Master's Degree Dissertation

Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Author: Ruodan Nan

Master's Degree in Health Economics and Pharmacoeconomics

UPF Barcelona School of Management

Academic Year 2018 – 2021 Mentor: Laura Vallejo

1

Project performed within the framework of the Health Economics and Pharmacoeconomics program taught by Barcelona School of Management, a centre associated with Pompeu Fabra University

2 Abstract

A rare disease is one that affects less than 1 in 2,000 in general population, and they are often chronic and life-threatening [1]. Due to the high cost to develop and small market for orphan drugs, historically manufacturers are reluctantly to explore the rare disease therapeutic areas. There is highly unmet need from patients with rare diseases. As the pharmaceutical expenditure rises, governments around the world are increasingly under pressure to contain the costs on drug reimbursement. Meanwhile patients with rare diseases need to be ensured for access to orphan drugs, and the industry needs to be incentivized to innovate. Health technology assessment and reimbursement bodies set out measures and policies for orphan drugs to be given market access. In this literature review, the landscape of health technology appraisals for orphan drugs in England UK is studied. The process for an orphan drug to gain marketing authorisation in the European Union (EU), the methods and criteria that used by National Institute for Health and Care Excellence (NICE) are reviewed. All orphan drugs with marketing authorisations from European Medicine Agency (EMA) are searched from the agency’s online database, whereas each of the authorised orphan drug is searched in NICE’s database for any technology appraisals and recommendations made for the orphan drug. The search results are then analysed to find factors that may influence NICE’s decisions on whether the drug should be considered cost-effective. Based on the analyses, suggestions are made for NICE to potentially improve its way of assessing orphan drugs.

Keywords: cost-effective; NICE; rare diseases; orphan drugs

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License

3 Table of contents

1. INTRODUCTION…………………………………………………………………………………………..5 1.1 Rare diseases and orphan drugs………………………………………………………5 1.2 Marketing authorisation of orphan drug in the EU………………………….5 1.3 Marketing authorisation routes for orphan drugs in England………….6 1.4 TA by NICE………………………………………………………………………………………7 1.5 HST by NICE…………………………………………………………………………………….8 1.6 Types of recommendations…………………………………………………………….9 1.7 Commercial arrangements……………………………………………………………..9 2. AIMS & SUBJECTIVES………………………………………………………………………………….10 3. DATA SOURCE & METHODOLOGY……………………………………………………………….11 4. RESULTS……………………………………………………………………………………………………..12 4.1 Orphan drugs granted a EU marketing authorisation………………………12 4.2 Assessment of orphan drugs by NICE………………………………………………13 4.3 Comparison of assessment results between cancer and non-cancer orphan drugs………………………………………………………………………………………………….16 4.4 Comparison of assessment results made through TA and HST routes…………………………………………………………………………………………………………….17 4.5 Characterisation of prevalence of indicated orphan diseases………….20 4.6 Characterisation of ICER values reached by the appraisals via TA and HST routes……………………………………………………………………………………………………..23 5. DISCUSSION……………………………………………………………………………………………….26 5.1 Uncertainty surrounding the evidence affects the appraisal results.26 5.2 ICER thresholds in TA are inappropriate for assessing orphan drugs……………………………………………………………………………………………………………..27 5.3 ICER threshold should be adjusted based on the prevalence………….28 References…………………………………………………………………………………………………….29 Appendix A. List of orphan medicinal products with European marketing authorisation…………………………………………………………………………………………………32 Appendix B. List of orphan drugs appraised by NICE………………………………………60

4 1.INTRODUCTION

1.1 Rare diseases and orphan drugs

A rare disease, defined by the European Union, is one that affects less than 1 in 2,000 individuals in the general population [1]. 80 % of rare diseases are genetic, and they are often chronic and life- threatening. There are about 6,000 to 8,000 identified rare diseases so far, which include some forms of cancers, auto-immune diseases, metabolic conditions and inherited malformations. Between 250 to 280 new rare diseases are discovered annually [2]. A large amount of people are affected by rare diseases. About 1 in 17 people will be affected by a rare disease at some point in their lives. [3]. Overall, 263 million to 446 million people worldwide are affected by one of these rare diseases. In the EU, an estimate of 30 million people are or will be affected. In the UK, approximately 3.5 million people are affected by rare diseases [4].

An orphan drug is a pharmaceutical product treating rare diseases. Due to the high costs in R&D for drug development, and small market for orphan drugs due to the low prevalence, their incremental cost-effectiveness ratio tend to be much higher than drugs targeting common diseases. Developing an orphan drug might therefore not allow the recovery of the capital invested for its research. As a result, drug developers are reluctant to develop orphan drugs under normal market conditions.

1.2 Marketing authorisation of orphan drug in the EU

In order to promote the development of orphan drugs, the European regulation on orphan medicinal products (Regulation (EC) No 141/2000) was adopted in December 1999 [5]. Orphan drug developers can apply for orphan designations from European Medicine Agency (EMA) which guarantee a range of incentives, including scientific advice at reduced price with no restriction on number of times of requesting, access to centralised authorisation procedure which allows companies to make a single application to EMA resulting in a single opinion and a single decision valid in all European Union (EU) Member States, 10 years of market exclusivity after the marketing authorisation when similar medicines for the same indication cannot be placed on the market, additional incentives for micro, small and medium-sized enterprises such as administrative and procedure assistance, reduced

5 fees for regulatory activities, and research grants from European Commission [6]. There are criteria to be fulfilled to qualify and maintain the orphan designation. Such criteria include that the disease must be life-threatening or chronically debilitating, the prevalence must be no more than 1 in 2,000 or the marketing of the drug is unlikely to be profitable enough to cover the investment, and there must be no available treatment or the drug must be of significant benefit over the already existing treatments. The orphan designation is granted on preliminary data and is re-evaluated at the time of market authorisation [7]. After orphan designation is granted, an annual report summarising the developing status must be submitted. Sponsors of some orphan drugs can? also apply for paediatric investigation plan (PIP) which offers a two-year marketing exclusivity extension to the ten-year marketing exclusivity [8]. In order to apply for marketing authorisation, sponsors need to submit a similarity report addressing the similarity between new medicinal products and the orphan drugs that are under market exclusivity protection. If there is no similarity, or if similar, one of the derogations provided for in the Orphan Regulation (EC) No 141/1200 applies, then the Committee for Medicinal Products for Human Use (CHMP) will conclude that the marketing authorisation application is not similar to any authorised orphan medicinal products. Otherwise, the application for market authorisation will be declined. The sponsors should also submit a report on maintenance of the orphan designation. The Committee for Orphan Medicinal Products (COMP) will review the report and adopt a decision following CHMP positive opinion on the market authorisation application. EMA sends the decision from COMP to the European Commission [9]. The sponsors can request an accelerated assessment which will be granted if CHMP decides that the product is of major interest for public health and therapeutic innovation [10]. Additional monitoring is needed for medicinal products of which the data is limited on its long-term use [11]. Conditional marketing authorisations could be granted to medicinal products where the benefit of immediate availability outweighs the risk of less comprehensive data than normally required, while it is likely to obtain comprehensive data within a certain timeframe, to address unmet needs of patients. The sponsor may apply for a marketing authorisation under exceptional circumstances when comprehensive data cannot be provided even after authorisation on the efficacy and safety under normal conditions of use [12].

1.3 Marketing authorisation routes for orphan drugs in England

The National Health Service (NHS) England plays a key role in determining the availability of a treatment, and has commissioning responsibility for majority of orphan drugs in England. There are five major ways for market access for orphan drugs in England. The effectiveness and cost-

6 effectiveness of orphan drugs are provided by the National Institute for Health and Care Excellence (NICE). The first two routes are being made available in England through NICE Health Technology Assessment (HTA) programme, including firstly the single technology appraisal (TA) and secondly the highly specialised technology evaluation (HST). Within the frame of TA, orphan drugs targeting cancer with limited data can be recommended via Cancer Drug Fund (CDF) which allows more data collection while the drug is being funded. If an orphan drug is not referred to NICE or NICE decided not to recommend the treatment, there are alternative commissioning routes such as being made available through NHS England Commissioning Policies (regional guidelines, clinical commissioning policies, service specification, and highly specialised criteria). Orphan drugs targeting haemophilia are not subject to NICE HTA so they are generally reviewed as part of national procurement processes led by Commercial Medicines Unit (CMU) of NHS England. Another alternative route for making orphan drugs available to the patients is through Individual Funding Requests (IFR) by clinicians on behalf of individual patients, only if the individual could not constitute a cohort. Very few IFRs are accepted by the NHS [13]. In this dissertation, only the first two routes through NICE HTA programme are discussed. Other alternatives routes are beyond the scope of this dissertation.

1.4 TA by NICE

NICE provides guidance to the NHS in England on the clinical and cost effectiveness of health technologies. The appraisals are carried out by NICE at the request of the Department of Health and Social Care. Once the technology is recommended, the NHS is legally obliged to fund and resource it. TA takes one of the following forms: single technology appraisal (STA) where only one single technology for a single indication is concerned; fast track appraisal (FTA) in which a shorter process time is applied to speed up access if the single technology for a single indication is the most cost- effective new treatment; and when the subjected technology covers more than one technology, or one technology for more than one indication, a multiple technology appraisal (MTA) is used. Through the TA process, NICE is able to produce guidance of the new technology soon after it is introduced in the UK. The sponsor needs to firstly submit the principal evidence about the clinical effectiveness and cost-effectiveness of the new technology. Then the evidence review group (ERG), which is an external academic organisation independent of NICE, produces a review on the submitted evidence mainly from the sponsor, also supported by testimonies from patients, healthcare professionals and commissioners. NICE also invites consultees, such as national groups representing patients and carers, to provide information. Clinical experts, patient experts, and NHS commissioning experts are also

7 invited to clarify issues about the submitted evidence. STA is the default route for appraisal for most of the orphan drugs. The consultant clinical adviser in the topic selection team performs the elimination, filtering and prioritisation of topics for TA. All new cancer drugs will be referred automatically to NICE for appraisal. Those technology to be recommended must meet a threshold of incremental cost-effective ratio (ICER) of between £20,000 and £30,000 per quality-adjusted life year (QALY) gained, or up to £50,000 per QALY gained if the technology qualifies as end-of-life therapy. When the most plausible ICER is above £20,000 per QALY gained, several other factors need to be taken into account for decision making, including the certainty of the evidence submitted, whether there are uncaptured health benefits and the innovative nature of the technology [14]. If the likely ICER of a technology is below £10,000 per QALY gained, then the technology is considered offering exceptional value for money, and is qualified for FTA [15].

1.5 HST by NICE

The process and the methods for HST is based on NICE’s guide to those of TA, with modification required to evaluate technologies targeting very rare conditions. Medicinal products that do not meet the criteria for referral into TA programme can be considered for the HST programme. The sponsors for orphan drugs often consider HST a more appropriate route for appraisal than STA. The technology has to full fill all the following criteria to be evaluated by HST: the target patient population is very small and is concentrated in very few centres in England; the target patient group is clinically distinct; the condition is seriously chronic and severely disabling; being used exclusively as a highly specialised service; the acquisition cost is very high; having potential for life long use; having significant need for national commissioning. In order to form a guidance for a technology, the evaluation committee will take into account factors including the nature of the condition, clinical effectiveness, value for money, and the impact of technology beyond the direct health benefit such as significant non-health benefits, and substantial cost-savings in the prospect of the whole society, etc. The ICER of the technology is an important part for consideration of value for money. A highly specialised technology will be recommended via HST if its most plausible ICER is below £100,000 per QALY gained. For those with the most plausible ICERs above £100,000, the committee will consider the level of therapeutic improvement in terms of the number of incremental QALY gained. A weight index will be assigned to the QALY benefits. The index will be 1 if the number of QALY gained is less than 10; between 1 and 3, using equal increments, for 11-29 QALY gained; and 3 for greater than or equal to 30 QALY gained [16]. The upper limit for the most plausible ICER varies according to the number of QALY gained. It is

8 £100,000 for technologies offer less than 10 incremental QALYs, and £300,000 for those that offer more than 30 additional QALYs to the patient in their lifetime [17].

1.6 Types of recommendations

After technology appraisal, the technology Appraisal Committee (TAC) prepare the type of recommendations. There are 5 different types, which are results from TA or HST approaches.

• Recommended. When a technology such as a drug is recommended ‘as an option’, it means that the technology is recommended for use in line with the marketing authorisation from EMA or Medicines and Healthcare Products Regulatory Agency (MHRA), or how it is used in clinical practice in the NHS. The NHS must make the technology available within 3 months of the date of publication of the recommendation, or otherwise specified date. • Optimised. TAC decided the subject technology is only cost-effective as a treatment for a specific group of people rather than the patient group stated in the marketing authorisation. In such cases, the technology is only recommended for the specific patient group for which it is cost-effective. Many orphan drugs are recommended under this category. • Recommended for use in the CDF (cancer appraisals only). If the early evidence of the subject technology shows clinical benefits, but more evidence are needed to prove its cost- effectiveness, then it can be recommended through CDF. • Only in research. This means that the technology is only recommended for use in a research study, for example, a clinical study. Such recommendations are made when not enough clinical evidence is available, it is plausible that the technology is cost-effective, and the research can be realistically carried out. • Not recommended. When there is a lack of evidence for the clinical effectiveness for the subject technology, or it is considered impossible to be cost-effective, then the technology is not recommended [18].

1.7 Commercial arrangements

The sponsor of an orphan drug can reach a commercial arrangement with the NHS to enable patients to gain access to high-cost treatments, if the sponsor is a member of the Pharmaceutical Price

9 Regulation Scheme (PPRS). PPRS is a voluntary agreement between the Association of the British Pharmaceutical Industry (ABPI) and the Department of Health (DH), on supplying branded medicine to the NHS. Due to the high cost, for orphan drugs to gain market access, most sponsors reach at least one form of commercial agreements with the NHS [15].

Members can submit proposals for patient access schemes (PAS) and flexible pricing proposals, as part of an ongoing or published technology appraisal. A PAS is an agreement where a medicine is not considered cost-effective by NICE using company’s list price, and a discount has been agreed on to lower the ICER during TA or HST process. It is the standard way of making a drug cost-effective if it is recommended as routine commission. The discount can be ‘simple’ meaning an agreed discount on the list price, or ‘Complex’ meaning the discount may include, for example, free stock, dose capping or discount based on patient outcome. Simple discount is strongly preferred by NICE, and can be treated as commercially confidential. When the initial launch price of a drug may not reflect its long- term value to patients, flexible pricing allows the sponsor to retain freedom to increase or decrease the original launch price as new evidence or new indications emerge. Sponsors can agree commercial access agreements (CAA) with the NHS if the drug is funded through CDF [15]. When there is uncertainty on the submitted evidence, identified by TAC, sponsors can seek to reach managed access agreements (MAA) with the NHS to enable market access for a limited time period at a discount rate. MAA involves an agreed rationale, a time frame, patient populations, methods and criteria for data collection to resolve uncertainty, together with a price discount agreed through CAA or PAS [19].

2. AIMS & SUBJECTIVES

This literature review is aimed to summarise the processes and methods NICE employs to conduct health technology appraisals for medicinal products which received orphan designation and market authorization in the EU, to build a comprehensive list of all technology appraisals published by NICE for orphan drugs, and to find factors in the appraisal processes that may influence the resulting recommendations. The appropriateness of NICE’s cost-effectiveness thresholds will be discussed. Possible suggestions will be made on how to improve NICE’s processes and methods of health technology appraisals for orphan drugs.

10 3. DATA SOURCE & METHODOLOGY

Data of orphan drugs with marketing authorisation from EMA was obtained from EMA database for medicine at https://www.ema.europa.eu/en/medicines. The search criteria that was used is as follows, Categories: human; Medicine: European public assessment report (EPAR); Authorisation status: Authorised; Medicine type: Orphan medicine; all other fields are left empty. EPAR is a set of documents in which the details of the evaluation of a medicine by CHMP and Committee for Medicinal Products for Veterinary Use (CVMP) are published. EPAR is published for every medicine application that has been granted or refused a marketing authorisation. Refused and withdrawn applications are excluded. For each orphan drug which full fills all the criteria, product details including brand name, active substance name, international non-proprietary name (INN), therapeutic area, anatomical therapeutic chemical (ATC) code; publication details including marketing-authorisation holder, date of issue of marketing authorisation valid throughout the European Union; whether the authorisation is with accelerated assessment, additional monitoring, conditional approval, and/or exceptional circumstances; and authorisation therapeutical indications (Appendix A). The list of orphan drugs granted marketing authorisations are double-checked with the lists of medicinal products for rare diseases in Europe, published on Orphanet, which employed a different search strategy [20].

For each orphan drug authorised in the EU, technology appraisal guidance was searched in NICE guidance database (https://www.nice.org.uk/guidance/published?type=hst,ta), where search is filtered by including 2 types: highly specialised technology guidance and technology appraisal guidance. Only published guidance are included, whereas those in consultation, in development, proposed or terminated are not included. For each published appraisal of each authorised orphan drug, method of appraisal, guidance reference number, date of publication, type of recommendation, and detail of recommendation are recorded. One orphan drug could be the subject of multiple technology appraisals. In cases where there are multiple ICER values in the technology appraisal guidance, only the ICER used for decision making by the committee is recorded. The ICERs for decision making could be from the evidence submitted from the company, and/or from revision of the evidence by ERG. In some appraisals, a value range, rather than a specific value, is used as ICER value, where multiple ICERs are produced by different valid economic models, or ICER is particularly sensitive to particular variables shown by sensitivity analyses. In cases where commercial arrangements are in place, the ICER after discount is commercial in confidence and therefore not-disclosed, the ICER obtained using list price is recorded if available. Other factors that may affect the decision including

11 whether the drug is considered end-of-life therapy, orthe innovative nature of the drug are also listed. Other information includes any commercial agreements reached between the company and NICE, and whether the drug is funded via CDF. Any commercial arrangement related to each technology appraisal can be found in the list of recommended technologies that include a commercial arrangement published on NICE website [21]. The prevalence for each indicated disease is obtained from Orphanet’s systematic review of prevalence and incidence of rare diseases. In cases where prevalence is not available, value of incidence or birth prevalence was used [22]. If the name of the indicated disease cannot be found in Orphanet’s review, the disease is searched in Orphanet’s database for rare diseases and orphan drugs at https://www.orpha.net/consor/cgi- bin/Disease.php?lng=EN, where a value range, rather than a specific value, of prevalence can be found.

4. RESULTS

4.1 Orphan drugs granted a EU marketing authorisation

The search conducted in EMA database described in Session 3.1 produced a list of all orphan medicinal products with European marketing authorisation, which can be found in Appendix A. Orphan medicinal products in Europe are medicinal products that have been granted a European orphan designation [5], then a European marketing authorisation by EMA, and a positive evaluation of significant benefit. The drugs withdrawn from the European Community register of orphan medicinal products, and the drugs for which the applications are refused are excluded. The medicinal products intended for rare diseases in Europe with European marketing authorisation without orphan designation status are also excluded. The list is classified and sorted by the brand names in alphabetical order. As a result, the search identified 109 orphan drugs which obtained marketing authorisation. The search result is validated by double-checking with Lists of medicinal products for rare diseases in Europe, published on Orphanet. The first identified European marketing authorisation for orphan drug happened in the year 2003, which is for Carbaglu for treating hyperammonaemia. The last authorisation happened before the conclusion date (1st September 2020) is identified on 25th August 2020. The number of authorisations approved every year since 2003 are compared (Figure 1). As shown by Figure 1, the annual number of authorisations follows an increasing trend, with the year 2018 showing the highest number of authorisations.

12 25 21 20

15 13 12 11 11 10 10 8 6 5 5 5 2 1 1 1 1 1 0 0 0

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

2020 (Jan- Sep)

no. of OD authorised

Figure 1. Comparison of the number of orphan drugs granted European marketing authorisation in each year since 2003 (sourced from Appendix A).

4.2 Assessment of orphan drugs by NICE

The search conducted in NICE database for technology appraisal guidance generated a list of orphan drugs appraised by NICE, which can be found in Appendix B. Only published appraisals are included, whereas those in consultation, in development or being proposed are excluded. There are 65 appraisals are identified as a result, which are sorted by the trade names of the subjected orphan drug authorised in the EU (Appendix B). One orphan drug can be the subject of more than one published appraisals. In total 45 unique authorised orphan drugs have been assessed by the 65 identified appraisals by NICE. Considering the total number of orphan drugs with marketing authorisation in the EU is 109, the rate for one orphan drug to be assessed by NICE is 42.3%. Out of 65 appraisals for orphan drugs, 59 appraisals ended in positive recommendations, meaning the result can be recommended, optimised, recommended or optimised for use through CDF (Table 1). The positive recommendation rate is 90.8%. According to the search result, the earliest technology appraisal which contains an orphan drug as a subject is a multiple technologies appraisal in the year 2009 for Bevacizumab, sorafenib, sunitinib and temsirolimus for the treatment of advanced and/or metastatic renal cell carcinoma, in which sorafenib (Nexavar) is an authorised orphan drug in the EU. The result of this appraisal is ‘not recommended’. The first technology of an orphan drug which resulted in being recommended for use happened in the year 2012, which is a STA assessing Mannitol (Bronchitol) dry powder for inhalation for treating cystic fibrosis. Since 2012, the number of technology appraisals of

13 orphan drugs per year, and the number of appraisals which produced positive results (recommended, optimised, recommended or optimised via CDF) per year, both followed an increasing trend, with the year 2018 showing the highest number of appraisals and positive recommendations (Figure 2).

Table 1. Annual number of technology appraisals by NICE for orphan drugs, number of these appraisals with positive recommendations, and number of these appraisals with results as ‘not recommended’, since 2009 (sourced from Appendix B).

Positive Not Year Appraisals recommendations recommended

2009 1 0 1

2010 0 0 0

2011 0 0 0

2012 1 1 0

2013 1 1 0

2014 1 0 1

2015 4 3 1

2016 4 3 1

2017 16 15 1

2018 19 19 0

2019 14 13 1

2020 (Jan- Sep) 4 4 0

Total number 65 59 6

14 20 18 16 14 12 10 8 6 4 2 0

2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

2020 (Jan- Sep)

Positive recommendations Not recommended

Figure 2. Comparison of the annual number of technology appraisals by NICE for orphan drug since 2009, with the proportion of positive recommendations (recommended, optimised, recommended or optimised via CDF) shown in blue, and the proportion of negative recommendations (not recommended) shown in orange (sourced from Appendix B).

15 Among the 65 technology appraisals by NICE for orphan drugs, 31 appraisals resulted in ‘recommended’ for routine use, and 20 appraisals have ‘optimised’ as results. 8 appraisals are recommended to be funded through CDF, out of which 5 have ‘recommended’ as results, and 3 have ‘optimised’ as results. Negative recommendations, meaning ‘not recommended’, only occurred for 6 out of 65 appraisals. No appraisal recommended for use ‘only in research’. The distribution of different types of results from the 65 appraisals by NICE for orphan drugs is shown in the pie chart below (Figure 3).

Not Optimised recommended (CDF) 9% 4% Only in research 0% Recommended (CDF) 8%

Recommended 48%

Optimised 31%

Recommended Optimised Recommended (CDF) Optimised (CDF) Only in research Not recommended

Figure 3. The distribution of the assessment results from the 65 technology appraisals by NICE for orphan drugs among the 5 different types of recommendations (sourced from Appendix B).

4.3 Comparison of assessment results between cancer and non-cancer orphan drugs

The CDF is a source of funding which was established in April 2012 by the British government to provide patients fast access to novel cancer treatments, if the treatment has plausible potential to

16 satisfy the criteria for routine commissioning but there is need for more data collection or clinical studies to resolve the uncertainty of clinical evidence [23]. Since its establishment, some drugs that were not considered cost-effective by NICE due to lack of clinical evidence can be funded through CDF. The impact of CDF on the results of technology appraisal of orphan drugs by NICE is studied, by analysing the number and the proportion of each recommendation type for either cancer or non- cancer orphan drugs that have been assessed by NICE (Table 2, Figure 4). Out of the 64 appraisals for orphan drugs since April 2012, 41 (64.1%) are for treatment of cancer, whereas 23 (35.9%) are for non-cancer treatments. For cancer-treating orphan drugs, the overall rate for positive recommendation (recommended; optimised; recommended or optimised via CDF) is 95.1%, which is higher than that rate (87.0%) for non-cancer treating orphan drugs. Without CDF, the decisions for the 8 orphan drugs to be recommended or optimised for use via CDF would have been ‘not recommended’, and therefore the positive recommendation rate would have been 75.6%. Within positive recommendations, the rate for the cancer-treating orphan drugs to be ‘recommended’ for use in line with the marketing authorisation, including those funded with and without CDF, is 63.4%, which is much higher than that rate for non-cancer orphan drugs, 43.5%. The rate to be ‘recommended’ would have been 51.2% without CDF. The analysis above showed that CDF increased the chance of a cancer-treating orphan drug to have positive appraisal results and also the chance to be recommended for use in line with its marketing authorisation.

4.4 Comparison of assessment results made through TA and HST routes

HST was firstly introduced by NICE in May 2013 as an interim method for assessing health technologies intended for use in the provision of services for rare and very rare conditions [24]. Since the introduction of HST, 62 appraisals for orphan drugs have been conducted by NICE, among which 51 (82.3%) appraisals were made through the default route TA which includes STA and MTA, and 11 (17.7%) appraisals were made via HST. In order to compare the assessment results made through TA and HST routes, the number in each type of recommendation was counted for the appraisals made through these two separate routes (Table 3). The proportions of different result categories made through either TA or HST routes are shown in Figure 5. The data analysis showed that all orphan drugs that were assessed through HST have received positive results, whereas 72.7% of orphan drugs appraised through HST were recommended for use in line with the marketing authorisation, with or

17 Table 2. Comparison of the number of different types of recommendations between appraisals of cancer and non-cancer orphan drugs since April 2012 (sourced from Appendix B).

Type Cancer Non-cancer

Recommended 21 10

Optimised 10 10

Recommended (CDF) 5 0

Optimised (CDF) 3 0

Only in research 0 0

Not recommended 2 3

Total number 41 23

45

40 5% 7% 35 12% 30

25 24% 13% 20

15 43.5%

10 51%

5 43.5%

0 Cancer Non-cancer

Recommended Optimised Recommended (CDF) Optimised (CDF) Only in research Not recommended

Figure 4. The number and the proportion of each type of recommendations resulting from the technology appraisals for cancer and non-cancer orphan drugs since April 2012. The percentage of each recommendation type in either cancer or non-cancer orphan drug appraisals is labelled in the corresponding portion of the column (sourced from Appendix B).

18 without CDF. On the other hand, through the default route TA, 92% of orphan drugs received positive appraisal results and the percentage being recommended for use in line with the marketing authorisation is 54.9%. This suggests that it is more likely for an orphan drug appraisal to be positive or results in ‘recommended’ if it is via HST route. Admittedly the HST method only came to force less than 8 years ago, and the data is still too limited to reach any definite conclusion.

Table 3. Comparison of the numbers of each recommendation category from appraisals made through TA and HST since May 2013. The category ‘recommended’ means being recommended for use via or not via CDF; the category ‘optimised’ means being recommended for optimised use via or not via CDF (sourced from Appendix B).

Recommended Optimised (with or (with or Not Route type without CDF) without CDF) recommended Total number

TA 28 18 5 51

HST 8 3 0 11

60

50 10%

40 35.3%

30

20

54.9% 10 27.3% 72.7% 0 TA HST

Recommended Optimised Not recommended

Table 5. Comparison of the proportions of different result categories made through either TA or HST routes since May 2013. The percentage of each recommendation category for appraisals made through TA or HST is labelled in the corresponding portion of the column (sourced from Appendix B).

19 4.5 Characterisation of prevalence of indicated orphan diseases

As mentioned in Session 4.4, HST method is designed for assessing health technologies targeting rare and ultra-rare conditions. However, there is no clear cut-off for the prevalence of the condition to be defined as either rare or ultra-rare condition, and indeed no clear threshold was drawn between the prevalence of the targeted conditions appraised through TA and those appraised through HST [25]. Here we analysed the prevalence values of the indicated diseases for orphan drugs appraised through TA and HST routes, and that for orphan drugs not recommended by NICE. In cases where within one appraisal, the subject treatment is targeting multiple conditions, the prevalence with the highest value is taken into account to represent that particular appraisal. The results are shown in Table 4 and Figure 6. Prevalence values were found for 50 out of 65 appraisals for orphan drugs, among which 41 appraisals are from TA route and 9 appraisals are from HST route. For TA appraisals, the majority (80.5%) of subject orphan conditions have prevalence values between 10 and 50 per 100,000 population. In comparison, most of the orphan conditions subjected in HST appraisals (77.7%) have prevalence values below 10 per 100,000 population. However, there is significant overlap between prevalence value range for conditions in TA appraisals and those in HST appraisals. There are 19.5% of known prevalence values for conditions in TA appraisals are below 10 per 100,000 population, and 22.2% of that in HST appraisals fall between 10 and 50 per 100,000 population. This overlap may be explained by the fact that low prevalence of the target disease is not the only criteria for an orphan drug to full-fill to be assessed through HST route, which has much higher ICER threshold to be considered cost-effective than that of TA route. Other criteria are described in Session 1.5.

Due to limited data, no correlation is found between the decision of ‘not recommended’ and the prevalence of orphan conditions in an appraisal. However, there are 2 appraisals with known prevalence values of the subject conditions that resulted in ‘not recommended’ due to lack of value for money. Both of them are conducted through TA route which has a lower ICER threshold. In another word, if these 2 appraisals are made via HST route, the results may be very different. The 2 appraisals are Appraisal TA398 which assessed Lumacaftor–ivacaftor for treating cystic fibrosis homozygous for the F508del mutation with a prevalence value in between 1 and 9 per 100,000 population, and Appraisal TA178 which assessed Bevacizumab, sorafenib, sunitinib and temsirolimus for the treatment of advanced and/or metastatic renal cell carcinoma, of which the prevalence value is between 10 and 50 per 100,000 population (Appendix B).

20 Table 4. Comparison of prevalence values of conditions in TA and HST appraisals, and that in appraisals resulted in ‘not recommended’. The number of prevalence values fall in each value range (below 1; between 1 and 10; between 10 and 50; above 50) is recorded (sourced from Appendix B).

Prevalence value range (/100,000) TA HST Not recommended

P ≦ 1 0 3 0

1 < P ≦ 10 8 4 1

10 < P ≦ 50 33 2 1

50 < P 0 0 0

P not available 13 2 4

P – Prevalence value.

(a) TA (b) HST 35 80.5% 4.5 44.4% 30 4 3.5 25 33.3% 3 20 2.5 22.2% 15 2 1.5 10 19.5% 1 5 0.5 0 0 0 0 0 1 1 ≦ ≦ 10 ≦ 50 ≦ 10 50 P 50 < P P ≦ ≦ 50 < P 1 < P 10 < P 1 < P 10 < P

Figure 6. Comparison of the distribution of prevalence values of the orphan conditions appraised through TA and HST routes. The percentage is calculated by dividing the number of prevalence values that fall in a range by the total number of appraisals with known prevalence values for TA or HST route. (a) Distribution of prevalence values in TA appraisals; (b) Distribution of prevalence values in HST appraisals (sourced from Appendix B).

21 4.6 Characterisation of ICER values reached by the appraisals via TA and HST routes

Different thresholds for the most plausible ICER are applied to the 2 appraisal routes including TA and HST for assessments of orphan drugs, as explained in Session 1.5. For TA, usually a value range between £ 20K to £ 30K per QALY gained is used as the ICER threshold, with exception for end-of-life therapies for which the threshold is £ 50K per QALY gained. On the other hand, the ICER threshold for HST appraisals is £ 100K, with the possibility to increase to £300K depending on the number of QALY gained. Therefore, the landscapes of the most plausible ICER values for orphan drugs recommended through TA and HST routes are supposed to be very different. Here, the distribution of ICER values from TA and HST appraisals are studied respectively (Table 5, Figure 7). In total 59 ICER values or value ranges are found for assessed orphan drugs from NICE database, among which 51 are from TA appraisals and 8 are from HST appraisals. ICER values after agreed discount between NHS England and manufacturers should be the appropriate values to use. However, in many cases, ICERs after discount are commercial in confidence and therefore not disclosed. In these cases ICERs before discount are used for analysis. In cases where a value range or several possible values were given for the most plausible ICER, the lowest given ICER value is taken for analysis here, for the purpose of practicality. The distributions for ICER values are shown in Figure 7. The results show that for TA appraisals the ICER values lead to positive recommendations fell mostly in the range £ 10K - £ 50K per QALY gained, with the highest number found in the range £ 20K - £ 30K (16 out of 45 positive appraisals). Some orphan drugs with ICERs above £ 30K also received recommendations, due to the fact that the drug is considered ‘end-of-life’ therapy or the fact that commercial arrangements were agreed to reduce ICER values to lower than the thresholds. For appraisals with result ‘not recommended’, the ICER values are all above £ 50K. In terms of HST appraisals, all appraisals received positive recommendations, and the recorded ICER values range from £ 97K to £1,818K per QALY gained, with 5 out of 8 appraisals giving ICER values below £ 200K per QALY gained. The orphan drugs above £ 100K received positive recommendations via HST because of the commercial arrangements (PAS and/or CAA) or due to the weight index assigned according to the number of the incremental QALY gained.

22 Table 5. Number of ICER values categorised in value ranges for TA and HST appraisals respectively. (a) ICERs from TA appraisals; (b) ICERs from HST appraisals (sourced from Appendix B).

(a) ICERs in TA appraisals Recommended Not recommended

ICER < 10K 0 0

10K < ICER ≦ 20K 6 0

20K < ICER ≦ 30K 16 0

30K < ICER ≦ 40K 8 0

40K < ICER ≦ 50K 11 0

50K < ICER ≦ 60K 3 1

60K < ICER ≦ 70K 1 1

70K < ICER ≦ 80K 0 0

80K < ICER ≦ 90K 0 0

90K < ICER ≦ 100K 0 0

100K < ICER ≦ 110K 0 2

110K < ICER ≦ 120K 0 0

120K < ICER ≦ 130K 0 0

130K < ICER ≦ 140K 0 0

140K < ICER ≦ 150K 0 1

150 < ICER 0 1

(b) ICERs in HST appraisals Recommended Not recommended

ICER < 100K 2 0

100K < ICER ≦ 200K 3 0

200K < ICER ≦300K 0 0

300K < ICER ≦400K 1 0

400K < ICER ≦500K 0 0

500K < ICER ≦600K 0 0

600K < ICER ≦700K 0 0

700K < ICER ≦800K 1 0

800K < ICER ≦900K 0 0

900K < ICER ≦1000K 0 0

1000K < ICER 1 0

23 (a) TA 18 16 14 12 10 8 6 4 2 0

20K 30K 40K 50K 60K 70K 80K 90K 100K 110K 120K 130K 140K 150K ≦ ≦ ≦ ≦ ≦ ≦ ≦ ≦ ≦ ≦ ≦ ≦ ≦ ≦ ICER < 10K 150 < ICER

10K < ICER20K < ICER30K < ICER40K < ICER50K < ICER60K < ICER70K < ICER80K < ICER 90K < ICER 100K < ICER110K < ICER120K < ICER130K < ICER140K < ICER

Recommended Not recommended

(b) HST 3.5 3 2.5 2 1.5 1 0.5 0

200K 300K 400K 500K 600K 700K 800K 900K ≦ ≦ ≦ ≦ ≦ ≦ ≦ 1000K ≦ ≦ ICER < 100K 1000K < ICER

200K < ICER 300K < ICER 400K < ICER 500K < ICER 600K < ICER 700K < ICER 800K < ICER 100K < ICER 900K < ICER

Recommended Not recommended

Figure 7. The Comparison of distribution of ICER values from TA and HST appraisals. (a) Distribution of ICERs from TA appraisals; (b) Distribution of ICERs from HST appraisals (sourced from Appendix B).

24 5. DISCUSSION

5.1 Uncertainty surrounding the evidence affects the appraisal results

Orphan drugs are intended to treat rare and ultra-rare conditions. Orphan drugs are likely to deliver benefit in an area of high unmet need, hence are given orphan drug designation by EMA. Clinical evidence for marketing authorisation and health technology assessment are usually randomised controlled trials (RCT) which requires sufficient number of participants and sometimes repeats. However, due to the very small size of patient population, or ethical reasons, the clinical trials for orphan drugs are often small or uncontrolled trial. In addition, there is often lack of knowledge of the natural history of the rare disease or demographic group which is essential for planning a clinical trial. Indeed, 77 out of 109 orphan drugs authorised in the EU require additional monitoring for adverse drug reactions, and 16 out of 109 orphan drugs only received conditional marketing authorisations (Appendix A). The limited availability of clinical and economic evidence presents significant challenges for health technology assessment and reimbursement bodies, such as NICE, to enable rare disease patients to access novel treatments. A large proportion (23 out of 65) of technology appraisals of orphan drugs by NICE, have recommended ‘optimised’ use. In another word, the use of the drug is restricted to a smaller population than that described in the marketing authorisation. The reason is often that clinical and economic data is only sufficient for restricted populations.

Uncertainty is caused by small sample size especially when the evidence from subgroups are extracted, short-term nature of the clinical trials, limited data on quality of life, extrapolation of short- term data over longer periods of time in economic modelling [13]. MAA is an effective approach for an orphan drug to be conditionally reimbursed by NHS while the evidence is still being developed. CDF as a form of MAA has been used to facilitate the market access to oncology medicines appraised through TA routes. CDF is corelated to the higher success rate for cancer drugs to be positively recommended than that for non-cancer drugs, as seen in Session 4.3. MAA is anticipated for most HST appraised orphan drugs. The first MAA for non-cancer orphan drugs was agreed for Elosulfase alfa (Vimizim) in 2015 treating Morquio A Sydrome which is a very rare inherited condition affecting only 109 children and young adults across the UK [26]. However, MAA is not commonly applied for non- cancer orphan drugs appraised through TA routes. This consequently created inequality between the rare cancer patients and patients with non-cancer rare conditions. Indeed, only 18.8% (9 out of 48) of positive recommendations made through TA are for non-cancer drugs, among which only 2 received

25 full recommendations in line with the marketing authorisations. To eliminate this inequality, NHS should consider to apply MAA more widely on TA appraised non-cancer drugs.

5.2 ICER thresholds in TA are inappropriate for assessing orphan drugs

As mentioned in the introduction, different ICER thresholds are applied to TA and HST appraisals respectively. Within HST, a slide scale of ICER thresholds from £ 100K to £300K is employed according to the scale of QALY benefits, in order to encourage the development of orphan drugs that can bring significant extension to the patients’ lifespans with quality. Within TA, the usual ICER threshold is £ 20K to £ 30K per QALY gained. Exceptions are given for drugs considered as ‘end-of-life’ therapies with £ 50K per QALY gained as the ICER threshold. The different ICER thresholds used in NICE technology appraisals are summarised in Table 6. The sliding scale for ICER limit in HST according to the benefits that the subject drug can bring allows the outstanding novel medicine products with ICER values above £ 100K per QALY gained to be accessed by patients. This is not the case for the orphan drugs appraised via the default TA routes, which make positive recommendations very difficult to achieve especially for the orphan drugs that are not ‘end-of-life’ therapies. In order to help patients with orphan conditions that are not qualified for HST to access novel therapies, and to encourage the manufacturers to develop orphan drugs which can significantly benefit the patients, NICE should consider to apply a sliding scale for ICER threshold based on the benefits the orphan drug can bring to the TA appraisal method.

Table 6. Summary of ICER thresholds applied to drugs according to different assessing methods (TA and HST) and characteristics of the drugs.

Drug category ICER threshold (per QALY gained)

HST providing 30 or more incremental QALYs £ 300K

HST providing 10 to 30 incremental QALYs slide scale from £ 100K to £ 300K

HST providing up to 10 incremental QALYs £ 100K

‘end-of-life' drugs £ 50K

Most of drugs £ 30K

Drugs qualified for FTA (exceptional value for money) £ 10K

26 5.3 ICER threshold should be adjusted based on the prevalence

As mentioned in the introduction, the R&D cost to develop an orphan drug is as high as that to develop a drug targeting common diseases, but due to the low prevalence of rare diseases, the market size is very small, and prices for orphan drugs are usually set high so that the developers can recover the R&D costs. The price is a deciding factor for ICER. To ensure the equal opportunities for patients with rare diseases which have different various prevalence to access novel therapies, NICE should consider to separate the assessments of orphan drugs from the TA system which is the default route to assess drugs targeting common diseases, and establish an independent appraisal system for all orphan drugs not just those qualified for the current HST system, with a sliding scale of ICER threshold taking prevalence of the disease into consideration. The current system which put some orphan drugs targeting rare diseases with very low prevalence through TA appraisals could be considered unfair. For example, cystic fibrosis has a prevalence value of 1 – 9 /100,000, which is comparable with that of targeted conditions appraised through HST. However, drugs treating cystic fibrosis are appraised through the TA route which has much lower ICER threshold to be considered cost-effective. In Appraisal TA398, Lumacaftor–ivacaftor for treating cystic fibrosis homozygous for the F508del mutation are not recommended for not being cost-effective, even after proposed price reductions. If all orphan drugs are assessed in the same system with a sliding scale for ICER adjusted according to the disease prevalence, Lumacaftor–ivacaftor is likely to be considered cost-effective, and cystic fibrosis patient may gain access to this novel therapy.

27 References

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2. Dawkins HJS, Draghia-Akli R, Lasko P, Lau LPL, Jonker AH, Cutillo CM, Rath A, Boycott KM, et al, Progress in Rare Diseases Research 2010-2016: An IRDiRC Perspective. Clin Transl Sci. 2018 Jan;11(1):11-20.

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28 10. European Medicines Agency, Accelerated assessment, https://www.ema.europa.eu/en/human- regulatory/marketing-authorisation/accelerated-assessment Accessed 10th November

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Accessed 10th November

12. European Medicines Agency, Conditional marketing authorisation, https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/conditional-marketing- authorisation Accessed 10th November

13. MAP BioPharma, Access to Orphan Medicines: A Case for Change, 2019, Available at: https://mapbiopharma.com/home/publications/access-to-orphan-medicines-a-case-for-change/ Accessed 10th November

14. National Institute of Health and Care Excellence, Guide to the methods of technology appraisal, 2013, Available at: https://www.nice.org.uk/process/pmg9/resources/guide-to-the-methods-of- technology-appraisal-2013-pdf-2007975843781 Accessed 10th November

15. National Institute of Health and Care Excellence, Guide to the processes of technology appraisal, 2018, Available at: https://www.nice.org.uk/Media/Default/About/what-we-do/NICE- guidance/NICE-technology-appraisals/technology-appraisal-processes-guide-apr-2018.pdf Accessed 11th November

16. National Institute of Health and Care Excellence, Interim Process and Methods of the Highly Specialised Technologies Programme Updated to reflect 2017 changes, 2017, Available at: https://www.nice.org.uk/Media/Default/About/what-we-do/NICE-guidance/NICE-highly-specialised- technologies-guidance/HST-interim-methods-process-guide-may-17.pdf Accessed 11th November

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Number CDP-2019-0022. Available at: https://commonslibrary.parliament.uk/research-briefings/cdp- 2019-0022/ Accessed 11th November

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19. York Health Economics Consortium, Managed access agreement, https://yhec.co.uk/glossary/managed-access-agreement/ Accessed 11th November

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21. National Institute of Health and Care Excellence, Patient access schemes liaison unit, https://www.nice.org.uk/about/what-we-do/patient-access-schemes-liaison-unit Accessed 11th November

22. Orphanet, Prevalence and incidence of rare diseases: Bibliographic data, 2020, Available at: https://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_ list.pdf Accessed 26th November

23. NHS England, Appraisal and Funding of Cancer Drugs from July 2016 (including the new Cancer Drugs Fund) A new deal for patients, taxpayers and industry, 2016, Available at: https://www.england.nhs.uk/wp-content/uploads/2013/04/cdf-sop.pdf Accessed 30th November

24. National Institute of Health and Care Excellence, Interim Process and Methods of the Highly Specialised Technologies Programme, 2013, Available at: https://www.nice.org.uk/Media/Default/About/what-we-do/NICE-guidance/NICE-highly-specialised- technologies-guidance/Highly-Specialised-Technologies-Interim-methods-and-process- statements.pdf Accessed 30th November

25. Barham L, NICE and Highly Specialised Technologies: three years on, 2016, Pharmaphorum, Available at: https://pharmaphorum.com/views-and-analysis/nice-and-highly-specialised- technologies-three-years-on/ Accessed 1st December

26. Harvey E, Can managed access agreements help unlock access through the NICE Highly Specialised Technology Appraisal Process?, 2018, Pharmaphorum, Available at: https://pharmaphorum.com/market-access-2/can-managed-access-agreements-help-unlock-access- through-the-nice-highly-specialised-technology-appraisal-process/ Accessed 1st December

30

Appendix A. List of orphan medicinal products with European marketing authorisation

Brand Active INN name therapeutic marketing authorisation indication marketing marketing Agency ATC code Accelerated Additional Conditional exceptional URL name substance area authorisation authorisation product assessment monitoring approval circumstances date holder number (DD/MM/YYY Y)

Adcetris Brentuximab Brentuximab Lymphoma, Indicated for adult patients with previously 25/10/2012 Takeda EMEA/H/C/00 L01XC12 N Y Y N https://www.ema.eu vedotin vedotin Non- untreated CD30+ Stage IV Hodgkin lymphoma Pharma A/S 2455 ropa.eu/en/medicine Hodgkin; (HL) in combination with doxorubicin, vinblastine s/human/EPAR/adcet

Hodgkin and dacarbazine (AVD). ris#overview-section Disease Treatment of adult patients with CD30+ HL at increased risk of relapse or progression following autologous stem cell transplant (ASCT). Treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL): -following ASCT, or -following at least two prior therapies when ASCT or multi-agent chemotherapy is not a treatment option. Adcetris in combination with cyclophosphamide, doxorubicin and prednisone (CHP) is indicated for adult patients with previously untreated systemic anaplastic large cell lymphoma (sALCL). Indicated for adult patients with relapsed or refractory sALCL. Indicated for adult patients with CD30+ cutaneous T cell lymphoma (CTCL) after at least 1 prior systemic therapy.

Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Adempas Riociguat Riociguat Hypertensi Treatment of adult patients with WHO Functional 27/03/2014 Bayer AG EMEA/H/C/00 C02KX05 N N N N https://www.ema.eu on, Class (FC) II to III with 2737 ropa.eu/en/medicine Pulmonary inoperable Chronic thromboembolic pulmonary s/human/EPAR/ade hypertension (CTEPH), persistent or recurrent mpas#authorisation-

CTEPH after surgical treatment, to improve details-section exercise capacity. As monotherapy or in combination with endothelin receptor antagonists, is indicated for the treatment of adult patients with pulmonary arterial hypertension (PAH) with WHO Functional Class (FC) II to III to improve exercise capacity. Efficacy has been shown in a PAH population including aetiologies of idiopathic or heritable PAH or PAH associated with connective tissue disease.

Alofisel Darvadstrocel Darvadstrocel Rectal Treatment of complex perianal fistulas in adult 23/03/2018 Takeda EMEA/H/C/00 L04 N Y N N https://www.ema.eu Fistula patients with non-active/mildly active luminal Pharma A/S 4258 ropa.eu/en/medicine Crohn’s disease, when fistulas have shown an s/human/EPAR/alofis inadequate response to at least one conventional el#authorisation-

or biologic therapy. Alofisel should be used after details-section conditioning of fistula.

Alprolix Eftrenonacog Eftrenonacog Hemophilia Treatment and prophylaxis of bleeding in 12/05/2016 Swedish EMEA/H/C/00 B02BD04 N Y N N https://www.ema.eu alfa alfa B patients with haemophilia B (congenital factor IX Orphan 4142 ropa.eu/en/medicine deficiency). Biovitrum AB s/human/EPAR/alpro

(publ) lix Amglidia Glibenclamide Glibenclamide Diabetes Treatment of neonatal diabetes mellitus, for use 24/05/2018 Ammtek EMEA/H/C/00 A10BB01 N N N N https://www.ema.eu Mellitus in newborns, infants and children. 4379 ropa.eu/en/medicine Sulphonylureas like Amglidia have been shown to s/human/EPAR/amgli

be effective in patients with mutations in the dia genes coding for the β-cell ATP-sensitive potassium channel and chromosome 6q24- related transient neonatal diabetes mellitus.

32 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Besponsa Inotuzumab Inotuzumab Precursor As monotherapy for the treatment of adults with 28/06/2017 Pfizer Europe EMEA/H/C/00 L01XC N Y N N https://www.ema.eu ozogamicin ozogamicin Cell relapsed or refractory CD22-positive B cell MA EEIG 4119 ropa.eu/en/medicine Lymphoblas precursor acute lymphoblastic leukaemia (ALL). s/human/EPAR/besp

tic Adult patients with Philadelphia chromosome onsa Leukemia- positive (Ph+) relapsed or refractory B cell Lymphoma precursor ALL should have failed treatment with at least 1 tyrosine kinase inhibitor (TKI).

Blincyto Blinatumoma Blinatumoma Precursor Treatment of adults with Philadelphia 23/11/2015 Amgen EMEA/H/C/00 L01XC N Y N N https://www.ema.eu b b Cell chromosome negative CD19 positive relapsed or Europe B.V. 3731 ropa.eu/en/medicine Lymphoblas refractory B-precursor acute lymphoblastic s/human/EPAR/blinc

tic leukaemia (ALL). yto Leukemia- As monotherapy for the treatment of adults with Lymphoma Philadelphia chromosome negative CD19 positive B-precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. As monotherapy for the treatment of paediatric patients aged 1 year or older with Philadelphia chromosome negative CD19 positive B-precursor ALL which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior allogeneic hematopoietic stem cell transplantation.

Brineura Cerliponase Cerliponase Neuronal Treatment of neuronal ceroid lipofuscinosis type 30/05/2017 BioMarin EMEA/H/C/00 A16AB Y Y N Y https://www.ema.eu alfa alfa Ceroid- 2 (CLN2) disease, also known as tripeptidyl International 4065 ropa.eu/en/medicine Lipofuscino peptidase 1 (TPP1) deficiency Limited s/human/EPAR/brine

ses ura

Bronchitol Mannitol Mannitol Cystic Treatment of cystic fibrosis (CF) in adults aged 18 13/04/2012 Pharmaxis EMEA/H/C/00 R05CB16 N N N N https://www.ema.eu Fibrosis years and above as an add-on therapy to best Europe 1252 ropa.eu/en/medicine standard of care. Limited s/human/EPAR/bron

chitol

33 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Cablivi Caplacizumab Caplacizumab Purpura, Treatment of adults experiencing an episode of 30/08/2018 Ablynx NV EMEA/H/C/00 B01A N Y N N https://www.ema.eu Thrombotic acquired thrombotic thrombocytopenic purpura 4426 ropa.eu/en/medicine Thrombocy (aTTP), in conjunction with plasma exchange and s/human/EPAR/cabli

topenic immunosuppression. vi

Carbaglu Carglumic acid Carglumic acid Amino Acid Treatment of: 24/01/2003 Recordati EMEA/H/C/00 A16AA05 N N N N https://www.ema.eu Metabolism hyperammonaemia due to N-acetylglutamate- Rare Diseases 0461 ropa.eu/en/medicine , Inborn synthase primary deficiency; s/human/EPAR/carba

Errors; hyperammonaemia due to isovaleric acidaemia; glu Propionic hyperammonaemia due to methymalonic Acidemia acidaemia; hyperammonaemia due to propionic acidaemia.

Cerdelga Eliglustat Eliglustat Gaucher Indicated for the long-term treatment of adult 19/01/2015 Genzyme EMEA/H/C/00 A16AX10 N Y N N https://www.ema.eu Disease patients with Gaucher disease type 1 (GD1), who Europe BV 3724 ropa.eu/en/medicine are CYP2D6 poor metabolisers (PMs), s/human/EPAR/cerd

intermediate metabolisers (IMs) or extensive elga metabolisers (EMs).

Chenodeox Chenodeoxyc Chenodeoxyc Xanthomat Indicated for the treatment of inborn errors of 10/04/2017 Leadiant EMEA/H/C/00 A05AA01 N Y N Y ycholic acid holic acid holic acid osis, primary bile acid synthesis due to sterol 27 GmbH 4061 Leadiant Cerebroten hydroxylase deficiency (presenting as (previously dinous; cerebrotendinous xanthomatosis (CTX)) in known as Metabolism infants, children and adolescents aged 1 month Chenodeox , Inborn to 18 years and adults. ycholic acid Errors sigma-tau)

Coagadex Human Human Factor X Treatment and prophylaxis of bleeding episodes 16/03/2016 BPL EMEA/H/C/00 B02BD13 Y Y N N https://www.ema.eu coagulation coagulation Deficiency and for perioperative management in patients Bioproducts 3855 ropa.eu/en/medicine factor X factor X with hereditary factor X deficiency. Coagadex is Laboratory s/human/EPAR/coag

indicated in all age groups. GmbH adex

34 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Cometriq Cabozantinib Cabozantinib Thyroid Treatment of adult patients with progressive, 21/03/2014 Ipsen Pharma EMEA/H/C/00 L01XE N Y Y N https://www.ema.eu Neoplasms unresectable locally advanced or metastatic 2640 ropa.eu/en/medicine medullary thyroid carcinoma. s/human/EPAR/come

triq

Cresemba Isavuconazole Isavuconazole Aspergillosi Indicated in adults for the treatment of: 15/10/2015 Basilea EMEA/H/C/00 J02AC N Y N N https://www.ema.eu s -invasive aspergillosis Pharmaceutic 2734 ropa.eu/en/medicine -mucormycosis in patients for whom a Deutschland s/human/EPAR/crese

amphotericin B is inappropriate GmbH mba Consideration should be given to official guidance on the appropriate use of antifungal agents.

Crysvita Burosumab Burosumab Hypophosp Treatment of X-linked hypophosphataemia with 19/02/2018 Kyowa Kirin EMEA/H/C/00 M05BX05 N Y Y N https://www.ema.eu hatemia, radiographic evidence of bone disease in children Holdings B.V. 4275 ropa.eu/en/medicine Familial; 1 year of age and older and adolescents with s/human/EPAR/crysv

Hypophosp growing skeletons. ita hatemic Rickets, X- Linked Dominant Cystadrops Mercaptamin Mercaptamin Cystinosis Indicated for the treatment of corneal cystine 18/01/2017 Recordati EMEA/H/C/00 S01XA21 N N N N https://www.ema.eu e e crystal deposits in adults and children from 2 Rare Diseases 3769 ropa.eu/en/medicine hydrochloride years of age with cystinosis. s/human/EPAR/cysta

drops

Dacogen Decitabine Decitabine Leukemia, Treatment of adult patients with newly 20/09/2012 Janssen-Cilag EMEA/H/C/00 L01BC08 N N N N https://www.ema.eu Myeloid diagnosed de novo or secondary acute myeloid International 2221 ropa.eu/en/medicine leukaemia (AML), according to the World Health N.V. s/human/EPAR/daco

Organization (WHO) classification, who are not gen candidates for standard induction chemotherapy.

35 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Darzalex Daratumumab Daratumumab Multiple Indicated: 20/05/2016 Janssen-Cilag EMEA/H/C/00 L01XC24 Y Y N N https://www.ema.eu Myeloma -in combination with lenalidomide and International 4077 ropa.eu/en/medicine dexamethasone or with bortezomib, melphalan N.V. s/human/EPAR/darza

and prednisone for the treatment of adult lex patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant. -in combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant. -in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. -as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy.

Daurismo Glasdegib Glasdegib Leukemia, Indicated, in combination with low-dose 26/06/2020 Pfizer Europe EMEA/H/C/00 L01XX63 N Y N N https://www.ema.eu maleate Myeloid, cytarabine, for the treatment of newly diagnosed MA EEIG 4878 ropa.eu/en/medicine Acute de novo or secondary acute myeloid leukaemia s/human/EPAR/dauri

(AML) in adult patients who are not candidates smo for standard induction chemotherapy.

Defitelio Defibrotide Defibrotide Hepatic Treatment of severe hepatic veno-occlusive 18/10/2013 Gentium S.r.l. EMEA/H/C/00 B01AX01 N Y N Y https://www.ema.eu Veno- disease (VOD) also known as sinusoidal 2393 ropa.eu/en/medicine Occlusive obstructive syndrome (SOS) in haematopoietic s/human/EPAR/defit

Disease stem-cell transplantation (HSCT) therapy. elio Indicated in adults and in adolescents, children and infants over 1 month of age.

36 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Deltyba Delamanid Delamanid Tuberculosi Indicated for use as part of an appropriate 27/04/2014 Otsuka Novel EMEA/H/C/00 J04AK06 N Y Y N https://www.ema.eu s, combination regimen for pulmonary multi-drug Products 2552 ropa.eu/en/medicine Multidrug- resistant tuberculosis (MDR-TB) in adult patients GmbH s/human/EPAR/delty

Resistant when an effective treatment regimen cannot ba otherwise be composed for reasons of resistance or tolerability. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Epidyolex Cannabidiol Cannabidiol Lennox Indicated for use as adjunctive therapy of 19/09/2019 GW Pharma EMEA/H/C/00 N03AX N N N N https://www.ema.eu Gastaut seizures associated with Lennox Gastaut (International) 4675 ropa.eu/en/medicine Syndrome; syndrome (LGS) or Dravet syndrome (DS), in B.V. s/human/EPAR/epidy

Epilepsies, conjunction with clobazam, for patients 2 years olex Myoclonic of age and older.

Esbriet Pirfenidone Pirfenidone Idiopathic Indicated in adults for the treatment of mild to 27/02/2011 Roche EMEA/H/C/00 L04AX05 N N N N https://www.ema.eu Pulmonary moderate idiopathic pulmonary fibrosis. Registration 2154 ropa.eu/en/medicine Fibrosis GmbH s/human/EPAR/esbri

et Farydak Panobinostat Panobinostat Multiple In combination with bortezomib and 28/08/2015 Secura Bio EMEA/H/C/00 L01XX42 N N N N https://www.ema.eu lactate Myeloma dexamethasone, is indicated for the treatment of Limited 3725 ropa.eu/en/medicine anhydrous adult patients with relapsed and/or refractory s/human/EPAR/faryd

multiple myeloma who have received at least ak two prior regimens including bortezomib and an immunomodulatory agent.

Firazyr Icatibant Icatibant Angioedem Indicated for symptomatic treatment of acute 11/07/2008 Shire EMEA/H/C/00 B06AC02 N N N N https://www.ema.eu as, attacks of hereditary angioedema (HAE) in Pharmaceutic 0899 ropa.eu/en/medicine Hereditary adults (with C1-esterase-inhibitor deficiency). als Ireland s/human/EPAR/firazy

Limited r

Galafold Migalastat Migalastat Fabry Indicated for long-term treatment of adults and 25/05/2016 Amicus EMEA/H/C/00 A16AX N Y N N https://www.ema.eu hydrochloride Disease adolescents aged 16 years and older with a Therapeutics 4059 ropa.eu/en/medicine confirmed diagnosis of Fabry disease (α- Europe s/human/EPAR/galaf

galactosidase A deficiency) and who have an Limited old amenable mutation.

37 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Gazyvaro Obinutuzuma Obinutuzuma Leukemia, In combination with chlorambucil is indicated for 22/07/2014 Roche EMEA/H/C/00 L01XC15 N Y N N https://www.ema.eu b b Lymphocyti the treatment of adult patients with previously Registration 2799 ropa.eu/en/medicine c, Chronic, untreated chronic lymphocytic leukaemia (CLL) GmbH s/human/EPAR/gazyv

B-Cell and with comorbidities making them unsuitable aro for full-dose fludarabine based therapy. In combination with chemotherapy, followed by Gazyvaro maintenance therapy in patients achieving a response, is indicated for the treatment of patients with previously untreated advanced follicular lymphoma. In combination with bendamustine followed by Gazyvaro maintenance is indicated for the treatment of patients with follicular lymphoma (FL) who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen.

Givlaari Givosiran Givosiran Porphyrias, Treatment of acute hepatic porphyria (AHP) in 02/03/2020 Alnylam EMEA/H/C/00 N/A N Y N N https://www.ema.eu Hepatic adults and adolescents aged 12 years and older. Netherlands 4775 ropa.eu/en/medicine B.V. s/human/EPAR/givla

ari Granupas Para- Para- Tuberculosi Indicated for use as part of an appropriate 07/04/2014 Eurocept EMEA/H/C/00 J04AA01 N N N N https://www.ema.eu (previously aminosalicylic aminosalicylic s combination regimen for multi-drug resistant International 2709 ropa.eu/en/medicine Para- acid acid tuberculosis in adults and paediatric patients B. V. s/human/EPAR/gran aminosalicy from 28 days of age and older when an effective upas-previously- lic acid treatment regimen cannot otherwise be para-aminosalicylic-

Lucane) composed for reasons of resistance or acid-lucane tolerability. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Hetlioz Tasimelteon Tasimelteon Sleep Indicated for the treatment of Non-24-Hour 03/07/2015 Vanda EMEA/H/C/00 N05CH N N N N https://www.ema.eu Disorders, Sleep-Wake Disorder (Non-24) in totally blind Pharmaceutic 3870 ropa.eu/en/medicine Circadian adults. als Germany s/human/EPAR/hetli

Rhythm GmbH oz

38 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Holoclar Ex vivo Ex vivo Stem Cell Treatment of adult patients with moderate to 17/02/2015 Chiesi EMEA/H/C/00 S01XA19 N Y Y N https://www.ema.eu expanded expanded Transplanta severe limbal stem cell deficiency (defined by Farmaceutici 2450 ropa.eu/en/medicine autologous autologous tion; the presence of superficial corneal S.p.A. s/human/EPAR/holoc

human human Corneal neovascularisation in at least two corneal lar corneal corneal Diseases quadrants, with central corneal involvement, and epithelial cells epithelial cells severely impaired visual acuity), unilateral or containing containing bilateral, due to physical or chemical ocular stem cells stem cells burns. A minimum of 1-2 mm2 of undamaged limbus is required for biopsy.

Iclusig Ponatinib Ponatinib Leukemia, Indicated in adult patients with: 01/07/2013 Incyte EMEA/H/C/00 L01XE24 Y Y N N https://www.ema.eu Myeloid; -chronic-phase, accelerated-phase or blast-phase Biosciences 2695 ropa.eu/en/medicine Leukemia, chronic myeloid leukaemia (CML) who are Distribution s/human/EPAR/iclusi

Lymphoid resistant to dasatinib or nilotinib, who are B.V. g intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation; -Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib, who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

Idefirix Imlifidase Imlifidase Desensitiza Indicated for desensitisation treatment of highly 25/08/2020 Hansa EMEA/H/C/00 L04AA N Y Y N https://www.ema.eu tion, sensitised adult kidney transplant patients with Biopharma AB 4849 ropa.eu/en/medicine Immunolog positive crossmatch against an available s/human/EPAR/idefir

ic; Kidney deceased donor. The use of Idefirix should be ix Transplanta reserved for patients unlikely to be transplanted tion under the available kidney allocation system including prioritisation programmes for highly sensitised patients.

39 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Idelvion Albutrepenon Albutrepenon Hemophilia Treatment and prophylaxis of bleeding in 11/05/2016 CSL Behring EMEA/H/C/00 B02BD04 N Y N N https://www.ema.eu acog alfa acog alfa B patients with haemophilia B (congenital factor GmbH 3955 ropa.eu/en/medicine IX deficiency). s/human/EPAR/idelvi

on Imbruvica Ibrutinib Ibrutinib Lymphoma, As a single agent is indicated for the treatment of 21/10/2014 Janssen-Cilag EMEA/H/C/00 L01XE27 N N N N https://www.ema.eu Mantle- adult patients with relapsed or refractory mantle International 3791 ropa.eu/en/medicine Cell; cell lymphoma (MCL). NV s/human/EPAR/imbr

Leukemia, As a single agent or in combination with uvica Lymphocyti obinutuzumab is indicated for the treatment of c, Chronic, adult patients with previously untreated chronic B-Cell lymphocytic leukaemia (CLL). As a single agent or in combination with bendamustine and rituximab (BR) is indicated for the treatment of adult patients with CLL who have received at least one prior therapy. As a single agent is indicated for the treatment of adult patients with Waldenström’s macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo immunotherapy. Imbruvica in combination with rituximab is indicated for the treatment of adult patients with WM.

40 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Imnovid Pomalidomide Pomalidomide Multiple In combination with bortezomib and 05/08/2013 Celgene EMEA/H/C/00 L04AX06 N Y N N https://www.ema.eu (previously Myeloma dexamethasone is indicated in the treatment of Europe B.V. 2682 ropa.eu/en/medicine Pomalidomi adult patients with multiple myeloma who have s/human/EPAR/imno de Celgene) received at least one prior treatment regimen vid-previously- including lenalidomide. pomalidomide-

In combination with dexamethasone is indicated celgene in the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy.

Isturisa Osilodrostat Osilodrostat Cushing Indicated for the treatment of endogenous 09/01/2020 Recordati EMEA/H/C/00 H02CA02 N Y N N https://www.ema.eu phosphate Syndrome Cushing’s syndrome in adults. Rare Diseases 4821 ropa.eu/en/medicine s/human/EPAR/isturi

sa Jorveza Budesonide Budesonide Esophageal Treatment of eosinophilic esophagitis (EoE) in 08/01/2018 Dr. Falk EMEA/H/C/00 A07EA06 Y N N N https://www.ema.eu Diseases adults (older than 18 years of age). Pharma GmbH 4655 ropa.eu/en/medicine s/human/EPAR/jorve

za Kaftrio Ivacaftor / Ivacaftor / Cystic Indicated in a combination regimen with 21/08/2020 Vertex EMEA/H/C/00 R07AX N Y N N https://www.ema.eu tezacaftor / tezacaftor / Fibrosis ivacaftor 150 mg tablets for the treatment of Pharmaceutic 5269 ropa.eu/en/medicine elexacaftor elexacaftor cystic fibrosis (CF) in patients aged 12 years and als (Ireland) s/human/EPAR/kaftri

older who are homozygous for the F508del Limited o mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or heterozygous for F508del in the CFTR gene with a minimal function (MF) mutation.

41 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Kalydeco Ivacaftor Ivacaftor Cystic Tablets are indicated for the treatment of 22/07/2012 Vertex EMEA/H/C/00 R07AX02 Y N N N https://www.ema.eu Fibrosis patients with cystic fibrosis (CF) aged 6 years and Pharmaceutic 2494 ropa.eu/en/medicine older and weighing 25 kg or more who have one als (Ireland) s/human/EPAR/kalyd

of the following gating (class III) mutations in the Limited eco CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R. Tablets are also indicated for the treatment of patients with cystic fibrosis (CF) aged 18 years and older who have an R117H mutation in the CFTR gene. Tablets are also indicated in a combination regimen with tezacaftor 100 mg/ivacaftor 150 mg tablets for the treatment of patients with cystic fibrosis (CF) aged 12 years and older who are homozygous for the F508del mutation or who are heterozygous for the F508del mutation and have one of the following mutations in the CFTR gene: P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272 26A→G, and 3849+10kbC→T. Granules are indicated for the treatment of children with cystic fibrosis (CF) aged 12 months and older and weighing 7 kg to less than 25 kg who have one of the following gating (class III) mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R (see sections 4.4 and 5.1).

Kanuma Sebelipase Sebelipase Lipid Indicated for long-term enzyme replacement 28/08/2015 Alexion EMEA/H/C/00 A16 Y Y N N https://www.ema.eu alfa alfa Metabolism therapy (ERT) in patients of all ages with Europe SAS 4004 ropa.eu/en/medicine , Inborn lysosomal acid lipase (LAL) deficiency. s/human/EPAR/kanu

Errors ma Ketoconazo Ketoconazole Ketoconazole Cushing Treatment of endogenous Cushing’s syndrome in 18/11/2014 HRA Pharma EMEA/H/C/00 J02AB02 Y Y N N https://www.ema.eu le HRA Syndrome adults and adolescents above the age of 12 Rare Diseases 3906 ropa.eu/en/medicine years. s/human/EPAR/ketoc

onazole-hra

42 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Kuvan Sapropterin Sapropterin Phenylketo Treatment of hyperphenylalaninaemia (HPA) in 02/12/2008 BioMarin EMEA/H/C/00 A16AX07 N N N N https://www.ema.eu dihydrochlorid nurias adults and paediatric patients of all ages with International 0943 ropa.eu/en/medicine e phenylketonuria (PKU) who have been shown to Limited s/human/EPAR/kuva

be responsive to such treatment. n Treatment of hyperphenylalaninaemia (HPA) in adults and paediatric patients of all ages with tetrahydrobiopterin (BH4) deficiency who have been shown to be responsive to such treatment.

Kymriah Tisagenlecleuc Tisagenlecleuc Precursor Treatment of: 22/08/2018 Novartis EMEA/H/C/00 L01 N Y N N https://www.ema.eu el el B-Cell -Paediatric and young adult patients up to 25 Europharm 4090 ropa.eu/en/medicine Lymphoblas years of age with B-cell acute lymphoblastic Limited s/human/EPAR/kymr

tic leukaemia (ALL) that is refractory, in relapse iah Leukemia- post-transplant or in second or later relapse. Lymphoma; -Adult patients with relapsed or refractory Lymphoma, diffuse large B-cell lymphoma (DLBCL) after two Large B- or more lines of systemic therapy. Cell, Diffuse

Kyprolis Carfilzomib Carfilzomib Multiple In combination with either lenalidomide and 19/11/2015 Amgen EMEA/H/C/00 L01XX45 Y Y N N https://www.ema.eu Myeloma dexamethasone or dexamethasone alone is Europe B.V. 3790 ropa.eu/en/medicine indicated for the treatment of adult patients with s/human/EPAR/kypr

multiple myeloma who have received at least olis one prior therapy.

Lamzede Velmanase Velmanase alpha- Treatment of non-neurological manifestations in 23/03/2018 Chiesi EMEA/H/C/00 A16AB15 N Y N Y https://www.ema.eu alfa alfa Mannosido patients with mild to moderate alpha- Farmaceutici 3922 ropa.eu/en/medicine sis mannosidosis. S.p.A. s/human/EPAR/lamz

ede Ledaga Chlormethine Chlormethine Mycosis Topical treatment of mycosis fungoides-type 03/03/2017 Helsinn Birex EMEA/H/C/00 L01AA05 N N N N https://www.ema.eu Fungoides cutaneous T-cell lymphoma (MF-type CTCL) in Pharmaceutic 2826 ropa.eu/en/medicine adult patients. als Ltd. s/human/EPAR/ledag

a Lutathera Lutetium Lutetium Neuroendo Treatment of unresectable or metastatic, 26/09/2017 Advanced EMEA/H/C/00 V10XX04 N Y N N https://www.ema.eu (177Lu) (177Lu) crine progressive, well differentiated (G1 and G2), Accelerator 4123 ropa.eu/en/medicine oxodotreotide oxodotreotide Tumors somatostatin receptor positive Applications s/human/EPAR/lutat

gastroenteropancreatic neuroendocrine hera tumours (GEP-NETs) in adults.

43 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Luxturna Voretigene Voretigene Leber Treatment of adult and paediatric patients with 22/11/2018 Novartis EMEA/H/C/00 N/A N Y N N https://www.ema.eu neparvovec neparvovec Congenital vision loss due to inherited retinal dystrophy Europharm 4451 ropa.eu/en/medicine Amaurosis; caused by confirmed biallelic RPE65 mutations Limited s/human/EPAR/luxtu

Retinitis and who have sufficient viable retinal cells. rna Pigmentosa

Mepsevii Vestronidase Vestronidase Mucopolys Treatment of non-neurological manifestations of 23/08/2018 Ultragenyx EMEA/H/C/00 A16AB18 N Y N Y https://www.ema.eu alfa alfa accharidosi Mucopolysaccharidosis VII (MPS VII; Sly Germany 4438 ropa.eu/en/medicine s VII syndrome). GmbH s/human/EPAR/meps

evii Mozobil Plerixafor Plerixafor Multiple Indicated in combination with granulocyte- 30/07/2009 Genzyme EMEA/H/C/00 L03AX16 N N N N https://www.ema.eu Myeloma; colony-stimulating factor to enhance Europe BV 1030 ropa.eu/en/medicine Hematopoi mobilisation of haematopoietic stem cells to the s/human/EPAR/mozo

etic Stem peripheral blood for collection and subsequent bil Cell autologous transplantation in patients with Transplanta lymphoma and multiple myeloma whose cells tion; mobilise poorly. Lymphoma

Myalepta Metreleptin Metreleptin Lipodystrop Indicated as an adjunct to diet as a replacement 29/07/2018 Amryt EMEA/H/C/00 A16AA N Y N Y https://www.ema.eu hy, Familial therapy to treat the complications of leptin Pharmaceutic 4218 ropa.eu/en/medicine Partial deficiency in lipodystrophy (LD) patients: als DAC s/human/EPAR/myal

with confirmed congenital generalised LD epta (Berardinelli-Seip syndrome) or acquired generalised LD (Lawrence syndrome) in adults and children 2 years of age and above; with confirmed familial partial LD or acquired partial LD (Barraquer-Simons syndrome), in adults and children 12 years of age and above for whom standard treatments have failed to achieve adequate metabolic control.

Mylotarg Gemtuzumab Gemtuzumab Leukemia, Indicated for combination therapy with 19/04/2018 Pfizer Europe EMEA/H/C/00 L01XC05 N Y N N https://www.ema.eu ozogamicin ozogamicin Myeloid, daunorubicin (DNR) and cytarabine (AraC) for the MA EEIG 4204 ropa.eu/en/medicine Acute treatment of patients age 15 years and above s/human/EPAR/mylo

with previously untreated, de novo CD33- targ-0 positive acute myeloid leukaemia (AML), except acute promyelocytic leukaemia (APL).

44 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Namuscla Mexiletine hcl Mexiletine hcl Myotonic Symptomatic treatment of myotonia in adult 18/12/2018 Lupin Europe EMEA/H/C/00 C01BB02 N N N N https://www.ema.eu Disorders patients with non-dystrophic myotonic disorders GmbH 4584 ropa.eu/en/medicine s/human/EPAR/nam

uscla Natpar Parathyroid Parathyroid Hypoparath Indicated as adjunctive treatment of adult 24/04/2017 Shire EMEA/H/C/00 H05AA03 N Y Y N https://www.ema.eu hormone hormone yroidism patients with chronic hypoparathyroidism who Pharmaceutic 3861 ropa.eu/en/medicine cannot be adequately controlled with standard als Ireland Ltd s/human/EPAR/natp

therapy alone. ar

Nexavar Sorafenib Sorafenib Carcinoma, Treatment of hepatocellular carcinoma. 19/07/2006 Bayer AG EMEA/H/C/00 L01XE05 N N N N https://www.ema.eu Hepatocell Treatment of patients with advanced renal cell 0690 ropa.eu/en/medicine ular; carcinoma who have failed prior interferon-alpha s/human/EPAR/nexa

Carcinoma, or interleukin-2 based therapy or are considered var Renal Cell unsuitable for such therapy. Treatment of patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine.

NexoBrid Concentrate Concentrate Debrideme Indicated for removal of eschar in adults with 18/12/2012 MediWound EMEA/H/C/00 D03BA03 N Y N N https://www.ema.eu of proteolytic of proteolytic nt deep partial- and full-thickness thermal burns. Germany 2246 ropa.eu/en/medicine enzymes enzymes GmbH s/human/EPAR/nexo

enriched in enriched in brid bromelain bromelain

Ninlaro Ixazomib Ixazomib Multiple In combination with lenalidomide and 21/11/2016 Takeda EMEA/H/C/00 L01XX50 N Y Y N https://www.ema.eu citrate Myeloma dexamethasone is indicated for the treatment of Pharma A/S 3844 ropa.eu/en/medicine adult patients with multiple myeloma who have s/human/EPAR/ninla

received at least one prior therapy. ro

Ocaliva Obeticholic Obeticholic Liver Treatment of primary biliary cholangitis (also 12/12/2016 Intercept EMEA/H/C/00 A05AA04 N Y Y N https://www.ema.eu acid acid Cirrhosis, known as primary biliary cirrhosis) in Pharma 4093 ropa.eu/en/medicine Biliary combination with ursodeoxycholic acid (UDCA) in International s/human/EPAR/ocali

adults with an inadequate response to UDCA or Ltd va as monotherapy in adults unable to tolerate UDCA.

45 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Onivyde Irinotecan Irinotecan Pancreatic Treatment of metastatic adenocarcinoma of the 14/10/2016 Les EMEA/H/C/00 L01XX19 N N N N https://www.ema.eu pegylated hydrochloride hydrochloride Neoplasms pancreas, in combination with 5 fluorouracil (5 Laboratoires 4125 ropa.eu/en/medicine liposomal trihydrate trihydrate FU) and leucovorin (LV), in adult patients who Servier s/human/EPAR/onivy (previously have progressed following gemcitabine based de-pegylated-

known as therapy. liposomal Onivyde)

Onpattro Patisiran Patisiran Amyloidosi Treatment of hereditary transthyretin-mediated 27/08/2018 Alnylam EMEA/H/C/00 N07 Y Y N N https://www.ema.eu sodium s, Familial amyloidosis (hATTR amyloidosis) in adult Netherlands 4699 ropa.eu/en/medicine patients with stage 1 or stage 2 polyneuropathy. B.V. s/human/EPAR/onpa

ttro

Opsumit Macitentan Macitentan Hypertensi As monotherapy or in combination, is indicated 20/12/2013 Janssen-Cilag EMEA/H/C/00 C02KX04 N N N N https://www.ema.eu on, for the long-term treatment of pulmonary International 2697 ropa.eu/en/medicine Pulmonary arterial hypertension (PAH) in adult patients of N.V. s/human/EPAR/opsu

WHO Functional Class (FC) II to III. mit Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated with connective tissue disorders, and PAH associated with corrected simple congenital heart disease.

Orphacol Cholic acid Cholic acid Digestive Treatment of inborn errors in primary bile-acid 12/09/2013 Laboratoires EMEA/H/C/00 A05AA03 N Y N Y https://www.ema.eu 5 System synthesis due to 3β-hydroxy-Δ -C27-steroid CTRS 1250 ropa.eu/en/medicine Diseases; oxidoreductase deficiency or Δ4-3-oxosteroid-5β- s/human/EPAR/orph

Metabolism reductase deficiency in infants, children and acol , Inborn adolescents aged one month to 18 years and Errors adults.

Oxervate Recombinant Cenegermin Keratitis Treatment of moderate (persistent epithelial 06/07/2017 Dompe EMEA/H/C/00 S01 Y Y N N https://www.ema.eu human Nerve defect) or severe (corneal ulcer) neurotrophic farmaceutici 4209 ropa.eu/en/medicine Growth factor keratitis in adults s.p.a. s/human/EPAR/oxerv

(rhNGF) ate

46 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Palynziq Pegvaliase Pegvaliase Phenylketo Treatment of patients with phenylketonuria 03/05/2019 BioMarin EMEA/H/C/00 A16AB19 N Y N N https://www.ema.eu nurias (PKU) aged 16 years and older who have International 4744 ropa.eu/en/medicine inadequate blood phenylalanine control (blood Limited s/human/EPAR/palyn

phenylalanine levels greater than 600 ziq micromol/l) despite prior management with available treatment options.

Plenadren Hydrocortison Hydrocortison Adrenal Treatment of adrenal insufficiency in adults. 03/11/2011 Shire Services EMEA/H/C/00 H02AB09 N N N N https://www.ema.eu e e Insufficienc BVBA 2185 ropa.eu/en/medicine y s/human/EPAR/plena

dren Polivy Polatuzumab Polatuzumab Lymphoma, In combination with bendamustine and rituximab 16/01/2020 Roche EMEA/H/C/00 L01XC N Y Y N https://www.ema.eu vedotin vedotin B-Cell is indicated for the treatment of adult patients Registration 4870 ropa.eu/en/medicine with relapsed/refractory diffuse large B-cell GmbH s/human/EPAR/poliv

lymphoma (DLBCL) who are not candidates for y haematopoietic stem cell transplant.

Poteligeo Mogamulizum Mogamulizum Sezary Treatment of adult patients with mycosis 22/11/2018 Kyowa Kirin EMEA/H/C/00 L01XC25 N Y N N https://www.ema.eu ab ab Syndrome; fungoides (MF) or Sézary syndrome (SS) who Holdings B.V. 4232 ropa.eu/en/medicine Mycosis have received at least one prior systemic s/human/EPAR/potel

Fungoides therapy. igeo

Pretomanid Pretomanid Pretomanid Tuberculosi In combination with bedaquiline and linezolid, in 31/07/2020 FGK EMEA/H/C/00 J04 N Y Y N https://www.ema.eu FGK s, adults, for the treatment of pulmonary Representativ 5167 ropa.eu/en/medicine Multidrug- extensively drug resistant (XDR), or treatment- e Service s/human/EPAR/preto

Resistant intolerant or nonresponsive multidrug-resistant GmbH manid-fgk (MDR) tuberculosis (TB). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

47 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Prevymis Letermovir Letermovir Cytomegalo Indicated for prophylaxis of cytomegalovirus 08/01/2018 Merck Sharp EMEA/H/C/00 J05 N N Y N https://www.ema.eu virus (CMV) reactivation and disease in adult CMV- & Dohme B.V. 4536 ropa.eu/en/medicine Infections seropositive recipients [R+] of an allogeneic s/human/EPAR/prevy

haematopoietic stem cell transplant (HSCT). mis Consideration should be given to official guidance on the appropriate use of antiviral agents.

Procysbi Mercaptamin Mercaptamin Cystinosis Treatment of proven nephropathic cystinosis. 05/09/2013 Chiesi EMEA/H/C/00 A16AA04 N N N N https://www.ema.eu e bitartrate e Cysteamine reduces cystine accumulation in Farmaceutici 2465 ropa.eu/en/medicine some cells (e.g. leukocytes, muscle and liver S.p.A s/human/EPAR/procy

cells) of nephropathic cystinosis patients and, sbi when treatment is started early, it delays the development of renal failure.

Qarziba Dinutuximab Dinutuximab Neuroblast Treatment of high-risk neuroblastoma in 08/05/2017 EUSA Pharma EMEA/H/C/00 L01XC N Y N Y https://www.ema.eu (previously beta beta oma patients aged 12 months and above, who have (Netherlands) 3918 ropa.eu/en/medicine Dinutuxima previously received induction chemotherapy and BV s/human/EPAR/qarzi

b beta achieved at least a partial response, followed by ba EUSA and myeloablative therapy and stem cell Dinutuxima transplantation, as well as patients with history b beta of relapsed or refractory neuroblastoma, with or Apeiron) without residual disease. Prior to the treatment of relapsed neuroblastoma, any actively progressing disease should be stabilised by other suitable measures. In patients with a history of relapsed/refractory disease and in patients who have not achieved a complete response after first line therapy, Qarziba should be combined with interleukin 2 (IL 2).

48 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Ravicti Glycerol Glycerol Urea Cycle Indicated for use as adjunctive therapy for 26/11/2015 Immedica EMEA/H/C/00 A16AX09 N Y N N https://www.ema.eu phenylbutyrat phenylbutyrat Disorders, chronic management of patients with urea cycle Pharma AB 3822 ropa.eu/en/medicine e e Inborn disorders (UCDs) including deficiencies of s/human/EPAR/ravict

carbamoyl phosphate-synthase-I (CPS), ornithine i carbamoyltransferase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), arginase I (ARG) and ornithine translocase deficiency hyperornithinaemia- hyperammonaemia homocitrullinuria syndrome (HHH) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. Ravicti must be used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, protein-free calorie supplements).

Raxone Idebenone Idebenone Optic Treatment of visual impairment in adolescent 08/09/2015 Santhera EMEA/H/C/00 N06BX13 N Y N Y https://www.ema.eu Atrophy, and adult patients with Leber’s Hereditary Optic Pharmaceutic 3834 ropa.eu/en/medicine Hereditary, Neuropathy (LHON). als s/human/EPAR/raxo

Leber (Deutschland) ne GmbH

Reblozyl Luspatercept Luspatercept Anemia; Treatment of adult patients with transfusion- 25/06/2020 Celgene EMEA/H/C/00 B03XA06 N Y N N https://www.ema.eu Myelodyspl dependent anaemia due to very low, low and Europe B.V. 4444 ropa.eu/en/medicine astic intermediate-risk myelodysplastic syndromes s/human/EPAR/reblo

Syndromes; (MDS) with ring sideroblasts, who had an zyl beta- unsatisfactory response to or are ineligible for Thalassemi erythropoietin-based therapy. a Treatment of adult patients with transfusion- dependent anaemia associated with beta thalassaemia.

49 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Revestive Teduglutide Teduglutide Malabsorpt Treatment of patients aged 1 year and above 30/08/2012 Shire EMEA/H/C/00 A16AX08 N Y N N https://www.ema.eu ion with Short Bowel Syndrome (SBS). Patients Pharmaceutic 2345 ropa.eu/en/medicine Syndromes should be stable following a period of intestinal als Ireland Ltd s/human/EPAR/reves

adaptation after surgery. tive Treatment of patients aged 1 year and above with Short Bowel Syndrome. Patients should be stable following a period of intestinal adaptation after surgery.

Rydapt Midostaurin Midostaurin Leukemia, Indicated: 18/09/2017 Novartis EMEA/H/C/00 L01XE N Y N N https://www.ema.eu Myeloid, -in combination with standard daunorubicin and Europharm 4095 ropa.eu/en/medicine Acute; cytarabine induction and high dose cytarabine Ltd s/human/EPAR/ryda

Mastocytos consolidation chemotherapy, and for patients in pt is complete response followed by Rydapt single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia (AML) who are FLT3 mutation positive; -as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM AHN), or mast cell leukaemia (MCL).

Scenesse Afamelanotid Afamelanotid Protoporph Prevention of phototoxicity in adult patients with 22/12/2014 Clinuvel EMEA/H/C/00 D02BB02 N Y N Y https://www.ema.eu e e yria, erythropoietic protoporphyria (EPP). Europe 2548 ropa.eu/en/medicine Erythropoie Limited s/human/EPAR/scen

tic esse Signifor Pasireotide Pasireotide Acromegaly Treatment of adult patients with Cushing’s 24/04/2012 Recordati EMEA/H/C/00 H01CB05 N N N N https://www.ema.eu ; Pituitary disease for whom surgery is not an option or for Rare Diseases 2052 ropa.eu/en/medicine ACTH whom surgery has failed. s/human/EPAR/signif

Hypersecre Treatment of adult patients with acromegaly for or tion whom surgery is not an option or has not been curative and who are inadequately controlled on treatment with another somatostatin analogue.

50 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Sirturo Bedaquiline Bedaquiline Tuberculosi Use as part of an appropriate combination 05/03/2014 Janssen-Cilag EMEA/H/C/00 J04AK05 N Y Y N https://www.ema.eu fumarate s, regimen for pulmonary multidrug resistant International 2614 ropa.eu/en/medicine Multidrug- tuberculosis (MDR TB) in adults and adolescent N.V. s/human/EPAR/sirtur

Resistant patients (12 years to less than 18 years of age o and weighing at least 30 kg) when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Soliris Eculizumab Eculizumab Hemoglobi Indicated in adults and children for the treatment 20/06/2007 Alexion EMEA/H/C/00 L04AA25 Y N N N https://www.ema.eu nuria, of: Europe SAS 0791 ropa.eu/en/medicine Paroxysmal -Paroxysmal nocturnal haemoglobinuria (PNH). s/human/EPAR/soliri

Evidence of clinical benefit is demonstrated in s patients with haemolysis with clinical symptom(s) indicative of high disease activity, regardless of transfusion history. -Atypical haemolytic uremic syndrome (aHUS). Indicated in adults for the treatment of: -Refractory generalized myasthenia gravis (gMG) in patients who are anti-acetylcholine receptor (AChR) antibody-positive. -Neuromyelitis optica spectrum disorder (NMOSD) in patients who are anti-aquaporin-4 (AQP4) antibody-positive with a relapsing course of the disease.

51 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

SomaKit Edotreotide Edotreotide Neuroendo This medicinal product is for diagnostic use only. 08/12/2016 Advanced EMEA/H/C/00 V09IX N Y N N https://www.ema.eu TOC crine After radiolabelling with gallium (68Ga) chloride Accelerator 4140 ropa.eu/en/medicine Tumors; solution, the solution of gallium (68Ga) Applications s/human/EPAR/soma

Radionuclid edotreotide obtained is indicated for Positron kit-toc e Imaging Emission Tomography (PET) imaging of somatostatin receptor overexpression in adult patients with confirmed or suspected well- differentiated gastro-enteropancreatic neuroendocrine tumours (GEP-NET) for localizing primary tumours and their metastases.

Spinraza Nusinersen Nusinersen Muscular Treatment of 5q Spinal Muscular Atrophy. 30/05/2017 Biogen EMEA/H/C/00 M09 Y Y N N https://www.ema.eu sodium Atrophy, Netherlands 4312 ropa.eu/en/medicine Spinal B.V. s/human/EPAR/spinr

aza Strensiq Asfotase alfa Asfotase alfa Hypophosp Indicated for long-term enzyme replacement 28/08/2015 Alexion EMEA/H/C/00 A16AB N Y N Y https://www.ema.eu hatasia therapy in patients with paediatric-onset Europe SAS 3794 ropa.eu/en/medicine hypophosphatasia to treat the bone s/human/EPAR/stren

manifestations of the disease. siq

Strimvelis Autologous Autologous Severe Treatment of patients with severe combined 26/05/2016 Orchard EMEA/H/C/00 L03 N Y N N https://www.ema.eu CD34+ CD34+ Combined immunodeficiency due to adenosine deaminase Therapeutics 3854 ropa.eu/en/medicine enriched cell enriched cell Immunodef deficiency (ADA-SCID), for whom no suitable (Netherlands) s/human/EPAR/strim

fraction that fraction that iciency human leukocyte antigen (HLA)-matched related BV velis contains contains stem cell donor is available CD34+ cells CD34+ cells transduced transduced with retroviral with retroviral vector that vector that encodes for encodes for the human the human adenosine ADA cDNA deaminase sequence (ADA) cDNA sequence from human haematopoiet ic stem/progenit or (CD34+) cells

52 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Sylvant Siltuximab Siltuximab Giant Treatment of adult patients with multicentric 22/05/2014 EUSA Pharma EMEA/H/C/00 L04AC11 Y N N N https://www.ema.eu Lymph Castleman’s disease (MCD who are human (Netherlands) 3708 ropa.eu/en/medicine Node immunodeficiency virus (HIV) negative and BV s/human/EPAR/sylva

Hyperplasia human herpesvirus-8 (HHV-8) negative. nt

Symkevi Tezacaftor; Tezacaftor / Cystic Indicated in a combination regimen with 31/10/2018 Vertex EMEA/H/C/00 R07AX31 N Y N N https://www.ema.eu Ivacaftor ivacaftor Fibrosis ivacaftor 150 mg tablets for the treatment of Pharmaceutic 4682 ropa.eu/en/medicine patients with cystic fibrosis (CF) aged 12 years als (Ireland) s/human/EPAR/symk

and older who are homozygous for the F508del Limited evi mutation or who are heterozygous for the F508del mutation and have one of the following mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: P67L, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272 26A→G, and 3849+10kbC→T.

Takhzyro Lanadelumab Lanadelumab Angioedem Indicated for routine prevention of recurrent 22/11/2018 Shire EMEA/H/C/00 B06AC05 Y Y N N https://www.ema.eu as, attacks of hereditary angioedema (HAE) in Pharmaceutic 4806 ropa.eu/en/medicine Hereditary patients aged 12 years and older. als Ireland Ltd s/human/EPAR/takhz

yro

Tegsedi Inotersen Inotersen Amyloidosi Treatment of stage 1 or Stage 2 polyneuropathy 05/07/2018 Akcea EMEA/H/C/00 N07 Y Y N N https://www.ema.eu sodium s in adult patients with hereditary transthyretin Therapeutics 4782 ropa.eu/en/medicine amyloidosis (hATTR). Ireland s/human/EPAR/tegse

Limited di

Tobi Tobramycin Tobramycin Cystic Indicated for the suppressive therapy of chronic 20/07/2011 Mylan IRE EMEA/H/C/00 J01GB01 N N N N https://www.ema.eu Podhaler Fibrosis; pulmonary infection due to Pseudomonas Healthcare 2155 ropa.eu/en/medicine Respiratory aeruginosa in adults and children aged 6 years Limited s/human/EPAR/tobi-

Tract and older with cystic fibrosis. Consideration podhaler Infections should be given to official guidance on the appropriate use of antibacterial agents.

53 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Translarna Ataluren Ataluren Muscular Treatment of Duchenne muscular dystrophy 31/07/2014 PTC EMEA/H/C/00 M09AX03 N Y Y N https://www.ema.eu Dystrophy, resulting from a nonsense mutation in the Therapeutics 2720 ropa.eu/en/medicine Duchenne dystrophin gene, in ambulatory patients aged 2 International s/human/EPAR/trans

years and older. Efficacy has not been Limited larna demonstrated in non-ambulatory patients. The presence of a nonsense mutation in the dystrophin gene should be determined by genetic testing.

Trepulmix Treprostinil Treprostinil Hypertensi Treatment of adult patients with WHO Functional 03/04/2020 SciPharm Sàrl EMEA/H/C/00 B01AC21 N N N N https://www.ema.eu sodium on, Class (FC) III or IV and: 5207 ropa.eu/en/medicine Pulmonary - inoperable chronic thromboembolic pulmonary s/human/EPAR/trepu

hypertension (CTEPH), or lmix - persistent or recurrent CTEPH after surgical treatment to improve exercise capacity.

Verkazia Ciclosporin Ciclosporin Conjunctivi Treatment of severe vernal keratoconjunctivitis 06/07/2018 Santen Oy EMEA/H/C/00 S01XA18 Y N N N https://www.ema.eu tis; Keratitis (VKC) in children from 4 years of age and 4411 ropa.eu/en/medicine adolescents. s/human/EPAR/verka

zia Vimizim Recombinant Elosulfase alfa Mucopolys Treatment of mucopolysaccharidosis, type IVA 27/04/2014 BioMarin EMEA/H/C/00 A16AB12 N Y N N https://www.ema.eu human n- accharidosi (Morquio A Syndrome, MPS IVA) in patients of all International 2779 ropa.eu/en/medicine acetylgalactos s IV ages. Limited s/human/EPAR/vimiz

amine-6- im sulfatase (rhgalns)

54 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Votubia Everolimus Everolimus Tuberous Renal angiomyolipoma associated with 02/09/2011 Novartis EMEA/H/C/00 L01XE10 N N N N https://www.ema.eu Sclerosis tuberous sclerosis complex (TSC) Europharm 2311 ropa.eu/en/medicine Treatment of adult patients with renal Limited s/human/EPAR/votu

angiomyolipoma associated with tuberous bia sclerosis complex (TSC) who are at risk of complications (based on factors such as tumour size or presence of aneurysm, or presence of multiple or bilateral tumours) but who do not require immediate surgery. The evidence is based on analysis of change in sum of angiomyolipoma volume. Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) Treatment of patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) who require therapeutic intervention but are not amenable to surgery. The evidence is based on analysis of change in SEGA volume. Further clinical benefit, such as improvement in disease-related symptoms, has not been demonstrated.

Vpriv Velaglucerase Velaglucerase Gaucher Indicated for long-term enzyme-replacement 26/08/2010 Shire EMEA/H/C/00 A16AB10 Y N N N https://www.ema.eu alfa alfa Disease therapy (ERT) in patients with type-1 Gaucher Pharmaceutic 1249 ropa.eu/en/medicine

disease. als Ireland Ltd s/human/EPAR/vpriv

Vyndaqel Tafamidis Tafamidis Amyloidosi Treatment of transthyretin amyloidosis in adult 16/11/2011 Pfizer Europe EMEA/H/C/00 N07XX08 N Y N Y https://www.ema.eu s patients with stage-1 symptomatic MA EEIG 2294 ropa.eu/en/medicine polyneuropathy to delay peripheral neurologic s/human/EPAR/vynd

impairment. aqel

Vyxeos Daunorubicin Daunorubicin Leukemia, Treatment of adults with newly diagnosed, 23/08/2018 Jazz EMEA/H/C/00 L01XY01 N N N N https://www.ema.eu liposomal hydrochloride / cytarabine Myeloid, therapy-related acute myeloid leukaemia (t- Pharmaceutic 4282 ropa.eu/en/medicine (previously / cytarabine Acute AML) or AML with myelodysplasia-related als Ireland s/human/EPAR/vyxe known as changes (AML-MRC). Limited os-liposomal Vyxeos)

55 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Wakix Pitolisant Pitolisant Narcolepsy Indicated in adults for the treatment of 31/03/2016 Bioprojet EMEA/H/C/00 N07XX11 N Y N N https://www.ema.eu narcolepsy with or without cataplexy. Pharma 2616 ropa.eu/en/medicine s/human/EPAR/waki

x Waylivra Volanesorsen Volanesorsen Hyperlipopr Indicated as an adjunct to diet in adult patients 03/05/2019 Akcea EMEA/H/C/00 N/A N Y Y N https://www.ema.eu sodium oteinemia with genetically confirmed familial Therapeutics 4538 ropa.eu/en/medicine Type I chylomicronemia syndrome (FCS) and at high Ireland s/human/EPAR/wayli

risk for pancreatitis, in whom response to diet Limited vra and triglyceride lowering therapy has been inadequate.

Xaluprine 6- Mercaptopuri Leukemia, Treatment of acute lymphoblastic leukaemia 09/03/2012 Nova EMEA/H/C/00 L01BB02 N N N N https://www.ema.eu (previously mercaptopuri ne Lymphoid (ALL) in adults, adolescents and children. Laboratories 2022 ropa.eu/en/medicine Mercaptop ne Ireland s/human/EPAR/xalup urine Nova monohydrate Limited rine-previously- Laboratorie mercaptopurine-

s) nova-laboratories

Xermelo Telotristat Telotristat Carcinoid Treatment of carcinoid syndrome diarrhoea in 17/09/2017 Ipsen Pharma EMEA/H/C/00 A16A N Y N N https://www.ema.eu etiprate ethyl Tumor; combination with somatostatin analogue (SSA) 3937 ropa.eu/en/medicine Neuroendo therapy in adults inadequately controlled by SSA s/human/EPAR/xerm

crine therapy. elo Tumors

Xospata Gilteritinib Gilteritinib Leukemia, Indicated as monotherapy for the treatment of 24/10/2019 Astellas EMEA/H/C/00 L01XE54 N Y N N https://www.ema.eu fumarate Myeloid, adult patients who have relapsed or refractory Pharma 4752 ropa.eu/en/medicine Acute acute myeloid leukaemia (AML) with a FLT3 Europe B.V. s/human/EPAR/xosp

mutation. ata

Yescarta Axicabtagene Axicabtagene Lymphoma, Treatment of adult patients with relapsed or 23/08/2018 Kite Pharma EMEA/H/C/00 L01X N Y N N https://www.ema.eu ciloleucel ciloleucel Follicular; refractory diffuse large B-cell lymphoma (DLBCL) EU B.V. 4480 ropa.eu/en/medicine Lymphoma, and primary mediastinal large B-cell lymphoma s/human/EPAR/yesca

Large B- (PMBCL), after two or more lines of systemic rta Cell, Diffuse therapy.

Zejula Niraparib Niraparib Fallopian Indicated as monotherapy for the maintenance 16/11/2017 GlaxoSmithKli EMEA/H/C/00 L01XX N Y N N https://www.ema.eu (tosylate Tube treatment of adult patients with platinum ne (Ireland) 4249 ropa.eu/en/medicine monohydrate) Neoplasms; sensitive relapsed high grade serous epithelial Limited s/human/EPAR/zejul

Peritoneal ovarian, fallopian tube, or primary peritoneal a Neoplasms; cancer who are in response (complete or partial) Ovarian to platinum based chemotherapy. Neoplasms

56 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Zolgensma Onasemnogen Onasemnogen Muscular Treatment of: 18/05/2020 AveXis EU EMEA/H/C/00 M09AX09 N Y Y N https://www.ema.eu e abeparvovec e abeparvovec Atrophy, -patients with 5q spinal muscular atrophy (SMA) Limited 4750 ropa.eu/en/medicine Spinal with a bi-allelic mutation in the SMN1 gene and a s/human/EPAR/zolge

clinical diagnosis of SMA Type 1, or nsma -patients with 5q SMA with a bi-allelic mutation in the SMN1 gene and up to 3 copies of the SMN2 gene.

Zynteglo Autologous Betibeglogene beta- Treatment of patients 12 years and older with 29/05/2019 bluebird bio EMEA/H/C/00 B06A Y Y Y N https://www.ema.eu CD34+ cell autotemcel Thalassemi transfusion-dependent β thalassaemia (TDT) (Netherlands) 3691 ropa.eu/en/medicine enriched a who do not have a β0/β0 genotype, for whom B.V. s/human/EPAR/zynte

population haematopoietic stem cell (HSC) transplantation is glo that contains appropriate but a human leukocyte antigen hematopoietic (HLA)-matched related HSC donor is not stem cells available. transduced with lentiglobin BB305 lentiviral vector encoding the beta-A-T87Q- globin gene

Y – Yes; N – No.

57 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Appendix B. List of orphan drugs appraised by NICE

Brand Generic Indications Estimated Population ICER (used Results Recommendation Method Guidance Guidence End-of- Commercial Cancer Innovation Reference link name name prevalence/ for ref. pulished life arrangement incidence decision date therapy (/100,000) making) (£/per QALY gained) Adcetris Brentuxim relapsed or 2.0 P adult 18,324 to Optimise Optimised STA TA478 04/10/20 no PAS (Simple yes yes. but all https://www.ni ab refractory patient 24,064 d recommendation for 17 Discount) benefits ce.org.uk/guida

vedotin systemic brentuximab vedotin as can be nce/ta478 anaplastic an option for treating captured in large cell relapsed or refractory the cost- lymphoma systemic anaplastic large effectivene cell lymphoma in adults, ss analysis only if: are •they have an Eastern captured. Cooperative Oncology Group (ECOG) performance status of 0 or 1 and •the company provides brentuximab vedotin according to the commercial access agreement with NHS England.

58 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Adcetris Brentuxim CD30-positiv Hodgkin Population Population Optimise Optimised STA TA524 13/06/20 no PAS (Simple yes no https://www.ni ab e Hodgkin lymphoma 1: adults 1: <30,000; d recommendation for 18 Discount) ce.org.uk/guida

vedotin lymphoma in is a group of with Population brentuximab vedotin as nce/ta524 adults with disorders relapsed or 2: >35,606; an option for treating relapsed or with 2.4 I; refractory Population: CD30-positive Hodgkin refractory disease ~40,000 lymphoma in adults with disease after relapsed or refractory autologous disease, only if: stem cell •they have already had transplant; autologous stem cell Population transplant or 2: adults •they have already had at with least 2 previous therapies increased when autologous stem risk of cell transplant or multi- disease agent chemotherapy are relapse or not suitable and progression •the company provides after brentuximab vedotin autologous according to the patient stem cell access scheme transplant; Population 3: adults with relapsed or refractory disease after at least 2 previous therapies when autologous stem cell transplant or multi- agent chemother apy is not an option.

59 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Adcetris Brentuxim CD30-positiv Primary adult 29,613 Optimise Optimised STA TA577 24/04/20 no PAS (Simple yes yes https://www.ni ab e cutaneous cutaneous patient d recommendation for 19 Discount) ce.org.uk/guida

vedotin T-cell T-cell brentuximab vedotin for nce/ta577 lymphoma lymphoma treating CD30-positive (CTCL) after is a group of cutaneous T-cell at least disorders lymphoma after at least 1 1 systemic with 10 - 50 systemic therapy in therapy P adults, only if they have mycosis fungoides stage IIB or over, primary cutaneous anaplastic large cell lymphoma or Sézary syndrome

Adcetris Brentuxim untreated 2.0 P adult 23,446 Recomm Brentuximab vedotin with STA TA641 12/08/20 yes PAS (Simple yes yes. but all https://www.ni ab systemic patient anded cyclophosphamide, 20 Discount) benefits ce.org.uk/guida

vedotin anaplastic doxorubicin and can be nce/ta641 large cell prednisone (CHP) is captured in lymphoma recommended, within its the cost- marketing authorisation, effectivene as an option for untreated ss analysis systemic anaplastic large are cell lymphoma in adults. It captured. is only recommended if the company provides brentuximab vedotin according to the commercial arrangement.

Alofisel Darvadstr complex N/A adults with Uncertain; Not Not recommended, within STA TA556 09/01/20 no N/A no yes https://www.ni ocel perianal non-active lack of recomme its marketing 19 ce.org.uk/guida

fistulas in or mildly long-term nded authorisation, for nce/ta556 Crohn’s active evidence; previously treated disease luminal 23,978 complex perianal fistulas Crohn’s from in adults with non-active disease company's or mildly active luminal base case Crohn's disease. with ERG's preferred input; 143,131 from the second best choice of

60 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

parametric curve for long-term extrapolati on of relapse rate

Bespons Inotuzum Relapsed or N/A adults between Recomm Recommended within its STA TA541 19/09/20 yes PAS (Simple yes yes https://www.ni a ab refractory B- 33,749 and ended marketing authorisation, 18 Discount) ce.org.uk/guida

ozogamici cell acute 37,497 as an option for treating nce/ta541 n lymphoblasti (ICER after relapsed or refractory c leukaemia PAS is not CD22-positive B-cell disclosed) precursor acute lymphoblastic leukaemia in adults. People with relapsed or refractory Philadelphia- chromosome-positive disease should have had at least 1 tyrosine kinase inhibitor. Inotuzumab ozogamicin is recommended only if the company provides it according to the commercial arrangement.

61 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Blincyto Blinatumo Acute Group of adults with between Optimise Recommended as an STA TA589 24/07/20 no PAS (Simple yes yes. but all https://www.ni mab lymphoblasti disorders; minimal 21,874 and d option for treating 19 Discount) benefits ce.org.uk/guida

c leukaemia 10 - 50 P residual 25,551 Philadelphia- can be nce/ta589 in remission disease (ICER after chromosome-negative captured in with minimal (MRD) of at PAS is not CD19-positive B-precursor the cost- residual least 0.1% disclosed) acute lymphoblastic effectivene disease leukaemia in adults with ss analysis activity minimal residual disease are (MRD) of at least 0.1%, captured. only if: -the disease is in first complete remission and -the company provides blinatumomab according to the commercial arrangement.

Blincyto Blinatumo Philadelphia- acute adults <49,190. Recomm Recommended within its STA TA450 28/06/20 yes PAS (Simple yes yes. but all https://www.ni mab chromosome lymphoblas Within the ended marketing authorisation 17 Discount) benefits ce.org.uk/guida

-negative tic range as an option for treating can be nce/ta450 acute leukaemia normally Philadelphia- captured in lymphoblasti is a group of considered chromosome-negative the cost- c leukaemia disorders; a cost- relapsed or refractory effectivene 10 - 50 P effective precursor B-cell acute ss analysis use of NHS lymphoblastic leukaemia are resources in adults, only if the captured. given that company provides it with the end-of- the discount agreed in the life criteria patient access scheme. apply.

62 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Bronchit Mannitol cystic 1.0 - 9.0 P adults the ICERs Optimise Mannitol dry powder for STA TA266 28/11/20 no none no no https://www.ni ol fibrosis for the d inhalation is 12 ce.org.uk/guida

subgroup recommended as an nce/ta266 of people option for treating cystic using fibrosis in adults who rhDNase cannot use rhDNase were because of ineligibility, between intolerance or inadequate 50,000 and response to rhDNase, 80,000 - and whose lung function not cost- is rapidly declining (forced effective; expiratory volume in 1 ICERs were second decline greater likely > than 2% annually), 30,000 in and for whom other people who osmotic agents are not cannot use considered appropriate. rhDNase because of ineligibility, intolerance or inadequate response to rhDNase - not cost- effective either; ICER in patients for whom hypertonic saline is not considered appropriate , who cannot use rhDNase, and whose lung function is rapidly declining would be under £30,000 per QALY gained - 63 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

cost- effective and therefore recommen ded.

Cometriq Cabozanti medullary 1.0 - 9.0 P adults <30,000 Recomm Recommended, within its STA TA516 28/03/20 no PAS (Simple yes There are https://www.ni nib thyroid (exact ended marketing authorisation, 18 Discount) no health- ce.org.uk/guida

cancer figure is not as an option for treating related nce/ta516 disclosed) progressive medullary benefits thyroid cancer in adults that are not with unresectable, locally captured in advanced or metastatic the disease, only if the analyses company provides cabozantinib with the discount agreed in the patient access scheme.

64 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Cometriq Cabozanti advanced Group of adults <50,000 Recomm Recommended, within its STA TA463 09/08/20 yes with PAS (Simple yes yes https://www.ni nib renal cell disorders; compared ended marketing authorisation, 17 axitinib Discount) ce.org.uk/guida

carcinoma 10 - 50 P with as an option for treating and nce/ta463 axitinib; advanced renal cell everolim dominated carcinoma in adults after us; no nivolumab vascular endothelial with growth factor (VEGF)- nivoluma targeted therapy, only if b the company provides cabozantinib with the discount agreed in the patient access scheme.

Cometriq Cabozanti untreated Group of adults <20,000 Recomm Recommended, within its STA TA542 03/10/20 no PAS (Simple yes N/A https://www.ni nib advanced disorders; (exact ended marketing authorisation, 18 Discount) ce.org.uk/guida

renal cell 10 - 50 P figure is not for adults with untreated nce/ta542 carcinoma disclosed) advanced renal cell carcinoma that is intermediate- or poor-risk as defined in the International Metastatic Renal Cell Carcinoma Database Consortium criteria. It is recommended only if the company provides cabozantinib according to the commercial arrangement.

65 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Darzalex Daratumu relapsed and 11.9 P adults The Optimise Recommended for use STA TA510 14/03/20 no PAS + CAA yes yes. but all https://www.ni mab refractory uncertainty d (CDF) within the Cancer Drugs 18 benefits ce.org.uk/guida

multiple in the Fund as an option for can be nce/ta510 myeloma current treating relapsed and captured in evidence refractory multiple the cost- was too myeloma in adults whose effectivene high for previous therapy included ss analysis NICE to a proteasome inhibitor are identify a and an captured. most immunomodulator, and plausible whose disease progressed ICER; on the last therapy, only if therefore it they have daratumumab is after 3 previous therapies considered and the conditions in the not cost- managed access effective agreement are followed.

Darzalex Daratumu previously 11.9 P adults between Recomm Daratumumab plus STA TA573 10/04/20 no PAS + CAA yes yes https://www.ni mab treated 40,000 and ended bortezomib plus 19 ce.org.uk/guida

multiple 50,000 (CDF) dexamethasone is nce/ta573 myeloma recommended for use within the Cancer Drugs Fund as an option for treating relapsed multiple myeloma in people who have had 1 previous treatment. It is recommended only if the conditions in the managed access agreement for daratumumab plus bortezomib plus dexamethasone are followed.

66 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Epidyole Cannabidi seizures 15 P people 33,721; Optimise Cannabidiol with STA TA615 18/12/20 no PAS (Simple no no https://www.ni x ol associated aged 2 additional d clobazam is 19 Discount) ce.org.uk/guida

with years and uncertainty recommended as an nce/ta615 Lennox– older ; There are option for treating Gastaut benefits seizures associated with syndrome that are not Lennox–Gastaut captured in syndrome in people aged the 2 years and older, only if company's the frequency of drop model but seizures is checked every are taken 6 months, and cannabidiol into is stopped if the account in frequency has not fallen decision by at least 30% compared making with the 6 months before starting treatment; the company provides cannabidiol according to the commercial arrangement.

Epidyole Cannabidi seizures 2.5 BP people 32,471; Optimise Cannabidiol with STA TA614 18/12/20 no PAS (Simple no no https://www.ni x ol associated aged 2 additional d clobazam is 19 Discount) ce.org.uk/guida

with Dravet years and uncertainty recommended as an nce/ta614 syndrome older ; benefits option for treating that are not seizures associated with captured in Dravet syndrome in the people aged 2 years and company's older, only if the model frequency of convulsive include seizures is checked every reducing 6 months, and cannabidiol the is stopped if the duration of frequency has not fallen convulsive by at least 30% compared seizures, with the 6 months before and the starting treatment the effect on company provides the quality cannabidiol according to of life of the commercial the siblings arrangement. of children or young people with Dravet 67 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

syndrome, and these benefits are taken into account in desicion making.

Esbriet Pirfenidon idiopathic 11.5 P adults Between Optimise Recommended as an STA TA504 06/02/20 N/A PAS (Simple no yes. but all https://www.ni e pulmonary 25,706 and d option for treating 18 Discount) benefits ce.org.uk/guida

fibrosis 28,870 for idiopathic pulmonary can be nce/ta504 people with fibrosis in adults only if captured in an FVC the person has a forced the cost- above 50% vital capacity (FVC) effectivene predicted; between 50% and 80% ss analysis uncertainti predicted; the company are es including provides pirfenidone with captured. that the the discount agreed in the modelled patient access scheme population and treatment is stopped did not if there is evidence of include as disease progression (an many absolute decline of 10% or people with more in predicted FVC an FVC within any 12-month above 80% period). predicted as expected in NHS practice, accounting for which may

68 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

increase the ICER.

69 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Farydak Panobinos multiple 11.9 P adult <25,000 Recomm Panobinostat in STA TA380 27/01/20 N/A PAS (Simple yes no https://www.ni tat myeloma patients anded combination with 16 Discount) ce.org.uk/guida

after at least with bortezomib and nce/ta380 2 previous relapsed dexamethasone is treatments and/or recommended, within its refractory marketing authorisation, multiple as an option for treating myeloma multiple myeloma, that is, who have for 'adult patients with received at relapsed and/or refractory least 2 multiple myeloma who prior have received at least 2 regimens prior regimens including including bortezomib and an bortezomib immunomodulatory and an agent' when the company immunomo provides panobinostat dulatory with the discount agreed agent in the patient access scheme.

Gazyvaro Obinutuzu Untreated B-cell adults For people Optimise Optimised STA TA343 02/06/20 no PAS (Simple yes yes. but all https://www.ni mab chronic chronic who cannot d recommendation for 15 Discount) benefits ce.org.uk/guida

lymphocytic lymphocytic have obinutuzumab in can be nce/ta343 leukaemia leukemia: bendamusti combination with captured in 10-50 P; T- ne, the chlorambucil as an option the cost- cell chronic most likely for adults with untreated effectivene lymphocytic ICERs (after chronic lymphocytic ss analysis leukemia: PAS) were leukaemia who have are N/A all in the comorbidities that make captured. range full-dose £20,000– fludarabine-based therapy 30,000. For unsuitable for them, only people who if: bendamustine-based can have therapy is not suitable bendamusti and the company provides ne, ICERs obinutuzumab with the after PAS discount agreed in the were above patient access scheme. the top end of the range £20,000– 30,000. 70 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Gazyvaro Obinutuzu follicular 37.0 P adults 15,045 Recomm Obinutuzumab with STA TA629 13/05/20 no PAS (Simple yes N/A https://www.ni mab lymphoma anded bendamustine followed 20 Discount) ce.org.uk/guida

after by obinutuzumab nce/ta629 rituximab maintenance is recommended, within its marketing authorisation, as an option for treating follicular lymphoma that did not respond or progressed up to 6 months after treatment with rituximab or a rituximab-containing regimen. It is recommended only if the company provides it according to the commercial arrangement.

Gazyvaro Obinutuzu Untreated 37.0 P adults <30,000 Recomm Obinutuzumab is STA TA513 21/03/20 no PAS (Simple yes no https://www.ni mab advanced (exact ended recommended as an 18 Discount) ce.org.uk/guida

follicular figure is not option for untreated nce/ta513 lymphoma disclosed) advanced follicular lymphoma in adults (that is, first as induction treatment with chemotherapy, then alone as maintenance therapy), only if the person has a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 or more; the company provides obinutuzumab with the discount agreed in the patient access scheme.

71 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Iclusig Ponatinib chronic chronic adults ICER could Recomm Recommended, within its STA TA451 28/06/20 yes for PAS (Simple yes yes https://www.ni myeloid myeloid fall ended marketing authorisation, 17 people Discount) ce.org.uk/guida

leukaemia leukaemia: anywhere as an option for treating with nce/ta451 and acute 1 - 9 P; within a chronic-, accelerated- or accelerat lymphoblasti acute range that blast-phase chronic ed and c leukaemia lymphoblas in all myeloid leukaemia in blast-pha tic instances adults when the disease is se CML, leukaemia: included resistant to dasatinib or and 10 - 50 P. cost- nilotinib or they cannot Ph+ ALL. effective tolerate dasatinib or values. For nilotinib and for whom those subsequent treatment groups in with imatinib is not whom the clinically appropriate or end-of-life the T315I gene mutation criteria is present. were met, the range Recommended, within its of ICERs for marketing authorisation, ponatinib as an option for treating compared Philadelphia- with its chromosome-positive relevant acute lymphoblastic comparator leukaemia in adults when were < the disease is resistant to 50,000. dasatinib or they cannot tolerate dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate or the T315I gene mutation is present.

Recommended only if the company provides the drug with the discount agreed in the patient access scheme.

72 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Imbruvic Ibrutinib relapsed or 3.5 P adults > 59,000 in Optimise Recommended as an STA TA502 31/01/20 yes CAA yes yes https://www.ni a refractory all but 1 of d option for treating 18 ce.org.uk/guida

mantle cell the relapsed or refractory nce/ta502 lymphoma scenarios mantle cell lymphoma in presented adults, only if they have by the had only 1 previous line of company; therapy and the company likely < provides ibrutinib with 49,848 for the discount agreed in the the 1 commercial access previous agreement with NHS therapy England. subgroup.

Imbruvic Ibrutinib previously B-cell adults <50,000 Recomm Recommended within its STA TA429 25/01/20 yes PAS (Simple yes yes https://www.ni a treated chronic ended marketing authorisation 17 Discount) ce.org.uk/guida

chronic lymphocytic as an option for treating nce/ta429 lymphocytic leukemia: chronic lymphocytic leukaemia 10-50 P; T- leukaemia in adults who and cell chronic have had at least 1 prior untreated lymphocytic therapy, or who have a chronic leukemia: 17p deletion or TP53 lymphocytic N/A mutation, and in whom leukaemia chemo-immunotherapy is with 17p unsuitable, and only when deletion or the company provides TP53 ibrutinib with the discount mutation agreed in the patient access scheme.

73 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Imbruvic Ibrutinib Waldenstro 1.0 - 9.0 P adults > 54,100 Recomm Recommended for use in STA TA491 22/11/20 no CAA yes yes https://www.ni a m’s ended the Cancer Drugs Fund as 17 ce.org.uk/guida

macroglobuli (CDF) an option for treating nce/ta491 naemia Waldenstrom's macroglobulinaemia in adults who have had at least 1 prior therapy, only if the conditions in the managed access agreement for ibrutinib are followed.

Imnovid Pomalido multiple 11.9 P adults 48,673 Recomm Pomalidomide in STA TA427 11/01/20 yes PAS (Simple yes yes https://www.ni (previous mide myeloma compared ended combination with 17 Discount) ce.org.uk/guida

ly previously with low-dose dexamethasone, nce/ta427 Pomalid treated with convention is recommended as an omide lenalidomide al option for treating Celgene) and chemother multiple myeloma in bortezomib apy; adults at third or <50,000 subsequent relapse; that compared is, after 3 previous with treatments including both bendamusti lenalidomide and ne, but bortezomib, only when with the company provides uncertainty pomalidomide with the ; ICER discount agreed in the compared patient access scheme. with panobinost at is not disclosed but pomalidom ide resulted in cost savings but also a QALY loss, producing ICERs that reflected 'savings per QALY lost'.

74 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Kalydeco Ivacaftor cystic 1.0 - 9.0 P people 12 When the Not Although NICE does not STA TA398 27/07/20 no none no N/A https://www.ni fibrosis years and company's recomme recommend lumacaftor– 16 ce.org.uk/guida

homozygous older arbitrary nded ivacaftor, NHS England nce/ta398 for the price has said that it is now F508del reduction available on the NHS for mutation was treating cystic fibrosis. removed, the company's base-case ICER increased from 218,000 to 349,000 for lumacaftor –ivacaftor plus standard of care compared with standard of care alone. The committee concluded that, even without including any of its preferred assumption s, the estimated ICERs were considerabl y higher than what is normally considered a cost- effective use of NHS resources.

75 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Kymriah Tisagenlec relapsed or 43 P adults after 42,991 to Recomm Recommended for use STA TA567 13/03/20 yes PAS + CAA yes yes. but all https://www.ni leucel refractory 2 or more 55,403 ended within the Cancer Drugs 19 benefits ce.org.uk/guida

diffuse large systemic after (CDF) Fund as an option for can be nce/ta567 B-cell therapies PAS+CAA treating relapsed or captured in lymphoma refractory diffuse large B- the cost- cell lymphoma in adults effectivene after 2 or more systemic ss analysis therapies, only if the are conditions in the managed captured. access agreement are followed.

Kymriah Tisagenlec relapsed or N/A people >30,000 Recomm Recommended for use STA TA554 21/12/20 no PAS (Simple yes yes. but all https://www.ni leucel refractory B- aged up to compared ended within the Cancer Drugs 18 Discount) benefits ce.org.uk/guida

cell acute 25 years with (CDF) Fund as an option for can be nce/ta554 lymphoblasti blinatumo treating relapsed or captured in c leukaemia mab; >45,0 refractory B-cell acute the cost- 00 lymphoblastic leukaemia effectivene compared in people aged up to 25 ss analysis with years, only if the are salvage conditions in the managed captured. chemother access agreement are apy (after followed. PAS).

Kyprolis Carfilzomi multiple 11.9 P adults substantiall Optimise Carfilzomib in STA TA457 19/07/20 no PAS (Simple yes yes https://www.ni b myeloma y higher d combination with 17 Discount) ce.org.uk/guida

than dexamethasone is nce/ta457 41,429 at recommended as an 3rd line; option for treating 27,629 at multiple myeloma in 2nd line adults, only if they have had only 1 previous therapy, which did not include bortezomib and the company provides carfilzomib with the discount agreed in the patient access scheme.

76 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Lutather Lutetium unresectable Group of adults <30,000 for Recomm Recommended, within its MTA TA539 29/08/20 no PAS (Simple yes yes. but all https://www.ni a (177Lu) or disorders pancreatic anded marketing authorisation, 18 Discount) benefits ce.org.uk/guida

oxodotreo metastatic NETs; as an option for treating can be nce/ta539 tide neuroendocr <30,000 for unresectable or captured in ine tumours gastrointes metastatic, progressive, the cost- tinal NETs; well-differentiated (grade effectivene exact 1 or grade 2), ss analysis figures are somatostatin receptor- are not positive captured. disclosed gastroenteropancreatic neuroendocrine tumours (NETs) in adults. It is recommended only if the company provides it according to the commercial arrangement.

77 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Mylotarg Gemtuzu untreated 10 - 50 P people list price Optimise Gemtuzumab ozogamicin, STA TA545 14/11/20 no PAS (Simple yes yes. but all https://www.ni mab acute aged ICER: d with daunorubicin and 18 Discount) benefits ce.org.uk/guida

ozogamici myeloid 15 years 19,556 for cytarabine, is can be nce/ta545 n leukaemia and over patients recommended as an captured in whose option for untreated de the cost- disease had novo CD33-positive acute effectivene favourable, myeloid leukaemia (AML), ss analysis intermediat except acute are e or promyelocytic leukaemia, captured. unknown in people 15 years and cytogenetic over, only if: s (ICER -they start induction after PAS is therapy when either the below cytogenetic test confirms 20,000. that the disease has Exact figure favourable, intermediate is not or unknown cytogenetics disclosed). (that is, because the test was unsuccessful) or when their cytogenetic test results are not yet available and they start consolidation therapy when their cytogenetic test confirms that the disease has favourable, intermediate or unknown cytogenetics (because the test was unsuccessful) and the company provides gemtuzumab ozogamicin according to the commercial arrangement.

78 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Nexavar Sorafenib advanced Group of adults 65,900 as Not At the time of appraisal, MTA TA178 26/08/20 yes none yes N/A https://www.ni and/or disorders; second-line recomme the technology was not 09 ce.org.uk/guida

metastatic 10 - 50 P treatment nded considered to be an nce/ta178 renal cell for people appropriate use of NHS carcinoma in whom resources based on the immunothe data available. rapy has failed; >72, 500 and 74,900 as second-line treatment for people in whom non- immunothe rapy first- line treatment has failed and who are unsuitable for immunothe rapy.

79 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Nexavar Sorafenib differentiate 10 I adults >30,000 Optimise Lenvatinib and sorafenib MTA TA535 08/08/20 yes PAS (Simple yes N/A https://www.ni d thyroid whose after PAS d are recommended as 18 Discount) ce.org.uk/guida

cancer after disease (exact options for treating nce/ta535 radioactive does not figure is not progressive, locally iodine respond to disclosed) advanced or metastatic radioactive differentiated thyroid iodine cancer (papillary, follicular or Hürthle cell) in adults whose disease does not respond to radioactive iodine, only if they have not had a tyrosine kinase inhibitor before, or they have had to stop taking a tyrosine kinase inhibitor within 3 months of starting it because of toxicity (specifically, toxicity that cannot be managed by dose delay or dose modification). Lenvatinib and sorafenib are recommended only if the companies provide them according to the commercial arrangements.

Nexavar Sorafenib advanced Hepatocellu people with >52,600 Optimise Recommended as an STA TA474 06/09/20 yes CAA yes N/A https://www.ni hepatocellul lar Child-Pugh before d option for treating 17 ce.org.uk/guida

ar carcinoma: grade A CAA; advanced hepatocellular nce/ta474 carcinoma 10 - 50 P liver <50,000 carcinoma only for people impairment after CAA with Child-Pugh grade A (exact liver impairment, only if figure is not the company provides disclosed) sorafenib within the agreed commercial access arrangement.

80 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Ninlaro Ixazomib relapsed or 11.9 P adults 31,691 Optimise Ixazomib, with STA TA505 07/02/20 no CAA yes All https://www.ni refractory (company's d (CDF) lenalidomide and 18 significant ce.org.uk/guida

multiple base case); dexamethasone, is health- nce/ta505 myeloma additional recommended for use related data within the Cancer Drugs benefits collection Fund as an option for were has the treating multiple captured in potential to myeloma in adults only if the QALY reduce the they have already had 2 calculation uncertainty or 3 lines of therapy and about the the conditions in the overall managed access survival agreement for ixazomib benefit; are followed. when the CAA was applied, ixazomib is potentially cost effective for the subgroup of people who had had 2 or 3 lines of therapy Ocaliva Obeticholi primary 21.05 P adult 33,458 Recomm Recommended in line STA TA443 26/04/20 no PAS (Simple no yes https://www.ni c acid biliary patient anded with marketing 17 Discount) ce.org.uk/guida

cholangitis authorisation and nce/ta443 following agreement of a patient access scheme.

81 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Onivyde Irinotecan metastatic N/A adults >51,000 Not Aflibercept in STA TA307 25/03/20 no PAS for yes All https://www.ni pegylate hydrochlo colorectal recomme combination with 14 aflibercept significant ce.org.uk/guida

d ride cancer that nded irinotecan and health- nce/ta307 liposoma trihydrate has fluorouracil-based related l progressed therapy is not benefits (previous following recommended within its were ly known prior marketing authorisation captured in as oxaliplatin- for treating metastatic the QALY Onivyde) based colorectal cancer that is calculation chemothera resistant to or has py progressed after an oxaliplatin-containing regimen.

Onivyde Irinotecan pancreatic N/A adults >100,000 Not Pegylated liposomal STA TA440 26/04/20 no N/A yes yes https://www.ni pegylate hydrochlo cancer after whose for recomme irinotecan, in combination 17 ce.org.uk/guida

d ride gemcitabine disease has pegylated nded with 5-fluorouracil and nce/ta440 liposoma trihydrate progressed liposomal leucovorin, is not l after irinotecan recommended, within its (previous gemcitabin plus 5-FU marketing authorisation, ly known e-based and LV for treating metastatic as therapy compared adenocarcinoma of the Onivyde) with 5-FU pancreas in adults whose plus LV disease has progressed after gemcitabine-based therapy.

Prevymis Letermovi preventing Cytomegalo adults who 24,269 Recomm Recommended, within its STA TA591 31/07/20 no PAS (Simple no yes. but all https://www.ni r cytomegalov virus are after PAS anded marketing authorisation, 19 Discount) benefits ce.org.uk/guida

irus disease disease in seropositiv as an option for can be nce/ta591 after a stem patients e for CMV preventing captured in cell with cytomegalovirus (CMV) the cost- transplant impaired reactivation and disease effectivene cell after an allogeneic ss analysis mediated haematopoietic stem cell are immunity transplant (HSCT) in adults captured. deemed at who are seropositive for risk has a CMV. It is recommended prevalence only if the company of 25.5 P. provides it according to the commercial arrangement.

82 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Qarziba Dinutuxim neuroblasto 11 P people >40,000 Recomm Recommended as an STA TA538 22/08/20 no PAS (Simple yes Some https://www.ni (previous ab beta ma aged 12 (exact ended option for treating high- 18 Discount) health- ce.org.uk/guida ly months figure is not risk neuroblastoma in related nce/ta538 Dinutuxi and over disclosed) people aged 12 months benefits mab and over whose disease are not beta has at least partially captured in EUSA responded to induction the and chemotherapy, followed economic Dinutuxi by myeloablative therapy model mab and stem cell transplant, beta only if: Apeiron) -they have not already had anti-GD2 immunotherapy and -the company provides dinutuximab beta according to the commercial arrangement.

Rydapt Midostaur untreated Group of adults <30,000 Recomm Recommended, within its STA TA523 13/06/20 no PAS (Simple yes yes https://www.ni in acute disorders; after PAS ended marketing authorisation, 18 Discount) ce.org.uk/guida

myeloid 10 - 50 P (exact as an option in adults for nce/ta523 leukaemia figure is not treating newly diagnosed disclosed) acute FLT3-mutation- positive myeloid leukaemia with standard daunorubicin and cytarabine as induction therapy, with high-dose cytarabine as consolidation therapy, and alone after complete response as maintenance therapy. It is recommended only if the company provides midostaurin with the discount agreed in the patient access scheme.

83 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Spinraza Nusinerse spinal 10 I children ICER above Optimise Recommended as an STA TA588 24/07/20 yes CAA no yes. but all https://www.ni n muscular and adults normal cost d option for treating 5q 19 benefits ce.org.uk/guida

atrophy effective spinal muscular atrophy can be nce/ta588 range; (SMA) only if people have captured in Exact figure pre-symptomatic SMA, or the cost- is not SMA types 1, 2 or 3, and effectivene disclosed; the conditions in the ss analysis All managed access are evidence agreement are followed. captured. was subject to uncertainty ; potential to be cost effective; Managed access agreement to address uncertainty .

84 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Takhzyro Lanadelu preventing Group of people <20,000 Optimise Recommended as an STA TA606 16/10/20 no PAS (Simple no yes. but all https://www.ni mab recurrent disorders; 1 aged 12 (exact ICER d option for preventing 19 Discount) benefits ce.org.uk/guida

attacks of - 9 P and over is not recurrent attacks of can be nce/ta606 hereditary disclosed) hereditary angioedema in captured in angioedema people aged 12 and older, the cost- only if they are eligible for effectivene preventive C1-esterase ss analysis inhibitor (C1-INH) are treatment in line with captured. NHS England's commissioning policy, that is, they are having 2 or more clinically significant attacks per week over 8 weeks despite oral preventive therapy, or oral therapy is contraindicated or not tolerated the lowest dosing frequency of lanadelumab is used in line with the summary of product characteristics, that is, when the condition is in a stable, attack-free phase and the company provides lanadelumab according to the commercial arrangement.

85 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Tobi Tobramyci pseudomona N/A people of dominate Optimise Tobramycin dry powder MTA TA276 27/03/20 no PAS (Simple no yes https://www.ni Podhaler n s lung 6 years and after PAS d for inhalation (DPI) is 13 Discount) ce.org.uk/guida

infection in over recommended as an nce/ta276 cystic option for treating chronic fibrosis pulmonary infection caused by Pseudomonas aeruginosa in people with cystic fibrosis only if nebulised tobramycin is considered an appropriate treatment, that is, when colistimethate sodium is contraindicated, is not tolerated or has not produced an adequate clinical response and the manufacturer provides tobramycin DPI with the discount agreed as part of the patient access scheme to primary, secondary and tertiary care in the NHS.

Votubia Everolimu organ N/A adults ICERs > Not Not recommended within STA TA348 22/07/20 N/A N/A no N/A https://www.ni s rejection in 184,000 for recomme its marketing 15 ce.org.uk/guida

liver everolimus nded authorisation for nce/ta348 transplantati with preventing organ on reduced-do rejection in people having se a liver transplant. tacrolimus compared with the mycopheno late mofetil treatment regimen and > 107,600 compared

86 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

with the azathioprin e treatment regimen.

87 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Votubia Everolimu unresectable Group of adults <30,000 for Recomm Everolimus and sunitinib MTA TA449 28/06/20 Everolim PAS (Simple yes All https://www.ni s or disorders everolimus ended are recommended, within 17 us and Discount) significant ce.org.uk/guida

metastatic and their marketing sunitinib health- nce/ta449 neuroendocr sunitinib authorisations, as options for related ine tumours for for treating well- or pancreati benefits in people pancreatic moderately differentiated c NETs were with NETs; unresectable or meet the captured in progressive <20,000 for metastatic end-of- the QALY disease everolimus neuroendocrine tumours life calculation for (NETs) of pancreatic origin criteria; gastrointes in adults with progressive Everolim tinal NETs; disease. us for <30,000 for Everolimus is gastroint everolimus recommended, within its estinal for lung marketing authorisation, NETs NETs. as an option for treating does not well-differentiated (grade meet the 1 or grade 2) non- end-of- functional unresectable or life metastatic NETs of criteria; gastrointestinal or lung Everolim origin in adults with us for progressive disease. lung Everolimus is NETs recommended only when does not the company provides it meet the with the discount agreed end-of- in the patient access life scheme. criteria

88 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Votubia Everolimu advanced Group of adults Before PAS: Recomm Recommended within its STA TA432 22/02/20 yes PAS (Simple yes yes https://www.ni s renal cell disorders; Determinist ended marketing authorisation 17 Discount) ce.org.uk/guida

carcinoma 10 - 50 P ic ICER of as an option for treating nce/ta432 after 49,300 advanced renal cell previous (derived by carcinoma that has treatment the progressed during or after manufactur treatment with vascular er) and the endothelial growth factor mean targeted therapy, only if probabilisti the company provides it c ICER of with the discount agreed £51,700 in the patient access per QALY scheme. (derived by the ERG). After PAS: <30,000 (exact figure is not disclosed) Votubia Everolimu previously Group of adults between Recomm Lenvatinib plus STA TA498 24/01/20 no PAS (Simple yes yes https://www.ni s treated disorders; 20,000 and ended everolimus is 18 Discount) ce.org.uk/guida

advanced 10 - 50 P 30,000 recommended as an nce/ta498 renal cell option for treating carcinoma advanced renal cell carcinoma in adults who have had 1 previous vascular endothelial growth factor (VEGF)- targeted therapy, only if their Eastern Cooperative Oncology Group (ECOG) performance status score is 0 or 1 and the company provides lenvatinib with the discount agreed in the patient access scheme.

89 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Votubia Everolimu advanced N/A postmenop Before PAS: Recomm Everolimus, in STA TA421 21/12/20 no PAS (Simple yes yes https://www.ni s breast ausal ERG's ended combination with 16 Discount) ce.org.uk/guida

cancer after women estimate is exemestane, is nce/ta421 endocrine 68,000; recommended within its therapy After PAS: marketing authorisation, considered as an option for treating cost- advanced human effective epidermal growth factor (exact receptor 2 (HER2)- figure is not negative, hormone- disclosed) receptor-positive breast cancer in postmenopausal women without symptomatic visceral disease that has recurred or progressed after a non- steroidal aromatase inhibitor. Everolimus is recommended only if the company provides it with the discount agreed in the patient access scheme.

Vyxeos Daunorub untreated Group of adults <50,000 Recomm Recommended, within its STA TA552 19/12/20 yes PAS (Simple yes yes. but all https://www.ni liposoma icin / acute disorders; ended marketing authorisation, 18 Discount) benefits ce.org.uk/guida

l cytarabin myeloid 10 - 50 P as an option for untreated can be nce/ta552 (previous e leukaemia therapy-related acute captured in ly known myeloid leukaemia or the cost- as acute myeloid leukaemia effectivene Vyxeos) with myelodysplasia- ss analysis related changes in adults. are It is recommended only if captured. the company provides it according to the commercial arrangement.

90 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Xospata Gilteritini relapsed or Group of adults <50,000 Recomm Monotherapy is STA TA642 12/08/20 yes PAS (Simple yes yes. but all https://www.ni b refractory disorders; (exact ended recommended as an 20 Discount) benefits ce.org.uk/guida

acute 10 - 50 P figure is not option for treating can be nce/ta642 myeloid disclosed) relapsed or refractory captured in leukaemia FLT3-mutation-positive the cost- acute myeloid leukaemia effectivene (AML) in adults only if the ss analysis company provides are gilteritinib according to captured. the commercial arrangement. Gilteritinib should not be given as maintenance therapy after a haematopoietic stem cell transplant.

Yescarta Axicabtag Diffuse large Diffuse adults after between Recomm Recommended for use STA TA559 23/01/20 yes CAA yes yes. but all https://www.ni ene B-cell large B-cell 2 or more 50,000 and ended within the Cancer Drugs 19 benefits ce.org.uk/guida

ciloleucel lymphoma lymphoma: systemic 100,000 (CDF) Fund as an option for can be nce/ta559 and primary 43 P; therapies treating relapsed or captured in mediastinal primary refractory diffuse large the cost- large B-cell mediastinal B-cell lymphoma or effectivene lymphoma large B-cell primary mediastinal large ss analysis after 2 or lymphoma: B-cell lymphoma in adults are more 5 P after 2 or more systemic captured. systemic therapies, only if the therapies conditions in the managed access agreement are followed.

91 Title: Appraisal of NICE’s cost-effectiveness thresholds for assessing orphan drugs

Zejula Niraparib maintenance Ovarian adults Between Optimise Recommended for use STA TA528 04/07/20 no CAA yes yes https://www.ni treatment of cancer: 49.5 23,795(com d (CDF) within the Cancer Drugs 18 ce.org.uk/guida

relapsed, P; fallopian pany) and Fund as an option for nce/ta528 platinum- tube 81,674(ERG treating relapsed, sensitive cancer: 1.0 ) after PAS platinum-sensitive high- ovarian, P; Primary for the grade serous epithelial fallopian peritoneal germline ovarian, fallopian tube or tube and cancer: mutation- primary peritoneal cancer peritoneal unknown negative-2L that has responded to the cancer prevalence. + group. most recent course of Between platinum-based 20,694(com chemotherapy in adults, pany) and only if they have a 54,632 germline BRCA mutation (ERG) for and have had 2 courses of the platinum-based germline chemotherapy or mutation- they do not have a positive-2L germline BRCA mutation group and have had 2 or more courses of platinum-based chemotherapy and the conditions in the managed access agreement for niraparib are followed.

BP – Birth prevalence; I – Incidence; P – Prevalence.

92