Development of medicines for rare diseases and inborn errors of metabolism: Toward novel public-private partnerships.

Medicine development for rare diseases, including inborn errors of metabolism (IEMs) is challenging. Many academic innovations fail to reach the patient, either by stranding in the translational stage or due to suboptimal patient access related to pricing or uncertain effectiveness. Expanding and solidifying the role of the academic in public-private partnerships (PPPs) may present an innovative solution to help overcome these complexities. This narrative review explores the literature on traditional and novel collaborative approaches to medicine development for rare diseases and analyzes examples of PPPs, with a specific focus on IEMs. Several academic institutions have introduced guidelines for socially responsible licensing of innovations for private development. The PPP model offers a more integrative approach toward academic involvement of medicine development. By sharing risks and rewards, failures in the translational stage can be mutually absorbed. If socially responsible terms are not included, however, high pricing can impede patient access. Therefore, we propose a framework for socially responsible PPPs aimed at medicine development for metabolic disorders. This socially responsible PPP framework could stimulate successful and accessible medicine development for IEMs as well as other rare diseases if the establishment of such collaborations includes terms securing joint data ownership and evidence generation, fast access, and socially responsible pricing.

Effectiveness and safety of mexiletine in patients at risk for (recurrent) ventricular arrhythmias: a systematic review.

AIMS: While mexiletine has been used for over 40 years for prevention of (recurrent) ventricular arrhythmias and for myotonia, patient access has recently been critically endangered. Here we aim to demonstrate the effectiveness and safety of mexiletine in the treatment of patients with (recurrent) ventricular arrhythmias, emphasizing the absolute necessity of its accessibility. METHODS AND RESULTS: Studies were included in this systematic review (PROSPERO, CRD42020213434) if the efficacy or safety of mexiletine in any dose was evaluated in patients at risk for (recurrent) ventricular arrhythmias with or without comparison with alternative treatments (e.g. placebo). A systematic search was performed in Ovid MEDLINE, Embase, and in the clinical trial registry databases ClinicalTrials.gov and ICTRP. Risk of bias were assessed and tailored to the different study designs. Large heterogeneity in study designs and outcome measures prompted a narrative synthesis approach. In total, 221 studies were included reporting on 8970 patients treated with mexiletine. Age ranged from 0 to 88 years. A decrease in ventricular arrhythmias of >50% was observed in 72% of the studies for pre-mature ventricular complexes, 64% for ventricular tachycardia, and 33% for ventricular fibrillation. Electrocardiographic effects of mexiletine were small; only in a subset of patients with primary arrhythmia syndromes, a relative (desired) QTc decrease was reproducibly observed. As for adverse events, gastrointestinal complaints were most frequently observed (33% of the patients). CONCLUSIONS: In this systematic review, we present all the currently available knowledge of mexiletine in patients at risk for (recurrent) ventricular arrhythmias and show that mexiletine is both effective and safe.

Cost-Based Price Calculation of Mexiletine for Nondystrophic Myotonia.

OBJECTIVES: Mexiletine is a long-known drug used for the treatment of arrhythmias and repurposed in the 1980s for patients with nondystrophic myotonia (NDM). Recently, the price of mexiletine in Europe increased significantly after registration as an orphan drug for NDM. This led to international discussions on affordability and willingness to reimburse mexiletine in the absence of background information that would justify such a price. Our objective was to calculate a cost-based price for mexiletine for adult patients with NDM based on detailed information on development costs. METHODS: We calculated a fair price based on a cost-based pricing model for commercial mexiletine to treat adults with NDM using a recent European drug-pricing model as a framework to include actual costs incurred. Three scenarios were applied: 1 with minimum estimated costs, 1 with maximum estimated costs, and 1 with costs as if mexiletine was innovative. RESULTS: The calculated fair price of mexiletine per patient per year (PPPY) is €452 for the minimum scenario and €1996 for the maximum scenario. By using hypothetical R&D costs used for innovative drugs, the price would be €6685 PPPY. In Europe, the list price of mexiletine ranges from €30 707-60 730 PPPY, based on 600 mg daily. CONCLUSIONS: The current list price for mexiletine in Europe is manifold higher than any scenario of the cost-based models. Accounting for the reduced costs for clinical development in a repurposing scenario, the cost-based pricing model provides a fair commercial price range, which can be used as benchmark for pricing negotiations and/or reimbursement decisions.

[Medicine compounding in the pharmacy]. / Bereiding van geneesmiddelen in de apotheek.

Pharmacy compounding of medicines is an essential part of patient care as it enables pharmacists to provide customized pharmaceutical care when no suitable commercial medicine is available. A distinction is made between individual preparations (on prescription for one patient) and stock preparations (for larger groups). Pharmacy compounded medicines can be of added value when specific pharmaceutical care is required, a commercial medicine is unavailable, or for use in clinical scientific research. A number of preconditions require attention to preserve pharmacy compounding in the future. Pharmacists should share technical knowledge on raw materials and pharmacy compounding more, and it is important that medicine development is retained as a basic skill in the education programme. Rational pharmacy compounded medicines should be eligible for reimbursement, taking room for innovation and research in consideration when determining tariffs. This is essential to ensure responsible implementation of pharmacy compounded medicines to improve healthcare availability and affordability.

Access to medicines for rare diseases: A European regulatory roadmap for academia.

Background: Novel or repurposed medicines for rare diseases often emerge from fundamental research or empirical findings in academia. However, researchers may be insufficiently aware of the possibilities and requirements to bring novel medicinal treatment options to the patient. This paper aims to provide an easily applicable, comprehensive roadmap designed for academic researchers to make medicines for rare diseases available for patients by addressing the relevant regulatory frameworks, including marketing authorization and alternative routes. Methods: Key points of the regulatory chapters "Placing on the Market" and "Scope" of Directive 2001/83/EC relating to medicinal products for human use were summarized. Provisions in EU directives regarding blood products, radiopharmaceuticals, and herbal and homeopathic medicinal products were excluded. Cross-referencing to other provisions was included. European case-law was retrieved from the InfoCuria database to exemplify the implications of alternative routes. Results: Medicines may only be placed on the market with a valid marketing authorization. To obtain such authorization in Europe, a "Common Technical Document" comprising reports on quality and non-clinical and clinical studies must be submitted to a "competent authority", a national medicine agency or the European Medicines Agency. Timely interaction of academic researchers with regulators via scientific advice may lead to better regulatory alignment and subsequently a higher chance for approval of academic inventions. Furthermore, reimbursement by national payers could be essential to ensure patient access. Apart from the marketing authorization route, we identified multiple alternative routes to provide (early) access. These include off-label use, named-patient basis, compassionate use, pharmacy compounding, and hospital exemption for Advanced Therapy Medicinal Products. Discussion: Aligning academic (non-)clinical studies on rare diseases with regulatory and reimbursement requirements may facilitate fast and affordable access. Several alternative routes exist to provide (early) pharmaceutical care at a national level, but case-law demonstrates that alternative routes should be interpreted strictly and for exceptional situations only. Academics should be aware of these routes and their requirements to improve access to medicines for rare diseases.

Modified Delphi procedure-based expert consensus on endpoints for an international disease registry for Metachromatic Leukodystrophy: The European Metachromatic Leukodystrophy initiative (MLDi).

BACKGROUND: Metachromatic Leukodystrophy (MLD) is a rare lysosomal disorder. Patients suffer from relentless neurological deterioration leading to premature death. Recently, new treatment modalities, including gene therapy and enzyme replacement therapy, have been developed. Those advances increase the need for high-quality research infrastructure to adequately compare treatments, execute post-marketing surveillance, and perform health technology assessments (HTA). To facilitate this, a group of MLD experts started the MLD initiative (MLDi) and initiated an academia-led European MLD registry: the MLDi. An expert-based consensus procedure, namely a modified Delphi procedure, was used to determine the data elements required to answer academic, regulatory, and HTA research questions. RESULTS: Three distinct sets of data elements were defined by the 13-member expert panel. The minimal set (n = 13) contained demographics and basic disease characteristics. The core set (n = 55) included functional status scores in terms of motor, manual, speech and eating abilities, and causal and supportive treatment characteristics. Health-related quality of life scores were included that were also deemed necessary for HTA. The optional set (n = 31) contained additional clinical aspects, such as findings at neurological examination, detailed motor function, presence of peripheral neuropathy, gall bladder involvement and micturition. CONCLUSION: Using a modified Delphi procedure with physicians from the main expert centers, consensus was reached on a core set of data that can be collected retrospectively and prospectively. With this consensus-based approach, an important step towards harmonization was made. This unique dataset will support knowledge about the disease and facilitate regulatory requirements related to the launch of new treatments.

Drug Repurposing for Rare Diseases: A Role for Academia.

Background: The European Commission highlights in its Pharmaceutical Strategy the role of academic researchers in drug repurposing, especially in the development of orphan medicinal products (OMPs). This study summarizes the contribution of academia over the last 5 years to registered repurposed OMPs and describes barriers to success, based upon three real world cases. Methods: OMPs granted marketing authorization between January 2016 and December 2020 were reviewed for repurposing and whether the idea originated from academia or industry. Three cases of drug repurposing were selected from different therapeutic areas and stages of development to identify obstacles to success. Results: Thirteen of the 68 OMPs were the result of drug repurposing. In three OMPs, there were two developments such as both a new indication and a modified application. In total, twelve developments originated from academia and four from industry. The three cases showed as barriers to success: lack of outlook for sufficient return of investments (abatacept), lack of regulatory alignment and timing of interaction between healthcare professionals and regulators (etidronate), failure to register an old drug for a fair price, resulting in commercialization as a high priced orphan drug (mexiletine). Conclusion: While the majority of repurposed OMPs originates in academia, a gap exists between healthcare professionals, regulators and industry. Future strategies should aim to overcome these hurdles leading to more patient benefit through sustainable access of repurposed drugs. Potential solutions include improved regulatory and reimbursement knowledge by academia and the right for regulators to integrate new effectiveness data into product labels.

[The assessment of the price of a medicine: not only on the basis of the value for the patient]. / Beoordeling van de prijs van een geneesmiddel.

Before admission to the insured package, the price of a medicine is usually assessed on the basis of the value of the medicine for the patient: a large effect size on health and survival may cost more than a small or uncertain effect. That seems like a fair starting point, but such 'value-driven' models sometimes lead to unreasonably high prices. This in turn leads to discussions about limitations within the healthcare budget and to delays in the accessibility of medicines. We argue that it would be more logical for different categories of medicines to base prices on average costs, possibly combined with a bonus for innovation: the so-called cost-plus method.

Registries for orphan drugs: generating evidence or marketing tools?

Independent disease registries for pre-and post-approval of novel treatments for rare diseases are increasingly important for healthcare professionals, patients, regulators and the pharmaceutical industry. Current registries for rare diseases to evaluate orphan drugs are mainly set up and owned by the pharmaceutical industry which leads to unacceptable conflicts of interest. To ensure independence from commercial interests, disease registries should be set up and maintained by healthcare professionals and patients. Public funding should be directed towards an early establishment of international registries for orphan diseases, ideally well before novel treatments are introduced. Regulatory bodies should insist on the use of data from independent disease registries rather than company driven, drug-oriented registries.