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Mind the gap Bridging the difference between efficacy and effectiveness of orphan drugs Schuller, Y.

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Citation for published version (APA): Schuller, Y. (2018). Mind the gap: Bridging the difference between efficacy and effectiveness of orphan drugs.

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Factors contributing to the efficacy-effectiveness gap in the case of orphan drugs for metabolic diseases

Y. Schuller, C.E.M. Hollak, C.C. Gispen-de Wied, V. Stoyanova-Beninska, M. Biegstraaten

Drugs. 2017 Sep;77(13):1461-1472. doi: 10.1007/s40265-017-0788-z. Chapter 3 The efficacy-effectiveness gap in orphan drugs for metabolic diseases

Abstract Introduction

Introduction In the European Union (EU), a disease is considered orphan if it is a life-threatening or seriously Authorization of orphan medicinal products (OMPs) is often based on studies with several debilitating disorder, with a prevalence of less than 5 in 10,000. Up to now, about 7000 rare methodological shortcomings. Hence, data are difficult to interpret and efficacy does not always diseases have been documented, affecting 30-40 million people in the EU.1 In the past 16 years, 130 correspond to real-world effectiveness. We investigated to what extent an efficacy-effectiveness orphan drugs have been marketed. Initially, the small consumer’s market offered little attraction gap exists for OMPs for metabolic diseases and set out to explore which factors contribute to it. to the pharmaceutical industry to develop drugs for rare diseases. To stimulate the development of orphan drugs, European legislation was introduced in 2000. The legislation implies that, for a Methods product with orphan status, the pharmaceutical industry is entitled to receive 1) a fee reduction We included all OMPs for rare metabolic diseases authorized in the EU up to 1 January 2016. for scientific advice, 2) reduction of fees for marketing authorization application, 3) centralized Efficacy data were obtained from European Public Assessment Reports, relative effectiveness registration in the EU and 4) 10 years’ market exclusivity after marketing authorization.2 Since the 3 data from the Dutch National Healthcare Institute website, and real-world effectiveness data implementation of the Orphan Drug Legislation and its incentives, orphan medicinal products from literature and interviews with experts and patients.Efficacy and effectiveness were scored (OMPs) are being developed at an increasing rate. In 2015, for example, the European Medicines as ‘no effect’, ‘unclear’ or ‘good’ based upon a prespecified scoring system. Agency (EMA) approved 14 OMPs, whereas in 2000 only three OMPs were approved.3 In addition, more than 40% of all registered OMPs have been developed in the past 5 years.4 Expectations are Results that the development rate of OMPs will only increase in the future.5 We identified 31 authorized OMPs, of which 21 had post-marketing studies available, thus making it possible to score real-world effectiveness. Eight of 21 (38%) OMPs had a ‘good’ real-world Since patients with rare diseases have the same right to access to effective and safe drugs as effectiveness. The use of a clinical or validated surrogate primary endpoint and a representative all other patients, robust evidence is needed regarding benefits and risks. At evaluation of study population seemed to be related to good effectiveness in the real world, as were type of OMPs, however, regulatory authorities are often confronted with difficulties that are inherent marketing authorization, study population and disease prevalence. to the rarity of the diseases for which the drugs are developed. Interpretation of data is often hampered, because clinical trials may lack a placebo control, are open label, or are performed Conclusions in a limited number of patients. Moreover, the heterogeneity of each disease and the frequent This study revealed that less than half of the authorized OMPs are effective in the real world. use of nonvalidated biomarkers or functional outcome measures (FOMs) may hamper reliable Since the type of primary endpoint used in the pivotal study seems to be associated with good interpretation of data.6-8 It is important to emphasize that biomarkers or FOMs are only ‘surrogate real-world effectiveness, it is important to agree upon study endpoints through early dialogues endpoints’ if they are validated (box 1). among relevant stakeholders. Box 1 Definitions of endpoints

Several terms are used to describe measurements of disease and treatment effects, such as biomarkers, surrogate markers, surrogate endpoints, intermediate endpoints etc. We applied the definitions of the Biomarker Definitions Working group.12 The definition of ‘functional outcome measure’ was inspired by an article on Duchenne Muscular Dystrophy.13 Biomarker: A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention Functional outcome measure: A characteristic that is measured by either a function test or a (disease) symptom score. Surrogate endpoint: A biomarker or functional outcome measure that is intended to substitute for a clinical endpoint and is expected to predict clinical benefit (or harm or lack of benefit or harm). Only a small subset of biomarkers and functional outcome measures may achieve surrogate endpoint status based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence. Clinical endpoint: A characteristic or variable that reflects how a patient feels, functions, or survives.

40 41 Chapter 3 The efficacy-effectiveness gap in orphan drugs for metabolic diseases

The regulatory authorities assess the benefit/risk ratio of OMPs based on the evidence provided to provide recommendations to be used by both investigators and regulators in order to reduce in the dossier submitted to the EMA. In case the evidence is insufficient to conclude on a positive this gap and improve both access to and appropriate use of such medicines. benefit/risk ratio and thereby to grant a full marketing authorization, the EU legislation allows two alternatives. The first is a ‘conditional approval’, which can be granted for drugs when the clinical data are limited, but indicate a positive benefit/risk ratio, and when it is likely that additional Methods data will be provided in a reasonable timeframe. If the additional data confirm the positive benefit/risk ratio, the conditional approval can be changed to a full marketing authorization. The The ‘Community register of orphan medicinal products for human use’ of the European second is a marketing authorization under ‘exceptional circumstances’, which is granted in cases Commission was used to identify all OMPs that were authorized for the treatment of metabolic when limited data are provided at the time of marketing authorization application, but additional diseases up to 1 January 2016.14 A detailed description of study methods can be found in data cannot reasonably be expected to be delivered in the future due to for example the rarity supplementary material 1. of the disease.9 Nonetheless, the marketing authorization holder (MAH) is generally requested 3 by the regulatory authorities to collect additional data on safety and long-term effectiveness in Pre-Marketing Data the post-marketing period. To collect information on the pivotal studies (pre-marketing data), European Public Assessment Reports (EPARs) were used, which are available on the website of the EMA. We assessed the After marketing authorization, regulatory authorities in each EU member state make their quality of evidence of the pivotal studies using the COMPASS (Clinical evidence of Orphan own assessment before granting reimbursement. These national assessments may for Medicinal Products – an ASSessment) tool.15 In addition, we scored the efficacy of the OMPs based example take into account relative effectiveness -the ‘net benefit’ of the new drug needs to be on the effect on primary and secondary endpoints in the pivotal studies and the considerations desirable, sufficiently big and a relevant addition to the present care-, probability of real-world of the EMA as set out in the EPARs as follows: category 3 = good efficacy, category 1 or 2 = unclear effectiveness as well as cost-effectiveness. The debate on real-world effectiveness has recently efficacy, and category 0 = no effect (table 1). been fueled by the authorization of a drug for mucopolysaccharidosis (MPS) IV, elosulfase alfa (Vimizim®). It was granted a full marketing authorization by the EMA on the basis of a favorable Post-Marketing Data benefit/risk ratio regarding quality, safety and efficacy data submitted by the manufacturer.10 We divided the evaluation of effectiveness in two phases: (1) relative effectiveness atthe This was mainly based on a short-term study that showed a significant increase in mobility, using time of reimbursement decisions by the Dutch National Health Care Institute, and (2) real- the 6-min walk test (6-MWT). However, it was rejected for reimbursement by several national world effectiveness, including all post-marketing literature that was available until June 2016, authorities (i.a. The Netherlands, Sweden, Belgium and Spain). The Dutch reimbursement supplemented with experts’ and patients’ opinions. If an OMP was authorized after January 2014 authority (Zorginstituut Nederland, ZiN) stated that the data are limited to a suboptimal short- it was assumed that no reliable estimate of the real-world effectiveness could be made. Similar term outcome in a heterogeneous population, showing a small effect with a wide confidence to pre-marketing data, the effectiveness of each OMP was divided into three categories as interval that is not clinically relevant, herewith estimating a small probability of good real-world defined by the authors: category 3 = good effectiveness, category 2 or 1 = unclear effectiveness, effectiveness. or category 0 = no effect (table 1). In addition, experts were interviewed and their opinions were used to up- or downgrade the category a drug received by one category at most. Also, expert This difference between the opinion of the EMA (or other regulatory authorities such as the US opinions were used to select relevant post-marketing studies. Patients were approached to fill in Food and Drug Administration) and the (estimated) real-world effectiveness is in the literature a short online survey with questions about their main symptoms and their opinion on the choice often referred to as the ‘efficacy-effectiveness gap’ and is particularly an issue in the field of of endpoints in clinical trials. Patients’ opinions were taken into consideration upon identifying orphan drugs.11 To support the harmonized decisions of the EMA and the national reimbursement relevant clinical endpoints. authorities in the future, it is important to bridge this gap. Hence, the purpose of our research project is to investigate whether data used for authorization (i.e. data from the pivotal studies) Statistical Analysis are predictive for real-world effectiveness (i.e. effect on clinical endpoints in clinical practice and To explore which factors contribute to the efficacy-effectiveness gap, the variables of the post-marketing), and to explore which factors contribute to the efficacy-effectiveness gap. In COMPASS tool as well as the relative and real-world effectiveness were dichotomized and this article we focus on OMPs for metabolic diseases. Based on the results of this study we aim compared with 2 x 2 tables. COMPASS variables were dichotomized as follows: type of primary

42 43 Chapter 3 The efficacy-effectiveness gap in orphan drugs for metabolic diseases

Table 1 Categories of efficacy and effectiveness multicenter (30/40, 75%) and multinational (25/40, 63%). In 26/40 (65%) studies the allocation was Conclusion Category Efficacy Effectiveness randomized and a control arm was used in 27/40 (67%). Nineteen of the 40 (47%) studies applied Clinically relevanta effect on ≥1 clinical or surrogate endpoint Efficacy is Effectiveness is 3 some type of blinding. In 6/40 (15%) studies, the study population was an extreme selection when compared with standard of care good good of the patient population due to strict inclusion criteria (i.e., only men included, considerable OMP is implemented in (inter)national state of the art guideline n/a Effectiveness is 3 and quality of evidence is good good proportion of patients were physically unable to perform primary outcome measure test, etc.). Statistically significant effect on ≥1 clinical endpoint or Efficacy is Effectiveness is 2 Five of the 31 (16%) OMPs were authorized on the basis of an improvement on a clinical endpoint, surrogate endpoint unclear unclear while changes in FOMs or biomarkers resulted in the approval of 6/31 (19%) and 20/31 (65%) No study on effect on clinical endpoints, but a statistically Efficacy is Effectiveness is 1 significant effect on (non-validated) biomarker or functional unclear unclear OMPs, respectively. Of the latter 20, seven used biomarkers that were classified as surrogate outcome measure endpoints. Studies provided by manufacturer fail to show clinically No clinical n/a 0 relevant or statistically significant effect on clinical endpoint(s). effect Post-marketing studies show that there is no clinically relevant n/a No clinical 0 Pre-Marketing Data - Efficacy 3 or statistically significant effect on clinical endpoint(s) effect Category 3 (good efficacy, see Table 1) was assigned to 11/31 (35%) OMPs, category 2 (unclear No reimbursement decision is made yet / No post-marketing n/a Cannot be n/a studies (or authorization after January 2014) evaluated efficacy) to 9/31 (30%) and category 1 (unclear efficacy) to 11/31 (35%) (Table 2). Supplementary table 2 gives an overview of the EMA considerations upon authorizing the individual OMPs, a defined as: The extent to which a new therapy contributes to a meaningful (positive) change in daily life activities. including the post-marketing commitments as agreed upon with the MAHs. n/a Not applicable Post-Marketing Data - Relative Effectiveness at the Time of Reimbursement Decisions endpoint was divided into clinical endpoints and surrogate endpoints versus non-validated Eleven OMPs were not yet assessed by the Dutch National Health Care Institute for one of biomarkers and FOMs, study population into extreme selection of patient population versus the following reasons: (1) marketing authorization was granted only recently, (2) the OMP representative selection of patient population, type of marketing authorization into exceptional did not carry a claim of added benefit, or (3) the OMP did not have an annual budget impact or conditional versus full authorization, study phase into phase III versus other phases, exceeding 2,5 million euros.5 Of the remaining 20 OMPs, 7/20 (35%) were classified as category randomization into yes or no, and disease prevalence into rare or ultra-rare. Relative and real- 3 (good effectiveness), while 13/20 (65%) OMPs were categorized as category 1 or 2 (unclear world effectiveness were divided into ‘no or unclear effect’ (category 0, 1 or 2) or ‘good effect’ effectiveness) (Table 2). (category 3). Fisher’s exact test was used to assess statistical significance. A similar analysis was performed to compare efficacy [dichotomized into ‘no or unclear efficacy’ (category 0, 1 or 2) Post-Marketing Data - Real-World Effectiveness or ‘good efficacy’ (category 3)] and effectiveness. All analyses were performed using IBM SPSS For ten OMPs either no post-marketing studies were performed, or a reliable judgement about Statistics version 22. effectiveness could not be made since marketing authorization was granted after January 2014 (Table 2). Of the 21 OMPs with post-marketing studies available, 8/21 (38%) were classified as category 3 (good effectiveness), 8/21 (38%) as category 2 (unclear effectiveness) and 4/21 (19%) Results as category 1 (unclear effectiveness). One OMP (5%) was categorized as category 0 (no effect). See supplementary table 3 for an overview of post-marketing evidence used. Forty-one experts Orphan Medicinal Products (OMPs) and Indications participated in an in-depth interview, resulting in a range of 0-3 experts per OMP. For two OMPs We included 27 OMPs in our study, which were authorized for 25 metabolic orphan diseases no experts were willing to participate. Eight experts were involved in the pivotal trials of eight (table 2). Four OMPs were authorized for two different indications (miglustat, carglumic acid OMPs. Of these, three OMPs were not included in our analysis since post-marketing data were and pasireotide) or for different age groups (alglucosidase alfa), adding up to a total of 31 OMPs. not (yet) available. Following expert opinions, the judgement on real-world effectiveness was upgraded for two OMPs and downgraded for one OMP (table 2). A sensitivity analysis without Pre-Marketing Data - Characteristics of Pivotal Studies up-/downgrading the categories according to expert opinion did not change the results. Seven From the EPARs of the abovementioned 31 OMPs, 40 ‘pivotal’ or ‘main’ studies were identified patient organizations (POs) were approached representing 25 orphan diseases and 27 OMPs. (table 3). Nineteen of these 40 (47%) studies were phase III studies, and the majority were Four out of seven POs (57%) were willing to participate. The remaining POs either did not want

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Table 2 Overview of OMPs for metabolic diseases authorized in the EU between 2000 and 2016 Generic name Drug Disease Year of Type of Primary endpoint+ in pivotal study Category Category Category authorization authorization at time of at time of real-world authorization reimbursement effectiveness (EMA) decision (ZiN) miglustat Zavescaa 1. Gaucher disease 2002 Exceptionalc Spleen and liver size 3 2 2 2. Niemann-Pick C 2006 Exceptional HSEM velocity 1 2 0d velaglucerase alfa Vpriv Gaucher disease 2010 Full Hemoglobin concentration 2 2 3e eliglustat Cerdelga Gaucher disease 2015 Full Spleen volume, hematological parameters 2 n/a n/a agalsidase beta Fabrazymea Fabry disease 2001 Exceptionalc GL-3 reduction in a kidney biopsy 1 3 2 agalsidase alfa Replagala Fabry disease 2001 Exceptionalc Neuropathic pain, myocardial GL-3 levels 3 2 2 alglucosidase alfa Myozyme Pompe disease 2006 Full Infants: survival (2 studies) 3 3 3 Adults: 6-MWT and FVC 1 1 2 laronidase Aldurazymea MPS 1 (Hurler disease) 2003 Exceptionalc 6-MWT and FVC 1 1 2 idursulfase Elaprase MPS 2 (Hunter disease) 2007 Exceptional 6-MWT and FVC 2 1 1 3 elosulfase alfa Vimizim MPS 4a (Morquio disease) 2014 Full 6-MWT 1 1 n/a galsulfase Naglazymea MPS 6 (Maroteaux-Lamy Syndrome) 2006 Exceptional 12-MWT 1 1 1 sebelipase alfa Kanuma Lysosomal acid lipase-deficiency 2015 Full Survival, ALAT normalization 3 n/a n/a sapropterin Kuvan Phenylketonuria (PKU) 2008 Full Phenylalanine concentration in blood 3 3 3 betaine Cystadane Homocystinuria 2007 Full Homocysteine levels 3 2 n/a mercaptamine Procysbib Cystinosis 2013 Full White blood cell cystine levels 2 n/a 3 nitisinone Orfadina Hereditary tyrosinemia type 1 2005 Exceptionalc Survival 3 3 3 alipogene tiparvovec Glybera Lipoprotein lipase deficiency 2012 Exceptional Fasting triglyceride levels 3 n/a n/a carglumic acid Carbaglua 1. Hyperammonemia (due to NAGS deficiency) 2003 Exceptionalc Plasma ammonia levels 3 3 3f 2. Hyperammonemia (due to organic acidurias) 2011 Full Plasma ammonia levels 1 n/a 2 zinc Wilzina Wilson’s disease 2004 Full Copper levels 3 3 3 cholic acid Kolbam Inborn errors in primary bile acid synthesis 2014 Exceptional Bile acid levels and liver function 2 n/a n/a cholic acid Orphacol Inborn errors in primary bile acid synthesis 2013 Exceptional Bile acid levels and liver function 3 n/a n/a hydrocortisone Plenadrenb Adrenal insufficiency 2011 Full Serum cortisol 1 n/a 1 pasireotide Signifor 1. Cushing’s disease 2012 Full Urinary free cortisol levels 1 1 1 2. Acromegaly 2012 Full Biochemical control (GH and IGF-I) 1 2 2 ketoconazole Ketoconazole Cushing’s syndrome 2015 Full Plasma cortisol levels, urinary FC 24h 1 3 3 pegvisomant Somaverta Acromegaly 2002 Full IGF-I concentrations 2 2 2 glycerol Ravicti Urea cycle disorders 2015 Full Blood ammonia levels 2 n/a n/a phenylbutyrate asfotase alfa Strensiq Hypophosphatasia 2015 Exceptional Rickets severity (2 studies) 2 n/a n/a afamelanotide Scenesse Erythropoietic protoporphyria 2014 Exceptional Duration of sunlight exposure 2 n/a n/a

6-MWT 6-minute walk test; 12-MWT 12-minute walk test; ALAT Alanine Aminotransferase; EMA c Although the type of approval is classified as ‘exceptional’ in the EPAR, it turned to ‘full approval’ after European Medicines Agency; FC free cortisol;FVC forced vital capacity; GH growth hormone; GL-3 additional data was provided by the marketing authorization holder, herewith implying that the original globotriaosylceramide; HSEM horizontal saccadic eye movement; IGF-I Insulin-like growth factor 1, NAGS approval was actually ‘conditional’ instead of ‘exceptional’. N-acetylglutamate synthetase; ZiN Zorginstituut Nederland (Dutch National Health Care Institute) d Score was downgraded following expert opinion. However, original score was 0, hence final score did not a withdrawn from the Community register of orphan medicinal products at the end of the 10-year period of change. market exclusivity e Score was upgraded following expert opinion. However, original score was 3, hence final score did not b ‘hybrid medicines’, indicating that they are similar to a ‘reference medicine’ containing the same active change. substance (cysteamine and hydrocortisone). The pharmaceutical forms of both drugs have been used for f Score was upgraded (from 2 to 3) following (impartial) expert opinion many years, but the novel tablets are available in a formulation that allows for a delayed release of the +Clinical endpoint; (validated) surrogate; functional outcome measure;biomarker active substance. Hereby, dosing frequency is reduced and adherence to treatment is improved.

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Table 3 Characteristics of pivotal studies (n = 40) Drug Study Study Multicenter Multinational Endpoint Control Randomized Blinding Study pop. Duration No. of QoL- phase Representative patients endpoint miglustat (Gaucher) OGT 918-001 I/II Yes Yes Surrogatea No No n/a Yes 12 months 28 No miglustat (NPC) OGT 918-007 II Yes Yes FOM St. of care Yes No Yes 12 months 31 Yes velaglucerase alfa HGT-GCB-039 III Yes Yes Surrogatea Active comp. Yes Yes Yes 9 months 35 No eliglustat GZD02507 III Yes Yes Surrogatea Placebo Yes Yes Yes 39 weeks 40 Yes GZGD02607 III Yes Yes Surrogatea Active comp. Yes No, but justified Yes 52 weeks 160 No agalsidase beta AGAL-1-002-98 III Yes Yes Biomarker Placebo Yes Yes No 20 weeks 58 Yes agalsidase alfa TKT-003 II No No Clinical Placebo Yes Yes No 6 months 26 Yes TKT-005 II No No Biomarker Placebo Yes Yes Yes 6 months 15 No alglucosidase alfa AGLU01602 II/III Yes Yes Clinical Diff. dose Yes No Yes 52 weeks 18 No AGLU01702 II Yes Yes Clinical Hist. control No n/a Yes 120 weeks 21 No 3 AGLU02704 NR Yes Yes FOM Placebo Yes Yes Yes 78 weeks 90 Yes laronidase ALID-003-99 III Yes Yes FOM Placebo Yes Yes No 12 months 45 Yes idursulfase TKT024 II/III Yes Yes FOM Placebo Yes Yes No 12 months 96 No elosulfase alfa MOR-004 III Yes Yes FOM Placebo Yes Yes No 24 weeks 176 Yes galsulfase ASB-03-05 III Yes Yes FOM Placebo Yes Yes No 24 weeks 39 No sebelipase alfa LAL-CL02 III Yes NR Biomarker Placebo Yes Yes Yes 20 weeks 66 Yes LAL-CL03 NR Yes Yes Clinical No No n/a Yes Up to 208 weeks 9 No sapropterin PKU-003 III Yes Yes Surrogatea Placebo Yes Yes Yes 6 weeks 88 No PKU-006 III Yes Yes Surrogatea Placebo Yes Yes Yes 10 weeks 45 No betaine Case reports n/a n/a n/a Biomarker n/a n/a n/a Yes n/a ±140 No mercaptamine RP103-03 III Yes Yes Surrogatea Active comp. Yes No, but justified Yes 8 weeks 43 Yes nitisinone NTBC study NR Yes Yes Clinical No No n/a Yes NR 207 No alipogene AMT-011-01 NR No No Biomarker No No n/a Yes 12 weeks 14 No tiparvovec AMT-011-02 NR Yes No Biomarker No No n/a Yes 18 weeks 5 Yes AMT-010-01 NR Yes Yes Biomarker No No n/a Yes 3 months 8 No carglumic acid (organic acidurias) OE-CGA001-OA2009 IIIb Yes Yes Biomarker No No n/a Yes 15 days 77 No carglumic acid (NAGS deficiency) Case reports n/a n/a n/a Biomarker n/a n/a n/a Yes n/a 20 No zinc Existing literature NR No No Biomarker No No n/a Yes ± 3 years 148 No cholic acid (Kolbam) CAC-91-10-10 III No No Biomarker No No n/a Yes Up to 17 years 52 No cholic acid (Orphacol) Case reports n/a n/a n/a Biomarker n/a n/a n/a Yes n/a 49 No hydrocortisone DC 06/02 II/III Yes No Biomarker Active comp. Yes No, but justified Yes 24 weeks 64 Yes pasireotide (Cushing) B2305 III Yes NR Biomarker Diff. dose Yes Yes Yes 12 months 162 Yes pasireotide C2305 III Yes Yes Biomarker Active comp. Yes Yes Yes 12 months 358 Yes (Acromegaly) C2402 III Yes Yes Biomarker Active comp. Yes Yes Yes 24 weeks 198 Yes ketoconazole Literature data n/a n/a n/a Biomarker n/a n/a n/a Yes n/a >800 n/a pegvisomant SEN-3614 III Yes Yes Biomarker Placebo Yes Yes Yes 12 weeks 112 Yes glycerol phenylbutyrate HPN-100-006 III NR NR Biomarker Active comp. Yes Yes Yes 4 weeks 44 No asfotase alfa ENB-006-09 II Yes Yes Clinical Hist. control + Yes No Yes 24 weeks 13 Yes diff. dose ENB-008-10 II Yes Yes Clinical Hist. control + Yes No Yes Ongoing (extension) 12 Yes diff. dose afamelanotide CUV039 III Yes No Clinical Placebo Yes Yes Yes 6 months 93 Yes

FOM functional outcome measure;n/a not applicable; NAGS N-acetylglutamate synthetase; NPC a endpoint is either i) validated as a surrogate endpoint in scientific studies, or ii) widely accepted by Niemann-Pick C; NR not reported clinical experts as a valid surrogate for a clinical endpoint.

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Table 4 Relationship between COMPASS variables and real-world effectiveness of orphan medicinal to participate N( = 1) or did not reply to e-mails (N = 2). On average 19 (range 4-40) patients products (OMPs) per participating PO filled in the online survey resulting in a total of 75 patients representing COMPASS variable Real-world effectiveness 14 diseases and 13 OMPs. Forty-two patients (56%) reported fatigue and 15 (20%) mentioned Good effect Unclear or no clinical Total Fisher’s pain as the most inconvenient symptom of their disease. When asked for which symptom of (category 3) effect (categories 0-2) exact Type of endpoint their disease patients preferred to see improvement upon treatment with the OMP, 29 (39%) Clinical or validated surrogate 5 2 7 mentioned fatigue and nine (12%) mentioned deterioration of their vital organs or cognition. In Biomarker or FOM 3 11 14 p=0.056 contrast, experts seemed to have a preference for endpoints that are convenient to measure, Total 8 13 21* e.g. by blood tests or function tests. A comparison of endpoints used pre- and post-marketing, and preferred endpoints of patients and experts can be found in Supplementary table 4. Study Population Representative for patient population 8 9 17 Not representative for patient population 0 4 4 p=0.131 COMPASS Variables Total 8 13 21* 3 Ten OMPs were excluded from the analysis of factors contributing to the efficacy-effectiveness gap since no post-marketing evidence was available, resulting in a total of 21 OMPs (Table 4). Disease Prevalence Regarding the type of primary endpoint, 5/7 OMPs (71%) that were authorized based on a study Rare 3 2 5 Ultra-rare 5 11 16 p=0.325 with a clinical or surrogate primary endpoint showed good effectiveness in the real world, versus Total 8 13 21* 3/14 (21%) OMPs that were authorized based on a study with a biomarker or FOM as primary endpoint (Fisher’s exact test: p = 0.056). Of the OMPs for which the study population was an Type of authorization extreme selection of the patient population, none showed good effectiveness in the real world Full 6 6 12 (category 3), compared to 47% of the OMPs for which the study population was representative Exceptional/conditional 2 7 9 p=0.367 Total 8 13 21* for the patient population (p = 0.131). Also, 5/16 OMPs (31%) that were authorized for ultra- rare orphan diseases (prevalence of less than 1 in 50,000) had good real-world effectiveness, FOM functional outcome measure * OMPs without post-marketing studies were excluded from the analysis: eliglustat, elosulfase alfa, sebelipase alfa, compared to 3/5 OMPs (60%) that were authorized for rare diseases (prevalence between 1 in betaine, alipogene tiparvovec, cholic acid (Kolbam and Orphacol), glycerol phenylbutyrate, asfotase alfa, afamelanotide 50,000 and 5 in 10,000) (p = 0.325). Of the OMPs that were granted a full marketing authorization, 50% had good real-world effectiveness, compared to 22% of the OMPs that were granted authorization under exceptional circumstances (p = 0.367). The other COMPASS variables (study Relationship Between Relative Effectiveness and Real-World Effectiveness phase and randomization) did not show a relevant association with the real-world effectiveness For 13 OMPs no relative effectiveness assessment or post-marketing evidence was available, (percentage difference ≤15%, data not shown). resulting in a total of 18 OMPS for this analysis. Six out of seven (86%) OMPs for which relative effectiveness was good also showed good real-world effectiveness, versus 1/11 (9%) OMPs with Relationship Between Efficacy and Effectiveness no or unclear relative effectiveness (Supplementary table 5). In total, eight out of 21 authorized OMPs (38%) showed good effectiveness in the real-world situation, and in 16/21 OMPs (76%) the efficacy category corresponded with the real-world effectiveness category. Five out of eight OMPs (63%) for which the efficacy was judged as ‘good’ Discussion showed good relative effectiveness versus 2/12 (17%) of OMPs with no or unclear efficacy (Supplementary table 5). With respect to the real-world effectiveness: five out of seven OMPs Bridging the gap between efficacy and effectiveness is difficult, particularly in the field of orphan (71%) for which the efficacy was judged as ‘good’ showed good effectiveness versus three out of diseases, where generation of evidence is often limited to a few studies with considerable 14 (21%) with no or unclear efficacy (Supplementary table 5). methodological shortcomings. This study reveals that less than half of the approved OMPs for which sufficient post-marketing evidence is available to judge the real-world effectiveness, show good effectiveness in the real-world situation. The exploratory analyses of factors contributing to this gap showed that the type of primary endpoint used in the pivotal study seems to be the most

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important factor. Additional important findings are that none of the OMPs for which the study Recommendations and Ways Forward population was an extreme selection of the patient population showed good effectiveness in the Improvements can be introduced at the pre-marketing and post-marketing stages. First, the real world, and that a very low disease prevalence and conditional/exceptional authorization also quality of pre-marketing studies has to be sufficient to allow an unbiased (independent) judgement more often led to disappointing real-world effectiveness. Relative effectiveness (at the time ofthe about the efficacy of an OMP at the time of marketing authorization. If biomarkers are used as the reimbursement decision) has been shown to be highly correlated with real-world effectiveness. primary endpoint, caution is required for their predictive value for real-world effectiveness and For this study, we chose to compare efficacy assessment from a centralized procedure with relative studies on long-term effectiveness are of great importance. Moreover, validation of biomarkers effectiveness assessment of a national reimbursement authority, which may not represent the or FOMs as a surrogate endpoint in the context of a specific disease seems appropriate. Since our situation in all EU countries. However, several general assumptions can be made. results suggest that patients’ and experts’ preferences regarding study endpoints may differ, it is important that all relevant stakeholders (patients, academia, industry and regulatory authorities) Study Design, Choice of Endpoints and Study Population agree upon what constitutes a sensitive and validated endpoint early in the development Due to the heterogeneity and slowly progressive nature of many rare diseases, there is often a process. Also, selection of the study population and the definition of what constitutes a 3 need to use biomarkers or FOMs as the primary study endpoint. Our study, however, suggests minimal clinically important difference (MCID) require close attention. Such discussion that improvements on a biomarker level may not correspond with improvements relevant for the may take place in the context of a validation procedure at the EMA or a protocol assistance. patient in the real-world setting. According to regulatory guidelines, biomarkers or FOMs may Second, since 50% of the OMPs with a full marketing authorization have good real-world be acceptable but only if validated, and thus labeled as surrogate endpoints. In this respect, it is effectiveness (in contrast to 22% of OMPs with exceptional circumstances authorization), this a common misconception that if an outcome is believed to be correlated to clinical outcomes it underlines the need for generation of coordinated, robust post-marketing evidence. Post- can be used as a surrogate endpoint.16 In-depth studies are needed to confirm that the surrogate marketing commitments currently often imply the set-up of an industry-sponsored drug endpoint responds to treatment, predicts clinical response and is related to the pathophysiology registry, which has several shortcomings.19 Moreover, access to real-world data across the EU is of the disease. When, at the time of marketing authorization, uncertainty exists about the hampered by the lack or inefficiency of cross-border collaborations, fragmentation of resources relationship between the biomarker or FOM and clinical benefit, adequate post-marketing studies and the lack of interoperability, which complicates decision making by health technology and registries may ideally be used to validate the endpoint. Our study shows that if an OMP is assessment (HTA) bodies. Hence, there is a need for the implementation of methods to integrate authorized based on a relevant effect on a surrogate endpoint, the real-world effectiveness is and analyze heterogeneous data. The concept of a self-regulatory market, in which an OMP will generally good. This is for example the case in phenylalanine levels in phenylketonuria 17 and automatically no longer be prescribed by doctors when effectiveness is not convincing, might fail platelet counts or spleen volume in Gaucher disease, for which the correlation with clinical in rare diseases with an unmet medical need. outcomes is well established. Interestingly, two of the three OMPs that were approved on the basis of an improvement in biomarker levels but showed good effectiveness in the real-world To accelerate access to new drugs, new pathways are increasingly being explored in the EU. situation used biomarkers that were –according to the experts– highly correlated with clinical The ‘adaptive pathway’, introduced by the EMA in 2015, enhances timely access of an OMP by symptoms. Experts’ opinions might thus be valuable in judging whether or not a specific endpoint approving it in a well-defined patient subgroup with a high (unmet) medical need, followed by could be used as a surrogate endpoint. Another important note to make is that if a biomarker widening of the indication to a larger patient population.20 In addition, HTAs are involved early or FOM is validated as a surrogate endpoint in a certain disease, this does not mean that it in the process. Again, the launch of improved disease registries, which can generate robust and can automatically be used as surrogate endpoint in other diseases. The 6-MWT is for example independent evidence, is of critical importance.19 Through this, the importance of timely access validated as a surrogate endpoint in pulmonary arterial hypertension, but not for many other is balanced with the need for adequate information on effectiveness and safety, rendering diseases. Another important limitation of using the 6-MWT as a primary endpoint is that only marketing authorization a continuous process.21 An evaluation on the adaptive pathways pilot patients who are able to walk can be included in the clinical study. Consequently, extrapolating showed that this procedure can promote multi-stakeholder dialogues and support development clinical study results to the entire patient population may be problematic.18 As was shown by our of drugs for which generation of evidence is difficult. Another promising development is the ‘real- study, none of the OMPs for which the study population was an extreme selection of the patient world evidence’ initiative that is currently being developed by the EMA, creating a framework population showed good effectiveness in the real world. This highlights the need for studies with that delivers access to and analysis of multinational real-world data to optimize decision making study populations that are a better reflection of the total patient population, thus having a high on medicinal products developed for areas with a high unmet medical need.22 external validity.

52 53 Chapter 3 The efficacy-effectiveness gap in orphan drugs for metabolic diseases

13. Straub V, Balabanov P, Bushby K, et al. Limitations References Stakeholder cooperation to overcome Despite the small sample, we believe that the results of our study may serve as a lead for future challenges in orphan medicine development: the example of Duchenne muscular dystrophy. studies. Our study is the first to systematically compare pre-marketing data with post-marketing 1. Orphanet. The portal for rare diseases and Lancet Neurol. 2016;15(8):882-90. data for OMPs. Studies about the quality of pivotal studies of orphan drugs have been published orphan drugs [Available from: http://www. orpha.net/consor/cgi-bin/index.php?lng=EN. 14. Community Register of orphan medicinal before 23-25, but they lack the inclusion of post-marketing effectiveness. Since the COMPASS tool is products for human use: European 2. Orphan incentives London: European Commission; 2016 [Available from: http:// not developed to score or rank the quality of clinical evidence, it was not possible to quantify the Medicines Agency; [Available from: ec.europa.eu/health/documents/community- level of pre-marketing evidence. Grading of Recommendations Assessment, Development and http://www.ema.europa.eu/ema/index. register/html/index_en.htm. jsp?curl=pages/regulation/general/general_ Evaluation (GRADE) is not appropriate to assess clinical studies of OMPs, as this approach does content_000393.jsp. 15. Picavet E, Cassiman D, Aertgeerts B, et al. not take into consideration the methodological drawbacks of these studies.15 To our knowledge, Development and validation of COMPASS: 3. EURORDIS Therapeutic Report - Update clinical evidence of orphan medicinal products no other quality assessment tools exist for evaluation of OMPs. Although clinical experts were on therapeutic development and patient - an assessment tool. Orphanet journal of rare involvement in EMA activities. July & August asked to complete our list of post-marketing studies with studies that they believed were of diseases. 2013;8:157. 2016. 3 value for the evaluation of post-marketing effectiveness, we may have missed some studies in 16. Fleming TR, DeMets DL. Surrogate end points 4. EMA Annual Report 2014. London. in clinical trials: are we being misled? Annals of the evaluation of post-marketing data. Moreover, since results of negative studies might not be 5. Desancic S, Stoimenova A, Savova A, et al. internal medicine. 1996;125(7):605-13. available due to publication bias, the real-world effectiveness as assessed in our study may be Pharmacoeconomics of rare diseases therapy 17. Waisbren SE, Noel K, Fahrbach K, et al. - An example of phenylketonuria. Acta Medica an overestimation.26 Phenylalanine blood levels and clinical Bulgarica. 2011;38(1):84-9. outcomes in phenylketonuria: a systematic 6. Gerss JW, Kopcke W. Clinical trials and rare literature review and meta-analysis. Molecular diseases. Advances in experimental medicine genetics and metabolism. 2007;92(1-2):63-70. Conclusion and biology. 2010;686:173-90. 18. Haas M, Vlcek V, Balabanov P, et al. European 7. Tambuyzer E. Rare diseases, orphan Medicines Agency review of ataluren for the drugs and their regulation: questions and treatment of ambulant patients aged 5 years We showed that less than half of the authorized OMPs show good effectiveness in the real-world misconceptions.Nature reviews Drug and older with Duchenne muscular dystrophy situation and that the most important contributor to the efficacy-effectiveness gap seemed to discovery. 2010;9(12):921-9. resulting from a nonsense mutation in the 8. Wilcken B. Rare diseases and the assessment dystrophin gene. Neuromuscular disorders : be the use of a biomarker in the pivotal study. Whether the results of our research on medicinal of intervention: what sorts of clinical trials can NMD. 2015;25(1):5-13. products for metabolic orphan diseases can be extrapolated to other orphan disease fields (e.g. we use? Journal of inherited metabolic disease. 19. Hollak CE, Aerts JM, Ayme S, et al. Limitations oncology, neurology), remains to be elucidated. 2001;24(2):291-8. of drug registries to evaluate orphan medicinal 9. Guideline on procedures for the granting of products for the treatment of lysosomal a marketing authorisation under exceptional storage disorders. Orphanet journal of rare circumstances, pursuant to article 14 (8) of diseases. 2011;6:16. Acknowledgements regulation (EC) No 726/2004 London: European 20. Adaptive pathways: European Medicines Medicines Agency; 2005. Agency; 2016 [Available from: http://www. 10. Vimizim London: European Medicines ema.europa.eu/ema/index.jsp?curl=pages/ We thank all participating clinical experts for sharing their opinions, and Angèl Link for providing Agency; 2014 [Available from: http://www. regulation/general/general_content_000601. the Dutch National Health Care Institute assessments. We also thank chairpersons of patient ema.europa.eu/ema/index.jsp?curl=pages/ jsp. medicines/human/medicines/002779/ 21. Liu Y, Lacombe D, Stupp R. The changing world organizations for approaching patients, and all patients for filling in the survey. smops/Positive/human_smop_000650. of drug development: an academic research jsp&mid=WC0b01ac058001d127. organization’s perspective on the “Seven 11. Eichler HG, Abadie E, Breckenridge A, et Wonders” of the future world of anticancer al. Bridging the efficacy-effectiveness gap: drug development. Chinese clinical oncology. a regulator’s perspective on addressing 2014;3(2):19. variability of drug response. Nature reviews 22. Update on Real World Evidence Data Drug discovery. 2011;10(7):495-506. Collection. European Medicines Agency 10 12. Biomarker Definitions Working Group. March 2016. Biomarkers and surrogate endpoints: preferred 23. Onakpoya IJ, Spencer EA, Thompson MJ, et definitions and conceptual framework. al. Effectiveness, safety and costs of orphan Clinical pharmacology and therapeutics. drugs: an evidence-based review. BMJ Open. 2001;69(3):89-95. 2015;5(6):e007199.

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24. Picavet E, Cassiman D, Hollak CE, et al. Clinical evidence for orphan medicinal products-a Supplementary Material 1 cause for concern? Orphanet journal of rare diseases. 2013;8:164. Study methods 25. Putzeist M, Heemstra HE, Garcia JL, et al. Determinants for successful marketing The ‘Community register of orphan medicinal products for human use’ of the European authorisation of orphan medicinal products Commission describes all OMPs that were authorized as an orphan drug in the EU.1 We used in the EU. Drug discovery today. 2012;17(7- this list to identify all OMPs that were authorized for the treatment of metabolic diseases until 8):352-8. 26. Mattila T, Stoyanova V, Elferink A, et al. January 2016. OMPs discontinued from the community register of OMPs at the end of the 10- Insomnia medication: do published studies year period of market exclusivity were also included. Compounds that have been designated reflect the complete picture of efficacy ‘orphan status’, but have not received EU marketing authorization, were excluded. and safety? Eur Neuropsychopharmacol. 2011;21(7):500-7. Pre-marketing data 3 To collect more detailed information on pre-marketing data, European Public Assessment Reports (EPARs) were used, which are available on the website of the EMA. These contain product characteristics and information on the pivotal studies that led to authorization. We assessed the quality of evidence of the pivotal studies by using the COMPASS (Clinical evidence of Orphan Medicinal Products – an ASSessment) tool which is a qualitative instrument.2 The tool itself is not developed to score the quality of clinical evidence, but rather to provide guidance on assessing the value of clinical evidence. One author (YS) completed all COMPASS assessments. If uncertainty existed, another author (MB) was consulted with whom the questions were discussed until consensus was achieved. Furthermore, we categorized the evidence of efficacy of the OMPs as described in the EPARs as category 3 = good efficacy, category 2 or 1 = unclear efficacy, or category 0 = no effect (table 1). Importantly, efficacy assessment was done by evaluating effects on both primary and secondary endpoints.

Post-marketing data We divided the evaluation of effectiveness in two phases (Figure 1); (1) relative effectiveness at the time of reimbursement decisions by the Dutch National Health Care Institute (Zorginstituut Nederland, ZiN) and (2) real-world effectiveness, including all post-marketing literature that was available until June 2016, supplemented with expert and patient opinions.

1) Relative effectiveness at the time of reimbursement decisions We retrieved documents on reimbursement decisions from the website of the Dutch National Health Care Institute and evaluated on which grounds an OMP was reimbursed or not.3 Upon deciding whether an OMP should be reimbursed, the Dutch National Health Care Institute verifies whether an OMP is included in professional, state of the art (inter)national treatment guidelines. In addition, the Institute assesses its relative effectiveness (compared to standard of care) based on all published studies. Of note, if additional data had become available between the decision for marketing authorization and the assessment by the Institute, these data were included in the assessment of the relative effectiveness. In its evaluation they take into account the choice of

56 57 Chapter 3 The efficacy-effectiveness gap in orphan drugs for metabolic diseases

3 was the highest category possible). A downgrade was done when a minimum of two experts graded the effectiveness of a drug as ‘bad’ or ‘very bad’. A sensitivity analysis was performed to verify whether up-/downgrading of the categories based on expert opinions influenced the test results. To gather data on expert opinions, we conducted semi-structured interviews with (international) clinical experts who were experienced in treating patients with the OMP. Experts were selected based upon literature and in consultation with one of the authors (C. Hollak). Experts that were interviewed were preferably not involved in the pivotal trial to avoid bias. However, this was not always possible due to the rarity of the diseases and the limited number of experts. Questionnaires were sent per email to four experts per OMP, with an assumption of 50% response. Two reminders were sent in case the response time was longer than two weeks. Questions covered the experts’ opinions about the endpoints used in the pivotal studies 3 and the effectiveness of the OMP in the real-world. Overall effectiveness was graded by giving marks 0-5: (0) don’t know, (1) very bad, (2) bad, (3) moderate, (4) good, (5) very good. If an Figure 1 Relationship between efficacy, relative effectiveness and effectiveness OMP was authorized (and prescribed by experts) after January 2014 or if the OMP was not yet reimbursed in the expert’s country, opinions about effectiveness were deemed non-reliable endpoints and their corresponding minimally clinically important difference (MCID), the quality and a grade 0 was granted. If an expert responded to the questionnaire, their responses were of the evidence, duration of studies, and the opinion of experts and patients. This is similar with discussed in detail during a telephone follow up meeting. Additionally, we approached the the procedures of the National Institute for Health and Care Excellence (NICE) of the United following Dutch patient advocacy groups: The Dutch Neuromuscular Diseases Association, Fabry Kingdom.4 For our study, relative effectiveness of each OMP was divided into three categories as Support & Information Group Netherlands, Dutch Association for Addison and Cushing Patients, defined by the authors: category 3 = good effectiveness, category 2 or 1 = unclear effectiveness, Dutch Phenylketonuria Association, Dutch Pituitary Foundation, Association of Patients with or category 0 = no effect (table 1). Erythropoietic Protoporphyria, and the Dutch Association of Adults and Children with Metabolic Disorders. Groups were contacted by phone and email at least twice. If the group indicated that 2) Real-world effectiveness they were willing to participate, 4 patients per disease were randomly chosen and were asked Post-marketing data were collected by review of the literature using the PubMed database. In per email to fill in a short online survey with questions about their main symptoms and their June 2016 a search was conducted for each OMP separately, using search terms that included the opinion on the choice of endpoints in clinical trials. Experts’ as well as patients’ opinions served name of the orphan disease and the OMP (EU and USA trade- and generic name), and different as a guiding principle for the identification of clinically relevant endpoints. notations. Articles published in English, Dutch, German, Spanish or French were selected. We focused on long-term follow up studies and phase IV studies, including randomized controlled trials and independent observational cohort studies. In very rare indications for which no studies were found, data were extracted from case series. Furthermore, studies were only included if the OMPs were used at the registered dosage. If an OMP was authorized after January 2014 it was assumed that no reliable estimate of the effectiveness could be made. In case there were several post-marketing studies, we evaluated the studies with the best possible evidence, based on study design, type of outcomes and study population. Similar to pre-marketing and relative effectiveness data, scoring of effectiveness was done as follows: category 3 = good effectiveness, category 2 or 1 = unclear effectiveness, or category 0 = no effect (table 1b). In addition, expert opinions were used to up- or downgrade the evidence obtained from literature by one category. An upgrade was only done if a minimum of two experts graded the effectiveness of a drug as ‘good’ or ‘very good’ and when the original category was lower than 3 (in other words, category

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References Supplementary Material 1

1. Community Register of orphan medicinal products for human use: European Commission; 2016 [Available from: http:// ec.europa.eu/health/documents/community- register/html/index_en.htm. 2. Picavet E, Cassiman D, Aertgeerts B, et al. Development and validation of COMPASS: clinical evidence of orphan medicinal products - an assessment tool. Orphanet journal of rare diseases. 2013;8:157. 3. Rapporten en standpunten. 2016; Available Post-marketing obligations Post-marketing of study open label, case-controlled Randomized, ERT. versus of miglustat safety and effectiveness study. observational history Natural on including data Niemann-Pick C registry of characteristics parameters, effectiveness long-term responders’’, / ‘’non ‘’responders’’ results. effectiveness (Gaucher observational registry Post-authorization study). by a sub- in patients safety long-term Investigate Gaucher Collaborative the International to registry Gaucher Registry. Group and safety long-term Antibody-formation, after regimens dosing maintenance effectiveness, of sphingolipids. clearance dose and optimal identifying study, Phase IV clinical and antibody- reactions Infusion dosing interval. formation. double-blind, placebo-controlled Randomized, with disease patients Pompe in late-onset study disease. moderate mild to safety and effectiveness of long-term Evaluation registry. Pompe through regimens. dosing on alternative study Clinical MPS I through and effectiveness safety Long-term program. registry from: https://www.zorginstituutnederland.nl/ publicaties/rapporten+en+standpunten. 4. Guide to the methods of technology appraisal 2013. 2013, National Institute for Health and Care Excellence.

1 Notes from EMA from Notes because of estimate to is difficult of miglustat of effect Size and lack patients of disease, small number evaluable heterogeneity on bone disease The lack of data comparison. of a placebo arm for reduction in spleen and significant However, is a clear deficiency. (from parameters and haematological and biochemical volumes liver from improvements significant clinically seen, as were baseline) was baseline in QoL parameters. study design it is to and due explorative are only analyses Efficacy effectiveness. term concerning long conclusions any draw to difficult number of patients by low results is limited of the Interpretation study design. by and investigated Open-label design is relevant. clinically considered used are Endpoints acceptable. to demonstrate it difficult makes presentation of clinical Variability is needed and special follow-up term. Longer in short benefits clinical of the assessment for an accurate studied to be need groups patient benefit. clinical but not abolished by disease is reduced pain in Fabry Neuropathic is magnitude of pain reduction the exact However, alfa. agalsidase overall The limitations. methodological to due estimate to difficult all the chosen endpoints is that be drawn can that conclusion with placebo. when compared improvement show consistently of of progression for the assessment markers surrogate Potential further and validated. disease should be explored alfa with alglucosidase treatment that showed study The pivotal aged less than 6 Pompe disease with infantile-onset of patients at survival ventilator-free and survival prolonged significantly months Studies subgroup. control a historical to compared of age 18-months Extrapolating Pompe disease patients. included only infantile-onset late-onset to Pompe disease patients in infantile-onset obtained data valid approach. is not a disease patients Pompe late-onset in Myozyme of effect a positive Study suggests of the disease. stages in mild or moderate probably disease, but more and appropriate are studied the endpoints that Experts consider relevant, is clinically efficacy although small, the demonstrated that, therapies. of alternative of the absence especially in the light 3 1 2 2 1 3 3 1 1 Category at time of at Category authorization EMA considerations and post-marketing obligations

Disease 1. Gaucher disease 2. Niemann-Pick C Gaucher disease Gaucher disease disease Fabry disease Fabry disease Pompe (infants) disease Pompe (adults) MPS 1 (Hurler disease) Drug miglustat alfa velaglucerase eliglustat beta agalsidase alfa agalsidase alfa alglucosidase laronidase Supplementary Table 2

60 Chapter 3 The efficacy-effectiveness gap in orphan drugs for metabolic diseases

Post-marketing obligations Post-marketing with a Survey Outcome of Hunter Establishment at for data to analyze continue to commitment data long-term gather to years, 10 the first least Studies in patients end-points. clinical on relevant <5years. registry. of disease-specific Set-up Ongoing, observational women. Studies in pregnant outcomes. and safety on clinical database Registry. effectiveness. trial on long-term Clinical elderly <4 yrs, children women, Studies in pregnant Long- insufficiency. renal of hepatic with patients and effectiveness. safety term on demographics, data gather to registry Patient profile. safety and drug utilization Not reported. a post-marketing through data safety Long-term program. surveillance obligations Post-marketing as metabolism chylomicron Assess postprandial Set- LPLD treatment. of successful marker surrogate program. / surveillance up of a disease registry patients deficient of all NAGS follow-up Systematic acid. with carglumic treated Not reported. Not reported. treated patients in effectiveness long term Monitor registry. a patient from with Kolbam treated patients in and effectiveness safety Monitor database. surveillance a patient from with Orphacol of registry European multicenter, Prospective Swedish insufficiency. adrenal with chronic patients of pattern the evaluating study, retrospective quality registries. Swedish use from Plenadren 3 4 Δ 5 Δ Overall, Overall, -Hydroxy- β -reductase deficiency are reported in literature. Cholic literature. in reported are deficiency -reductase 1 1 : Given the rareness of the conditions, comparison of the conditions, the rareness : Given : Given the rarity of the disease, one cannot expect expect of the disease, one cannot the rarity : Given β Notes from EMA from Notes is not barrier and therefore the blood brain does not cross Idursulfase on CNS disease. effect any have to expected No acceptable. are criteria Study design and inclusion exclusion sensitive be more would (than 6-MWT) that other single endpoint time. present at the be identified could ERT. by unaffected tissues appears avascular Disease in relatively appear to studies in the clinical demonstrated Improvements benefits. clinical represent with significant positive, trials were in the pivotal observed Results size, liver histology, liver molecular markers, in survival, improvements phase 2/3 open-label trial and QOL. Study design (combined growth and as the disease is lethal arm) is acceptable without a comparison available. treatment is no effective there levels shown in Phe was effect related dose significant A statistically with PKU in all patients does not work Product studies. in both pivotal effect. a definite shown but only in those who have alone, it is difficult with betaine has been treated Since no patient from those betaine to attributable benefits the clinical distinguish to Homocysteine supportive). (diet, to other treatments attributable endpoint as a surrogate accepted generally are plasma concentrations betaine that be considered it can of disease. Therefore, the severity for with homocystinuria. patients to benefit offers as accepted generally is level WBC cystine The primary endpoint effect. treatment for endpoint surrogate HT-1, particularly for treatment effective to be an Nitisinone seems The risk for damage. liver is irreversible there early before if started the risk of failure, to liver due transplantation liver the need for death, porphyria-like and the risk of life-threatening carcinoma hepatocellular is treatment in whom nitisinone be small in patients crises appear to of age. six months before started EMA from Notes although hampered data, efficacy overall by generated The evidence to a clinically leads that Glybera suggested limitations, statistical by or severe with patients risk only in of pancreatitis reduction relevant affected severely of This is a subgroup attacks. multiple pancreatitis need. medical with a high unmet patients NAGS-deficiency it has However, trials. clinical controlled through efficacy prove to terms in size effect acid has an important carglumic that been shown no to compared development and psychomotor growth of mortality, therapy. or conventional treatment MMA, or IVA PA, based was acid and NH3 scavengers carglumic between of treatment very quality or low comparison and yields retrospective on paired acid on its with carglumic treatment that showed The study strength. rapid decrease induced a with sodium benzoate in combination or own the risk of neurological reducing groups, in all age in ammonia levels IVA. PA, MMA, and with in patients complications with Wilson’s patients in zinc is effective that is clear evidence There in non ceruloplasmin decrease copper, of urine disease; Reduction and symptoms of clinical or improvement stabilization plasma copper, symptoms of clinical of the occurrence prevention tests, function liver patients. in presymptomatic would be it because information comprehensive collect Inability to principles. ethics medical to contrary use’ (‘well-established data based on literature Effectiveness studies impossible. clinical controlled rarity made Disease application). concerns. are potential bias and publication Reporting with 3 38 patients for results cholic acid treatment with patients and seven deficiency oxidoreductase -C27-steroid -3-Oxosteroid-5 the need for or obviate postpone to: has been shown acid therapy improve parameters, normal laboratory restore transplantation, liver all of the improve and significantly lesions of the liver, histological symptoms. patient’s well-being should be and tolerability concerning data Efficacy studies. to the open-label design of due with caution interpreted 2 1 1 3 3 3 2 3 3 3 1 3 2 3 1 Category at time of at Category authorization time of at Category authorization Continued

Disease MPS 2 (Hunter disease) MPS 4a (Morquio disease) MPS 6 (Maroteaux- Syndrome) Lamy acid Lysosomal lipase-deficiency Phenylketonuria (PKU) Homocystinuria Cystinosis Hereditary type 1 tyrosinemia (HT-1) Disease lipase Lipoprotein deficiency 1. Hyperammonemia NAGS (due to deficiency) 2. Hyperammonemia organic (due to MMA acidurias PA, and IVA) disease Wilson’s in Inborn errors primary bile acid synthesis in Inborn errors primary bile acid synthesis insufficiency Adrenal Drug idursulfase alfa elosulfase galsulfase sebelipase alfa sapropterin betaine mercaptamine nitisinone Drug alipogene tiparvovec acid carglumic zinc (Kolbam) acid cholic cholic acid (Orphacol) hydrocortisone Supplementary Table 2

62 63 Chapter 3 The efficacy-effectiveness gap in orphan drugs for metabolic diseases

2 0 3 9 2 2 3 2 propionic propionic IVA Category of Category evidence PA 9-13 15, 17, 19, 20 19, 17, 15, 5-8 1-4 21-33 Hereditary tyrosinemia type 1; N-acetylglutamate synthase; synthase; N-acetylglutamate Post-marketing obligations Post-marketing to document study surveillance Post-marketing and effectiveness. safety and effectiveness. safety Study on long-term study. safety authorisation Post in patients of tumor volume study Long-term on study Clinical with pegvisomant. treated using somatostatin treatment combination analogues with pegvisomant. outcomes and clinical safety long-term Document safety post-authorisation in a non-interventional study. long-term longitudinal, prospective, Observational, collect information to with HPP of patients registry quality of outcomes, clinical on the epidemiology, and safety. life study. safety and long-term Disease registry 14-18 3 HT-1 Post-marketing studies included Post-marketing 2004, 2009, Elstein 2006, Giraldo Giraldo 2007 Pastores 2015, Patterson 2015, Fecarotta 2010 Wraith 2010, Patterson Dussen 2014, Smith Hughes 2015, Van 2015 2015, Elstein 2015, Zimran n/a 2013, 2007, Rombach Banikazemi 2014, Watt 2013, Rombach Weidemann 2010 2014 2013, Rombach Rombach 2012, Bembi Case 2015, Spiridigliozzi der Ploeg den Hout 2000, Van 2010, Van 2012, der Ploeg 2012, De Vries 2010, Van Regnery 2012, Vianello 2010, Strothotte 2016, 2016, Güngör 2013, Stepien 2013 Güngör NAGS The studies had The studies

mucopolysaccharidosis; mucopolysaccharidosis; MPS enzyme replacement therapy; enzyme therapy; replacement ERT

1

methylmalonic acidemia; acidemia; methylmalonic Notes from EMA from Notes adverse effect and therapeutic (unsatisfactory rate High drop-out profile safety and the efficacy for account into should be taken events) of pasireotide. considered are criteria Study design and inclusion exclusion adequate. use’ (‘well-established data based on literature Effectiveness appropriate. considered described is population Patient application). efficacy conclusion on the does not allow a documentation Submitted statistically analogues. Although somatostatin versus of pegvisomant compared score symptoms signs and total in improvements significant with pegvisomant treatment shown, were with the placebo group tumor size. does not reduce reduction of both blood ammonia in the was demonstrated Efficacy groups treatment between differences No significant and glutamine. it is However, sodium phenylbutyrate). vs phenylbutyrate (glycerol a provided characteristics release the sustained that acknowledged during the day. control better of clinical course During the studied is acceptable. population Patient to the regard with variously changed were the main objectives studies, data, In addition, based on the basis of emerging primary endpoint. drug and the inclusion of study the dosage made to were changes cautious these reasons, subjects. For of study criteria / exclusion Based on 1) the improvement required. is of data interpretation of bone biopsy appearance 2) the histological appearance, in x-ray in demonstrated height-gain catch-up and 3) the apparent material very limited, is although the data considered, CHMP some patients, supports a specific and limited submitted of evidence the totality that efficacy. clinical claim for small. considered is size The magnitude of the effect to the pharmacodynamic blinded due as insufficiently be regarded to this, the afamelanotide. Despite of in pigmentation) (increase effect afamelanotide with Treatment effect. a beneficial show studies pivotal of the secondary The results in sun exposure. a small increase led to group. the afamelanotide favour numerically endpoints central nervous system; white blood cell blood white : four post-marketing studies. 6-MWT distance and Walton Scale Scale Walton and studies. 6-MWT distance post-marketing : four MMA CNS : 6-MWT distance and FVC significantly improve with ERT compared with compared with ERT improve significantly and FVC : 6-MWT distance WBC

1 1 1 2 2 2 2 Main results of included post-marketing studies of included post-marketing Main results improvements significant studies, all open-label. Statistically post-marketing Four volume, hematological and spleen (liver endpoints in all major effectiveness of QoL similar as in ERT-treated Improvement and BMD Z-score). parameters patients. of extensions studies, including 2 open-label post-marketing uncontrolled Four EMA. Studies mainly use to commitment and one post-approval studies pivotal stabilization deterioration, results: discrepant showing disability scores, composite with treatment. or improvement switching after results report studies studies, of which two post-marketing Five platelet (hemoglobin concentration, endpoints Surrogate imiglucerase. from with or improve stable remain generally volumes) and spleen liver counts, of ERT effects long-term which evaluates One study, treatment. alfa velaglucerase that and shows endpoints includes clinical and imiglucerase) alfa (velaglucerase complications, and bone reduce the incidence of splenectomy effectively can ERT malignancies. in the risk of developing in a reduction result likely and will most a similar effectiveness. have to expected are and imiglucerase alfa Velaglucerase studies. No post-marketing studies, many In ERT. despite progression disease is there that show studies Several comparative far, So effect of both therapies. the between is made no distinction agalsidase between effectiveness in differences substantial not shown have studies but with ERT, is delayed event clinical first Time to beta. and agalsidase alfa is unclear. magnitude of effect studies, many In ERT. despite progression disease is there that show studies Several comparative far, So effect of both therapies. the between is made no distinction agalsidase between effectiveness in differences substantial not shown have studies but with ERT, is delayed event clinical first Time to beta. and agalsidase alfa is unclear. magnitude of effect onset Infantile Significantly remain unchanged. Cognition and lung function significantly. improve group. in ERT survival prolonged onset Late placebo. lower in the is significantly exacerbations to pulmonary due rate Hospitalization assessment. in HRQoL observed No change receiving ERT. patients Category at time of at Category authorization phenylketonuria; Continued Summary of included post-marketing studies tetrahydrobiopterin; PKU BH4 lipoprotein lipase deficiency;

Indication Gaucher disease Niemann-Pick C Gaucher disease Gaucher disease disease Fabry disease Fabry disease Pompe LPLD Disease disease 1. Cushing’s 2. Acromegaly syndrome Cushing’s Acromegaly disorders cycle Urea Hypophosphatasia Erythropoietic protoporphyria phenylalanine; phenylalanine;

Phe

6-minute walk test; Drug Miglustat* (Zavesca) Miglustat (Zavesca) alfa Velaglucerase (Vpriv) Eliglustat (Cerdelga) beta* Agalsidase (Fabrazyme) alfa* Agalsidase (Replagal) alfa Alglucosidase (Myozyme) Drug pasireotide ketoconazole pegvisomant glycerol phenylbutyrate alfa asfotase afamelanotide Notes are copied from EPARs, available at http://www.ema.europa.eu/ema/ Supplementary Table 2 isovaleric acidemia; acidemia; isovaleric acidemia; 1 6-MWT Supplementary Table 3

64 65 Chapter 3 The efficacy-effectiveness gap in orphan drugs for metabolic diseases 2 1 9 1 9 3 9 3 3 9 3 2 3 9 9 1 1 2 3 Category of Category evidence Category of Category evidence 63, 64 63, 73, 74 73, 43, 44 43, 53-61 34, 35 34, 69-71 36-42 52 62 72 72

65-68 3 Post-marketing studies included Post-marketing 2007 2009, Wraith Clarke 2015, Giugliani 2014, Tomanin Parini 2014, Sohn 2015, Jones 2013, Muenzer 2011, Zuber 2014 n/a 2014, Giugliani 2014 Harmatz n/a 2013, 2013, Shintaku 2015, Keil Longo 2012, Douglas 2013, Ziesch 2012, Leuret Lee 2008 45-51 n/a Langman 2014 Bendadi 2014, Thimm 2012, El-Karaksy 2012, 2011, Larochelle 2011, De Laet 2008, Bartlett Schlune 2012, Santra 2007 2014, Masurel-Paulet n/a Post-marketing studies included Post-marketing Haberle 2011 2016 2013, Valayannopoulos Abacan 2005, Santiago Ranucci 2014, Marcellini 2015 n/a n/a 2016, Quinkler 2015, Giordano 2015 Bergthorsdottir Biller 2008 2016 2015, Bronstein Sheppard Biller 2008 NB: neurological NB: neurological Main results of included post-marketing studies of included post-marketing Main results volumes and spleen and liver levels studies. GAG open-label post-marketing Two motion with of sleep quality and joint or stabilization Improvement reduced. in QoL. Little improvement therapy. study and several studies, of which one open-label phase IV post-marketing Eight disease, otological in changes significant No statistically studies. disease registry only contradictory; often Results are evaluation. orthopedic and neurological Urinary GAGs and growth. in 6-MWT distance improvement showed some studies has a positive ERT studies. Overall, in all reduced upon treatment significantly volumes. and spleen on liver influence studies. No post-marketing study in 4 study and one phase IV studies; one survey post-marketing Two the progression but does not prevent levels, GAG decreases Treatment patients. is lower rate but mortality remains unchanged, (n=4). QoL multiplex of dysostosis group. in ERT studies. No post-marketing reduction in serum phenylalanine a studies show studies. All post-marketing Seven QoL is improved tolerance. phenylalanine in dietary an improvement and/or levels children. healthy age-matched to or comparable studies. No post-marketing are levels cysteine Mean WBC study. single-arm post-marketing One prospective improvement Significant with mercaptamine. control under optimal maintained Pediatric on the scores function total in social function, school and remains. Inventory Quality of Life reduced in all is transplantation for liver studies. The need Nine post-marketing HT-1 of complications for acute hospitalizations as the need for as well studies, of 4 duration a mean treatment after 97.8% in 1 study rate Survival (1 study). complications long-term prevent does not seem to Treatment 9 months. years late. treatment started that such as cirrhosis and HCC in patients patients! may be impaired in treated development studies. No post-marketing Main results of included post-marketing studies of included post-marketing Main results remain within in which ammonia concentrations study, cohort One long-term and psychomotor and neurological therapy, normal limits during the maintenance baseline). from deteriorated (none of the patients is good outcome study (n=41). In all retrospective recent studies, of which one post-marketing Two start of therapy. after quickly normalize concentrations plasma ammonia patients, with therapy. improve symptoms Clinical disease. and liver scores histologic and ASAT, in ALAT decreases Significant for the Study of Liver. Association in guideline of the European Implemented studies. No post-marketing studies. No post-marketing trial. Significant controlled studies; of which one prospective post-marketing Three in hydrocortisone conventional to in BMI and HbA1c when compared changes AddiQoL outcomes: in secondary no improvement shows Plenadren all studies. does increase studies, Plenadren Only in the non-controlled scores. and fatigue AddiQoL. pasireotide that states which guideline, in Implemented studies. post-marketing No and safety determine to are needed trials but longer-term be effective, might effectiveness. Biochemical with octreotide. comparing pasireotide studies, post-marketing Two patients (=GH <2.5 μg/L more in significantly control and normal IGF-1) is achieved signs of acromegaly in clinical Improvement than octreotide. with pasireotide in guideline. implemented Not yet groups. in both treatment outcome) (secondary in guideline. studies. Implemented No post-marketing Continued

Indication MPS1 (Hurler disease) MPS2 (Hunter disease) MPS4a (Morquio disease) of MPS 6 (Syndrome Maroteaux-Lamy) acid lipase Lysosomal deficiency Phenylketonuria (PKU) Homocystinuria Cystinosis Hereditary type 1 tyrosinemia lipase Lipoprotein deficiency Indication Hyperammonemia NAGS (due to deficiency) Hyperammonemia organic (due to acidurias) disease Wilson’s in Inborn errors primary bile acid synthesis in Inborn errors primary bile acid synthesis insufficiency Adrenal – Hypopituitarism disease Cushing’s – Hypopituitarism Acromegaly syndrome Cushing’s

Carbaglu) Drug Laronidase* (Aldurazyme) Idursulfase (Elaprase) alfa Elosulfase (Vimizim) Galsulfase (Naglazyme) Sebelipase alpha (Kanuma) Sapropterin (Kuvan) Betaine (Cystadane) Mercaptamine (Procysbi) Nitisinone* (Orfadin) tiparvovec Alipogene (Glybera) Drug acid* Carglumic ( acid* Carglumic (Carbaglu) Zinc* (Wilzin) Cholic acid (Kolbam) Cholic acid (Orphacol) Hydrocortisone (Plenadren) Pasireotide (Signifor) Pasireotide (Signifor) Ketoconazole HRA) (Ketoconazole Supplementary Table 3

66 67 Chapter 3 The efficacy-effectiveness gap in orphan drugs for metabolic diseases

References Supplementary Table 3 glycated 2 9 9 9 Category of Category evidence 1. Giraldo P, Alfonso P, Atutxa K, et al. Real-world reduces the incidence of splenectomy and clinical experience with long-term miglustat bone complications.Orphanet journal of rare bone mineral

HbA1c maintenance therapy in type 1 Gaucher diseases. 2014;9:112.

BMD disease: the ZAGAL project. Haematologica. 11. Smith L, Rhead W, Charrow J, et al. Long-term

somatostatin receptor 2009;94(12):1771-5. velaglucerase alfa treatment in children with

SRL 2. Elstein D, Hollak C, Aerts JM, et al. Sustained Gaucher disease type 1 naive to enzyme therapeutic effects of oral miglustat (Zavesca, replacement therapy or previously treated N-butyldeoxynojirimycin, OGT 918) in type I with imiglucerase. Molecular genetics and 75-83

growth hormone; growth hormone; Gaucher disease. Journal of inherited metabolic metabolism. 2015.

GH disease. 2004;27(6):757-66. 12. Zimran A, Wang N, Ogg C, et al. Seven-year

quality of life; quality life; of 3. Pastores GM, Elstein D, Hrebicek M, et al. safety and efficacy with velaglucerase alfa

QoL Effect of miglustat on bone disease in adults for treatment-naive adult patients with 3 Post-marketing studies included Post-marketing 2009, Buhk 2009, Berg Ghigo 2007, Schreiber 2009, Pivonello Trainer 2014, der Lely 2001, Giustina 2007, Van 2014 Katznelson n/a n/a n/a

aspartate aminotransferase; with type 1 Gaucher disease: a pooled analysis type 1 Gaucher disease. American journal of of three multinational, open-label studies. hematology. 2015;90(7):577-83. ASAT Clinical therapeutics. 2007;29(8):1645-54. 13. Elstein D, Mehta A, Hughes DA, et al. Safety 4. Giraldo P, Latre P, Alfonso P, et al. Short-term and efficacy results of switch from imiglucerase glycosaminoglycan ; effect of miglustat in every day clinical use in to velaglucerase alfa treatment in patients with

GAG treatment-naive or previously treated patients type 1 Gaucher disease. American journal of with type 1 Gaucher’s disease. Haematologica. hematology. 2015;90(7):592-7. 2006;91(5):703-6. 14. Banikazemi M, Bultas J, Waldek S, et al.

insulin-like growth factor I; 5. Fecarotta S, Romano A, Della Casa R, et al. Agalsidase-beta therapy for advanced Fabry Long term follow-up to evaluate the efficacy disease: a randomized trial. Annals of internal IGF-1 of miglustat treatment in Italian patients with medicine. 2007;146(2):77-86. alanine aminotransferase; alanine Niemann-Pick disease type C. Orphanet journal 15. Rombach SM, Smid BE, Bouwman MG, et al. ALAT of rare diseases. 2015;10:22. Long term enzyme replacement therapy for 6. Patterson MC, Vecchio D, Jacklin E, et al. Fabry disease: effectiveness on kidney, heart Long-term miglustat therapy in children with and brain. Orphanet journal of rare diseases. enzyme replacement therapy; enzyme therapy; replacement Niemann-Pick disease type C. Journal of child 2013;8:47.

ERT neurology. 2010;25(3):300-5. 16. Weidemann F, Niemann M, Stork S, et al. 7. Wraith JE, Vecchio D, Jacklin E, et al. Miglustat Long-term outcome of enzyme-replacement in adult and juvenile patients with Niemann- therapy in advanced Fabry disease: evidence Pick disease type C: long-term data from for disease progression towards serious hereditary tyrosinemia type 1; a clinical trial. Molecular genetics and complications.Journal of internal medicine. metabolism. 2010;99(4):351-7. 2013;274(4):331-41. ; HT-1 8. Patterson MC, Mengel E, Vanier MT, et al. 17. Rombach SM, Smid BE, Linthorst GE, et al.

Main results of included post-marketing studies of included post-marketing Main results in IGF-1 levels a decrease studies, all of them showing post-marketing Seven describe some studies Furthermore, in majority of studies). (primary endpoint mass. However cardiac less apneas and decreased volume, tongue decreased no significant found and one study overall does not decrease tumor size and numbness or tingling of limbs. fatigue, in sweating, improvement after the use of pegvisomant guidelines, both recommending in two Implemented of evidence although level SRL therapy), to (and if no response of surgery failure is low. studies. No post-marketing studies. No post-marketing studies. No post-marketing Stable or improved neurological manifestations Natural course of Fabry disease and the during miglustat therapy in patients from the effectiveness of enzyme replacement therapy: Addison’s disease-specific Addison’s quality-of-life;

European medicines agency; European international disease registry for Niemann-Pick a systematic review and meta-analysis: disease type C: an observational cohort study. effectiveness of ERT in different disease Continued EMA Orphanet journal of rare diseases. 2015;10:65. stages. Journal of inherited metabolic disease. AddiQoL 9. Hughes DA, Gonzalez DE, Lukina EA, et 2014;37(3):341-52.

al. Velaglucerase alfa (VPRIV) enzyme 18. Watt T, Burlina AP, Cazzorla C, et al. Agalsidase Indication Acromegaly disorders cycle Urea Hypophosphatasia Erythropoietic protoporphyria replacement therapy in patients with Gaucher beta treatment is associated with improved health-related lifequality of disease: Long-term data from phase III clinical quality of life in patients with Fabry disease: trials. American journal of hematology. findings from the Fabry Registry. Genetics HRQoL body mass index; white blood cell blood white 2015;90(7):584-91. in medicine : official journal of the American

BMI College of Medical Genetics. 2010;12(11):703- 6-minute walk test;

WBC 10. van Dussen L, Biegstraaten M, Dijkgraaf MG, et al. Modelling Gaucher disease progression: 12.

Drug Pegvisomant (Somavert) Glycerol phenylbutyrate (Ravicti) alfa Asfotase (Strensiq) Afamelanotide (Scenesse) long-term enzyme replacement therapy Supplementary Table 3 6-MWT density; hemoglobin; ligand;

68 69 Chapter 3 The efficacy-effectiveness gap in orphan drugs for metabolic diseases

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Zuber Z, Rozdzynska-Swiatkowska A, Jurecka 2013;11:218. 20. Mehta A, Beck M, Elliott P, et al. Enzyme Enzyme replacement therapy improves A, et al. The effect of recombinant human 51. Longo N, Arnold GL, Pridjian G, et al. Long-term replacement therapy with agalsidase respiratory outcomes in patients with late- iduronate-2-sulfatase (Idursulfase) on growth safety and efficacy of sapropterin: the PKUDOS alfa in patients with Fabry’s disease: an onset type II glycogenosis and high ventilator in young patients with mucopolysaccharidosis registry experience. Molecular genetics and analysis of registry data. The Lancet. dependency. Lung. 2013;191(5):537-44. type II. PloS one. 2014;9(1):e85074. metabolism. 2015;114(4):557-63. 2009;374(9706):1986-96. 31. Stepien KM, Hendriksz CJ, Roberts M, et al. 41. Parini R, Rigoldi M, Tedesco L, et al. Enzymatic 52. Langman CB, Greenbaum LA, Grimm P, et al. 21. Case LE, Bjartmar C, Morgan C, et al. 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Bendadi F, de Koning TJ, Visser G, et al. with infantile Pompe disease treated with with Pompe disease. Molecular genetics and Outcome Survey (HOS). Molecular genetics and Impaired cognitive functioning in patients with enzyme replacement therapy: long-term metabolism. 2013;109(2):174-8. metabolism. 2013;109(1):41-8. tyrosinemia type I receiving nitisinone. The follow-up. American journal of medical 33. Gungor D, Kruijshaar ME, Plug I, et al. Quality 43. Harmatz PR, Garcia P, Guffon N, et al. Journal of pediatrics. 2014;164(2):398-401. genetics Part C, Seminars in medical genetics. of life and participation in daily life of adults Galsulfase (Naglazyme(R)) therapy in infants 54. Thimm E, Richter-Werkle R, Kamp G, et al. 2012;160C(1):22-9. with Pompe disease receiving enzyme with mucopolysaccharidosis VI. Journal of Neurocognitive outcome in patients with 23. Bembi B, Pisa FE, Confalonieri M, et al. Long- replacement therapy: 10 years of international inherited metabolic disease. 2014;37(2):277-87. hypertyrosinemia type I after long-term term observational, non-randomized study follow-up. Journal of inherited metabolic 44. Giugliani R, Lampe C, Guffon N, et al. treatment with NTBC. Journal of inherited of enzyme replacement therapy in late-onset disease. 2016;39(2):253-60. Natural history and galsulfase treatment in metabolic disease. 2012;35(2):263-8. glycogenosis type II. Journal of inherited 34. Clarke LA, Wraith JE, Beck M, et al. Long- mucopolysaccharidosis VI (MPS VI, Maroteaux- 55. De Laet C, Munoz VT, Jaeken J, et al. metabolic disease. 2010;33(6):727-35. term efficacy and safety of laronidase in Lamy syndrome)--10-year follow-up of patients Neuropsychological outcome of NTBC- 24. Van den Hout H, Reuser AJ, Vulto AG, et the treatment of mucopolysaccharidosis I. who previously participated in an MPS VI treated patients with tyrosinaemia type 1. al. Recombinant human alpha-glucosidase Pediatrics. 2009;123(1):229-40. Survey Study. American journal of medical Developmental medicine and child neurology. from rabbit milk in Pompe patients. Lancet. 35. Wraith JE, Beck M, Lane R, et al. Enzyme genetics Part A. 2014;164A(8):1953-64. 2011;53(10):962-4. 2000;356(9227):397-8. replacement therapy in patients who have 45. Keil S, Anjema K, van Spronsen FJ, et al. 56. Larochelle J, Alvarez F, Bussieres JF, et al. 25. van der Ploeg AT, Clemens PR, Corzo D, et al. mucopolysaccharidosis I and are younger Long-term follow-up and outcome of Effect of nitisinone (NTBC) treatment on the A randomized study of alglucosidase alfa in than 5 years: results of a multinational study phenylketonuria patients on sapropterin: clinical course of hepatorenal tyrosinemia in late-onset Pompe’s disease. The New England of recombinant human alpha-L-iduronidase a retrospective study. Pediatrics. Quebec. 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Genetics in medicine : official journal of 27. de Vries JM, van der Beek NA, Hop WC, et Tetrahydrobiopterin (BH4) in PKU: effect on 58. Bartlett DC, Lloyd C, McKiernan PJ, et al. Early the American College of Medical Genetics. al. Effect of enzyme therapy and prognostic dietary treatment, metabolic control, and nitisinone treatment reduces the need for liver 2014;16(6):435-41. factors in 69 adults with Pompe disease: an quality of life. Journal of inherited metabolic transplantation in children with tyrosinaemia open-label single-center study. Orphanet 37. Muenzer J, Beck M, Eng CM, et al. Long-term, disease. 2012;35(6):983-92. type 1 and improves post-transplant renal journal of rare diseases. 2012;7:73. open-labeled extension study of idursulfase in 48. Leuret O, Barth M, Kuster A, et al. Efficacy function. Journal of inherited metabolic 28. Strothotte S, Strigl-Pill N, Grunert B, et the treatment of Hunter syndrome. 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72 73 Chapter 3 The efficacy-effectiveness gap in orphan drugs for metabolic diseases Patient opinion Patient fatigue, Bone events, volume, spleen and liver parameters hematological speech, swallowing Tremor, tinnitus, Fatigue, pain neuropathic n/a n/a function, bone Cognitive fatigue, growth, deformities, complications, cardiac macroglossia stiffness, function, Cognitive breathing, swallowing, ear problems, joint mobility, infections pulmonary function, Pain, fatigue opinion Patient and cardiac Growth, pulmonary function, pain, physical bone deformities, endurance n/a n/a n/a renal growth, Fatigue, QoL complications, n/a n/a n/a

3 Expert opinion platelet Spleen volume, BMB bone events, counts, score function, cognitive Swallowing, QoL mobility, following Death cardiomyopathy, and therapy replacement renal albuminuria, GFR, renal stroke, levels (lyso)GL3 n/a vital 6MWT, ADL-ability, expiratory maximal capacity, inspiratory maximal pressure, test Sniff pressure, function, cardiac QoL, mobility, fine hand movements, JROM, growth deformities, tracheal QoL, cognitive FVC, 6-MWT, function 6-MWT, QoL, mobility, plethysmography, body box pain, muscular strength, tracks that device activity (by rate) sleep and heart activity, Expert opinion motion, pain, joint Growth, pulse oximetry, night function, cardiac spirometry, of health QoL, utilization 12-MWT resources, histology liver ALAT, Survival, function, Phe QoL, cognitive Phe concentration tolerance, events, Cardiovasculary prevention osteoporosis, of homocystinuria-related (thrombosis, complications function) cognitive kidney survival, Renal GFR, WBC transplantation, hypothyroidism, levels, cystine mellitus, myopathy, diabetes pulmonary function liver disease, HCC, Liver renal disease, transplantation, executive function, cognitive functions episodes, long- Pancreatitis and fasting on effect term levels TG postprandial function, neurological Survival, amino plasma ammonia levels, acid spectrum

Endpoints used post-marketing Endpoints parameters, hematological volume, Spleen and liver (chitotriosidase, response biochemical growth, in BMD CCL18), change (ambulation, disability scores Composite swallowing), and language manipulation, (gait score severity composite neurological dysarthria, dysmetria, abnormalities, dystonia, impairment), delay/cognitive and developmental cognition or cardiac, (renal, event clinical first Time to TIA, cardiac stroke, or death), event cerebrovascular ventricular new mass, fibrosis, (LV complications renal disease, death, renal end-stage tachycardia), QoL levels, (lyso)GL3 GFR), and (albuminuria function and proximal status, function, functional Motor strength, muscular function and skeletal distal QoL, mental/ function, health-related respiratory heart function development, cognitive function, gross motor QoL, (in society), participation muscle and distal proximal status, functional pulmonary fatigue, function, respiratory strength, 6-MWT function, FVC, sleep, apnea/hypopnea excretion, Urinary GAG mental 6-MWT, FVC, disability score, JROM, index, development heart organomegaly, excretion, Urinary GAG of range joint ENT symptoms, valvulopathies, involvement, neurological 6-MWT, motion, growth, milestones developmental studies. No post-marketing used post-marketing Endpoints and fine gross levels, urinary GAG dysplasia, Skeletal function, vision, hearing,cardiac function, motor survival, 6-MWT, height, utilization, health resource QoL studies. No post-marketing QoL, Phe blood concentrations, Phe tolerance, treatment to and adherence diet to adherence studies. No post-marketing GFR QoL, in estimated change levels, WBC cystine growth, function, hospitalization, Cognitive disease, survival, liver transplantation, liver urine tubular function, blood alpha-fetoprotein, compliance and succinylacetone, d-aminolevulinate to bone disease secondary and diet, with treatment tubular impairment renal studies. No post-marketing response clinical Plasma ammonia levels, , ASAT, serum , ASAT, , dietary Phe , dietary , cardiomyopathy, , cardiomyopathy, , fasting median , fasting , plasma amino

, QMT assessment, MMT , QMT assessment, liver index, , apnea/hypopnea and liver JROM, , passive , swallowing, evoked potentials, potentials, evoked , swallowing, Endpoints used and patients’ and experts’ opinions , biochemical response, QoL, BMD response, , biochemical , 3-MSCT, urinary GAG levels urinary GAG , 3-MSCT, 3-MSCT, urinary KS levels urinary KS 3-MSCT, , liver function, liver failure, liver liver failure, function, liver , liver , composite score of GL-3 inclusions in score , composite

Endpoints used pre-marketing in pivotal study in pivotal used pre-marketing Endpoints (primary and secondary) hematological Spleen and liver volume, parameters score HSEM velocity neuropsychological performance, physical nerve examination, neurological tests, organ velocity and tremor, conduction speech, muscle strength, isometric volumes, QoL markers, biochemical pulmonary tests, and renal GL-3 Neuropathic pain, myocardial levels endothelium, skin and heart capillary kidney, tissue and urinary of kidney score composite function and mass, renal cardiac GL-3 levels, in plasma and urine GL-3 levels Survival, alive and free of % of patients support ventilator invasive and head circumference length weight, 6-MWT and FVC functional activities assessment, assessment, use time QoL, ventilator 6-MWT and FVC QoL, JROM volume, 6-MWT and FVC left cardiac levels, urine GAG spleen volume, mass ventricular 6-MWT, study in pivotal used pre-marketing Endpoints (primary and secondary) 12-MWT normalization Survival, ALAT mid-upper arm height, weight, ferritin, hemoglobin levels circumference, in blood Phe concentration tolerance levels Plasma homocysteine levels WBC cystine acid gastric use of concomitant (exploratory: QoL) therapies, reduction Survival serum α-fetoprotein, HCC, transplantation, biochemical symptoms, neurological renal parameters, hematological parameters, function levels triglyceride Fasting chylomicron-triglyceride and/or chylomicrons signs clinical of severity and/or frequency ratio, and symptoms Plasma ammonia levels growth, physical acids (including glutamine), symptoms clinical development, psychomotor decompensation hyperammaemic of acute and survival

Disease Gaucher disease Niemann-Pick C disease Fabry disease Pompe (infants) disease Pompe (adults) MPS 1 (Hurler disease) MPS 2 (Hunter disease) MPS 4a (Morquio disease) Disease MPS 6 (Maroteaux- Syndrome) Lamy acid Lysosomal lipase-deficiency Phenylketonuria (PKU) Homocystinuria Cystinosis Hereditary type 1 tyrosinemia lipase Lipoprotein deficiency Hyperammonemia NAGS (due to deficiency) Supplementary Table 4

74 75 Chapter 3 The efficacy-effectiveness gap in orphan drugs for metabolic diseases

QMT BMB GAG insulin-likegrowth Patient opinion Patient n/a n/a Patient opinion Patient shortness of breath Fatigue, n/a n/a pain, libido, Fatigue, memory/concentration, myalgia, mood swings, weight, muscular strength, headache, nausea endurance, physical Fatigue, pain, weight, joint myalgia, insomnia edema, peripheral Fatigue, sleep in society, participation headache, diabetes quality, soft tissue mellitus, obesity, swelling restrictions Diet IGF-1 forced vital capacity; transient ischemic attack; alanine aminotransferase; alanine FVC TIA

ALAT 3 hepatocellular carcinoma; Expert opinion n/a time without pain, Exposure QoL Expert opinion of Frequency crises, hyperammonemic plasma ammonia levels transplantation, Liver disease, neurological liver speech function, progression, and zinc, 24 hour urine copper function, non- liver ceruloplasmin-bound plasma copper and profile Bile salts, steroid function liver QoL,24 hour serum cortisol, lipids, insulin, bone weight, HbA1c, BMI markers, urinary Plasma and/or muscular weight, cortisol, function, cognitive strength, diabetes, blood pressure, QoL, osteoporosis, of blood clotting normalization QoL, IGF-1 concentrations, tumor mass (pituitary) reduction of frequency Mortality, of severity hospitalizations, decompensations, metabolic QoL, neurocognitive outcome and behavioral glutamine parameters, Phenylalanine; Phenylalanine; ear nose throat; HCC Phe ENT activities of daily living; ADL glycated hemoglobin; manual muscle testing; CC-chemokine ligand 18; HbA1c MMT CCL18 6-minute walk test; 6-MWT Endpoints used post-marketing Endpoints studies. No post-marketing studies. No post-marketing Endpoints used post-marketing Endpoints response clinical Plasma ammonia levels, hepatic excretion, urinary copper γ-GT, ASAT, ALAT, effects adverse histology, liver content, copper studies. No post-marketing waist body weight, HbA1c, BMI, QoL, glucose, circumference studies. No post-marketing symptom signs and acromegaly IGF-I concentrations, volume, tongue QoL, tumor volume, ring size, scores, fasting condition, physical sleep apnea, general performance cardiac levels, glucose studies. No post-marketing left ventricular; LV globotriaosylceramide; globotriaosylceramide; body mass index; white blood cell GL3 BMI WBC , combined sun , combined 12-minute walk test; clinical symptoms and symptoms clinical keratan sulfate; sulfate; keratan , number and severity , number and severity , GH levels, tumor volume, tumor volume, , GH levels, KS 12-MWT , bone mineralization, growth, growth, , bone mineralization, , QoL, fatigue Continued quality of life; quality life; of , speech, neurological function, , speech, neurological QoL bone mineral density; plasma ACTH and serum cortisol levels, levels, and serum cortisol plasma ACTH glomerular filtration rate;

BMD Endpoints used pre-marketing in pivotal study in pivotal used pre-marketing Endpoints (primary and secondary) severity Rickets motor muscle strength, ability, walking pulmonary function function, pain, disability, exposure Duration of sunlight pain, QoL, pain, and phototoxic exposure episodes phototoxic Endpoints used pre-marketing in pivotal study in pivotal used pre-marketing Endpoints (primary and secondary) Plasma ammonia levels, markers Copper levels , bilirubin, albumin γ-GT ALAT, ASAT, and serum transaminases, Bile acid levels histology liver weight, bilirubin, height, Serum cortisol cortisol plasma levels, Urinary free cortisol levels, QoL tumor volume, symptoms, clinical IGF-I concentrations swelling, (soft-tissue symptoms acromegaly fatigue), and headache, perspiration arthralgia, hand, QoL of the non-dominant size ring finger Blood ammonia levels crises, hyperammonemic of symptomatic phenylbutyrate, urinary phenylacetate, phenylacetylglutamine levels GFR joint range of motion; JROM 3-minute stair climb test; Disease Hypophosphatasia Erythropoietic protoporphyria Disease Hyperammonemia organic (due to acidurias) disease Wilson’s in Inborn errors primary bile acid synthesis Adrenal insufficiency disease Cushing’s Acromegaly disorders cycle Urea Supplementary Table 4 3-MSCT bone marrow burden; glycosaminoglycan; factor 1; quantitative muscle testing;

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Supplementary Table 5 Relationships between efficacy, relative effectiveness and real-world effectiveness

Table a Relationship between efficacy and relative effectiveness

Relative effectiveness Good effectiveness Unclear or no clinical effect Total (category 3) (categories 0-2) Good efficacy (category 3) 5 3 8 Efficacy Unclear or no clinical effect (categories 0-2) 2 10 12

Total 7 13 20

Table b Relationship between efficacy and real-world effectiveness

Real-world effectiveness Good effectiveness Unclear or no clinical effect Total (category 3) (categories 0-2) Good efficacy (category 3) 5 2 7 Efficacy Unclear or no clinical effect 3 11 14 (categories 0-2) Total 8 13 21

Table c Relationship between relative effectiveness and real-world effectiveness Real-world effectiveness Good effectiveness Unclear or no clinical effect Total (category 3) (categories 0-2) Good efficacy (category 3) 6 1 7 Relative Unclear effectiveness or no 1 10 11 effectiveness clinical effect (categories 0-2) Total 7 11 18

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