetic disorder. Genetic c LwC LwC LwC LwC 2016 2017 2017 2018 <$500 <$500 <$500 <$500 From reimbursement recommendation report; report; recommendation reimbursement From b c c Pulmonary arterial II & III classes hypertension, Urea cycle disorders Urea Biliary cholangitis Biliary Giant cell arteritis Giant (Continued) Reimbursement Recommendation and Price Negotiation Outcome for Non-Oncology Drugs for Rare Rare Drugs for Non-Oncology Outcome for and Price Negotiation Recommendation Reimbursement (Continued) a . 1 Selexipag (Uptravi) Selexipag Glycerol Glycerol phenylbutyrate (Ravicti) Obeticholic acid Obeticholic (Ocaliva) Tocilizumab Tocilizumab (Actemra) Disorders with prevalence of ≤20 to >2 per 100,000; >2 per ≤20 to of prevalence with Disorders TABLE Disorders DNR = do not reimburse, LwC = list with conditions. with = list LwC reimburse, not = do DNR a

e53 Alignment of health technology assessments and price negotiations in Canada Most recent recent Most outcome agreement No Completed Completed negotiation No negotiation No Completed negotiation No Completed Completed Completed agreement No Completed Completed Completed Completed Completed Completed Price negotiation Price Year 2016 2014 2015 2017 2015 2018 2017 2018 2018 2018 2018 2018 2018 2018 2018 2018 2018 Attention drawn to high to cost drawn Attention without cost-effective Not reduction price substantial reduction Price reduction price Substantial high to cost drawn Attention assessable not Cost-effectiveness to reduction price Substantial cost-effectiveness improve reduction price Substantial for reduction 97% price $100,000 of ratio cost incremental for reduction 80% price $100,000 of ratio cost incremental exceed drugs similar to Not for reduction 95% price >$400,000 of ratio cost incremental drugs exceed comparable to Not for reduction 95% price >$100,000 of ratio cost incremental for reduction >74% price <$100,000 of ratio cost incremental reduction 60% price reduction 74% price Cost comment Genetic disorder. DNR = do not reimburse; LwC = list with conditions. with = list LwC reimburse; not = do DNR disorder. Genetic c Reimbursement recommendation Reimbursement Outcome DNR LwC LwC LwC DNR DNR LwC LwC LwC LwC LwC LwC LwC LwC LwC LwC LwC Year 2013 2013 2014 2014 2015 2015 2015 2016 2016 2016 2017 2017 2018 2018 2018 2018 2018 b Estimated Estimated daily cost >$1,000 $500–$999 Redacted $500–$999 >$1,000 $500–$999 $500–$999 >$1,000 Redacted Redacted >$1,000 >$1,000 $500–$999 $500–$999 <$500 <$500 <$500 c c c c c c c c ‡ c c c c From reimbursement recommendation report; report; recommendation reimbursement From c b c c Clinical indication hemolytic Atypical syndrome uremic G551D fibrosis Cystic mutation gating angioedema Hereditary gating fibrosis Cystic mutations familial Homozygous hypercholesterolemia disease Gaucher’s R117H fibrosis Cystic mutation gating Hypophosphatasia Mucopolysaccharidosis IVA Short bowel syndrome disease Gaucher’s muscular Spinal atrophy Fabry disease Nephropathic cystinosis type 1 Tyrosinemia type 1 Tyrosinemia type 1 Tyrosinemia Reimbursement Recommendation and Price Negotiation Outcome for Non-Oncology Drugs for Ultra-Rare Ultra-Rare Drugs for Non-Oncology Outcome for and Price Negotiation Recommendation Reimbursement a . 2 Generic name (brand name) Eculizumab (Soliris) (Kalydeco) Ivacaftor (Firazyr) Icatibant (Kalydeco) Ivacaftor (Juxtapid) Lomitapide alfa (Elelyso) Taliglucerase (Kalydeco) Ivacaftor alfa (Strensiq) Asfotase Elosulfase alfa (Vimizim) (Revestive) Teduglutide (Cerdelga) Eliglustat (Spinraza) Nusinersen (Galafold) Migalastat (Procysbi) Cysteamine (Orfadin) Nitisinone (MDK-Nitisinone) Nitisinone (Nitisinone) Nitisinone Disorders with prevalence of ≤2 per 100,000; ≤2 per of prevalence with Disorders TABLE Disorders a

e54 Alignment of health technology assessments and price negotiations in Canada a Attention Attention d Most recent recent Most outcome Completed Completed Completed Completed negotiation No negotiation No Completed Completed Price negotiation Price Year 2017 2015 2015 2016 2016 2016 2017 2018 d d Not cost-effective and attention drawn to high cost; cost; high to drawn attention and cost-effective Not c c c Reimbursement recommendation Reimbursement Outcome improvement cost-effectiveness on conditional Fund improvement cost-effectiveness on conditional Fund improvement cost-effectiveness on conditional Fund improvement cost-effectiveness on conditional Fund reimburse Do not reimburse Do not improvement cost-effectiveness on conditional Fund improvement cost-effectiveness on conditional Fund Year 2014 2015 2015 2015 2016 2016 2016 2017 b <$500 <$500 <$500 <$500 <$500 <$500 From reimbursement recommendation report; report; recommendation reimbursement From Redacted b Estimated Estimated daily cost $500–$999 Clinical indication Gastrointestinal stromal tumor t-cell Peripheral lymphoma myeloid Chronic leukemia disease Castleman’s Waldenstrom’s macroglobulinemia or Liposarcoma leiomyosarcoma cell Mantle lymphoma thyroid Medullary cancer Reimbursement Recommendation and Price Negotiation Outcome for Oncology Drugs for Ultra-Rare Disorders Ultra-Rare Drugs for Oncology Outcome for and Price Negotiation Recommendation Reimbursement . 3 Generic name (brand name) (Stivarga) Regorafenib (Istodax) Romidepsin Bosutinib (Bosulif) (Sylvant) Siltuximab (Imbruvica) Ibrutinib (Yondelis) Trabectedin (Imbruvica) Ibrutinib (Caprelsa) Vandetanib Oncology disorders with prevalence of ≤2 per 100,000; ≤2 per of prevalence with disorders Oncology TABLE a cost. high to drawn

e55 Alignment of health technology assessments and price negotiations in Canada

TABLE 4. Public Drug Plan Listings for Non-Oncology Drugs for Rare Disordersa Price negotiation Drug plan listingsb Generic name Clinical indication Most recent (brand name) Year No. % outcome Riociguat (Adempas) Pulmonary arterial hypertension, 2015 Completed 8 72.7 class IV Stiripentol (Diacomit) Dravet syndromec 2015 Completed 10 90.9 Pirfenidone (Esbriet) Idiopathic pulmonary fibrosis 2016 Completed 11 100.0 Nintedanib (Ofev) Idiopathic pulmonary fibrosis 2016 Completed 11 100.0 Sodium phenylbutyrate Urea cycle disordersc 2017 Completed 8 72.7 (Pheburane) Selexipag (Uptravi) Pulmonary arterial hypertension, 2017 Completed 10 90.9 classes II and III Glycerol phenylbutyrate Urea cycle disordersc 2017 Completed 9 81.8 (Ravicti) Obeticholic acid (Ocaliva) Biliary cholangitisc 2018 Completed 10 90.9 Tocilizumab (Actemra) Giant cell arteritis 2018 Completed 9 81.8 Macitentan (Opsumit) Pulmonary arterial hypertension, 2015 No agreement 1 9.1 classes II and III Riociguat (Adempas) Pulmonary arterial hypertension, 2017 No agreement 9 81.8 classes I, II, and III Pasireotide (Signifor) Cushing’s disease 2015 No negotiation 0 0.0 Everolimus (Afinitor) Subependymal giant cell astrocytoma 2015 No negotiation 1 9.1 associated with tuberous sclerosis complexc Tolvaptan (Jinarc) Autosomal dominant polycystic 2016 No negotiation 0 0.0 kidney disease Lumacaftor/ivacaftor Cystic fibrosis, homozygous 2016 No negotiation 0 0.0 (Orkambi) F508del mutationc aDisorders with prevalence of ≤20 to >2 per 100,000; bAs of September 30, 2019; cGenetic disorder. negotiation led to listing in six or more of the taliglucerase alfa for Gaucher’s disease, and tedu- public drug programs of 100% of the non-oncol- glutide for short bowel syndrome) all had pCPA ogy DRDs and 83.3% of the oncology DURDs negotiations completed in 2018. but only 33.3% of the non-oncology DURDs. A Table 7, which shows numbers of listings of negative recommendation usually led to no nego- the DRDs, DURDs, and oncology DURDs in tiation and no listing. The non-oncology DURDs each of the provincial and federal plans as of with a successful price negotiation listed by less September 30, 2019, demonstrates that more than than half the public drug programs (asfotase alfa three-quarters of the DRDs with a completed for hypophosphatasia, elosulfase alfa for muco- pCPA negotiation were listed in nine plans (the polysaccharidosis IVA, migalastat for Fabry dis- exceptions were Prince Edward Island and the ease, nitisinone for tyrosinemia type 1, Non-Insured Health Benefits plan), and more

e56 Alignment of health technology assessments and price negotiations in Canada

TABLE 5. Public Drug Plan Listings for Non-Oncology Drugs for Ultra-Rare Disordersa Drug plan Price negotiation listingsb Generic name (brand name) Clinical indication Most recent Year No. % outcome Ivacaftor (Kalydeco) Cystic fibrosis G551D gating mutationc 2014 Completed 8 72.7 Icatibant (Firazyr) Hereditary angioedemac 2015 Completed 10 90.9 Taliglucerase alfa (Elelyso) Gaucher’s diseasec 2018 Completed 4 36.4 Asfotase alfa (Strensiq) Hypophosphatasiac 2018 Completed 2 18.2 Elosulfase alfa (Vimizim) Mucopolysaccharidosis IVAc 2018 Completed 1 9.1 Teduglutide (Revestive) Short bowel syndrome 2018 Completed 5 45.5 Nusinersen (Spinraza) Spinal muscular atrophyc 2018 Completed 7 63.6 Migalastat (Galafold) Fabry diseasec 2018 Completed 4 36.4 Cysteamine (Procysbi) Nephropathic cystinosisc 2018 Completed 7 63.6 Nitisinone (Orfadin) Tyrosinemia type 1c 2018 Completed 5 45.5 Nitisinone (MDK-Nitisinone) Tyrosinemia type 1c 2018 Completed 4 36.4 Nitisinone (Nitisinone) Tyrosinemia type 1c 2018 Completed 4 36.4 Eculizumab (Soliris) Atypical hemolytic uremic syndromec 2016 No agreement 1 9.1 Eliglustat (Cerdelga) Gaucher’s diseasec 2018 No agreement 0 0.0 Lomitapide (Juxtapid) Homozygous familial 2015 No negotiation 1 9.1 hypercholesterolemiac Ivacaftor (Kalydeco) Cystic fibrosis R117H gating mutationc 2017 No negotiation 0 0.0 Ivacaftor (Kalydeco) Cystic fibrosis gating mutationsc 2017 No negotiation 0 0.0 aDisorders with prevalence of ≤2 per 100,000; bAs of September 30, 2019; cGenetic disorder.

TABLE 6. Public Drug Plan Listings for Oncology Drugs for Ultra-Rare Disordersa Price negotiation Drug plan listingsb Generic name (brand name) Clinical indication Year No. No. % Regorafenib (Stivarga) Gastrointestinal stromal tumor 2017 Completed 10 90.9 Romidepsin (Istodax) Peripheral t-cell lymphoma 2015 Completed 9 81.8 Bosutinib (Bosulif) Chronic myeloid leukemia 2015 Completed 9 81.8 Siltuximab (Sylvant) Castleman’s disease 2016 Completed 5 45.5 Ibrutinib (Imbruvica) Mantle cell lymphoma 2017 Completed 10 90.9 Vandetanib (Caprelsa) Medullary thyroid cancer 2018 Completed 6 54.5 Ibrutinib (Imbruvica) Waldenstrom’s macroglobulinemia 2016 No negotiation 0 0.0 Trabectedin (Yondelis) Liposarcoma or leiomyosarcoma 2016 No negotiation 0 0.0 aOncology disorders with prevalence of ≤2 per 100,000; bAs of September 30, 2019.

e57 Alignment of health technology assessments and price negotiations in Canada d No (n = 2) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) negotiation negotiation

oncology disorders Drugs for ultra-rare Drugs for (n = 6) 5 (83.3%) 5 (83.3%) 6 (100.0%) 6 (100.0%) 3 (50.0%) 4 (66.7%) 6 (100.0%) 1 (16.7%) 3 (50.0%) 6 (100.0%) 4 (66.7%) completed completed Negotiation Oncology disorders with prevalence of ≤2 of prevalence with disorders Oncology d No (n = 3)

0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (33.3%) 0 (0.0%) 1 (33.3%) 0 (0.0%) 0 (0.0%) negotiation negotiation c No (n = 2) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (50.0%) 0 (0.0%) 1 (50.0%) 0 (0.0%) 0 (0.0%) agreement agreement disorders

Drugs for ultra-rare Drugs for (n = 12) 1 (8.3%) 9 (75.0%) 8 (66.7%) 2 (16.7%) 9 (75.0%) 7 (58.3%) 2 (16.7%) 8 (66.7%) 4 (33.3%) 0 (0.0%) completed completed 11 (91.7%) Negotiation Disorders with prevalence of ≤2 per 100,000; ≤2 per of prevalence with Disorders c No (n = 4) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (25.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) negotiation negotiation

b No (n = 2) 0 (0.0%) 0 (0.0%) 1 (50.0%) 1 (50.0%) 1 (50.0%) 1 (50.0%) 1 (50.0%) 1 (50.0%) 1 (50.0%) 1 (50.0%) 2 (100.0%) disorders agreement agreement Drugs for rare rare Drugs for

(n = 9) 7 (77.8%) 8 (88.9%) 9 (100.0%) 9 (100.0%) 8 (88.9%) 9 (100.0%) 9 (100.0%) 5 (55.6%) 7 (77.8%) 9 (100.0%) 6 (66.7%) completed completed Negotiation Disorders with prevalence of ≤20 to >2 per 100,000; >2 per ≤20 to of prevalence with Disorders b a Numbers of Listings for Drugs for Rare Disorders, Ultra-Rare Disorders, and Ultra-Rare Oncology Disorders, by by Disorders, Oncology and Ultra-Rare Disorders, Ultra-Rare Disorders, Numbers of Rare Drugs for Listings for . 7 Drug plan Alberta British Columbia Manitoba Brunswick New Labrador and Newfoundland Scotia Nova Ontario Island Edward Prince Quebec Saskatchewan Benefits Health Non-Insured As of September 30, 2019; September of As TABLE Drug Plan Public a 100,000. per

e58 Alignment of health technology assessments and price negotiations in Canada than two-thirds of the oncology DURDs with rates for the non-oncology DRDs and DURDs, a completed negotiation were listed in eight and both showed an increase in the positive recom- plans (the exceptions were Newfoundland and mendation rate after 2015. In post-2015 recom- Labrador, Prince Edward Island and Quebec). In mendations for both DRDs and DURDs, there addition, nine of the plans listed at least one of was an increase in the number of reports with a the two DRDs for which there was no price agree- specified percentage reduction in the drug’s list ment. However, only five plans listed two-thirds price to achieve an incremental cost ratio of or more of the non-oncology DURDs with a $50,000 for DRDs and $100,000 (or in some cases, completed negotiation, with British Columbia, a higher value) for DURDs. These percentages Newfoundland and Labrador, Prince Edward were frequently large, particularly for DURDs Island, Saskatchewan, and the Non-Insured where they were 60% or higher. Nevertheless, a Health Benefits plan listing none to a third. successful price negotiation was completed for Coverage in a public drug program is almost 45.5% of the DRDs and 78.6% of the DURDs always conditional upon clinical criteria being with a positive CDR recommendation report spec- satisfied; only pirfenidone and nintedanib for ifying the need for a substantial price reduction. idiopathic pulmonary fibrosis and glycerol phen- Since pCPA negotiations are confidential, any bar- ylbutyrate for urea cycle disorders were accessible gained reduction in price is only known to the in Quebec without conditions. The criteria gener- manufacturer and governments, but it is reason- ally required patients to have been diagnosed with able to assume that the agreement required a con- the disorder, under the care of a physician experi- cession from the company. However, it seems enced with treating the disorder, and perhaps an unlikely that price reductions exceeded 60%. age limitation, failed control on current therapy, Positive recommendations issued by pCODR or a dietary restriction. Other criteria were more almost always state that the drug should be extensive, for example, the initiation criteria for funded conditional on cost-effectiveness improve- spinal muscular atrophy.17 However, the public ment but do not specify the level of price reduc- drug program access criteria were usually consis- tion desired. Price negotiations for all the tent with the CADTH recommended criteria. oncology DURDs with a positive reimbursement recommendation were successful and, unlike the DISCUSSION non-oncology DURDs, were listed in most pro- This evaluation has some limitations. A rela- vincial formularies. Oncology drugs tend to have tively small number of drugs were included. The a higher priority in Canada, with a higher pro- analysis is based on the publicly available infor- portion receiving an expedited regulatory review18 mation in the formularies and benefit lists of the and a higher positive reimbursement recommen- public drug programs, which do not always dation rate.2–4 include all covered medications. Although the The evaluation indicates that the alignment prevalence of the indications of the drugs was between CADTH and the pCPA is working for obtained from reliable sources, estimating the the federal, provincial, and territorial govern- prevalence for rare disorders accurately can be ments who own, fund, and manage not only the difficult. Nevertheless, the categorization used public drug programs but also CADTH and the was designed to ensure that the assessment pCPA,10,19 because drugs that receive a negative focused on indisputably rare disorders. reimbursement recommendation usually do not The evaluation demonstrated similarities undergo a price negotiation and those that receive between positive reimbursement recommendation a positive recommendation generally have a

e59 Alignment of health technology assessments and price negotiations in Canada successful negotiation. However, since the public per million individuals,23 noted that no random- drug programs participating in a successful pCPA ized controlled trials were identified so that the negotiation are not mandated to cover the medi- CDR’s assessment was based on three uncon- cation, something of a “no means no and yes trolled studies, which led to a negative recommen- means maybe”20 approach appears to remain for dation because “the clinical benefit of eculizumab non-oncology DURDs. A successful price nego- could not be adequately established.”24 Numerous tiation is not conditional upon a positive health case reports demonstrating the benefits of eculi- technology assessment recommendation nor zumab and expert opinions that the drug rep- does it guarantee that the drug will be listed in resents a breakthrough in treating aHUS seem to most plans. have played no role in the CDR evaluation. In Moreover, drugs may only be covered if a contrast, England’s National Institute for Health patient satisfies clinical criteria that apply to few and Care Excellence recommended funding for individuals and are excessive. Thus, the listing of eculizumab for aHUS under its highly specialized a drug in a public program does not necessarily technologies program, which has a much higher result in every patient with the disorder being able cost-effectiveness threshold, because studies of to access it. For example, eculizumab for atypical the drug produced cost-effective benefit “gains of hemolytic uremic syndrome (aHUS) is listed in a magnitude that is rarely seen for any new drug Ontario but only some patients have been able to treatment.”25 Pasireotide for Cushing’s disease, obtain coverage, while the age limit on access to everolimus for subependymal giant cell astrocy- nusinersen prevents adults with spinal muscular toma associated with tuberous sclerosis complex, atrophy from receiving benefits the drug may pro- tolvaptan for autosomal dominant polycystic vide.21 Access for some drugs may be approved on kidney disease, lomitapide for homozygous famil- a case-by-case basis, but without information ial hypercholesterolemia, taliglucerase alfa for regarding the selection criteria, it is unknown Gaucher’s disease, ibrutinib for Waldenstrom’s whether access is appropriate or fair or whether it macroglobulinemia, and trabectedin for liposar- is arbitrary or discriminatory. coma were also recommended for funding by the Health Canada’s regulatory review is designed National Institute for Health and Care Excellence to ensure that only drugs with demonstrated effi- but not by CADTH or Quebec’s agency. A spe- cacy, safety, and manufacturing quality are cialized approach to health technology assess- approved for use by Canadians. Once a drug has ment with a higher value threshold for DRDs and passed this review, Canadians want to be able to particularly for DURDs is needed in Canada. access its potential benefits without needing to be Recent changes introduced or planned by the a billionaire. They are especially concerned when federal government will radically alter the CADTH duplicates part of Health Canada’s reg- Canadian pharmaceutical environment, espe- ulatory role and comes to a negative conclusion cially in relation to access to drugs for patients regarding a drug’s efficacy, which is commonly with unmet needs for new therapies. As part of its one of the reasons for a negative reimbursement present focus on “affordability, accessibility and recommendation.22 CADTH’s approach to health appropriate use of prescription drugs,”26 the cur- technology assessment tends to be a narrow one rent government has made major revisions in the requiring evidence from randomized clinical tri- price review regulations of the agency that sets als, which are often difficult to accomplish for rare ceiling prices for patented medicines sold in disorders. The assessment report of eculizumab Canada. The new regulations and guidelines for aHUS, which has an incidence of one to two replace countries that have relatively higher drug

e60 Alignment of health technology assessments and price negotiations in Canada prices with lower price countries in the agency’s those that do have coverage but cannot afford the international price comparison analysis, enforce required copayments and deductibles are able to a hard and low cost-effectiveness threshold using access commonly prescribed, primary care medi- CADTH assessments as the benchmark, impose cines. Although this is an important goal, national a reduction in a drug’s price if its annual sales in pharmacare should do more. The government has Canada exceed a defined level, and require phar- also laid out its intention to implement a national maceutical companies to divulge information to strategy for access to medicines for rare disorders, the agency on confidential rebates and other which includes funding of $500 million per year commercial terms negotiated with payers in starting in 2022–2023, but the expense of these Canada.27 These changes will force manufactur- drugs is over-emphasized, moving the issue from ers of high-cost drugs to reduce their list prices by providing access to medicines that can deliver sig- 45–75%,28 perhaps more, which is an unsustain- nificant benefits to one of affordability. High-cost able business model. breakthrough drugs that fulfill unmet needs for These changes will endanger the launch of all patients and also reduce expensive hospitalizations new medicines in Canada because the country’s and other health services but are unaffordable for attractiveness as a jurisdiction in which pharma- the average Canadian must also be part of national ceutical companies want to perform clinical trials pharmacare, especially if the desire for equity or seek regulatory approval for new products will across Canada is to be realized.35 be significantly reduced.29–31 Manufacturers of new specialty high-cost medications, many of CONCLUSION which are for rare disorders, will be particularly The CADTH-pCPA alignment is working for impacted and may decide that the Canadian mar- the governments who own CADTH, the pCPA, ket is not worth the risk of failing to secure a rea- and the public drug programs, but it has yet to sonable price, especially if confidential rebates and lead to improved access in a timely manner for all other commercial terms negotiated with Canadian appropriate patients in all provinces. There is still drug insurance programs become known in other a way to go to ensure that patients with unmet jurisdictions. If this occurs, it will eliminate access needs can access high-cost innovative medicines for all patients, including those with private insur- that alleviate suffering, prevent premature death ance. Even if manufacturers decide to bring their and/or significantly improve their quality of life. medicines to Canada, they may only do so after CADTH staff have suggested that it may be inap- launching them in other countries first, which will propriate for CADTH to apply its standard not deny access to Canadians but will certainly appraisal approach to DURDs,36 but a more lead to considerable delays with additional suffer- urgent need exists for the federal, provincial, and ing beyond that already endured. territorial governments to implement a long-over- Another significant change on the horizon is due, comprehensive rare disease strategy37 that the federal government’s intention to introduce a would include ensuring that medications for these national pharmacare program,32 which could fur- disorders are reviewed and reimbursed quickly ther delay or deny access to new innovative drugs and equitably to provide adequate health care to if it is limited in scope,33 as the resources promised all Canadians that need these treatments. The fed- in the government’s recent election platform sug- eral government’s revisions to the pharmaceutical gest will be the case.34 The present focus of the gov- environment in Canada are more likely to reduce ernment in this initiative appears to be on ensuring access to costly breakthrough medicines, rather that Canadians who do not have drug coverage or than enhance it.

e61 Alignment of health technology assessments and price negotiations in Canada

CONFLICTS OF INTEREST 3. Griffiths EA, Hendrich JK, Stoddart SDR, Walsh SCM. Acceptance of health technology assess- In the past 3 years, the author has received con- ment submissions with incremental cost-effective- sultant fees from Cohn & Wolfe and Janssen ness ratios above the cost-effectiveness threshold. Canada Inc.; research and publication fees from Clinicoecon Outcomes Res. 2015;7:463–76. Bayer Inc, the Canadian Health Policy Institute, the https://doi.org/10.2147/CEOR.S87462 Fraser Institute, Medicines New Zealand, Merck 4. Rawson NSB. Drug safety: Problems, pitfalls and Sharp & Dohme (New Zealand) Ltd., RAREi and solutions in identifying and evaluating risk. Ward Health; publication processing expenses from Victoria, BC: Friesen Press, 2016. BIOTECanada, Canadian PKU and Allied 5. Rawson NSB. Health technology assessment of new Disorders Inc, and Shire Pharma Canada ULC; drugs for rare disorders in Canada: Impact of disease and honorarium and compensation for travel from prevalence and cost. Orphanet J Rare Dis. 2017;12:59. La Fondation DEVENIR. No conflict of interest https://doi.org/10.1186/s13023-017-0611-7 6. The pan-Canadian Pharmaceutical Alliance exists between these activities and the present work. [Internet]. 2019 [cited 2020 Jan 22]. Available Funding from: http://www.canadaspremiers.ca/pan-canadian- No funding was received for this work from pharmaceutical-alliance any source. 7. Husereau D, Dempster W, Blanchard A, Chambers J. Evolution of drug reimbursement in Canada: ACKNOWLEDGEMENTS The pan-Canadian Pharmaceutical Alliance for The author thanks John Adams from new drugs. Value Health. 2014;17:888–94. https:// Canadian PKU & Allied Disorders Inc. for his doi.org/10.1016/j.jval.2014.08.2673 comments on an earlier draft of the manuscript. 8. Rawson NSB. Pan-Canadian pharmaceutical alliance: Another hurdle for Canadian patients to Data Availability Statement access new drugs? Can Health Policy [Internet]. Data derived from public domain resources. Toronto: Canadian Health Policy Institute; 2016 [cited 2020 Jan 22]. Available from: https://www. Compliance with Ethical Standards canadianhealthpolicy.com/products/pan-canadi- This article does not contain any studies with an-pharmaceutical-alliance--another-hurdle-for-ca- human participants or animals performed by the nadian-patients-to-access-new-drugs-.html author. 9. pCPA Brand Process Guidelines [Internet]. 2018 [cited 2020 Jan 22]. Available from: http://www.can- REFERENCES adaspremiers.ca/wp-content/uploads/2018/11/ 1. Rawson NSB. Has pCODR improved access to pCPA_Brand_Process_Guidelines.pdf oncology drugs? Timeliness and provincial accep- 10. Rawson NSB. Pan-Canadian Pharmaceutical tance of pan-Canadian Oncology Drug Review Alliance negotiations 2014–2018 [Internet]. Can recommendations [Internet]. Vancouver: Fraser Health Policy. Toronto: Canadian Health Policy Institute; 2014 [cited]. Available from: https://www. Institute; 2019 [cited 2020 Jan 22]. Available from: fraserinstitute.org/sites/default/files/has-pCODR- https://www.canadianhealthpolicy.com/products/ improved-access-to-oncology-drugs-rev.pdf pan-canadian-pharmaceutical-alliance-negotia- 2. Rocchi A, Miller E, Hopkins RB, Goeree R. tions-2014-2018-.html Common drug review recommendations: An evi- 11. Orphanet: The portal for rare diseases and dence base for expectations? Pharmacoeconomics. orphan drugs [Internet]. 2020 [cited 2020 Jan 22]. 2012;30:229–46. https://doi.org/10.2165/115930 Available from: https://www.orpha.net/consor/ 30-000000000-00000 cgi-bin/Disease.php?lng=EN

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