The introduction of the Orphan Drug Act in the USA in 1983, followed by adoption of the Orphan Drug Regulation No 141/2000 in the EU in 2000, changed the landscape of drug development for rare diseases (1, 4). Both the FDA and the EMA subsequently issued multiple guidances and programs to help drug developers navigate implementation of respective Act and Regulation and provided various incentives to encourage drug development for rare diseases. To evaluate the potential impact that guidances could make on the development of treatments for rare diseases we conducted a search of EMA and FDA websites and identified rare disease specific guidances. 35 FDA guidances and 12 EMA guidances were identified, all guidances are listed under Reference section for ease of the review (5–52). In our opinion, the number of published guidances demonstrates interest and support for the rare disease community by both the EMA and FDA. However, the fact that FDA published almost 3 times more guidances than EMA may indicate that FDA has more dedicated resources and this could encourage sponsor to prioritize engagement with FDA during the product development, approval and access strategy. For ease of comparison and to avoid duplication we excluded general guidances that are applicable to product development for all products. For example, ICH guidances on quality, efficacy and safety are deliberately excluded from the evaluation, as all sponsors should consider ICH guidances during drug development, regardless of whether the drug is being developed for treatment of rare disease or not. It should be noted that while the FDA has a website on Guidance Documents for Rare Disease Drug Development, the EMA guidelines relevant to rare diseases are published separately and could be found through a search of general guidances on the EMA website (53, 54).

The summary of guidances and the trend in guidance publication are presented in Figure 1 with the detailed titles and dates of publications presented in the Reference section (1, 4–53). There was a notable uptick in the annual number of guidances published by the FDA starting from 2015, albeit with an obvious drop in 2020 when everyone was focused on addressing the COVID-19 pandemic. Rare disease guidances publication from the EMA has been consistent since the 2000. In our opinion the most impactful guidances are the ones that encourage sponsor to use innovative and collaborative approaches to drug development, for example, FDA Draft Guidance Pediatric Rare Diseases-A Collaborative Approach for Drug Development Using Gaucher Disease as a Model (12) and EMA Guideline on clinical trials in small populations (43). The evaluation of regulatory guidances reveals some differences in FDA and EMA approaches to providing regulatory directions. In general, the FDA guidances focus on common issues and specifics of product development for all rare diseases with the exception of disease specific guidances for Duchenne and Gaucher diseases, the latter of which was done in collaboration with the EMA. The EMA issues more disease specific guidances, with the intent to help sponsors with drug development guidance for specific diseases. For the purpose of this paper, we only focused on guidances, however, it should be noted that both Agencies expanded their work outside of just publishing guidances. There were multiple incentives and engagements with major stakeholders in rare disease drug development in addition to collaborative efforts between EMA and FDA in a Rare Diseases Cluster, which was established in 2016. Another noticeable EU initiative, supported by EMA, is Medicines Adaptive Pathways to Patients (MAPPs) which is a concept that seeks to foster access to novel/beneficial treatments for the right patient groups at the earliest appropriate time in the product life-span, in a sustainable fashion. MAPPs is not an official designation and is not intended to create new regulatory or legal frameworks (55). Both FDA and EMA have multiple incentives to facilitate drug development for life-threatening and debilitating diseases. Although, the discussion of these incentives is outside of the scope of this paper, a high-level overview of these incentives and timeline of implementation is presented in Table 1. These incentives in combination with regulatory guidances created a supportive network for rare diseases drug development and reflected in significant increase in orphan drug designation and approvals. For example, FDA approved 470 orphan drugs in the period 2013–2022, which is a 6 fold increase compared to the 80 orphan drugs approvals in the period 1983–1992 (56).

In totality the cumulative efforts that were made by both EMA and FDA resulted in significant increase in drugs for rare diseases, as presented in the next section.

To evaluate the impact of changes in the regulatory and access landscapes on the number of rare disease treatments available in US and EU we accessed the GlobalData system. As a “baseline” we extracted all marketed products for the treatment of rare diseases that were listed in the database from 1990–2000, before the ODA and Orphan Drug Regulations in USA and EU, respectively could have reasonably impacted drug approvals. To evaluate the impact of changes in regulatory and access environment we used the same criteria and extracted products for rare disease treatments marketed from 2013–2023. The 1990–2000, timeframe was selected because the drugs marketed during this period were unlikely to have benefited from orphan drug legislative incentives. The 2013–2023 timeframe was chosen, because drugs marketed during this period were considered to have both the time and opportunity to have benefited from orphan drug incentives. We selected all types of products for treatment of rare diseases, including but not limited to small molecules, biologics and combination products. During the EU data analysis it was not possible to establish a clean dataset for EU marketed products due to multiple factors, including but not limited to placement of the same product on the market under duplicate licenses. Therefore, the analysis proceeded with the data from the US only, however, some specific examples of access considerations in EU were evaluated and presented further in this publication. The graphical representation is provided in Figures 2, 3. Figure 2 depicts the total number of products marketed in the USA during the two periods as well as a breakdown of the data by branded and generic products.

Overall, the number of marketed products per decade increased from 255 in 1990–2000 to 1,571 in 2013–2023, a 6-fold increase. This increase clearly indicates that incentives and support, provided to rare disease drug developers, including, but not limited to increase in guidances, had a significant impact on access. When looking at the changes for branded innovator products and generic products separately, both showed a marked increase in availability (3-fold and 11-fold respectively) between 1990–2000 and 2013–2023. The increase in the availability of new treatments is much higher in some therapeutic areas than others, as presented in Figure 3. Therapeutic areas showing a higher increase in new products for Rare Diseases included oncology, metabolic, hematological disorders and central nervous system and cardiovascular disorders. These areas are also ones which in general are current areas of focus for pharmaceutical R&D. Despite the clear increase in the number of products reaching the market for Rare Diseases in 2013–2023 access to these products has presented a variety of challenges, as discussed in the next section.

Timely access to medicines is essential to reduce morbidity and mortality of orphan diseases. However, regulatory approval still does not guarantee access for patients. According to the European Federation of Pharmaceutical industries and Associations there is still considerable variation in time across the EU Member states between the authorization and reimbursement of new medicines with mean time to reimbursement ranging from 102 days in Germany to 993 days in Poland (57).

The US Orphan Drug Act, and the European Orphan Medicinal Product Regulation were big steps toward greater availability of orphan medicines. While orphan designations directly translate into easier access to therapies via compassionate use, and early access programs, the effective access to orphan medicines in a targeted population of interest remains complex as healthcare decision makers need to allocate resources for drug funding within already constrained healthcare budgets. The complexity of access challenges is multifaceted, and may include:

Although it is beyond the scope of this publication to describe the evolution of the pricing, reimbursement and access landscape of both the USA and the EU member countries, we have explored access context of the leading European markets such as Germany and France to compare to the evolution of regulatory policies previously described. Although reimbursement legislation and policies vary across the EU member states, they all provide public healthcare coverage. We delve into Germany and France as the first two countries in terms of pharmaceutical market value in Europe (€47.588 billion and €32.077 billion sales in 2021, respectively) (70). Among the key five European markets (4 EU member states and UK) Germany and France had historically the best access indicators for orphan medicines (number of medicines reimbursed and months to reimbursement) (71). In both countries reimbursement is linked to the outcomes of national health technology assessment (HTA) and medicines with positive HTA recommendation are funded through healthcare payer budgets. In contrast to primarily cost-effectiveness HTA framework, both countries have a system driven by assessment of clinical benefit and reimbursed price based on the demonstrated level of additional clinical benefit over standard of care therapies, German policies incentivize access to all medicines through a 6-month free pricing mechanism and availability immediately upon EMA regulatory approval (117). Moreover, access to orphan drugs is facilitated given that these medicines are exempt from the full HTA (i.e., the need to demonstrate benefit versus an appropriate comparator) and approval is granted based on a minimum level of additional benefit. Orphan medicines are required to undergo full HTA only after exceeding the threshold of €30.0 million annual sales (117). In contrast, there is no designated market access pathway for orphan medicines in France, but there are early access (EA) mechanisms in place allowing innovative medicines to be funded prior to the EMA regulatory approval and/or prior to the completion of the HTA (72). The EA mechanism has proven particularly effective for rare genetic conditions that are highly debilitating, especially those with early-onset: since 2016 the EA program facilitated access of three innovative therapies for spinal muscular atrophy (SMA) type 1, 2 or 3: 48 patients were enrolled in the nusinersen EA program (Oct 2016–Jun 2017), 14 patients enrolled in onasemnogene abeparvovec EA program of (Jun 2019–May 2020) and 110 patients enrolled in risdiplam EA program (Dec 2020–Apr 2021) (73, 74).

While there are additional similarities and differences in the reimbursement processes between Germany, France, and other EU member states, these are not expected to significantly impact access to orphan medicines and are outside the focus of this publication.

In the US, access to orphan drugs, like other drug products, is governed by the major purchasers of healthcare in the US which are largely the government programs of Medicare, Medicaid, and health insurance exchanges, and the employer-sponsored insurance market. Typically, orphan drugs require prior authorization, which is a mechanism payers use to manage utilization and ensure that physician drug choices are clinically appropriate and within label. Orphan drugs, due to their high cost, usually have fairly detailed prior authorizations, which may require submission of clinical documentation and justification of medical necessity. Prior authorizations for orphan drug products often include some key inclusion/exclusion criteria from clinical trials, in an effort to achieve the clinical outcomes seen in that setting. While a critical tool to ensure appropriate use, prior authorizations can result in delays in treatment. Most patients in the US market experience some form of cost sharing for drugs as well, which can create another barrier to access.

In Germany and France, the reimbursement of orphan medicines in therapeutic areas in which an increase in availability was noted (oncology, central nervous system, hematological and metabolic disorders) has largely followed the regulatory pace with some delays in time to effective access driven by the time taken for the HTA assessment and price negotiation (e.g., in France). The areas with more prominent differences between the number of regulatory approvals, access in the US and that in the EU members states are rare genetic diseases with recent approvals of novel gene therapies. Among the 7 non-oncology gene therapies which had FDA and EMA regulatory approvals (<etranacogene dezaparvovec for severe haemophilia B, betibeglogene autotemcel for transfusion-dependent beta-thalassemia, onasemnogene abeparvovec for spinal muscular atrophy, valoctocogene roxaparvovec for severe hemophillia A, voretigene neparvovec for retinal dystrophy, exagamglogene autotemcel for sickle cell disease and transfusion-dependent β-thalassemia, and lovotibeglogene autotemcel for metachromatic leukodystrophy), all 7 are funded and available in the US, 5 received positive HTA recommendations in Germany and France (etranacogene dezaparvovec, onasemnogene abeparvovec, valoctocogene roxaparvovec, atidarsagene autotemcel, and voretigene neparvovec), but information on effective access including price were not identified for etranacogene dezaparvovec, nor valoctocogene roxaparvovec in France (64–67, 73, 75–91, 118). Potential uncertainties associated with perceived drug value and long-term treatment benefits were mitigated with mandatory data collection and/or re-assessment upon more evidence being available. In addition to the evidence driven hurdles during the HTA process, access to orphan medicines in the EU-member states, such as Germany and France, may be driven by manufacturer decision to opt out in instances when healthcare payer acceptable price is not commercially viable for manufacturers. Although these are rather exceptions, after unsuccessful price and reimbursement negotiations in Germany Bluebird decided to focus betibeglogene autotemcel efforts on the US market citing “challenges of achieving appropriate value recognition and market access in Europe” (92). Which lead to complete withdrawal of the EMA authorization in 2022 (75).

Manufacturers of orphan drug products sold in the US are free to set and change price according to market demand, and all payers are compelled to provide access to products deemed medically necessary (or justify why it is not medically necessary for that patient). This has resulted in multi-million dollar prices for one-time administrations of gene therapies, albeit with substantial authorization criteria from payers, both government and private. Yet, these are sometimes life-saving and life-changing therapies, so from a health economic perspective, many gene therapies are cost-effective in the short and long term views.

The pricing of many orphan drug products in the US has created an access environment in which they are likely to be covered for eligible patient populations, but with real financial impact to public and private payers. This has spurred the development of risk-sharing agreements in which failure to achieve a clinical outcome is tied to some level of financial remuneration. These agreements, when in place, offer some downside protection to payers while also ensuring access to these medications for patients.

Overall, access to orphan medicines is complex and multi-faceted. Local healthcare decision makers have made steps and progress in implementing mechanisms to facilitate access, but the work is still ongoing in making therapies timely available to all the patients in need.