In recent years, there have been significant technological advances in biomedical research that have been quickly translated into clinical practice (Zeggini et al., 2019; Tsimberidou et al., 2020). The pharmaceutical industry is shifting its focus from traditional research and development programs targeting common diseases to a new approach of discovering treatments for rare and hard-to-treat illnesses with unmet medical needs (Attwood et al., 2018). However, these advances also come with a significant increase in healthcare costs (Keehan et al., 2015).

The European Medicines Agency (EMA) plays a significant role in evaluating pharmacological innovations and issuing opinion for their commercialization in the European Union (EU) countries (European Medicines Agency, 2020a). The European Commission then ultimately authorizes the marketing of these medicines in the EU (EUR-Lex, 2004). However, the decision on the pricing and financing of these medications with public funds is a competence of the individual member states (Antoñanzas et al., 2005; Löblová, 2021; Vončina et al., 2021). Finally, regional or local governments, health centers, and healthcare professionals are responsible for deciding which medications to prioritize for certain patients or circumstances in a domestic context.

There is a demand that the process of access to innovative medicines should be faster, and patients should have timely access to new and innovative medicines (Annemans et al., 2011; Baird et al., 2014; Panteli and Edwards, 2018). For life-threatening or debilitating diseases that have limited or no treatment options, access to new drugs can provide relief and improve the quantity and quality of life for existing patients with ominous prognosis. However, many healthcare stakeholders claim that numerous patients with life-threatening or debilitating diseases still do not have access to new and innovative medicines (Baird, et al., 2014; Panteli and Edwards, 2018; Horgan, et al., 2022).

The EMA has acknowledged the existence of unmet medical needs and have established laws and regulations aimed at expediting the development and approval of drugs to address these specific diseases (EUR-Lex, 2004). A group of experts with representatives from the rare disease community, researchers, patient advocates, investors, and pharmaceutical companies has proposed several measures to promote rare disease medicine, including a faster regulatory process (Aartsma-Rus et al., 2021). However, when it comes to regulatory processes enabling quick access to new medicines, it entails accepting a higher level of uncertainty during the approval stage. This has sparked ongoing discussions regarding the most suitable trade-off between speed and the evidence required for the development of new medicines.

In this article we will delves into the complex subject of medications authorized with limited clinical evidence. There are several reasons for granting access to medicines with limited evidence (Table 1). We aim to examine various scenarios encountered in clinical research, including trials conducted without a control group, studies involving a restricted number of participants and limited available information, utilization of surrogate endpoints, accelerated authorizations based on promising initial results pending confirmation from more robust data, as well as conditional authorizations granted under exceptional circumstances. Furthermore, our attention is directed towards the intricate challenges that arise during the decision-making process concerning the funding of these medications. This is particularly noteworthy due to the limited clinical evidence and frequently elevated costs associated with such treatments. Therefore, a thorough evaluation of resource allocation and an assessment of the value and cost-effectiveness associated with these interventions are needed.

Medicine regulation by the EMA aims to ensure that only medicines with a favorable balance of benefits and risks are authorized for marketing. This requires the assessment of three criteria: quality, efficacy, and safety (European Medicines Agency, 2020a). However, conducting the necessary studies to evaluate these criteria can be costly and time-consuming. Incentives have been put in place to encourage research and innovation in areas with high unmet medical need, which can result in a flexibility of regulatory requirements and shortened assessment timelines to avoid delays in access to treatment, especially for serious and urgent illnesses. Therefore, in some cases the regulation procedure offers incentives and is faster and more flexible.

The European Union incentivizes the development of medicines that are intended to treat small patient populations, assuming that the development of these types of medicines may not be financially viable under normal market conditions. The EMA’s Committee for Orphan Medicinal Products (COMP) grants orphan designation to medicines that treat life-threatening diseases with a low prevalence in the EU and offer significant benefits over existing treatments or fill a gap where no satisfactory treatments exist. Orphan drug designation recognizes that the drug is addressing a relevant unmet need, and offers several incentives, including reduced or waived fees, protocol assistance (scientific advice specific to orphan drugs), and 10 years market exclusivity in the EU (EUR-Lex, 2000; European Medicines Agency, 2022a). Orphan medicinal products (OMP) are qualified as such after receiving a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) (European Medicines Agency, 2022a).

Accelerated review processes have been developed to reduce the time required by the EMA to review a marketing authorization application for medicines that are considered important therapeutic innovations and are of great public health interest. This expedited review process reduces the review procedure time from 210 days to 150 days, if the applicant provides good cause for an expedited review (European Medicines Agency, 2021a).

The PRIME (PRIority MEdicines) program is an initiative developed by the EMA to improve and accelerate the evaluation and approval process of medicinal products aimed to treat serious and life-threatening conditions with unmet medical needs. The program offers ongoing assistance for the advancement of qualified medications, which have been chosen based on their potential to provide substantial therapeutic benefits compared to current treatments or to benefit patients who lack treatment options altogether. The primary objective is to streamline the medicine development process and expedite access to these innovative treatments (European Medicines Agency, 2023a). The PRIME program provides early and proactive support to medicine developers to generate robust data on the benefits and risks of a drug, and to accelerate the assessment of applications for medicine approvals through early interaction and dialogue with regulators. PRIME allows applicants to receive confirmation during the clinical development phase on whether their drug may be eligible for accelerated assessment (European Medicines Agency, 2023a).

A comprehensive review of the PRIME scheme’s experience since inception and up to June 2021 has been carried out (European Medicines Agency, 2018a; European Medicines Agency, 2022b). The monthly average of PRIME applications in the period was 6.1, with a total of 384 requests of which 25% (N = 95) being granted. Oncology products made up the majority of applications (29%), while advanced therapy medicinal products (ATMPs) had the highest success rate (46%). Orphan-designated products made up 42% of PRIME eligibility applications, and 56% of PRIME products granted eligibility had an orphan designation. Medicines with a PRIME designation more often have conditional authorizations than medicines without this designation (European Medicines Agency, 2022b).

The impact of the regulatory procedures mentioned above has been a progressive increase in the authorization of medicines with orphan and advanced therapies designations (European Commission, 2020; Technopolis Group, 2020) (Table 2). In addition, conditional marketing authorizations and marketing authorizations under exceptional circumstances have also increased, as well as, PRIME designation and accelerated authorization procedures (Table 2) (European Medicines Agency, 2016; European Medicines Agency, 2017; European Medicines Agency, 2018b; European Medicines Agency, 2019; European Medicines Agency, 2020b; European Medicines Agency, 2021b; European Medicines Agency, 2022c; European Medicines Agency, 2023b). The number of orphan drugs and advanced therapies with positive opinion of CHMP to treat diseases in different Therapeutic Areas from 2016 to 2021 is shown in Figure 1. The number of accelerated assessments, conditional and exceptional marketing authorizations, and PRIME designations for medicines with positive opinion from the CHMP for treating diseases in different therapeutic areas from 2015–2021 is shown in Figure 2. Oncology is the therapeutic area with more orphan drugs, advanced therapies, accelerated assessments, conditional and exceptional marketing authorizations, and PRIME designations.

It must be emphasized that currently the European Commission is proposing a review of European Union pharmaceutical legislation, consisting of a new Directive and a Regulation to simplify and replace the previous legislation. The new legislation will promote innovation in the development of new medicines by speeding up the authorization process with simplified procedures, offering tailored scientific support and advice for innovative products, and providing special incentives for rare diseases. The reform aims to provide all patients in the EU with timely and equitable access to safe and effective medicines, and offering incentives for the development of innovative medicines addressing unmet medical needs (European Commission, 2023).

Access to innovative medicines for patients with rare diseases and unmet medical needs is crucial. However, the uncertainties inherent in developing those medicines with a limited evidence pose significant challenges to traditional health technology assessment, and P&R processes.

Firstly and foremost, it is vital to enhance the scientific evidence of those medications. Classic confirmatory clinical trial designs with randomization and control groups, with the best available treatment option, should be the best option, as longas it is feasible (Hulley et al., 2013). This approach ensures rigorous evaluation of treatment efficacy and safety. In addition, it is important to evaluate variables that are clinically relevant, rather than surrogate variables, and demonstrate benefits that are of clinical relevance. This means focusing on outcomes that directly impact patients’ health and wellbeing. Broadening eligibility criteria and avoiding unnecessary exclusions can help to increase the number of included patients in clinical trials, particularly when addressing rare diseases. However, within the realm of rare diseases, where patient populations tend to exhibit a notable heterogeneity, the mere expansion of participant numbers could potentially complicate the interpretation of trial outcomes. This complication might give rise to challenges in pinpointing the specific subgroups that derive benefits from treatments, owing to the inadvertent inclusion of patients with disparate phenotypes. If the traditional design is not feasible, alternative designs such as adaptive designs, and trial designs that aim to gather the maximum amount of useful data from a reduced number of patients could be considered (Pallmann et al., 2018; Subbiah, 2023). Post-marketing real world data has been put forth as a potential surrogate in the absence of good evidence from clinical trials (Swift et al., 2018). However, pragmatic post-marketing research produces a less robust evidence than pre-marketing experimental studies (Makady et al., 2019a).

Secondly, payers may have doubts about the effectiveness, safety, and therapeutic value of a treatment that has not been fully confirmed because they need accurate information to decide P&R of these innovative medicines (Simoens, 2011). There is a concern that payers and society may be burdened with the costs of unproven yet expensive treatments. Healthcare stakeholders should take a comprehensive approach to assess decision-making on access to innovative medicines with limited evidence. This may include restrictive access decisions for conditionally approved products through requesting robust evidence based on well-designed clinical trials able to evaluate both relevant clinical and non-clinical outcomes, in order to ensure guarantees of efficacy and safety of those products and economic sustainability at the population level (Lau and Dranitsaris, 2022).

The regulatory approval process has undergone meticulous review and adaptation to facilitate access of innovative medicines. Similarly, there seems to be a need to revisit the P&R system, through a transparent and evidence-based approach, as well as an effective price regulation, that is able to manage the greater amount of uncertainty resulting from regulatory measures to accelerate access of innovation (World Health Organization Regional office for Europe, 2018).

Fixing a price on a population level, as well as a spending cap per patient, in an uncertain setting should not result in premium prices based on expectations, but on prices that are proportional to its value at the time of P&R, considering the magnitude of benefit but also the strength and different levels of the evidence supporting it. If the evidence for a medicine’s efficacy and safety is weak, the price should also be lower, regardless of other factors, at least until the expectations can be robustly confirmed.

A strategy often applied to manage clinical uncertainty of expensive medicines aimed to small populations are risk-sharing agreements or managed access agreements (MAA) (Bouvy et al., 2018; Dabbous et al., 2020). Thus, when weak clinical evidence, and value and economic uncertainties derive from a large budget impact, an option is measuring outcomes in clinical practice, and linking actual effectiveness to sharing of financial risks. The collection of additional data after conditional authorization aids to confirm that the benefits outweigh the risks, and to ensure that the medicine is able to meet the needs of the population. In this way, risk-sharing arrangements may balance the need to provide rapid access to potentially beneficial medicines with the need to circumscribe uncertainty, obtaining the best value for money and ensuring affordability (Dabbous et al., 2020). Nevertheless, MAA that require collecting additional data by stakeholders (companies and healthcare professionals) may result in biases in support of access, led by conflicts of financial and clinical interests, respectively.

Curiously, the introduction of a medical product to the market with substantial uncertainty, does not inherently lead to the implementation of performance-based agreements. Between 2006 and 2016, managed entry agreements based on clinical outcomes were not commonly used for products that had a conditional marketing authorization or those that were authorized under exceptional circumstances. Of the 48 products that received marketing authorization under exceptional or conditional circumstances in recent years, only a few were found to have managed entry agreements involving the collection of additional data. The complexity of collecting outcomes data in clinical practice led stakeholders to refrain from utilizing MAA approaches (Bouvy et al., 2018). Besides, risk-sharing agreements can be challenging to implement due to their logistical complexities and the resources required, but also, may not be able to meet their goal of clearing uncertainty. A review of conditional financing agreements in the Netherlands (2006–2012) showed that, in 41% of cases, the data on effectiveness obtained were insufficient to draw conclusions, in 50% additional conditions were required, and in 17% cases there were reasons that advised to suspend reimbursement, but this was unfeasible to implement (Makady et al., 2019b).

Collaboration and early dialogue between stakeholders, including patients, is also crucial to manage expectations and to ensure that access mechanisms are transparent and appropriate (Simoens et al., 2022). The new scenario of accepted uncertainty in some relevant therapeutic areas, such as oncology and orphan diseases, will require further innovative approaches that account for such uncertainty in quantifying therapeutic added value and price. Thus, European countries have adopted different mechanisms for addressing these challenges in oncology. These include approaches aimed directly at the issue, such as multi-year-multi-indication agreements, flexible access agreements for new indications with clinical uncertainty, development of a new agreement for each new indication, and immediate access for new indications and bundled assessments. It is important that policymakers, payers and manufacturers engage in early discussions and are willing to find new solutions to manage appropriately decision on access to innovative medicines (Lawlor et al., 2021).

The Oslo Medicines Initiative (OMI) is a collaborative effort between the WHO Regional Office for Europe, the Norwegian Ministry of Health and Care Services, and the Norwegian Medicines Agency. The OMI aims to provide a neutral platform for the public and the private sectors to jointly outline a vision for equitable and sustainable access to and affordability of effective, novel and high-priced medicines, OMI in a technical report summarizes existing policy options for payers that support innovation and access to medicines in the WHO European Region. It identifies various tools, such as early assessment schemes, managed entry agreements, and innovation funds in 48 countries. The report describes methods for generating evidence and manage access to innovation, such as value-based pricing, pooled procurement, and subscription fee-based procurement. It also acknowledges potential limitations of the identified policies, such as financial sustainability of healthcare systems and trade-offs between incentivizing innovation and principles of evidence generation, transparency, and budget impact (Vogler, 2022).

The health and economic impact of making decisions on access to innovative medicines with limited evidence are significant, and it is essential communicating these issues more effectively to the public. Medicines regulation is designed to protect public health, and the requirement of robust evidence is an ethical obligation to ensure that new treatments are safe and effective. The decision-making process on the price and financing of these innovative medicines must be transparent and based on efficacy, efficiency and affordability, to ensure best use of resources and health system sustainability. Both are safety measures aimed to improve the good for the most, acting as filters rather than barriers, and it would be desirable to ensure that this is perceived as such by the public. Filters are a necessary step to ensure that innovative medicines are safe and effective and that they provide value for money, rather than being bureaucratic obstacles to access. A better communication can help to build a more informed and engaged society, trusting and empowering bodies in charge of veiling for public interests, and ultimately improve public health outcomes.

In summary, while the EU regulatory process for access to medicines with limited evidence demonstrates flexibility in addressing rare diseases and unmet medical needs, it also introduces substantial clinical uncertainty for public system payers regarding the efficacy and safety of marketed medicines. The consequence of this is uncertainty about the therapeutic place of these drugs in clinical practice, difficulties in making decisions about the price and financing of medicines, and increased budgets for spending on drugs with little evidence.

Based on the above concepts, it is recommended to ensure a balance between flexibility in order to facilitate access to medicines for rare diseases and unmet medical needs, and the need for rigorous clinical research to provide evidence of safety and efficacy at reasonable and affordable prices in order to make the health system sustainable. This could involve implementing well designed clinical trial and gathering post-marketing real world data for innovative medicines granted accelerated authorization, as well as the implementation of a balanced P&R system, through a transparent price regulation, evidence-based approach withprices proportional to the strength and level of evidence and value-based pricing or managed access agreements.

Lastly, it is crucial to communicate the reasoning behind regulatory and financing decisions in a balanced manner. Presently, when regulatory and financing entities seek substantial evidence to guarantee the efficacy, safety, and efficiency of new innovative treatments, the messaging conveyed by media to healthcare professionals and the broader society often frames it as “barriers to innovation”. While there is always area for improvement in procedural efficiency, it is important to visualize the role of public administration bodies in pursuing the best interest for the most. An excessive simplification of messages may push political decisions on access in absence of guarantees on efficacy and safety of those innovative medicines that eventually could be against the general interest. New treatments must be made available to patients as soon as possible, but in a safe, efficient and responsible way. Being fast should not mean rushing but being more responsive. In the fast-paced world of modern medicine, it is easy to get caught up in the race for speed and efficiency. However, true progress lies in balancing speed with accuracy, and we must strive to move forward quickly without sacrificing the essential elements of patient care.