Medicine Development and Access for Rare Diseases: Can We Do Better?

ABSTRACT

Recent advances in molecular biology and genomics have significantly enhanced our understanding of rare diseases. While enabling the development of highly targeted therapies, it also leads to complexity in the development, regulation, and accessibility of orphan medicines. Unmet need and great promise of new medicines, combined with high prices and uncertain effectiveness, highlight the shortcomings of the system, particularly evident for highly specialized treatment options, such as advanced therapy medicinal products and RNA‐based treatments. While all stakeholders in this field must take responsibility, academic researchers and clinicians have a vital role which must be strengthened to improve access to and affordability of medicines. Regarding academia‐driven orphan medicine development, academic contributions are predominantly concentrated in the early research phases, often lacking continuity throughout the full development pipeline. There is limited expertise in regulatory affairs and market access, and little involvement in medicine pricing or licensing negotiations. Recommendations include sustained academic engagement across all development stages, integration of regulatory and market access training into educational programs, and the implementation of socially responsible frameworks. Strategies promoting the rational use of orphan medicines should be embedded across the entire product lifecycle. Industry‐driven development typically interacts primarily with regulatory agencies and payers, with academia playing a reactive and, at times, conflicted role. Independent academic–industry interaction is recommended, with early involvement in clinical trial design. Additionally, academia should proactively contribute to the evaluation of new therapies, development of controlled access models, and exploration of sustainable pricing frameworks. Establishing independent, multi‐purpose disease registries would enhance post‐authorization monitoring and evidence generation.

1. Introduction

Advancements in molecular biology, genomics, and other basic scientific techniques have dramatically enhanced our understanding of disease pathophysiology, particularly in conditions with a genetic etiology. This progress has been pivotal for rare diseases—often referred to as orphan diseases—defined in the EU as disorders that each affect no more than 5 in 10 000 people [1]. Currently, over 6000 different conditions are recognized, but many lack effective treatments [2]. While the definition originally focused on specific rare diseases, unraveling of molecular mechanisms also revealed that within more prevalent diseases, subgroups with distinct molecular profiles and therapeutic targets can be distinguished. This has driven a shift toward developing highly specific therapies for increasingly narrow patient populations.

The emergence of these highly specific treatments has been incentivized by the Regulation on Orphan Medicinal Products, enacted by the European Parliament and the Council in 1999, inspired by the U.S. Orphan Medicine Act of 1983. This legislation offers benefits such as market exclusivity, fee reductions, and protocol assistance to encourage the development of treatments for rare diseases, [1]. As a result, the number of orphan designations and marketing authorizations has risen markedly over the past two decades, addressing unmet medical needs for previously underserved patient populations [3].

However, the system is not without criticism. Concerns have emerged regarding the potential exploitation of the regulation. Pharmaceutical companies can segment larger patient populations into artificially narrow subgroups to qualify for orphan status, or “orphanize” a therapy through orphan medicine authorization of an existing medicine, thereby benefiting from regulatory incentives while maintaining monopolistic pricing [4]. In addition, the high cost of many orphan medicines raises ethical and economic concerns, particularly when the clinical benefit remains uncertain or marginal. While uncertain effectiveness and high prices are separate issues, they often pose a joint problem which may lead to delays and unequal access within EU member states [5, 6]. Addressing the uncertainty surrounding effectiveness in the real‐world clinical practice after medicine approval also poses a particular challenge. These issues have complicated access, reimbursement, and long‐term evaluation of orphan medicines over the last two decades. It is expected that this will become even more pressing with the development of the newer highly specialized treatments such as advanced therapy medicinal products (ATMPs) and RNA‐based treatments.

A further complication lies in the divide between the origins of therapeutic innovation and its eventual commercialization. Much of the foundational work identifying novel disease mechanisms and therapeutic targets originates in academic institutions [7]. This is particularly the case for repurposing of existing medicines for orphan medicine development [8]. Yet academic involvement typically wanes during the later stages of medicine development and access, which are dominated by commercial actors interacting mainly with regulators and payers required for market approval and reimbursement. Consequently, academia usually has limited influence, raising questions about the fairness of a system in which publicly funded research underpins products that may generate substantial private profits with limited public influence over affordability or access.

This review explores the complex interplay between scientific discovery, regulatory frameworks, commercial development, and healthcare access to orphan drugs. It differentiates between innovations driven primarily by academic research and those led by the pharmaceutical industry, while examining the roles of regulatory agencies, payers, and healthcare professionals. Understanding these “system dynamics” is essential to understand how the different elements of orphan medicine development are interconnected, so that we can effectively implement changes into the current system that better aligns future innovation with affordability in order to continue to treat our patients effectively and timely.

2. Medicine Development, Pricing, and Access in the EU: Implications and Hurdles for Rare Diseases

Traditionally, medicine development follows a structured path: discovery, non‐clinical, clinical, regulatory and post‐authorization phases. Non‐clinical studies assess safety and biological activity through lab and animal models. Promising candidates enter clinical trials: Phase I tests safety and dosage; Phase II evaluates efficacy; Phase III confirms benefit through larger randomized trials [9]. Upon success, manufacturers can submit marketing authorization applications to competent authorities performing benefit/risk assessments [10]. For orphan medicines, the EMA is the relevant authority [1]. Next, access and pricing strategies are being employed, often before or at the same time as post‐authorization studies (Phase IV) that assess long‐term safety and sometimes effectiveness in broader populations (Figure 1).

FIGURE 1.

Traditional stages of medicine development. After discovery, non‐clinical work and establishing “proof of concept” clinical trials need to be performed to show the right dose and benefit/safety profile. After marketing authorization, follow‐up studies are sometimes necessary. These studies may examine not only safety but also effectiveness. This is not always aligned with the procedures for access and reimbursement of a medicine.

This traditional medicine development path applies to orphan medicine development as well, whether driven by academia or industry. Both manufacturers of medicines for rare diseases and academic researchers can apply for orphan designation during development. The benefits of an orphan designation include regulatory support and financial incentives that can stimulate commercial development [11]. Studies on rare diseases face significant obstacles, primarily due to small and heterogeneous patient populations, which can hinder study design and generalizability. Furthermore, the lack of natural history data and sometimes the limited availability of validated, clinically relevant endpoints contribute to the complexity of conducting sound research [12]. These factors can lead to difficulties in recruiting participants, obtaining meaningful data, and ultimately developing effective treatments [13]. To overcome this, orphan medicines are more likely to be granted special approval types (conditional approval, approval under exceptional circumstances, and additional monitoring), which points to uncertainty about the long‐term clinical benefit. Indeed, these non‐standard marketing authorizations represent about one‐third (32%) of the orphan medicines authorized between 2010 and 2022 [14]. Together, these factors hinder the extrapolation of trial efficacy to real‐world effectiveness. Notably, when comparing clinical trial data of orphan medicines to real‐world evidence, fewer than half of these showed strong performance in real‐world settings, including, for example, elosulfase alfa for Morquio A syndrome, showing only statistical significance on the 6‐min walking test, with questionable clinical relevance at authorization [15]. This also has to do with a lack of alignment of results obtained in clinical practice versus the data collected and analyzed in the post‐authorization setting. The post‐authorization obligations imposed by the EMA often lead to the creation of industry‐run and funded treatment registries [16]. These industry‐driven registries may fall short in effectively evaluating the real clinical benefit because of small and often incomplete datasets and lack of appropriate stratification of patients to improve our understanding of benefit in subgroups of patients. In addition, results are reported to the EMA and may not align with national requirements to inform relative effectiveness needed for member states' decisions on access and reimbursement. For such decisions, payers usually rely on published pivotal studies without the results of the post‐authorization studies. For decisions on reimbursement, different value assessment frameworks in the context of orphan medicines are used across the EU [17]. Almost all member states follow a value‐based pricing and reimbursement model, where the price reflects clinical benefit, innovation, and relative effectiveness. National HTA bodies evaluate cost‐effectiveness, using cost per quality‐adjusted life year (QALY) thresholds to guide reimbursement decisions [17, 18]. As mentioned earlier, therapies for rare diseases are often expensive. This is usually justified by the perceived high development and production costs and the small patient population, or simply because comparable orphan medicines are already reimbursed at a similarly high price. This is illustrated by the prices of enzyme replacement therapies after the first became available for Gaucher disease, which cost more than €200 000 per patient per year. As a result, many struggle to meet cost‐effectiveness criteria, despite addressing significant unmet needs [19, 20]. At the same time, as discussed, new orphan medicines carry uncertainty about real‐world effectiveness and measuring quality of life is challenging in rare diseases. It is therefore not always feasible to capture their value in conventional cost‐effectiveness analysis [21]. Combined, the high prices, clinical uncertainty, and budget constraints may result in prolonged assessment and appraisal periods, and reimbursement negotiations can delay or restrict patient access.

Two other trends are relevant to orphan medicine development. The first is drug repurposing, where previously approved active ingredients are developed for a new indication [8]. The second trend concerns ATMPs and RNA‐based treatments, enabling the development of n‐of‐few or even n‐of‐1 therapies. Given the highly personalized approach of some of these platform technologies, this may require a new way of thinking about how patient access in combination with quality and safety can be achieved [22, 23].

While this system failure requires action from all stakeholders, the next section focuses on academic stakeholders and their potential role in contributing to improving the current system.

3. Academia Driven Orphan Medicine Development: A Path Towards Socially Responsible Valorization

Currently, academia mostly plays a fragmented role in orphan medicine development. Although they may be involved in target identification, medicine discovery, and execution of clinical trials, they do not have a continuous role in valorization including access and pricing [24]. Valorization is often a priority within academic institutions these days. This refers to the process of creating value from research by translating knowledge into products, in this case, medicines. Their pivotal role along the entire development chain, however, suggests that this could be an area where they can strengthen their position.

3.1. Academia‐Driven Medicine Development (Areas That Are Suited to Development by Academia)

Repurposing is particularly important for academia because academic researchers are often the first to repurpose a drug for a rare disease [8]. Repurposing holds the promise of shorter development timelines and fewer studies are needed to evaluate safety and specific knowledge of effects in other diseases [25]. The development of ATMPs and RNA‐based therapies is also a field with a strong basis in academia. In inherited metabolic diseases (IMDs), several examples exist of ATMPs and RNA‐based or base/gene editing treatments with already proven effectiveness such as gene therapy for metachromatic leukodystrophy, initially developed in academia [26] or high promise of prime editing in intestinal organoids from patients with DGAT1‐deficiency and liver organoids in Wilson disease [27]. Alongside these advanced therapies, nutritional therapy products also remain essential to IMD management, often functioning as medicines and supported by substantial academic evidence. Even so, industry has rarely taken steps toward marketing authorization, meaning patients rely on food supplements despite growing concerns regarding their quality and availability [28, 29]. In practice, patients often have to switch to another product or a shortage occurs, while quality control is also inadequate.

All these areas serve well to pioneer with academia‐driven medicine development in collaboration with manufacturers, patient organizations, and regulators [30]. Instruments that could be part of these new socially responsible public private partnerships (PPPs) to bring these therapies to patients are discussed in more detail below.

3.2. Public Investments Require Public Returns

The traditional linear model of medicine development—where academic discoveries are handed off to the pharmaceutical industry—no longer meets societal demands for affordability and equitable access. Recent insights underscore the need for novel PPPs that prioritize technological innovation as well as social value and fair access to medicines. One of the pioneers drawing attention to the fact that public inventions often result in private profit only is Mariana Mazzucato [31, 32, 33]. In her work, she advocates for a redefinition of the role of the state in innovation. Rather than merely correcting market failures, she argues that governments should actively shape markets through mission‐oriented policies and strategic investment. In her view on pharmaceutical innovation, she states that public investment in research and development should be tied to conditions that ensure public returns, including fair pricing and broad accessibility of the resulting therapeutics [34].

Rosenberg et al. highlighted that there is a growing need for socially‐responsible public‐private partnerships (PPP's) between academia and industry, stipulating a framework for socially‐responsible terms [35]. These terms include that pricing shall be transparent, based on costs plus a reasonable profit margin, and that said profits shall benefit a revolving fund for the development of new treatments. To prioritize not only technological innovation but also social value and access to medicines, it is becoming apparent that academia should take on a more substantial position in medicine development.

3.3. Socially Responsible Licensing: A Tool for Equitable Access

University knowledge transfer offices (KTOs) have been installed in the last two decades of the 20th century and become instrumental in the commercialization of academic innovations [36]. Traditionally, they have been structuring this around out‐licensing of patents to industry and obtaining royalties financially benefiting researchers and the university [36]. However, when considering Mazzucato's definition of innovation, there is a need for these entities to adopt socially responsible licensing (SRL) models that involve integrating conditions into license agreements, including considerations for pricing and access provisions, such as affordability clauses and global access conditions [37]. A guideline has been developed by the Dutch umbrella association of university hospitals to support KTOs and academic researchers [38]. This concept applies to medicine development by academia in a broader sense but is specifically relevant for orphan medicines, as previously discussed.

3.4. Governance in Social Public‐Private Partnerships: Towards Socially Responsible Valorisation

In addition to strategies to remain committed to the accessibility and affordability of academic discoveries, academic parties can also play a more guiding role in (PPPs). New governance structures in academia‐driven spin‐off companies are relevant in this regard. Traditional PPPs often struggle to align public health objectives with private commercial interests. To mitigate these challenges, steward‐owned companies may offer a relevant governance structure, guarding the social impact. Rather than a fixed model, steward‐owned represents an overarching principle that can be implemented in various ways. As discussed by Sanders and Neitzel [39], these entities separate voting rights from rights to profit distribution. Control is held by stewards who have no entitlement to the business's profit: key decisions are made by individuals or organizations committed to the enterprise's purpose, rather than solely by external shareholders [40]. Profit therefore becomes a means to achieve the organizations purpose, rather than an end in itself. This governance principle can be institutionalized through diverse mechanisms such as foundation‐held voting rights, golden shares, or statutory limits on profit distribution. Reinvestment of profit requires careful investor alignment by attracting long‐term capital from social impact investors, avoiding shareholder pressures for short‐term returns. Companies like purpose evergreen capital have helped establish health‐focused steward‐owned firms that commit to affordable pricing and reinvestment in underserved disease areas [41]. In addition to steward‐owned governance, other models exist that secure maintaining the mission separate from focusing on profit only. To complement the principles laid down in such socially responsible models, other aspects of “socially responsible valorization” are of importance, including incorporating patient and societal needs and supporting regulatory pathways for sustainable access.

The flexibility and social goal of these models make them suitable and attractive for academia‐driven medicine development.

3.5. Education: Necessary for Academic Professionals

As discussed before, academics—including clinicians, pharmacists, and researchers—play a critical role throughout the medicine development lifecycle. In addition to basic scientific discoveries, clinicians, both academics and non‐academic, are usually well positioned to identify unmet medical needs based on real‐world patient experiences, often in close collaboration with patients and patient organizations. However, they usually lack sufficient knowledge on routes toward marketing authorization and reimbursement [42]. Also, academic researchers and clinicians may have limited experience with tools necessary for socially responsible drug development and valorization.

A more proactive role requires training at both the individual and institutional levels, as well as protected time for medicine development. Individual healthcare professionals and academic researchers should be able to identify known unknowns—areas in which they should consult other experts—and know where to find them. Specific courses should be made available, for example, on the valorization of new gene editing technologies or reimbursement issues. At an institutional level, a single point of contact for medicine development through the KTO would be most appropriate. In addition, education is needed on how to effectively interact with regulatory agencies like the EMA and payers. This includes understanding the regulatory processes, data requirements, and communication strategies necessary for successful interactions and ultimately, market access for new medicines [43]. Importantly, the EMA has incentivized academic researchers by offering free scientific advice on product development since 2020. This support is intended to encourage the development of new medicines, particularly for rare diseases.

4. Industry Driven Orphan Medicine Development: Transparent Collaborations to Improve Access

4.1. Orphan Business Models Set Up by Industry

The traditional model of the pharmaceutical industry is shaped by shareholder needs, developing and commercializing medicines in ways that prioritize financial return over broader social benefit. Most large pharmaceutical companies are publicly traded, and their executives are under constant pressure to deliver quarterly financial results, increase stock prices, and generate dividends. This often results in high medicine prices, rigorous patent protection strategies, and a focus on marketing over innovation. Orphan medicine development, with its regulatory incentives and market exclusivity, reduces development risk and creates a protected niche for companies, allowing them to charge premium prices for treatments [44]. An example is the development of sapropterin, Kuvan, a small‐molecule medicine that reduces blood phenylalanine levels in responsive patients with the rare but relatively frequent metabolic disease phenylketonuria, PKU [45]. BioMarin priced Kuvan at around $100 000–$200 000 per year in the US and, typically, a somewhat lower but still very high price in the EU. The price was based upon its perceived value: supporting patients to be able to relax or completely stop their protein‐restricted diet, but found to be not cost‐effective in adults and therefore subject to arrangements for example in the United Kingdom, including a discount patient access scheme [46]. In addition, its precise indication was the subject of controversies among healthcare professionals, due to disagreements over treatment in adults and phenylalanine threshold values [47]. Notwithstanding these issues, it became a major revenue stream for the company. BioMarin followed up with pegvaliase, Palynziq, an injectable enzyme therapy for PKU, at an even higher price. Patients may be approached directly by the company for their views [48]. This example, while not isolated, illustrates some key problems with the orphan drug model: there is a significant unmet need and little to no competition, allowing for higher prices; strong patient advocacy and regulatory incentives drive approval; unequal access is primarily caused by the high price and there is a lack of knowledge about rational use.

Clearly this model is not sustainable for rare diseases in the long‐term as it does not adequately combine affordability and innovation. At the same time, the innovative force, capital and expertise of commercially‐driven companies is undoubtedly needed for high‐risk innovations to reach the market as authorized medicinal products. Changes in orphan medicine legislation, currently under revision [49], as well as combined HTA approaches [50] on an EU level may help to improve access and affordability. In this article, we aim to focus on what academic professionals can do to break the impasse in the field of rare diseases and ensure that patients have access to these technological developments. Outlined below are potential actions across different stages of medicine development: help to reduce costs of studies while maintaining independence, proactive access planning, and early life‐cycle management including strategies for rational use.

4.2. Reducing Costs of Studies and Marketing

Costs of clinical studies have grown tremendously, carrying an enormous risk for industry. Specifically, small start‐ups frequently have to give up their independent position and partner with a larger company that can absorb potential failure. Acquisition costs may be high and studies sometimes need to be repeated to comply with regulations, which drives the investment costs and thus the price of the medicine. Academics contribute to high study costs, as the financial position of university medical centers partially relies on industry funding. Prices for laboratory tests or imaging studies are frequently higher for industry than for academic partners. This is justified as necessary income to support investigator‐initiated studies advancing scientific knowledge. However, this dependence has several drawbacks. First, there is a risk of conflicts of interest, especially when industry pays for educational activities and charters key opinion leaders involved in these studies for industry‐sponsored events. These are frequently satellite meetings where early, often positive, results of studies are presented, which do not always prove themselves later, but which should really be seen as marketing rather than education. Next, there is also a trend that industry commits to the life cycle of a medicine, for example, by developing strategies to identify more patients with the relevant disorder. In the field of genetic (metabolic) disorders, this can lead to the identification of more individuals with specific genetic traits that are then referred to as patients, but who may not actually show clinically relevant manifestations. A good example is the increasing number of industry‐sponsored studies on the benefit of newborn screening for specific disorders [51]. Industry provides financial support for studies with lower scientific standards for application compared to other funding bodies. As already mentioned and discussed further below, post‐authorization registries may also generate income for academics to support their research, but may function as marketing tools rather than providing necessary information on real‐world data [16]. All these activities may be attractive for academic researchers and clinicians who have to build their careers on a strong publication record and who need funding opportunities to continue their research. The high prices of clinical studies and the costs of all these post‐authorization activities are, in the end, recovered from society: the marketing costs make up a particularly large part of the price of a medicine [52]. The financial and career advantage we gain during the development of a medicine is thus repaid by society. The price we pay for this is also high: the possible loss of independence and the unintentional contribution to pressure on the healthcare budget.

This means that academic researchers and clinicians need to deal with the industry differently: transparently, ideally without compensation for consultancy, and by conducting studies at cost price. We also need to monitor the life cycle of a medicine much more ourselves. This requires a system change including more generous public funding. While this will undoubtedly take a significant amount of time, it will eventually pay for itself through lower medicine prices. We can make a start by supporting our younger generation of clinicians and researchers in their independence, for example, by helping them find independent funding so they can attend important conferences without being financially dependent on pharmaceutical companies.

4.3. Access and Pricing Strategies

Being independent from industry does not imply that collaborations cannot exist. Specifically, when it comes to access strategies, interaction with industry may be necessary. A market authorization holder needs to reach out to healthcare professionals for crucial reimbursement dossier information. This should ideally be provided by disease experts, who are mandated by their scientific associations. By answering only strictly necessary predefined questions and without a fee for services, they can do this without conflicting interests. Most codes of conduct for physicians provide a framework but often go less far or are not specific on this point. It can be helpful to refine and specify these to maintain independence.

Collaborations with regulators and payers are necessary as well. Ideally, healthcare professionals are proactive, anticipating the development of new medicines and providing advice on the potential value of a new medicine to regulators. This is currently being implemented in the Netherlands through interaction between the Dutch Healthcare Institute, responsible for the evaluation of new medicines, their Horizon scanning tool and the medicines committees of the scientific associations [53]. As orphan medicines are seen as risky by payers because of price and uncertain effects, these collaborations, including interactions with industry, are also needed to pave the way to access. A new collaborative route for orphan medicines in the Netherlands is the orphan drug access protocol (ODAP) [54], that is designed to expeαdite access to promising, non‐oncological orphan medicines, supported by Dutch health insurers (Zorgverzekeraars Nederland). It focuses on controlled access through clear arrangements regarding medicine use, data collection, and pricing, while also ensuring a “socially acceptable price” and rational use. Access is granted under a specific protocol, developed by healthcare professionals with input from patients, including criteria for starting, stopping, and measuring the medicine's effect. This is combined with a three‐phase pricing strategy, where the price reflects the remaining uncertainty about effectiveness. In this way, risks are shared by the industry and society. Through the ODAP route, three medicines have now become available, including lumasiran, an RNA interfering (RNAi) therapy for primary hyperoxaluria type 1, showing that centralized decision‐making results in rational use and cost minimization [55]. The controlled strategy also aims to accelerate access, as demonstrated by another medicine made available through this route: sutimlimab, indicated for the treatment of cold agglutinin disease. Through ODAP, this orphan medicine became available to patients within 9 months of EMA approval, significantly earlier than in most other EU countries [56].

A crucial issue, relevant for these controlled early access routes, is how to determine a socially responsible price when there is uncertainty about the precise indication and the long‐term clinical benefit. As explained before, a value‐based approach is common in most EU member states to determine a socially acceptable price, but in these cases, calculating a reliable incremental cost effectiveness ratio can be challenging or even impossible. Novel investment‐based models need to be developed, such as those already proposed in the literature [57, 58, 59, 60] By transparently and systematically mapping real investments, risk, and expected market size, such models enable early‐stage pricing based on objective, auditable inputs, which can be updated over time as more clinical evidence becomes available. This not only enhances transparency and predictability but also fosters more informed negotiations between manufacturers and payers, especially relevant when there is uncertainty about a products effectiveness, as in conditional access routes like ODAP. Importantly, disaggregating the price into its underlying components allows for more meaningful discussions about what society is willing to pay for each element– such as what level of profit margin is reasonable, or how far the price should accommodate cost‐of‐failure and investment risk– rather than debating the final price in isolation. However, such investment‐based models would require greater disclosure from pharmaceutical companies regarding actual R&D expenditures, reinforcing ongoing calls for increased transparency from scholars and policy organizations [19, 57, 58]. Investment‐based models have also been proposed as a more realistic and defensible approach for medicines that have been hijacked by industry such as chenodeoxycholic acid for the treatment of cerebrotendinous xanthomatosis or mexiletine for the treatment of non‐dystrophic myotonia [4, 59]. In both cases, the medicines were already used for decades but the availability was variable since no formal marketing authorization existed. Taking the efforts to bring such a needed product to the market, guaranteeing sustainable access, is worth something. But in these cases the subsequent extreme prices charged, in the range of an innovative small molecule for which years of investigations, clinical studies and production investments needed to be made, are not defendable [4, 59]. By using an investment‐based model in these cases, an estimate can be made of a realistic price that reflects the effort made to bring the product to market.

4.4. Post‐Authorization Assessments, Registries and Rational Use

Post‐authorization studies or assessments of real‐world outcomes are often required either for EMA or reimbursement purposes. Registries can be particularly useful to determine long‐term safety and effectiveness of newly introduced medicines. However, previous registries have not always been designed to capture the information necessary for regulators to be able to re‐evaluate the long‐term effectiveness. Therefore, it is important to create a structured approach of planned data collection and evaluation to ensure timely and high‐quality evidence generation which can also be used in decision‐making [3, 60]. Although registries can be used to inform clinical, reimbursement and regulatory questions, it is important to note that some registries imposed on industry by EMA may differ in design from what healthcare professionals and patients envision as useful, which can hamper proper patient reporting and registry data collection. This emphasizes the need for a multi‐stakeholder collaboration of healthcare professionals, patients, industry, and decision‐makers to optimize the usability of evidence generated using real‐world data [61, 62].

For orphan medicines, setting up registries is very common. Recent work by a group of international experts has shown what the basic requirements should be for a rare disease registry, exemplified by rare neurological diseases [63]. In brief, such a registry should be set up early, ideally before new orphan medicines come to the market. It should be led by healthcare professionals and patients, be open to multiple stakeholders, and align with regulatory requirements. Starting with setting up an academic consortium and performing a consensus procedure when establishing a registry can be helpful. High quality data and implementing the FAIR‐data principles (findable, accessible, interoperable, and reusable data) are considered to improve registry robustness. In this way, multi‐purpose disease registries can assist in generating evidence in all phases of medicine development and medicine use/implementation. The MLDI, metachromatic leukodystrophy initiative, has followed these principles and is now widely used both for research, improvement of patient care, and addressing post‐marketing questions such as whom to select for gene therapy (Libmedly) [64].

Registries are not only useful for identifying long term outcomes of newly introduced medicines. They should also evaluate existing treatments for which the level of evidence is low. In the field of inborn errors of metabolism, frequently only a couple of case series or even only case reports exist that underpin the use of certain medicines. Here too, we need to organize ourselves better: collecting existing data and designing prospective studies to monitor the outcomes of medicines in a sometimes very heterogeneous population with a variable, slowly progressive course. This is where the concept of rational use becomes essential. In its official definition by the WHO, rational use means: “Patients receiving medications appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and their community” [65]. While a “treatabolome” can raise awareness, it carries the risk of incorrect treatment or false hope if only a few studies are cited [66]. To implement rational use, we must first consult all available literature and, in cases of uncertainty, establish new studies or registries to expand our knowledge. This should be conducted by groups of experts with knowledge and experience of the conditions in question. The treatment of Fabry disease is an example of this. Only after many years of intensive, independent research did it become clear that enzyme replacement therapy, if started in time, slows disease progression in a subset of patients. Ultimately, it was only 15 years after market approval that a consensus was reached on start and stop criteria [67]. When the effectiveness of the medicine is established sufficiently, further refinement of rational use can take place through strategies such as dose reduction, interval lengthening or by replacement with generics or biosimilars.

5. Summary and Recommendations

The role of academic researchers and clinicians is just one in a complex interplay of different stakeholders, each representing their own or group interest. Currently, within the traditional pathway, their role is fragmented and falls short in different parts of the medicine development chain (Figure 2). While we recognize that this traditional route should remain an option, we believe that academics and healthcare professionals could be more proactively involved throughout the entire drug development chain. As discussed above, this could break the current status quo and contribute to a system change that will give innovations a greater chance of reaching the patient quickly, provide us with better evidence of effectiveness and stimulate more independent entrepreneurship in academia to address market failures. This novel pathway is depicted in the figure and Table 1 as new roles, which are relevant to both academia‐driven medicine development and industry‐driven medicine development. Clearly, this also requires changes in government, regulators, payers and industry so that academics can take on this task.

FIGURE 2.

Role of academia in medicine development. Traditionally, academia plays a fragmented, reactive role after out‐licensing an academic discovery. Industry is in the lead, with a usually paid role of academia that carries a risk for conflicts of interest. The post authorization phase is primarily a one‐to‐one interaction between industry and academia, with academia taking up a role in post‐authorization research or as a consultant in education. This pathway will remain an option. In addition, the suggested new role of academia can be split into academia‐driven or industry‐driven pathways. Within academia‐driven pathways, academia can stay in the lead in public‐private partnerships with private investors, For example, in a steward‐owned company, or engage in an agreement with industry following socially responsible terms. Academia should also play a more proactive role in industry‐driven developments by trying to reduce risk by performing trials at cost price and collaborating with regulators and industry on access pathways. In return, socially acceptable pricing should be applied, if needed in the context of rational use protocols that usually require disease registries.

TABLE 1.

Current state and recommendations for the role of healthcare professionals in academia and industry‐driven orphan medicine development and access.

Aspect	Current state	Recommendations
Academia driven
Orphan medicine development	Fragmented across early stages	Promote academic participation throughout the full medicine development cycle
Knowledge on regulatory aspects	Lack of knowledge and how to receive adequate support	Include regulatory, health economics and market access training in academic translational programs
Valorization and pricing	Largely absent from academic focus	Create a single point of contact for medicine development at institutional level; implement socially responsible principles in licensing or partnership agreements
Regulatory engagement (EMA)	Free advice offered since 2020	Increase awareness and utilization of EMA's academic support initiatives
Rational use	Limited incentives for rational use strategies	Integrate rational use strategies throughout the entire life cycle of a medicine
Industry driven
Industrial medicine development pathway	Academia participates but often not continuously and with risk for conflicts of interest	Develop long‐term academic‐industry partnerships while maintaining independence; involve academia in trial design; keep trial costs at cost price
Evaluation of potential benefit of a new orphan medicine	Academia has a reactive role as consultant for regulators and payers	Proactive role, anticipating on entry of new medicines, in collaboration with all stakeholders
Access pathways and pricing	Largely absent from academic focus	Collaborate with regulators, payers and industry to develop controlled access pathways; support research into pricing models
Post‐authorization studies and registries	Academia participates but often reactive and depending on industry	Proactive, independent participation; Set up multi‐purpose disease registries accessible to all stakeholders

6. Conclusions

The current system is unfit for purpose to enable the timely, equitable, and affordable entry of novel highly specialized therapies into the market. Fragmented academic involvement, limited transparency in pricing, and uncertain post‐approval evidence undermine both access and sustainability. A more integrated model is needed—one that aligns scientific innovation with regulatory, economic, and societal considerations. Strengthening public–private collaboration, ensuring early academic engagement, and embedding socially responsible frameworks are essential to balance innovation incentives with public value and patient access.

Academia bears a key responsibility to engage beyond discovery—contributing to trial design, regulatory dialogue, and value‐based access to ensure that public research delivers equitable health outcomes.

Author Contributions

C.H. and S.v.d.B. drafted the article. All other authors revised the article critically for important intellectual content. All authors read and approved the final version of the manuscript and agree with submission. This work has not been published/submitted elsewhere.

Funding

This work was supported by the Nationale Postcode Loterij as a part of the platform Medicines for Society: Lottery Health Research.

Conflicts of Interest

C.H. is chair of RARE‐NL foundation and member of governmental advisory committees related to medicine evaluation and access and initiator of Medicijn voor de Maatschappij. S.v.d.B. is director of RARE‐NL and coordinator of Medicijn voor de Maatschappij. S.d.V. is employed by FAST. V.v.d.W. is shareholder of Orfenix and director of commercial companies under social terms. K.V. and N.R. are supported by a grant from healthcare insurers for ODAP. M.L. is involved in premarketing studies with Sanofi and Chiesi. Financial arrangements were made through AMC Research BV. No fees, travel support, or grants were obtained from the Pharmaceutical Industry. All other authors are financially supported by Nationale Postcode Loterij as part of Medicijn voor de Maatschappij.

Hollak C. E. M., Rosenberg N., Post C., et al., “Medicine Development and Access for Rare Diseases: Can We Do Better?,” Journal of Inherited Metabolic Disease 49, no. 2 (2026): e70146, 10.1002/jimd.70146.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.