Standardized Data Structures in Rare Diseases: CDISC User Guides for Duchenne Muscular Dystrophy and Huntington's Disease.

Interest in drug development for rare diseases has expanded dramatically since the Orphan Drug Act was passed in 1983, with 40% of new drug approvals in 2019 targeting orphan indications. However, limited quantitative understanding of natural history and disease progression hinders progress and increases the risks associated with rare disease drug development. Use of international data standards can assist in data harmonization and enable data exchange, integration into larger datasets, and a quantitative understanding of disease natural history. The US Food and Drug Administration (FDA) requires the use of Clinical Data Interchange Consortium (CDISC) Standards in new drug submissions to help the agency efficiently and effectively receive, process, review, and archive submissions, as well as to help integrate data to answer research questions. Such databases have been at the core of biomarker qualification efforts and fit-for-purpose models endorsed by the regulators. We describe the development of CDISC therapeutic area user guides for Duchenne muscular dystrophy and Huntington's disease through Critical Path Institute consortia. These guides describe formalized data structures and controlled terminology to map and integrate data from different sources. This will result in increased standardization of data collection and allow integration and comparison of data from multiple studies. Integration of multiple data sets enables a quantitative understanding of disease progression, which can help overcome common challenges in clinical trial design in these and other rare diseases. Ultimately, clinical data standardization will lead to a faster path to regulatory approval of urgently needed new therapies for patients.

The implementation of health technology assessment principles in public decisions concerning orphan drugs.

PURPOSE: Over the last few years, the share of public spending for orphan drugs (ODs) has increased in several western countries, raising concern on the exemptions granted to this sector with respect to the implementation of health technology assessment (HTA) principles. The aim of this paper is to shed light on both the HTA criteria adopted and the international agreements implemented in the OD regulation, given the new challenges imposed on western countries by a growing number of therapies for rare diseases. METHODS: We carried out a literature review to analyse the development of the international debate on the adaptability of HTA criteria for the OD assessment and regulation. The time span lies between January 1990 and May 2018, and the policies considered relate to both market authorization and reimbursement decisions within western countries. We focus specifically on HTA criteria in some of the dimensions included in the Core Model of the European net for HTA (EUnetHTA). RESULTS: OD high prices, the absence of clarity on the possible high revenues realized by the distribution of a new OD outside the national borders, the risk that - once marketed - a new OD can be used to treat common diseases, are all issues that raise concern on OD regulation and have to be carefully monitored by policymakers in the next future. CONCLUSIONS: Across western countries, the preferential track granted to ODs in the implementation of HTA principles is not homogeneous, but fragmented and differentiated. The need for common rules at an international level is underlined, with a view to assessing the sustainability of a sector which, due to this regulatory void, can lend itself to producers' strategic and opportunistic behaviours.

Patient-Reported Outcomes in Orphan Drug Labels Approved by the US Food and Drug Administration.

OBJECTIVES: In recent years, there has been increasing recognition of the need to assess treatment benefit from the patient's perspective. The extent of patient-reported outcome (PRO) data included in labeling for rare disease treatment is largely unknown. The objective of this study was to review trends over time for PRO-based labeling granted by the US Food and Drug Administration (FDA) for orphan drugs. STUDY DESIGN: Review of FDA package inserts. METHODS: Products included in this analysis were all new molecular entities (NMEs) and biologic license applications (BLAs) with orphan designations approved by the FDA from 2002 through 2017. For identified products, package inserts were reviewed to determine the number and type of PRO claim(s) granted, endpoint status, and PRO measure named. Two trends were analyzed: (1) over all years 2002 to 2017 and (2) 2002 to 2017 stratified into 3 periods (before draft FDA PRO guidance [2006], between draft and final guidance release, and after final guidance [2009] release. RESULTS: A total of 156 NMEs and BLAs with orphan designations were approved between 2002 and 2017. Of these, 13 products (8.3%) had PRO-based labeling, and 7 of 13 were symptom-related. The percent of orphan drugs approved with PRO-based labeling between 2002 and 2005, 2006 and 2008, and 2009 and 2017 was 0, 10.5, and 9.9, respectively. CONCLUSIONS: In FDA-approved labeling for orphan therapies, PRO measures used as primary and secondary endpoints increased after draft FDA PRO guidance release but remained relatively low thereafter. It is important to understand barriers to PRO measure use to ensure that treatments capture perspectives of patients with rare diseases.

Evaluating Canadians' Values for Drug Coverage Decision Making.

BACKGROUND: Decision makers are facing growing challenges in prioritizing drugs for reimbursement because of soaring drug costs and increasing pressures on financial resources. In addition to cost and effectiveness, payers are using other values to dictate which drugs are prioritized for funding, yet there are limited data on the Canadian public's priorities. OBJECTIVES: To measure the relative societal importance of values considered most relevant in informing drug reimbursement decisions in a representative sample of Canadians. METHODS: An online survey of 2539 Canadians aged 19 years and older was performed in which 13 values used in drug funding prioritization were ranked and then weighted using an analytic hierarchy process. RESULTS: Canadians value safe and efficacious drugs that have certainty of evidence. The values ranked in the top 5 by most of our subjects were potential effect on quality of life (65.4%), severity of the disease (62.6%), ability of drug to work (61.1%), safety (60.5%), and potential to extend life (49.4%). Values related to patient or disease characteristics such as rarity, socioeconomic status, and health and lifestyle choices held the lowest rankings and weights. CONCLUSIONS: Canadians value, above all, treatment-related factors (eg, efficacy and safety) and disease-related factors (eg, severity and equity). Decision makers are currently using additional justifications to prioritize drugs for reimbursement, such as rarity and unmet need, which were not found to be highly valued by Canadians. Decision makers should integrate the public's values into a Canadian reimbursement framework for prioritization of drugs competing for limited funds.

Monitoring evidence on overall survival benefits of anticancer drugs approved by the European Medicines Agency between 2009 and 2015.

OBJECTIVE: The introduction provisional approval strategies increases the approval of anticancer drugs with ambiguous benefit-risk profiles. Thus, in many instances, there is lacking evidence about overall survival (OS) at the time of marketing authorisation. Our objective was to monitor and characterise therapies with ambiguous benefit-risk profiles and identify any postapproval updates on median OS after at least 3 years of approval by the European Medicines Agency (EMA). METHODS: We included all originator anticancer drugs with initially ambiguous benefit-risk profiles that received marketing authorisation by the EMA between January 1, 2009 and May 31, 2015. Our monitoring timeframe was at least 3 years after EMA approval. To identify study updates, the following three sources were included: clinicaltrials.gov, European Public Assessments Reports and PubMed. RESULTS: In total, we identified 102 eligible approval studies. Out of these, a negative difference in median OS or no information was available in 43 (42.2%) instances. During monitoring, 14 updates with accessible positive information on OS could be identified. Including monitoring results, there are still 29 remaining therapies (28.4%) where no or negative information (n = 24 [23.5%] and n = 5 [4.9%], respectively) regarding OS is present at least 3 years after EMA approval. CONCLUSION: One-third of oncology drugs with ambiguous benefit-risk profiles at the time of approval fail to demonstrate a survival benefit even after several years of marketing authorisation. Systematic and transparent postapproval monitoring mechanisms will be of high relevance to assure a clinically relevant patient benefit, since the trend towards faster access to medicines with uncertain benefit is increasing rather than declining.

EU decision-making for marketing authorization of advanced therapy medicinal products: a case study.

A comparative analysis of assessment procedures for authorization of all European Union (EU) applications for advanced therapy medicinal products (ATMPs) shows that negative opinions were associated with a lack of clinical efficacy and identified severe safety risks. Unmet medical need was often considered in positive opinions and outweighed scientific uncertainties. Numerous quality issues illustrate the difficulties in this domain for ATMP development. Altogether, it suggests that setting appropriate standards for ATMP authorization in Europe, similar to elsewhere, is a learning experience. The experimental characteristics of authorized ATMPs urge regulators, industry, and clinical practice to pay accurate attention to post-marketing risk management to limit patient risk. Methodologies for ATMP development and regulatory evaluations need to be continuously evaluated for the field to flourish.

Unlicensed pharmaceutical preparations for clinical patient care: Ensuring safety.

Most medicinal products dispensed to patients have marketing authorization (MA) to ensure high quality of the product, safety, and efficacy. However, in daily practice, to treat patients adequately, there is a medical need for drugs that do not hold MA. To meet this medical need, medicinal products are used in clinical care without MA (unlicensed), such as products prepared by (local) pharmacies: the pharmaceutical preparations. Three types of pharmaceutical preparations are distinguished: (i) reconstitution in excess of summary of product characteristics; (ii) adaptation of a licensed medicinal product (outside its official labeling); (iii) medicinal products from an active pharmaceutical ingredient. Although unlicensed, patients may expect the same quality for these unlicensed pharmaceutical preparations as for the licensed medicinal products. To assure this quality, a proper risk-benefit assessment and proper documentation in (centralized) patient registries and linking to a national pharmacovigilance database should be in place. Based on a risk assessment matrix, requirements for quality assurance can be determined, which has impact on the level of documentation of a pharmaceutical preparation. In this paper, the approach for good documentation including quality assurance and benefit-risk assessment will be discussed and possibilities for patient registries are described to make these crucial preparations available for regular patient care. KEY POINTS Ensuring pharmaceutical quality and performing a proper benefit-risk assessment will guarantee safe use of pharmaceutical preparations. Good documentation of (ultra-)orphan treatments can be collected in centralized patient registries and should be combined with existing information in (inter)national databases and self-reflection of patients. Linking patient registries to a centralized database for adverse drug events is highly recommended as it increases safety control of the (ultra) orphan pharmaceutical preparations.

HEALTH TECHNOLOGY ASSESSMENT IN EVALUATION OF PHARMACEUTICALS IN THE CZECH REPUBLIC.

OBJECTIVES: In the Czech Republic, the health technology assessment (HTA) approaches have been implemented in evaluation of medicinal products since 2008. The aim of this study was to provide an overview of the implementation of HTA and different levels thereof in the evaluation process conducted by the State Institute for Drug Control (SUKL) and to describe the impact of HTA on the entrance of new medicinal entities into out-patient healthcare system including highly innovative and orphan drugs. METHODS: Materials supporting this overview were collected using the records in the database of administrative proceedings of SUKL, in-house standard operating procedures, and the legislation in force. Based on these sources as well as the hands-on knowledge of the current practice, a brief description of the general rules of administrative proceedings involving HTA of varying complexity was elaborated. Characteristic features of the individual types of proceedings, basic differences in the complexity of HTA employed, and its most important challenges were summarized. RESULTS: In Czech Republic, HTA in the formal administrative proceedings ensures a transparent process of introduction of new medicinal products into clinical practice and leaves space for restriction of reimbursement conditions to minimize budget impact. CONCLUSIONS: As a robust as well as pragmatic HTA methodology has been implemented by SUKL, relevant stakeholders (marketing authorization holders, Health Care Funds, clinical expert groups) are now able to influence reimbursement of new technologies.

Affordable orphan drugs: a role for not-for-profit organizations.

AIMS: The success of the Regulation on Orphan Medicinal Products in the European Union is evidenced by the 127 orphan drugs that have had market authorization since 2000. However, the incentives aimed at stimulating research and development have had the unintended consequence of increasing drug cost, resulting in many orphan drugs not being cost-effective. Orphan drugs command an increasing share of the pharmaceutical market and account for a disproportionate amount of healthcare expenditure. Orphan drug ownership by socially motivated, not-for-profit organizations may facilitate access to more affordable orphan drugs, for the benefit of patients and healthcare systems alike. This study aims to describe opportunities for such organizations to become orphan drug Market Authorization Holders. METHODS: We reviewed data on the ownership of EMA designated and approved orphan drugs, identified funding opportunities and business models for not-for-profit organizations, and summarised relevant legal and policy documents concerning intellectual property rights and drug regulation. RESULTS: Using repurposed drugs as a paradigm, this narrative review navigates the regulatory hurdles, describes the legal context and identifies funding opportunities, in a bid to facilitate and encourage not-for-profit organizations to lead on the development of affordable orphan drugs. CONCLUSIONS: Although the regulatory steps required to obtain an MA for an orphan drug are numerous and challenging, they are not insurmountable and can be achieved by not-for-profit organizations that are socially motivated to reduce the costs of orphan drugs to the payers of healthcare. Opportunities for orphan drug development resulting in affordable products lie mainly with repurposed drugs.

Priorities for the Priority Review Voucher.

The U.S. Congress created the priority review voucher program in 2007 to encourage development of drugs for neglected diseases. Under the voucher program, the developer of a drug for a neglected or rare pediatric disease that is approved by the U.S. Food and Drug Administration receives a bonus priority review voucher for another drug. As of 2016, four vouchers have sold for an average price of $200 million. Recent experience with the voucher program indicates strengths and weaknesses of the program, as well as a need for legislative changes.

The Tropical Disease Priority Review Voucher: A Game-Changer for Tropical Disease Products.

The Neglected Tropical Disease Voucher Program is a Congressionally-mandated program intended to promote approval of products for tropical diseases because it provides spectacular financial compensation consequent to FDA approval of a priority product. Three drug approvals-artemether/lumifantrine for malaria, bedaquiline for multidrug resistant tuberculosis, miltefosine for leishmaniasis-have received Tropical Disease Vouchers to date. We give our view of the type of products that might qualify for a Tropical Disease Voucher, financial considerations in venturing capital to support product development, clinical ramifications of a successful product approval, and an overall evaluation of the Program.

Challenges and Opportunities in Rare Disease Drug Development.

Each month, Clinical Pharmacology & Therapeutics focuses on a particular theme. Twice a year, the associate editors, editors, and staff get together to discuss journal business and spend time setting up the calendar of themes. Often, there are no experts among us to take on a particular topic that we have chosen. The consequence is that one or two of us take on the theme and then have a crash course to learn as much as they can about it in order to solicit meaningful articles. This month's theme on rare diseases is such a case.

The correlation between HTA recommendations and reimbursement status of orphan drugs in Europe.

BACKGROUND: The aim of this study was to review and compare types of reimbursement recommendations for orphan drugs issued by eight European health technology assessment (HTA) agencies and the reimbursement status of these drugs in the corresponding countries. Separate calculations were also performed for three sub-groups: ultra-orphan drugs, oncology orphan drugs and other (non-ultra, non-oncology) orphan drugs. RESULTS: We reviewed drugs authorized by the European Medicine Agency (EMA) between 1 November 2002 and 30 September 2015. Among these, we identified 101 orphan drugs. Seventy-nine of them were assessed by eight European HTA agencies. The average rates of positive, conditional and negative reimbursement recommendations issued by these agencies were 55.7 %, 15.3 % and 29.0 %, respectively. On average, 21.2 % of EMA-authorized orphan drugs were reimbursed in the eight European countries studied: 49.0 % of those with positive, 53.6 % of those with conditional, and 16.0 % of those with negative reimbursement recommendations. In addition, 5.4 % of orphan drugs that had not been assessed by any of the eight HTA agencies were also reimbursed. The shares of oncology, ultra, and other orphan drugs that were assessed by HTA agencies were similar, with the lowest share observed in ultra-orphan drugs (72 %) and the highest in other orphan drugs (80 %). In terms of reimbursement, 20 % of oncology orphan drugs, 25 % of ultra-orphan drugs and 21 % of other orphan drugs were reimbursed. CONCLUSIONS: Reimbursement of orphan drugs does not always correspond to the type of HTA recommendation. While the highest rate of reimbursement is observed (unsurprisingly) among drugs with positive or conditional recommendation, a high rate of reimbursement (11 %) is also observed among ultra-orphan drugs that had never been assessed by any HTA agency.

A clinical pharmacology-regulatory perspective on the approval of drugs for rare diseases.

Orphan drugs or drugs for rare diseases represents a particular regulatory conundrum. There is a desperate need for effective therapies for these patients, who have been historically underserved by the drug development community. However, there is also a need to make sure these therapies are both safe and effective. In response, the US Food and Drug Administration (FDA) has evolved new approaches to facilitate drug development in this area.

Don't Do Different Things Do Things Differently! Drug Development in Rare Diseases.

Although definitions of rare disease vary, most acknowledge that there are small numbers of affected patients compared with other conditions. Small numbers of patients, overlapping involvement of investigators as researchers and caregivers, as well as close relationships between researchers and manufacturers require a different pattern of drug development. Regulatory guidances for rare diseases are available, as well as ones for specific rare diseases. Maintaining drug supply for rare diseases also demands innovative approaches.

Drugs Against Rare Diseases: Are The Regulatory Standards Higher?

The US Food and Drug Administration (FDA) recently issued a draft Guidance for Industry for Rare Diseases: Common Issues in Drug Development (referred to as "Rare Diseases Guidance"). In our opinion, the FDA should consider: (a) explicitly acknowledging the standards are higher for rare diseases for the reasons presented in this article; and (b) illustrating innovative development pathways that may be acceptable for rare diseases, including case studies.

Reimbursement of Drugs for Rare Diseases through the Public Healthcare System in Canada: Where Are We Now?

INTRODUCTION: Over the past 20 years, the number of therapies developed for rare diseases has rapidly increased. Often, these therapies represent the only active treatment for debilitating and/or life-threatening conditions. However, they create significant challenges for public and private payers. Because they target small patient populations, clinical evidence of efficacy/effectiveness is typically limited, while the cost per patient is high. In Canada, each province/territory establishes its own mechanisms for determining which drugs for rare diseases (DRDs) to provide. OBJECTIVES: To compare current mechanisms across provinces and territories, and explore their impact on access. METHODS: A systematic review of relevant published and unpublished documents was performed. Electronic bibliographic databases, the internet, and government websites were scanned using structured search strategies. Information was extracted independently by two researchers, and included aspects such as program type, condition/patient/therapy eligibility criteria, role of health technology assessment (HTA), decision options, ethical assumptions, and stakeholder input. It was validated through member-checking with provincial/territorial policy experts and tabulated to facilitate qualitative analyses. Impact on access was assessed through a cross-province/territory comparison of the coverage status of all non-cancer therapies reviewed by the Common Drug Review for indications affecting <1/2,000 Canadians using the Kappa statistic. Reasons for variations were explored using qualitative techniques. RESULTS: Each province/territory has formal and informal mechanisms through which such therapies may be accessed. In most cases, formal mechanisms constitute the centralized HTA processes that also apply to common therapies. While several provinces have established dedicated processes/programs, whether they have affected access is not clear. Despite broadly comparable approaches, there is less than perfect agreement on publicly funded DRDs across jurisdictions. CONCLUSIONS: Individual jurisdictions have developed different approaches to providing access to these therapies. However, as the number increases, a more systematic approach to decision-making may be needed.

[Medication: 15 years 'EU-directive orphan drugs']. / WEESGENEESMIDDELEN: 15 Jaren "EU-directive orphan drugs".

The article describes the compounding, dispensing and reimbursement of orphan drugs in Belgium 15 years after the implementation of the EU Directive on orphan drugs. Despite the fact that they are life-threatening and free of charge, patient compliance to oral orphan medication seems to be a major problem that needs to be handled by the dispensing pharmacist. Parenteral orphan medication needs to be compounded in the hospital pharmacy following strict guidelines concerning handling and storage. For ultra-rare disorders the medication needs to be compounded using sometimes chemical grade ingredients without any pharmaceutical monograph. Cost-effectiveness will always remain a subject for debate.