Development and validation of COMPASS: clinical evidence of orphan medicinal products – an assessment tool

BACKGROUND: Rare diseases are defined as life-threatening or chronically debilitating diseases with a prevalence of 50 out of 100,000 individuals or less. Orphan medicinal products (OMPs) are intended for the treatment of rare diseases. The assessment of quality of evidence in small populations is often complex. Many generic tools are unfit. Therefore, the aim of this study was to develop and validate a new tool to assess the quality of OMPs' clinical evidence (COMPASS). METHODS: Firstly, a draft version of the COMPASS tool, developed by the authors and consisting of three parts, was amended based on suggestions obtained in four rounds of expert consultation. Secondly, the tool was put through three rounds of validation. The data source was information provided on the Orphanet website and in European Public Assessment Report (EPAR) document of the European Medicines Agency. RESULTS: The first pilot round revealed a high (92.2%) inter-rater agreement for part one of the tool. After further improvements, the final inter-rater agreement was 86.4% for part two (on methodological quality) and three (on quality of reporting) of the tool. The COMPASS tool does not attempt to score or rank the quality of clinical evidence, but rather to give an outline of various, key elements with respect to quality of clinical evidence of OMP studies. CONCLUSIONS: The COMPASS tool can be applied to assess the quality of evidence of an OMP based on information in the registration dossier, for example by local reimbursement agencies, pharmacists or clinicians. In that way, the tool can contribute to making reimbursement and/or treatment decisions increasingly more founded on the principles of evidence-based decision making.status: publishe

Congenital cutaneous fibropapillomatosis in a warmblood foal

In this report, clinical and histological findings of a rare case of a large congenital fibropapilloma on the forehead of a warmblood foal are reported. Surgical excision was curative and no recurrence was observed after nine months. The foal did not present any other abnormalities. Morphologically, the lesion was classified as a fibro-epithelial type of skin hamartoma. The fibrous component has thus far only been reported in pigs. Although fibropapillomas are common in adult animals and are associated with papillomavirus infection, this association has not been demonstrated in foals and piglets. Additionally, there were no histopathological indications of papillomavirus infection in the present study, nor could PCR reveal the presence of papillomavirus DNA

Analysis of market access of orphan drugs for rare diseases

This project carries out an analysis of market access of orphan drugs for rare diseases. In the European Union (EU), orphan drugs are intended for the diagnosis, prevention or treatment of rare diseases. These rare diseases are life-threatening or chronically seriously debilitating conditions affecting no more than five in 10,000 persons in the EU. Worldwide, policies are available to stimulate the development and marketing of orphan drugs. Such policies serve to compensate industry for the risks and lower potential return on investment due to the low number of patients. Part 1 of this project, the general introduction, provides the definitions and background related to orphan drugs and rare diseases and presents an overview of the different steps of market access of orphan drugs in the EU. The contents of this project reflect these steps, i.e. orphandesignation and marketing authorization are discussed in part 2, pricing is discussed in part 3, reimbursement in part 4 and uptake in part 5. The general introduction also provides an overview of the arguments for and against attributing special status to orphan drugs. Studies on the registration of orphan drugs are reported in part 2. An evaluationof the orphan drug policies in the EU by orphan drug experts is provided in chapter 2.1. Experts perceive the orphan drug policies in the EU asuseful. Within the context of continuing to optimize patient access to orphan drugs, several policy recommendations were formulated such as defining the concept of sufficiently profitable in the context of reducing the period of market exclusivity for highly profitable orphan drugs, determining the level of clinical evidence needed to authorize orphan drugs, etc. Chapter 2.2 describes the development and validation of a new tool, COMPASS, to assess the quality of orphan drugs clinical evidence presented for orphan drugs at the time of marketing authorization.The tool was drawn up based on elements derived from existing checklists supplemented with items specifically related to rare diseases and orphan drugs as recommended by six experts. The COMPASS tool can for examplebe used by local reimbursement agencies for the review of clinical evidence in orphan drug registration dossiers or by clinicians and pharmacists upon considering a (new) orphan drug treatment. The COMPASS tool was used in chapter 2.3 to quantitatively evaluate the characteristicsand quality of pivotal studies presented for orphan drugs authorised inthe EU before July 1st, 2012. These studies were found to exhibit methodological flaws such as lack of blinding in the study design, lack of QoL-related endpoints as outcome, use of surrogate endpoints, etc. Additionally, there were important shortcomings in the reporting of those studies, which further complicates the interpretation of the clinical evidence. This study shows that a more demanding regulatory process for orphan drugs is needed. Studies on the pricing of orphan drugs are reported in part 3. The influence of orphan designation status on prices of drugs for rare indications is demonstrated in chapter 3.1. The analysis showed that the median price per defined daily dose was higher for drugs with an orphan designation ( 138.56) than for drugs without an orphan designation used for rare indications ( 16.55). Chapter 3.2 providesseveral examples of repurposed drugs for rare indications for which theeffectiveness evidence was published prior to the application for orphan designation status. Upon comparing Belgian hospital prices per defineddaily dose of selected drugs for common diseases with the price of repurposed drugs for the rare disease indication, differences of up to 200 fold were reported. This pricing practice adds to the budget impact of treating rare diseases. An overview of the international scientificliterature on the drivers of pricing of ultra-orphan drugs in describedin chapter 3.3. Ultra-rare diseases constitute an informal subcategory,within rare diseases, to describe very rare diseases (i.e. occurring inless than one per 50,000 individuals). The pricing process of ultra-orphan drugs is a complex and non-transparent issue. Evidence in the literature seems to indicate that ultra-orphan drugs are priced based on rarity of the indication and the number of available alternatives. Chapter 3.4 shows how various drug- and disease-specific variables relate toannual treatment costs per patient and per orphan drug indication in six EU Member States. Additionally, it was investigated if certain country-specific pricing and reimbursement policies affect the price level of orphan drugs. Repurposed 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. Current debate about the affordabilityof high-priced orphan drugs highlights the need for more transparency in orphan drug price setting. The topic of reimbursement of orphan drugs is discussed in part 4. Because of their high price and difficulties in demonstrating effectiveness, orphan drugs are often perceived as not able to provide value for money. In chapter 4.1 an overview of the evidence on the value for money of orphan drugs is given. Results show that orphan drugs can provide value for money. Considering a threshold of £30,000 per quality-adjusted life years (QALY) (i.e. threshold for reimbursement applied in England and Wales) ten out of a total of nineteen orphan drugs for which data was available, offer value for money. Factors other than cost-effectiveness are also taken into account at the time of reimbursement In chapter 4.2 qualitative research methods were applied to establish that various official (i.e. therapeutic value, budget impact, price and impact in clinical practice) and non-official (i.e. pricing and reimbursement in other countries, interference by patient organisations and experts, arguments related to quality of pharmaceutical compounding, media attention, innovative character, economic importance, ethical arguments and the political climate) factors might influence reimbursement decisions for orphan drugs in Belgium. The identification of these factors is crucial in the development of a transparent and consistent framework which will guide future decision-making for reimbursement of orphan drugs. A study on the uptake of orphan drugs is reported in part 5. Chapter 5.1 shows that the uptake of orphan drugs varies across EU Member States. The highest volumes of orphan drugs in the first year occurred in Member States with a high gross domestic product (GDP) and implicitly, a higher budget for health care, independently of the existence of a formal health technology assessment (HTA) organisation. In contrast, in countries with a low GDP, orphan drugs were less available incountries with a formal HTA-organisation. There, budgetary restrictionscan cause the exclusion of less cost-effective orphan drugs. These variations have important implications with respect to access to orphan drugs. Recommendations for a sustainable orphan drug market are proposed in the general discussion in part 6. These recommendations relate toone (or more) of the steps of market access. Several recommendations toimprove quality of clinical evidence (for instance by setting trial standards imposing the use of at least one hard endpoint) are formulated. Furthermore, to capture what is valued by patients, patient(s) (organizations) should be able to provide input in an early stage on what endpoints should be considered when developing a new drug for a rare disease. Development of new orphan drugs can be improved by adopting a public-private partnership approach for orphan drug development. Patient registries are an important tool to gather knowledge about the natural course of a rare disease and/or the long-term effectiveness of an orphan drug. Long-term data is required for marketing authorization and to guide reimbursement decisions. Recommendations relating to pricing of orphan drugs include measures to increase transparency in orphan drug pricing, a proposalto prescribe repurposed orphan drugs by international non-proprietary name and a call to revise orphan drug status of sufficiently profitable orphan drugs. Timely access to new orphan drugs can be achieved by implementing managed entry agreements to deal with the uncertainty about cost-effectiveness and by optimizing reimbursement procedures for orphan drugs across EU Member States. Finally, there is a need to define prioritiesin funding and reimbursement of orphan drugs. Upcoming challenges for the orphan drug pharmaceutical industry are also discussed. For instance,adaptive licensing is expected to reduce the overall cost of development and to have a positive effect on timely access to new drugs. Future research could focus on pricing and budget impact orphan drugs, an issue of continued importance in the aftermath of the financial and economic crisis.status: publishe

What is known about the cost-effectiveness of orphan drugs? Evidence from cost-utility analyses

In times of financial and economic hardship, governments are looking to contain pharmaceutical expenditure by focusing on cost-effective drugs. Because of their high prices and difficulties in demonstrating effectiveness in small patient populations, orphan drugs are often perceived as not able to meet traditional reimbursement threshold value for money. The aim of this study was to provide an overview of the available evidence on the cost-effectiveness of orphan drugs.status: publishe

Shining a light in the black box of orphan drug pricing

The 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.status: publishe

Clinical evidence for orphan medicinal products - a cause for concern?

BACKGROUND: The difficulties associated with organising clinical studies for orphan medicinal products (OMPs) are plentiful. Recent debate on the long-term effectiveness of some OMPs, led us to question whether the initial standards for clinical evidence for OMPs, set by the European Medicines Agency (EMA) at the time of marketing authorization, are too low. Therefore, the aim of this study was to quantitatively evaluate the characteristics and quality of clinical evidence that is presented for OMPs to obtain marketing authorization in Europe, using the new and validated COMPASS tool. METHODS: We quantitatively assessed the characteristics and quality of clinical evidence of the pivotal studies of 64 OMPs as described in the European Public Assessment Report and/or the Scientific Discussion document prepared by the Committee for Human Medicinal Products of the EMA. RESULTS: The 64 OMPs were altogether authorized for 78 orphan indications, for which 117 studies were identified as 'pivotal' or 'main' studies. In approximately two thirds of the studies, the allocation was randomized (64.8%) and a control arm was used (68.5%). Half of the studies applied some type of blinding. Only a minority (26.9%) of the studies included a Quality-of-Life (QoL) related endpoint, of which a third claim an improvement in QoL. Upon analyzing the quality of reporting, we found that some aspects (i.e. the endpoints, the sampling criteria, and the interventions) are well described, whereas other items (i.e. a description of the patients and of potential biases) are not reported for all studies. CONCLUSIONS: In conclusion, the pivotal studies that are the basis for marketing authorization of OMPs are a cause for concern, as they exhibit methodological flaws i.e. the lack of QoL-related endpoints as outcome, lack of blinding in the study design and the use of surrogate endpoints. Additionally, there are shortcomings in the reporting of those studies that complicate the interpretation. A more demanding regulatory process for OMPs is needed to guide evidence-based clinical decision-making.status: publishe

Clinical evidence for orphan medicinal products-a cause for concern?

The difficulties associated with organising clinical studies for orphan medicinal products (OMPs) are plentiful. Recent debate on the long-term effectiveness of some OMPs, led us to question whether the initial standards for clinical evidence for OMPs, set by the European Medicines Agency (EMA) at the time of marketing authorization, are too low. Therefore, the aim of this study was to quantitatively evaluate the characteristics and quality of clinical evidence that is presented for OMPs to obtain marketing authorization in Europe, using the new and validated COMPASS tool. We quantitatively assessed the characteristics and quality of clinical evidence of the pivotal studies of 64 OMPs as described in the European Public Assessment Report and/or the Scientific Discussion document prepared by the Committee for Human Medicinal Products of the EMA. The 64 OMPs were altogether authorized for 78 orphan indications, for which 117 studies were identified as 'pivotal' or 'main' studies. In approximately two thirds of the studies, the allocation was randomized (64.8%) and a control arm was used (68.5%). Half of the studies applied some type of blinding. Only a minority (26.9%) of the studies included a Quality-of-Life (QoL) related endpoint, of which a third claim an improvement in QoL. Upon analyzing the quality of reporting, we found that some aspects (i.e. the endpoints, the sampling criteria, and the interventions) are well described, whereas other items (i.e. a description of the patients and of potential biases) are not reported for all studies. In conclusion, the pivotal studies that are the basis for marketing authorization of OMPs are a cause for concern, as they exhibit methodological flaws i.e. the lack of QoL-related endpoints as outcome, lack of blinding in the study design and the use of surrogate endpoints. Additionally, there are shortcomings in the reporting of those studies that complicate the interpretation. A more demanding regulatory process for OMPs is needed to guide evidence-based clinical decision-makin

The orphan drug pipeline in Europe

status: publishe