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

Abstract

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.

Keywords: alternative drug-to-market routes; marketing authorization; orphan drugs; patient access; rare diseases; regulatory framework.

FIGURE 1

Route to patient access via marketing authorization. Following proof of concept there are multiple steps, including (1) dialogue with stakeholders, deciding what (2) type of dossier and (3) application procedure are suitable, (4) building the Common Technical Dossier, (5) submitting the marketing authorization application, (6) applying for the Health Technology Assessment (HTA) at a national HTA body, and (7) complying to post-authorization obligations such as pharmacovigilance. *Exemptions for certain (elements of) modules of the Common Technical Dossier may be applicable for authorized medicines. Y, yes; N, no; HTA, health technology assessment; CA, conditional approval; AA, accelerated assessment; EC, exceptional circumstances.

FIGURE 2

Routes to access following the need for a medicine in the European Union (EU), including alternative routes. There are multiple (decision) steps from unmet need to patient access (green boxes). Names of the routes are indicated in bold font. First step is that, in case of a patient need for medication, the academic should examine if product development is necessary, for example, because the product consists of a new active substance or a new formulation. When product development is needed, one should proceed with the marketing authorization route (see Figure 1). For products already authorized for another indication, off-label prescription is a viable option. However, the marketing authorization route can still be exploited to bring this indication on-label. If the product is authorized in another EU Member State, import on a named-patient basis could be suitable. In case the product is still under development by another party, it might be relevant to explore compassionate use programs or ways to prescribe an investigational product on named-patient basis. If these option are unattainable, pharmacy compounding via the magistral or officinal formula can offer a solution. In all cases, national reimbursement should be arranged in order to provide patient access. *Ideally, the marketing authorization route is executed to bring off-label uses on-label. **Reimbursement may following automatically, dependent on national legislation. Frequently, products facilitated via compassionate use programs are free of charge.