Lessons learned from the RE(ACT) conference on medical devices for rare diseases.

The field of rare disease therapeutics has witnessed significant growth in recent years, highlighting the need for diverse therapeutic approaches to cater to the unique needs of individuals with rare diseases. Rare disease therapies encompass a broad spectrum of interventions, including orphan medicinal products, orphan medical devices, rehabilitative therapies, and digital therapeutics, with the lines between these categories blurring. This paper covers the session of the RE (ACT)-IRDiRC Conference 2023 and delves into the landscape of orphan medical device research and development, shedding light on the challenges and opportunities in this burgeoning field. It provides a short overview of the different international legislations in the field. In addition, it highlights several exemplary orphan medical devices. The first example is an exoskeleton for boys with Duchenne Muscular Dystrophy, enabling them to maintain arm functionality and independence. Another example presented was an EEG device linked to an app detecting seizures in rare epilepsy conditions, which alerts caregivers to seizures in real-time but also facilitates objective seizure reporting for clinicians, aiding in diagnosis and treatment optimization. It also showcases the role of gamification and enabling technologies in addressing rare diseases, by showing a game designed for children with cystic fibrosis, and a telemedicine system for rehabilitation therapy. Both solutions aim to improve patients' understanding of their conditions and enhance their self-management. In conclusion, this paper underscores the critical need for patient-centric orphan and pediatric medical devices to provide therapeutic options for individuals with rare diseases. It highlights the impact of existing devices on enhancing the quality of life for rare disease patients and emphasizes the necessity for greater incentives and support for research and development in this field.

Orphan and paediatric medical devices in Europe: recommendations to support their availability for on-label and off-label clinical indications.

INTRODUCTION: The Medical Device Regulation (EU)745/2017, increased the regulatory requirements and thus the time and the cost associated with marketing medical devices. For a majority of medical device manufacturers, this has lead to reconsiderations of their product portfolio. The risk of important or essential devices being withdrawn is particularly relevant for pediatric patients and other rare disease patients where limited numbers of devices can be sold and hence the investment needed may not be recovered. This generates critical challenges and opportunities from a regulatory and public health perspective. AREAS COVERED: This paper is based upon the experience of the authors who contributed to working groups, guidance development and research related to orphan and pediatric devices. We examine the use of medical devices in orphan and pediatric conditions, the relevant aspects of regulations and associated guidance, and we suggest possible policy and practice interventions to ensure the continued availability of essential devices for children and people with rare diseases. EXPERT OPINION: We recommend a more proactive approach to identifying devices at risk and essential devices, increasing the use of exceptional market approvals, expanding the role of expert panels, engaging with the rare disease communities and supporting registries and standards.

Global health for rare diseases through primary care.

Rare diseases affect over 300 million people worldwide and are gaining recognition as a global health priority. Their inclusion in the UN Sustainable Development Goals, the UN Resolution on Addressing the Challenges of Persons Living with a Rare Disease, and the anticipated WHO Global Network for Rare Diseases and WHO Resolution on Rare Diseases, which is yet to be announced, emphasise their significance. People with rare diseases often face unmet health needs, including access to screening, diagnosis, therapy, and comprehensive health care. These challenges highlight the need for awareness and targeted interventions, including comprehensive education, especially in primary care. The majority of rare disease research, clinical services, and health systems are addressed with specialist care. WHO Member States have committed to focusing on primary health care in both universal health coverage and health-related Sustainable Development Goals. Recognising this opportunity, the International Rare Diseases Research Consortium (IRDiRC) assembled a global, multistakeholder task force to identify key barriers and opportunities for empowering primary health-care providers in addressing rare disease challenges.

Targeting shared molecular etiologies to accelerate drug development for rare diseases.

Rare diseases affect over 400 million people worldwide and less than 5% of rare diseases have an approved treatment. Fortunately, the number of underlying disease etiologies is far less than the number of diseases, because many rare diseases share a common molecular etiology. Moreover, many of these shared molecular etiologies are therapeutically actionable. Grouping rare disease patients for clinical trials based on the underlying molecular etiology, rather than the traditional, symptom-based definition of disease, has the potential to greatly increase the number of patients gaining access to clinical trials. Basket clinical trials based on a shared molecular drug target have become common in the field of oncology and have been accepted by regulatory agencies as a basis for drug approvals. Implementation of basket clinical trials in the field of rare diseases is seen by multiple stakeholders-patients, researchers, clinicians, industry, regulators, and funders-as a solution to accelerate the identification of new therapies and address patient's unmet needs.

A fair share for the orphans: ethical guidelines for a fair distribution of resources within the bounds of the 10-year-old European Orphan Drug Regulation.

For a significant number of patients, there exists no, or only little, interest in developing a treatment for their disease or condition. Especially with regard to rare diseases, the lack of commercial interest in drug development is a burning issue. Several interventions have been made in the regulatory field in order to address the commercial disinterest in these conditions. However, existing regulations mainly focus on the provision of incentives to the sponsors of clinical trials of orphan drugs, and leave unanswered the overarching question about the rightful place of orphan drugs in resource allocation systems. In this article, we analyse the ethical aspects of funding research and development in the field of rare diseases. We then propose an ethical framework that can help health policy makers move forward in the difficult matter of fairly allocating resources for the prevention, diagnosis and treatment of rare diseases.

Orphan Drugs, Compounded Medication and Pharmaceutical Commons.

Regulatory agencies installed orphan drug regulations to stimulate research and development of new innovative treatments for life-threatening diseases with a low prevalence (rare diseases). We established a list of well-known food-related ingredients with clinical evidence for rare diseases in the open medical literature that obtained marketing authorization as an expensive "orphan drug", protected by intellectual property (IP) rights. We show that these ingredients are part of an established practice of medicinal compounding-a form of point of care manufacturing. We argue that these ingredients should be considered as "pharmaceutical commons", and that regulatory incentives for private companies and market protection mechanisms such as IP rights are not justified in this case.

Orphan Medicine Incentives: How to Address the Unmet Needs of Rare Disease Patients by Optimizing the European Orphan Medicinal Product Landscape Guiding Principles and Policy Proposals by the European Expert Group for Orphan Drug Incentives (OD Expert Group).

Today policy makers face the challenge to devise a policy framework that improves orphan medicinal product (OMP) development by creating incentives to deliver treatments where there are none and to authorize innovative and transformative treatments where treatments already exist. The European Expert Group on Orphan Drug Incentives (hereafter, OD Expert Group) came together in 2020 to develop policy proposals to facilitate EU policy makers to meet this challenge. The group brings together representatives of the broad rare disease community, including researchers, academia, patient representatives, members of the investor community, rare disease companies and trade associations. The group's work builds on the recognition that only an ambitious policy agenda developed in a multi-stakeholder setting can bring about the quantum leap needed to address unmet needs of rare disease patients today. Along the OMP development path, the OD Expert Group has identified four main needs that a policy revision should address: 1) Need to improve the R&D ecosystem for basic research and company take-up of development. 2) Need to improve the system of financial incentives and rewards. 3) Need to improve the flexibility, predictability and speed of the regulatory pathway. 4) Need to improve the coherence and predictability of demand and pricing for OMPs. This article presents the results of the OD Expert Group work as a set of guiding principles that the revision of the policy framework should follow and a set of 14 policy proposals that address the main needs of OMP development in Europe today.

Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders.

Rare diseases are life-threatening or chronically debilitating low-prevalent disorders caused by pathogenic mutations or particular environmental insults. Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Since new drug discovery is a very costly and time-consuming process, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high cost of investments compared to the low market return of the product. Drug repurposing-based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases. In this article, we discuss the scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington's disease, Friedreich's ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis. The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation will also be discussed.

A Comparative Analysis of Pricing and Reimbursement of Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Europe.

Objectives: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, Kalydeco® (ivacaftor), Orkambi® (lumacaftor/ivacaftor) and Symkevi® (tezacaftor/ivacaftor), have substantially improved patients' lives yet significantly burden healthcare budgets. This analysis aims to compare pricing and reimbursement of aforementioned cystic fibrosis medicines, across European countries. Methods: Clinical trial registries, national databases, health technology assessment reports and grey literature of Austria, Belgium, Denmark, France, Germany, Ireland, Poland, Spain, Sweden, Switzerland, Netherlands, the United Kingdom were consulted. Publicly available prices, reimbursement statuses, economic evaluations, budget impact analyses and managed entry agreements of CFTR modulators were examined. Results: In Belgium, lowest list prices were observed for Kalydeco® (ivacaftor) and Symkevi® (tezacaftor/ivacaftor) at €417 per defined daily dose (DDD) and €372 per average daily dose (ADD), respectively. Whereas, Switzerland had the lowest price for Orkambi® (lumacaftor/ivacaftor) listed at €309 per DDD. Spain had the highest prices for Kalydeco® (ivacaftor) and Symkevi® (tezacaftor/ivacaftor) at €850 per DDD and €761 per ADD, whereas Orkambi® (lumacaftor/ivacaftor) was most expensive in Poland at €983 per DDD. However, list prices were subject to confidential discounts and likely varied from actual costs. In all countries, these treatments were deemed not to be cost-effective. The annual budget impact of the CFTR modulators varied between countries and depended on factors such as local product prices, size of target population, scope of costs and discounting. However, all modulators were fully reimbursed in ten of the evaluated countries except for Sweden and Poland that, respectively, granted reimbursement to one and none of the therapies. Managed entry agreements were confidential but commonly adopted to address financial uncertainties. Conclusion: Discrepancies concerning prices, reimbursement and access were detected for Kalydeco® (ivacaftor), Orkambi® (lumacaftor/ivacaftor) and Symkevi® (tezacaftor/ivacaftor) across European countries.

Clinical Research in Neonates: Redesigning the Informed Consent Process in the Digital Era.

Background: Currently, many initiatives are devoted to optimizing informed consent for participation in clinical research. Due to the digital transformation in health care, a shift toward electronic informed consent (eIC) has been fostered. However, empirical evidence on how to implement eIC in clinical research involving neonates is lacking. Methods: Semi-structured interviews were conducted with 31 health care professionals active in Belgium or the Netherlands. All health care professionals had experience in conducting clinical research involving neonates. Interviews were audio-recorded, transcribed and analyzed using the framework method. Results: Interviewees generally supported the use of eIC in clinical research involving neonates. For example, eIC could enable parents to receive study feedback via the eIC system. Requirements were expressed for parental involvement to decide on which feedback would be appropriate to return. Moreover, experts specialized in presenting information and designing electronic systems should be involved. Broad consensus among health care professionals indicates that the face-to-face-interaction between parents and the research team is vital to establish a relationship of trust. Therefore, it is necessary that the use of eIC runs alongside personal interactions with the parents. Concerns were raised about the accessibility of eIC to parents. For this reason, it was suggested that parents should always be given the possibility to read and sign a paper-based informed consent form or to use eIC. Conclusions: Health care professionals' views indicate that the use of eIC in clinical research with neonates may offer various opportunities. Further development and implementation will require a multi-stakeholder approach.

Allergic contact dermatitis from fragrance components in specific topical pharmaceutical products in Belgium.

OBJECTIVES: To determine which topical pharmaceutical products marketed in Belgium contain fragrances and to examine the nature of the fragrance allergens in specific pharmaceutical products having caused iatrogenic contact dermatitis. METHODS: All topical pharmaceutical products marketed in Belgium, that is 3820 products, were examined as to their fragrance content as labelled. Data of 18, 960 patients investigated for contact allergy between 1978 and 2008 were retrieved from our database, including information on the nature of the topical pharmaceutical products used, the results of patch tests, and the sensitization sources. RESULTS: Three hundred and seventy (10%) of 3280 of the topical pharmaceutical products were found to contain a total of 66 fragrance substances. Among 3378 patients suffering from iatrogenic allergic contact dermatitis, 127 were found to react to 48 specific products, for which 38 different fragrance substances gave relevant positive reactions. Women were more affected than men, and legs, hands, and face were the most commonly affected body sites. CONCLUSIONS: Fragrances, the presence of which is in most cases unnecessary, do contribute to iatrogenic allergic contact dermatitis. Moreover, sensitized patients have difficulties in avoiding their specific allergens because standardized labelling of the ingredients in pharmaceutical products is lacking.

Information needs of physicians regarding the diagnosis of rare diseases: a questionnaire-based study in Belgium.

BACKGROUND: Late and misdiagnoses of rare disease patients are common and often result in medical, physical and mental burden for the patient, and financial and emotional burden for the patient's family. Low rare disease awareness among physicians is believed to be one of the reasons for these late and misdiagnoses of rare disease patients. The aim of this study was to investigate how information and education could be tailored to the needs and preferences of physicians in Belgium to increase their rare disease awareness and support them in diagnosing patients with a rare disorder. Nine exploratory interviews with Belgian rare disease experts were performed in December 2016 to help the development of a questionnaire on information needs of physicians and their consulted information sources in rare disease awareness and diagnosis. This online questionnaire was then completed by Belgian physicians (n = 295), including general practitioners (GPs), pediatricians and other specialists (i.e. neurologists, pediatric neurologists, endocrinologists and pediatric endocrinologists) during January and February 2017. RESULTS: Rare disease knowledge and awareness were the lowest among GPs and the highest among specialists. Interviewed experts indicated that physicians' academic and continuous medical education should be focused more on "red flags" to increase rare disease attentiveness in daily clinical practice. GPs scored their academic education on rare diseases as insufficient but pediatricians and other specialists scored it significantly better (p < 0.001). Even though GPs declared to only need information on rare diseases when having a rare disease patient in their practice, specialists indicated to need more rare disease information in general. Most physicians confirmed that they had specific information needs regarding rare diseases. Unlike specialists, the majority of GPs were unaware of information sources such as Orphanet. CONCLUSION: In order to effectively support physicians in Belgium to diagnose rare diseases early, the academic medical education on rare diseases should be revised. Teaching methods should be focused more on casuistry and "red flags". An Orphanet-like digital platform about rare disease symptoms, diagnostic tests and reference centers might be ideal to support correct and timely diagnosis.

Reimbursement Status and Recommendations Related to Orphan Drugs in European Countries.

Objective: To review the reimbursement recommendations issued by selected European health technology assessment agencies for orphan drugs and the reimbursement status of these drugs; to assess the relationship between the type of recommendation and reimbursement status. Methods: The list of orphan drugs to be included in the analysis was obtained from the European Medicines Agency and Orphanet. Seven European states were included in the analysis: Belgium, England, France, Germany, Poland, Scotland, and Spain. For all identified orphan drugs, relevant data on the reimbursement status and type of recommendation were collected for each country. The relationship between the type of recommendation and reimbursement status was evaluated separately for each considered country, using Cohen's kappa coefficient for the measurement of agreement; sub-analyses for oncology and metabolic drugs were performed. Results: Most reimbursement recommendations for orphan drugs were positive (71%), while approximately 17% were negative and almost 13% were conditional. The highest percentage of positive reimbursement recommendations was observed in Spain (97%) and France (95%) and the highest percentage of negative reimbursement recommendations was revealed for Poland (49%). On average, 65% of the 163 analyzed orphan drugs were reimbursed from public funds. The highest number of reimbursed orphan drugs was observed in Germany (n = 148), while the lowest, in Poland (n = 41). Considering all analyzed drugs, the highest agreement between recommendations and reimbursement status was observed for Spain (value of 1), and the lowest, for Germany (κ = -0.03). Conclusions: On average, more than 60% of identified orphan drugs were reimbursed from public funds in the included countries, and the majority of reimbursement recommendations were found to be positive. The agreement between reimbursement recommendations and reimbursement status differed between the countries, but overall, it did not show any patterns, as it ranged from -0.03 to 1 (κ coefficient).

Compounded medication for patients with rare diseases.

BACKGROUND: When there is no authorized on- or in absence even no off-label treatment for patients with rare diseases, pharmacists have to compound medicinal products to meet the patients special needs. However it is important that there is evidence in the medical and/or pharmaceutical literature for such compounded medications. POSITION STATEMENT: Pharmaceutical compounding must be performed in the best possible circumstances by certified practitioners (pharmacists) using validated standard operating procedures (standardized formulations) in order to obtain medicinal products of the highest quality to assure patient safety. More than 60 compounding procedures were identified in 17 on-line pharmaceutical compounding reference sources worldwide but more operating procedures still need to be validated. All ingredients used in the preparation of the compounded medication must be accompanied by a certificate of analysis and full records of the pharmaceutical production process need to be kept for full traceability and accountability.

Noninvasive prenatal testing: a survey of young (future) parents in Flanders.

AIM: To explore the opinions of young (future) parents toward noninvasive prenatal testing. MATERIALS & METHODS: A questionnaire was administrated. RESULTS: A total of 1006 surveys were completed by visitors of 40 secondhand clothing fairs spread equally over Flanders (Belgium). The respondents expressed an overall positive opinion toward the use and implementation of a noninvasive prenatal test (NIPT). Most respondents claimed that they would test their unborn child for genetic disorders, even if this was to result in a termination of the pregnancy. CONCLUSION: The participants agreed nearly unanimously that NIPT must be offered to pregnant women with an increased risk of having a child with a genetic disorder, but they were also positive about extending NIPT screening to all pregnant women.

Patient Involvement in the Lifecycle of Medicines According to Belgian Stakeholders: The Gap Between Theory and Practice.

Background: Patient involvement is often acknowledged as an important aspect of the lifecycle of medicines. Although different typologies exist, patient involvement has been described as the involvement of patients in decision-making regarding medicines. In view of the diversity of stakeholders and types of decisions in which patients might be involved, an in-depth understanding of these stakeholders' views toward involving patients in the lifecycle of medicines is essential. Methods: Interviews and surveys were used to gain insights into the perspectives and experiences of Belgian healthcare stakeholders. Interviews (n = 22) were conducted with academics, hospital pharmacists and representatives from health insurance funds, the Belgian reimbursement agency, pharmaceutical industry and patient organizations. Interviews underwent a framework analysis. Surveys (n = 108) were completed by hospital visitors and analyzed descriptively. Results: Despite an increasing amount of efforts to involve patients, interviewees labeled the level of actively involving patients as rather low and scattered across the different phases of the lifecycle of medicines. The main opportunities for patient involvement highlighted by interviewees were for: (i) informing early development decisions on which treatments to develop, (ii) clinical trial endpoint selection and (iii) clinical trial protocol design. However, remaining questions surrounding patient knowledge, and particularly how and which patients to involve represent important barriers toward implementing patient involvement in the lifecycle of medicines. Of survey participants, 77% indicated to be willing to participate in patient preference studies. Reasons for participating mentioned most frequently were "to improve development of treatments," because "it is important to explore and listen to patient preferences" and "to have a voice as patients". Conclusions: The barriers identified in this study hamper transitioning patient involvement from theory to practice. Bridging this gap requires addressing the identified barriers and unresolved questions surrounding the right methodology for involving patients, the "right patients" to involve and means to increase patient knowledge. In order to do so, further research should focus on assessing the value of methods that allow to indirectly capture patients' perspective both in the context of development as well as in the context of evaluation.

From promising molecules to orphan drugs: Early clinical drug development.

Phase-1 (also known as "First-in-Man") clinical trials initiate the early clinical development of possible new medicines. Patient participation in this early phase of clinical trials is rather limited. After successful phase 1 trials, further phase 2 and phase 3 clinical trials in patients may lead to a marketing authorization. In the first 15 years of the European Union Orphan Drug Directive, 4.5% of the orphan drug applications were authorized. However, for many of these orphan drugs, no phase 1 studies were required, as these products were already well known pharmaceutical substances, with a clearly defined pharmacological profile. Furthermore, for 19 orphan drugs, already authorized by the European Medicines Agency (EMA), the original rare indication was extended to another rare disease and no phase 1 trials were needed. Phase 1 studies need to be performed in a sufficient number of volunteers even for medicinal products intended for a very limited number of patients.

Off-label use of medicines: The need for good practice guidelines.

BACKGROUND: 'Off-label use' is the term used for the prescription and dispensing of a medicinal product for any indication, patient group, route of administration, dosage or treatment regimen other than that listed in the Summary of Product Characteristics. OBJECTIVE: In this article the authors present a brief overview of current practices of off-label use in Europe and the applicable European law and jurisprudence. They then go on to present a set of guidelines for best practice in off-label use which underlines the need for guidance on prescription to be firmly rooted in the need to ensure patient safety above all other concerns. METHODS: The article was written from desk research and expert engagement, including a presentation and Q&A in the European Parliament. RESULTS: This article intends to demonstrate that off-label use entails increased risks for patients, especially when it is not underpinned by rigorous clinical studies or the reporting routes for use are not well defined. CONCLUSIONS: Europe is seeing a growing trend the promotion of off-label prescription of medicinal products for reasons other than pure medical need, including motives such as cost-containment. This poses a numer of questions for the ethical and legal framework for medicine prescription and dispensing in Europe.

Orphan devices: yesterday is history; tomorrow is mystery: towards a European orphan device directive?

BACKGROUND: Regulatory and economic frameworks stimulated the research and development of orphan drugs, but very little has been done for devices necessary for the in-vivo diagnosis, prevention and treatment of life-threatening conditions with a low prevalence/incidence. DISCUSSION: A general public consultation in Europe has shown a positive attitude towards an "orphan device" directive. The United States of America have a Humanitarian Use Device exemption, but Europe is still waiting for such a stimulating framework. Post-marketing surveillance ("materio-vigilance") will be necessary for follow-up, patient-reported outcome measures (quality of life versus survival) needed and off-label use data available for patient-safety reasons. The marketing period for devices is shorter than for medicinal products. Incentives are necessary to stimulate research and development of such "orphan devices" especially when surgical intervention is the only option.