Thomas Morel

Reconciling uncertainty of costs and outcomes with the need for access to orphan medicinal products: a comparative study of managed entry agreements across seven European countries

BackgroundNational payers across Europe have been increasingly looking into innovative reimbursement approaches – called managed entry agreements (MEAs) – to balance the need to provide rapid access to potentially beneficial orphan medicinal products (OMPs) with the requirements to circumscribe uncertainty, obtain best value for money or to ensure affordability. This study aimed to identify, describe and classify MEAs applied to OMPs by national payers and to analyse their practice in Europe.MethodsTo identify and describe MEAs, national health technology assessments and reimbursement decisions on OMPs across seven European countries were reviewed and their main characteristics extracted. To fill data gaps and validate the accuracy of the extraction, collaboration was sought from national payers. To classify MEAs, a bespoke taxonomy was implemented. Identified MEAs were analysed and compared by focusing on five key themes, namely by describing the MEAs in relation to: drug targets and therapeutic classes, geographical spread, type of MEA applied, declared rationale for setting-up of MEAs, and evolution over time.Results42 MEAs for 26 OMPs, implemented between 2006 and 2012 and representing a variety of MEA designs, were identified. Italy was the country with the highest number of schemes (n=15), followed by the Netherlands (n=10), England and Wales (n=8), Sweden (n=5) and Belgium (n=4). No MEA was identified for France and Germany due to data unavailability. Antineoplastic agents were the primary targets of MEAs. 55% of the identified MEAs were performance-based risk-sharing arrangements; the other 45% were financial-based. Nine of these 26 OMPs were subject to MEAs in two or three different countries, resulting in 24 MEAs. 60% of identified MEAs focused on conditions whose prevalence is less than 1 per 10,000.ConclusionsThis study confirmed that a variety of MEAs were increasingly used by European payers to manage aspects of uncertainty associated with the introduction of OMPs in the healthcare system, and which may be of a clinical, utilisation, or budgetary nature. It remains unclear whether differences in the use of MEAs reflect differences in how ‘uncertainty’ and ‘value’ are perceived across healthcare systems.

Cost-Effectiveness Assessment of Orphan Drugs

In September 2012, the Dutch Healthcare Insurance Board issued advice not to reimburse orphan drugs that target lysosomal storage disorders: agalsidase alfa and agalsidase beta for Fabry disease and alglucosidase alfa for Pompe disease [1, 2].With respect to the former, the Healthcare Insurance Board concluded that enzyme replacement therapy offered an added therapeutic value compared with symptomatic treatment of Fabry disease [1]. However, enzyme replacement therapy was not cost effective at an incremental cost of euro3.3 million per quality-adjusted life-year gained. The unfavourable cost effectiveness originated from the limited additional therapeutic value (as a result of the slow progression of the disease) and high costs: enzyme replacement therapy costs euro200,000 per patient per year, resulting in a total budget impact of euro11 million per year for the Netherlands. The Healthcare Insurance Board argued that continued reimbursement of enzyme replacement therapy for Fabry disease would imply that limited resources are not available to reimburse other, more cost effective health technologies.With respect to the latter, the Healthcare Insurance Board recommended to restrict reimbursement of alglucosidase alfa for Pompe disease to patients who suffer from the classic form of the disease and to patients who show symptoms of the (non-)classic disease during their infancy [2]. Alglucosidase alfa was found to generate an added therapeutic value over best supportive care, was cost effective at an incremental cost of euro0.3-0.9 million per quality-adjusted life-year gained in the classic form of Pompe disease, but was not cost effective at an incremental cost of euro15 million per quality-adjusted life-year gained in the non-classic form of Pompe disease. The annual cost of treating a patient with alglucosidase alfa amounted to euro0.4-0.7 million.1 A Scientific ConundrumThese two examples highlight some of the scientific challenges involved in assessing the cost effectiveness of orphan drugs.Uncertainty tends to surround the safety and effectiveness of orphan drugs at the time of market launch. This clinical uncertainty may result from difficulties involved in recruiting a sufficient number of patients across countries, the lack of randomized controlled trials, and the use of surrogate efficacy measures [3]. As a result, there is an urgent need for the development of methodological guidelines about the assessment of the (cost) effectiveness of orphan drugs for (ultra-)rare diseases. In England and Wales, the National Institute for Health and Clinical Excellence (NICE) will be responsible for assessing orphan drugs from April 2013 onwards and has committed itself to developing methods to guide such an assessment [4].Dutch physicians who are involved in treating patients with these lysosomal storage disorders have argued that the Healthcare Insurance Board is not able to issue an informed advice due to the lack of long-term data on safety and effectiveness [5]. For instance, on the occasion of the public hearing of the Dutch Healthcare Insurance Board on 21 September 2012, Professor Hollak stressed that the main challenge with enzyme replacement therapy is that effectiveness is different across patient subgroups [6]. While a clear benefit was shown in some patients, in others, such as those with end-renal or cardiac disease, a lesser benefit was observed. No conclusions can nonetheless be drawn as the overall amount of data remains too small, resulting from the low number of Dutch patients. To address this issue, the idea has been proposed to launch a compulsory Europeanwide registry following marketing authorization of an orphan drug [5]. The establishment of such registries for rare diseases is supported by the European Medicines Agency and by many member states, although registries are not without methodological limitations [3].The ethical principle underlying economic evaluation is that scarce resources are allocated to the most cost-effective health technologies with a view to maximizing population health. …

Shining a light in the black box of orphan drug pricing

BackgroundThe pricing mechanism of orphan drugs appears arbitrary and has been referred to as a “black box”. Therefore, the aim of this study is to investigate how drug- and disease-specific variables relate to orphan drug prices. Additionally, we aim to explore if certain country-specific pricing and reimbursement policies affect the price level of orphan drugs.MethodsAnnual treatment costs per indication per patient were calculated for 59 orphan drugs with a publicly available price in Belgium, the Netherlands, Czech Republic, France, Italy and the United Kingdom. A multiple linear regression model was built with 14 drug- and disease-specific variables. A Mann-Whitney U test was used to explore whether there is a correlation between annual treatment costs of orphan drugs across countries with different pricing and reimbursement policies.ResultsRepurposed orphan drugs, orally administered orphan drugs or orphan drugs for which an alternative treatment is available are associated with lower annual treatment costs. Orphan drugs with multiple orphan indications, for chronic treatments or for which an improvement in overall survival or quality-of-life has been demonstrated, are associated with higher annual treatment costs. No association was found between annual treatments cost of orphan drugs across countries and the different pricing and reimbursement systems.ConclusionsThis study has shown that prices of orphan drugs are influenced by factors such as the availability of an alternative drug treatment, repurposing, etc. Current debate about the affordability of orphan drugs highlights the need for more transparency in orphan drug price setting.

Quantifying benefit-risk preferences for new medicines in rare disease patients and caregivers

BackgroundRare disease patients and caregivers face uncommon, serious, debilitating conditions often characterised by poor prognosis and limited treatment options. This study aimed to explore what they consider of value when choosing between hypothetical therapeutic options and to quantify both their benefit-risk preferences and the influence of disease context.MethodsA mixed-methods survey with patients and caregivers was conducted in the United Kingdom across a range of rare diseases. Discrete-choice experiments that compared hypothetical treatment profiles of benefits and risks were used to measure respondent preferences across a set of seven attributes related to health outcomes, safety, and process of care. Bespoke questions on current disease management and the joint use of the 12-item WHODAS 2.0 questionnaire and of two Likert scales capturing self- and proxy-assessed disease-induced threat to life and impairment were implemented to describe disease context. Additionally, qualitative insights on the definitions of value and risk were collected from respondents.ResultsFinal study sample included 721 patients and 152 informal caregivers, across 52 rare diseases. When choosing between hypothetical novel treatments for rare diseases, respondents attributed most importance to drug response, risk of serious side effects, and the ability to conduct usual activities while on treatment. In contrast, attributes related to treatment modalities were the least important. Respondents expressed a willingness to accept risks in hopes of finding some benefit, such as a higher chance of drug response or greater health improvement potential. Increasing disease severity, impairment or disability, and the lack of effective therapeutic options were shown to raise significantly the willingness to gain benefit through increased risk.ConclusionsThis is the first study performing a quantitative discrete choice experiment amongst patients and caregivers across 52 rare conditions. It enables a more detailed understanding of the relationship between disease context, treatment attributes and the degree of risk respondents are willing to take to gain a specific degree of benefit. Researchers of novel therapeutics for rare diseases should be encouraged to invest in preference elicitation studies to generate rigorous patient evidence and specific regulatory guidance should be issued to acknowledge their importance and their use in marketing authorisations.

A mixed treatment comparison of gabapentin enacarbil, pramipexole, ropinirole and rotigotine in moderate-to-severe restless legs syndrome

Abstract Objective: A mixed treatment comparison (MTC) was performed to investigate the relative efficacy and safety of licensed pharmaceuticals for moderate-to-severe restless legs syndrome (RLS). Methods: RLS trials published over the past 10 years were identified via systematic literature searches of MEDLINE, Embase, Cochrane CENTRAL, and manufacturers’ websites. MTC was performed with WinBUGS software using a Bayesian approach. Identified primary outcomes: change in International RLS Study Group Rating Scale (IRLS) at week 12 and end of maintenance (EoM). Secondary outcomes: IRLS and Clinical Global Impression – Improvement Scale (CGI-I) responders, RLS-6 items and adverse events (AEs). Results: Twenty-eight clinical trials were identified. Fifteen were included in the primary analysis. Indirect comparisons were established among gabapentin enacarbil, pramipexole, ropinirole, rotigotine and placebo. Overall, the four active treatments showed similar efficacies as assessed by changes in IRLS scores, IRLS responders, CGI-I responders, and RLS-6 scores. The sole exception was change in IRLS at week 12, for which rotigotine was likely more efficacious than ropinirole (mean difference: −2.52 [95% CrI: −4.74, −0.40]). Indirect comparisons on safety endpoints indicated ropinirole was associated with a higher risk of nausea than the other agents, and was more likely to result in discontinuations due to lack of efficacy than pramipexole. Nausea was likely more frequent with pramipexole than gabapentin enacarbil, and rotigotine was more likely to result in discontinuation due to AEs than ropinirole and pramipexole. Conclusions: This MTC confirmed the superiority of gabapentin enacarbil, pramipexole, ropinirole, and rotigotine above placebo in alleviating RLS symptoms. Compared to ropinirole, rotigotine showed some additional benefit in terms of change in IRLS at Week 12. Choice of RLS drugs requires careful evaluation of effectiveness and safety profiles in clinical practice. Due to lack of head-to-head trials, inconsistency could not be assessed in our analysis. Head-to-head trials on a more homogeneous population are needed to validate the MTC results.

Regulatory watch: The orphan drug pipeline in Europe

The European framework for orphan medicinal products offers a range of incentives to encourage the development of medicinal products for the treatment of rare diseases. To qualify for these incentives, sponsors must obtain — at any stage of development — orphan designation status from the European Medicines Agency (EMA) by fulfilling a set of criteria (see Supplementary information S1 (box)). Once designation is granted, sponsors are required to submit annual reports to the EMA summarizing progress in development. However, little is known about the current state of development of the orphan designations (ODs) that have not yet obtained marketing authorization. With this in mind, we analysed the orphan drug pipeline in Europe by reviewing the active ODs granted between 2002 and 2012 for which an annual report was available in 2013 or 2014. For each OD, data related to the latest completed study, target therapeutic area and sponsor type were collected. We also applied standard success rates for each development phase to our dataset to estimate the number of ODs that may receive marketing authorization (see Supplementary information S1 (box) for details of the dataset and analysis). Between 2002 and 2012, our sample of ODs (n = 605) was spread across a portfolio of 21 therapeutic areas (FIG. 1a), suggesting that translation of rare disease research into product development and healthcare innovation is happening across an increasing number of diseases — notably R E G U L ATO RY WAT C H

Market watch: Are orphan drug companies the pick of the pharmaceutical industry?

Gross margin R&D as percentage of sales EBITDA margin ROE (accounting) ROE (market capitalization) Specialized orphan drug companies Large pharmaceutical companies Medium-sized pharmaceutical companies Small pharmaceutical companies Biotechnology companies There is a common perception that companies that focus on drugs for rare diseases — orphan drugs — offer opportunities for greater returns on investment compared to other companies, owing to factors such as the higher pricing, financial incentives, accelerated regulatory filings and smaller sales force requirements for orphan drugs. Here, we analyse whether the evidence supports this perception by comparing 5 years of historical financial data (from 2007 to 2011) from specialized orphan drug companies with data from other companies that focus most of their research and development (R&D) efforts on drugs for non-rare diseases. Our data set included 33 publicly listed companies, divided into five baskets of six to seven companies in the following groups: specialized orphan drug companies, large, medium-sized or small pharmaceutical companies, and biotechnology companies (FIG. 1; see Supplementary information S1 (box) for details of the data set and methodology). The average gross margin of our sample of orphan drug companies was 11 percentage points higher than that of non-orphan drug companies across all categories considered (85.9% versus 74.8%; FIG. 1). This higher gross margin for orphan drug companies results from the relatively higher pricing and market exclusivity associated with their products. We believe that the perception of the financial success of orphan drug companies mainly derives from this financial indicator. However, taking into account the commitment to R&D by these groups of companies reveals a contrasting perspective. R&D investment as a percentage of sales in our sample of orphan drug companies was on average twice as high as that of companies in the other groups, accounting for 33.9% versus 17.3% of sales, respectively (FIG. 1). As a consequence of higher R&D costs, the operating profitability of orphan drug companies (as measured by the EBITDA margin: earnings before interest, tax, M A R K E T WAT C H

Measuring what matters to rare disease patients – reflections on the work by the IRDiRC taskforce on patient-centered outcome measures

Our ability to evaluate outcomes which genuinely reflect patients’ unmet needs, hopes and concerns is of pivotal importance. However, much current clinical research and practice falls short of this objective by selecting outcome measures which do not capture patient value to the fullest. In this Opinion, we discuss Patient-Centered Outcomes Measures (PCOMs), which have the potential to systematically incorporate patient perspectives to measure those outcomes that matter most to patients. We argue for greater multi-stakeholder collaboration to develop PCOMs, with rare disease patients and families at the center. Beyond advancing the science of patient input, PCOMs are powerful tools to translate care or observed treatment benefit into an ‘interpretable’ measure of patient benefit, and thereby help demonstrate clinical effectiveness. We propose mixed methods psychometric research as the best route to deliver fit-for-purpose PCOMs in rare diseases, as this methodology brings together qualitative and quantitative research methods in tandem with the explicit aim to efficiently utilise data from small samples. And, whether one opts to develop a brand-new PCOM or to select or adapt an existing outcome measure for use in a rare disease, the anchors remain the same: patients, their daily experience of the rare disease, their preferences, core concepts and values. Ultimately, existing value frameworks, registries, and outcomes-based contracts largely fall short of consistently measuring the full range of outcomes that matter to patients. We argue that greater use of PCOMs in rare diseases would enable a fast track to Patient-Centered Care.

Challenges in Research and Health Technology Assessment of Rare Disease Technologies: Report of the ISPOR Rare Disease Special Interest Group

BACKGROUND Successful development of new treatments for rare diseases (RDs) and their sustainable patient access require overcoming a series of challenges related to research and health technology assessment (HTA). These impediments, which may be unique to RDs or also apply to common diseases but are particularly pertinent in RDs, are diverse and interrelated. OBJECTIVE To develop for the first time a catalog of primary impediments to RD research and HTA, and to describe the cause and effect of individual challenges. METHODS Challenges were identified by an international 22-person expert working group and qualitative outreach to colleagues with relevant expertise. A broad range of stakeholder perspectives is represented. Draft results were presented at annual European and North American International Society for Pharmacoeconomics and Outcomes Research (ISPOR) congresses, and written comments were received by the 385-strong ISPOR Rare Disease Review Group from two rounds of review. Findings were refined and confirmed via targeted literature search. RESULTS Research-related challenges linked to the low prevalence of RDs were categorized into those pertaining to disease recognition and diagnosis, evaluation of treatment effect, and patient recruitment for clinical research. HTA-related challenges were classified into issues relating to the lack of a tailored HTA method for RD treatments and uncertainty for HTA agencies and health care payers. CONCLUSIONS Identifying and highlighting diverse, but interrelated, key challenges in RD research and HTA is an essential first step toward developing implementable and sustainable solutions. A collaborative multistakeholder effort is required to enable faster and less costly development of safe, efficacious, and appropriate new RD therapies that offer value for money.

Are products with an orphan designation for oncology indications different from products for other rare indications? A retrospective analysis of European orphan designations granted between 2002-2012

BackgroundOrphan designated medicinal products benefit from regulatory and economic incentives for orphan drug development. Approximately 40% of orphan designations target rare neoplastic disorders, referring to rare cancers. In order to provide more insights in drugs for rare neoplastic disorders that are under development and to better understand the role of orphan designation in the development of oncology drugs, this study investigates the characteristics of the product, the indication and the applicants as well as the stage of development of products with an orphan designation for rare neoplastic disorders and compares them with products with an orphan designation for other rare indications. Therefore, orphan designation application files and annual reports submitted by the applicant were reviewed at the premises of the European Medicines Agency.ResultsAt the time of application, 41.6% of products with orphan designation for rare neoplastic disorders were in pre-clinical phase; this was 65.1% for other rare conditions (p < 0.05). Thirty percent of orphan designations for rare neoplastic disorders had reached phase 1; compared to 19.3% of orphan designations targeting other rare conditions (p < 0.05). The same trend was observed for the stage of development at the time of the latest annual report. Significant benefit was more often considered for orphan designations for rare neoplastic disorders compared to orphan designations for other rare conditions.ConclusionOrphan designations for rare neoplastic disorders involve products that are in a more advanced stages of development compared to orphan designations for other (non-oncology) rare conditions.