Editorial: Repurposing for small population needs

EU Pharmaceutical legislation, notwithstanding it includes EU-wide rules on repurposing for the first time (4); this seems a major step ahead in the pharmaceutical field, as data on off-label use are expected to be included in marketing authorization documents.Both profit and not-for-profit organisations (academia, patients' associations, not-for profit research entities, etc) are involved in repurposing research & development programmes to gather and generate evidence for new indications of medicines for small populations. This is also reflected in the Research Topic.Medicinal products development is becoming increasingly expensive, complex and with significant attrition rate. So, from a commercial perspective, drug repositioning is appealing: pharmaceutical companies integrate it as a strategy in the life cycle management of their products. By leveraging a product's existing knowledge, the use of well-known drugs is expected to reduce time, costs, and development risks, as compared to de novo drug development (Jonker et al, Wang & Giannuzzi).In the context of an academic research programme, a case study on the repurposing of the old drug guanabenz was presented. It outlines as an old alpha-2 adrenergic receptor agonist used as an antihypertensive became a therapeutic strategy for amyotrophic lateral sclerosis, a rare severe neurological disease (Ambrosini et al).However, while academic research often supports repurposing, the pharmaceutical industry tends to view it as a suboptimal investment, mostly because payers at national level are reluctant to assign favourable prices, that adequately reward the research efforts, even when these medicines prove effective (Paquot et al). This is consistent with the outcomes from the systematic analysis of the outcomes from EU investments, like the FP7 funding program, to date (Ruggieri et al): 20 EU-funded projects based on public-private partnerships studying 24 active substances developed 22 repurposing plans to address unmet medical needs in paediatrics. Out of them, 1 paediatric investigation plan was officially discontinued due to commercial reasons, but financial difficulties/budgeting negatively impacted on the conduct of 8 PIPs, as reported by project coordinators.What is already known is that the collaboration between academia and industry is usually established to undertake R&D processes of medicines with a poor commercial interest A repurposing R&D plan looks for novel therapeutic indications for known/authorised or investigational drugs, but a regulatory approval is needed to demonstrate efficacy, safety and quality (with some data already available) and to authorise new indications with appropriate dosing, efficacy and safety in specific populations. If needed, in the paediatric setting, it might be also relevant developing new formulations, allowing medicines use in target subsets, or new strengths, allowing appropriate dosing Today, one of the most recent examples is within the paediatric oncologic field, where a drug may be useful for more tumours, due to its mechanism of action and/or its target.However, repurposing often turns an off-label use of medicines, as a unique therapeutic opportunity for clinicians to treat patients when no alternative treatment is available, and only a limited part turns into an authorised use.In the paediatric field, a specific marketing authorisation is available in the EU, i.e. the Paediatric-Use Marketing Authorisation (PUMA). It covers the indication(s) and appropriate formulation(s) for medicines developed exclusively for use in the paediatric population and, once obtained, it grants holders the benefit of 8 plus 2 years of data and market protection, if studies are performed as per an agreed (voluntary) PIP (6). Poor attractiveness of repurposing off-patent medicines through the PUMA scheme has been revealed (Ruggieri et al, Wang & Giannuzzi); developers likely prefer to apply under the simplified procedure outlined in the Directive 2001/83/EC for off-patent drugs rather than following the Paediatric Regulation route (Ruggieri et al).In the context of 20 projects funded under the Seventh Framework Programme for Research by the European Commission, three new PUMAs were obtained through the centralized procedure and three out of 18 agreed PIPs were successfully completed within 3-10 years. Other outcomes were achieved, including the successful completion of paediatric clinical trials, the development of new patents and technologies, dissemination of results through scientific publications, updating of clinical guidelines, conducting EU-wide surveys on paediatric clinical practice and updating state-of-the-art in niche therapeutic subsets, such as neonatal-only diseases and paediatric pain.Therefore, besides regulatory barriers and financial constraints, it seems that turning off-label uses into authorised ones is contingent upon the commercial interest.The lack of available appropriate paediatric formulations is still a challenge for optimal treatment in children. Therefore, repurposing, including reformulation strategies, has the potential to cover paediatric unmet needs and to ensure relevant 'on label' use. Wang & Giannuzzi discuss the potential solutions to incentivize the development of new formulations for children, like specific inclusion of reformulation in repurposing R&D initiatives, specific R&D funding initiatives on reformulation, specific measures and incentives at regulatory level to attract manufacturers.All these scenarios could potentially fulfil unmet medical needs, and make relevant clinical use 'on label', all core elements of repurposing (Ambrosini et al, Fuchs et al, Ruggieri et al).Regardless the positive or negative results from a repurposing programme or its promoter being academic or commercial, this Research Topic demonstrates that even if it does not result in successful outcomes, it may provide important insights into the disease knowledge, pave the way to new treatments and new studies, and generate innovation and interest from industry partners, provided it is based on a sound rationale, the study design is adequate to ensure meaningful results, and the investigators keep the full clinical development picture in mind (Ambrosini et al, Fuchs et al, Jonker et al, Ruggieri et al)."No drug is ever understood completely, and repositioning, no matter how unlikely, often remains a possibility" (7).The use of real-world data (RWD), pharmacometrics, Artificial Intelligence (AI) and other innovative methods has emerged due to the recognised benefits of gaining evidence to developing medicines for small populations and for regulatory approvals, when limited data are available. As an example, the challenge for addressing an ultra-rare disease remains in a sufficient level of accessible knowledge on the drug and on the disease in order to derisk the development in the new indication (Paquot et al). This Research Topic has collected concrete applications of innovative methods in drug repurposing for small populations.Healy et al and Lava et al ) showed that model-based approaches are useful in special pediatric settings characterized by unsatisfactory therapies for children, e.g. heart failure, or practical and ethical challenges, like paediatric intensive care unit. This maximizes the information content and reduces patient burden. The application of modelling, simulation and extrapolation principles do inform about suitable dosing regimens, as demonstrated for lorazepam, currently used off-label for analgosedation in paediatric intensive care unit with limited data on its pharmacokinetics and pharmacodynamics (Healy et al), and in a context of a prospective trial with gliflozines where a model-based approach can optimize the study design, thus increasing the probability of the trial success (Lava et al ).RWD can be analysed to identify potential associations between existing drugs and new therapeutic indications, as well as for post-marketing surveillance of both the safety and efficacy of approved products (Jonker et al). The c4c consortium worked on the standardization of paediatric clinical trial data that can be used for RWD, too (Owen et al).Advanced computational methods, machine learning, AI and platforms created or under construction in the EU like REMEDI4ALL, REPO4EU, are increasingly used to identifying potential drug repurposing candidates (Jonker et al, Cortial et al).Systematic phenotypic screening (Paquot et al), AI-driven initiatives, organoids and gene expression datasets (Cortial et al) catalyse the development of drugs for ultra-rare diseases by evaluating drug candidates based on their observable effects on cellular or organismal phenotypes. In addition, recent advancements screening and computational techniques, offer the unique opportunity to predict drugdisease interactions and prioritize candidate compounds for further investigation (Fuchs et al).All these tools and methods would be expected to be useful if/when the proposed rules from the upcoming EU pharmaceutical legislation issuing 1) the possibility to include data on repurposing use in marketing authorization documents and 2) conducting paediatric studies within a PIP in a disease different from the one proposed by the developer, based on the drug's mechanism of action will be applicable.Taken together, the manuscripts included in the Research Topic Repurposing for Small Population Needs offer a snapshot of the opportunities from repurposing medicines for small populations.Repurposing study with an old product has the potential to generate innovation and interest from industry partners, provided it is based on a sound rationale, the study design is adequate to ensure meaningful results, and the investigators keep the full clinical development picture in mind (Ambrosini et al). But this is an opportunity not only to get evidence, but also to share clinical information, and advance scientific knowledge. -regulatory issues; -limited financial resources and public funding, especially in a multi-national setting; -poor economic interest (cheaper options like off-label medicines and extemporaneous galenic preparations are anyway available); complex negotiation of existing product intellectual property (IP)/patents/ license between noncommercial academic entities and companies, thus affecting the supply of (old and new) drugs in the context of clinical studies; -recruitment challenges of clinical trials due to the poor feasibility of clinical trials given unlicensed/off-label access.Several initiatives have been launched in Europe to support drug repurposing, including innovation platforms, regulatory initiatives, funded projects and programmes. The outcomes of these emerging activities are highly anticipated for the benefit of patients, public health and medicines developers.