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Gahl et al. Orphanet J Rare Dis (2021) 16:308 https://doi.org/10.1186/s13023-021-01923-0 RESEARCH Open Access Essential list of medicinal products for rare diseases: recommendations from the IRDiRC Rare Disease Treatment Access Working Group William A. Gahl1, Durhane Wong‑Rieger2* , Virginie Hivert3, Rachel Yang4, Galliano Zanello5 and Stephen Groft6 Abstract Background: Treatments are often unavailable for rare disease patients, especially in low‑and‑middle‑income coun‑ tries. Reasons for this include lack of fnancial support for therapies and onerous regulatory requirements for approval of drugs. Other barriers include lack of reimbursement, administrative infrastructure, and knowledge about diagnosis and drug treatment options. The International Rare Diseases Research Consortium set up the Rare Disease Treatment Access Working Group with the frst objective to develop an essential list of medicinal products for rare diseases. Results: The Working Group extracted 204 drugs for rare diseases in the FDA, EMA databases and/or China’s NMPA databases with approval and/or marketing authorization. The drugs were organized in seven disease categories: metabolic, neurologic, hematologic, anti‑infammatory, endocrine, pulmonary, and immunologic, plus a miscellane‑ ous category. Conclusions: The proposed list of essential medicinal products for rare diseases is intended to initiate discussion and collaboration among patient advocacy groups, health care providers, industry and government agencies to enhance access to appropriate medicines for all rare disease patients throughout the world. Introduction available therapies for conditions afecting large patient A signifcant unmet need for individuals living with rare populations, such as diabetes, HIV and cancer, there has diseases is access to benefcial therapies, even those that been little action to improve access to drugs for those are approved by major regulatory bodies and are con- sufering from rare conditions [4]. sidered as standards of care by experts throughout the To stimulate a broad response to this unmet need, world. Tis issue is especially apparent in low-and-mid- the International Rare Diseases Research Consortium dle-income countries (LMICs) [1] but also afects a sub- (IRDiRC) established the Rare Disease Treatment Access stantial proportion of eligible patients in high-income Working Group (RDTAWG) with three aims: (1) To jurisdictions. Of course, this inequity in access applies improve standards of care for RD patients by promot- not only to rare disease drugs but also therapies for com- ing access to approved medicines; (2) To initiate research mon, chronic diseases [2]. However, the disparity is even into the barriers to accessing RD drugs, especially in greater for rare disease treatments [3]. Moreover, while LMICs; and (3) To defne opportunities to address those there are international initiatives and programs to make barriers. Tis paper is the frst of a three-part series with spe- *Correspondence: [email protected] cial focus on lack of access to orphan and rare disease 2 Canadian Organization for Rare Disorders, Toronto, Canada drugs in LMICs and also inequitable access in high- Full list of author information is available at the end of the article income countries. Tis frst paper presents a curated list © The Author(s) 2021. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gahl et al. Orphanet J Rare Dis (2021) 16:308 Page 2 of 11 of medicines considered to be essential for rare disorders WHO indication was often not for a rare disease but a and already approved by the US Food and Drug Admin- more common condition. Some key exceptions are medi- istration (FDA), the European Medicines Agency (EMA), cines for treating hemophilia, cystic fbrosis, Marfan syn- and/or China’s National Medical Products Administra- drome, Prader–Willi syndrome, myasthenia gravis, and tion (NMPA). Te second paper will discuss the barriers sickle cell disease. to access stratifed by types of therapy, characteristics of It is important to note that this collated list does not rare disease populations, and key country parameters include any rare cancer drugs. Given the large number such as investment in health, health system capabilities, and the uniqueness, rare cancers deserve a separate list and rare disease priorities. Tat paper will also review [15]. Te European Joint Action on Rare Cancers initiated some existing mechanisms for providing therapeutic this work by conducting a survey for health professionals access for rare and non-rare conditions. Te third paper leading to the identifcation of 68 essential medicines for will consider strategies for improving access directed the treatment of pediatric malignancies according to best toward barriers identifed along the patient pathway, in standards [16]. general and specifc to rare conditions. Te core WG collated the initial list of medicinal prod- ucts by eliminating duplicates and combining medicines Methods that were ostensibly versions of a single drug therapy. Te IRDiRC RDTAWG developed a list of essential While strict inclusion and exclusion criteria were not medicinal products for rare conditions; the list was not employed in compiling the RD drug list, all the entries intended to include all medicines used to treat rare dis- were required to be approved by a major regulatory eases but those that could be considered as essential agency. In addition, all were recognized by the authors based on approvals by key regulatory agencies in the and the consultant group to have a reasonable risk/bene- USA, the European Union (EU) and China for the treat- ft ratio and to represent accepted treatments for the dis- ment of rare conditions. Two approaches were used eases under consideration. Drugs were excluded if they to compile the list. Te frst approach was to start with had orphan designation but lacked approval, if approval databases of medicinal products with designated orphan was withdrawn, or if the drug was known to have unac- status or marketing authorizations for rare disease ceptable side efects. Some medications in Table 1 are indications. Te initial references were the USA FDA indicated for common disorders but are also treatments Orphan Drug Product Designation database for products for rare subsets of the disorder (e.g., pediatric ulcerative approved in the USA [5], the Orphanet list of medici- colitis). nal products for rare diseases in Europe (2020) [6], and Te goal of the RDTAWG for this frst stage of work the EMA database of approved products and designa- was identifed as the creation of a list of RD medicines tions [7]. All drugs with orphan designations and FDA that, based on orphan designation and approval or mar- approval were extracted and a list was created, arranged keting authorization, were efcacious, safe and having a by rare condition usage, generic (medicinal) name, and signifcant impact on the quality and/or duration of life. regulatory approval status. Medicinal products for rare In some cases, they could be considered standards of care diseases that have European Union marketing authori- based on widespread and long-term use; however, no zations (with or without orphan drug designation) were attempt was made to categorize the drugs according to then collated by using the Orphanet and EMA databases. life-saving, curative, or benefcial properties. To round out the list, China’s frst published Rare Dis- Moreover, while it was desirable that the medicines on eases Catalog [8, 9] of 121 rare diseases/disease types and the list could be managed across a variety of countries at China’s Lists of Novel Drugs Approved in Other Jurisdic- diferent stages of health system development, there was tions with Urgent Clinical Needs [10–12] were consulted no detailed assessment on the basis of cost-efectiveness, to develop a list of medicines that were approved for the complexity of management, or requirements for admin- treatment of recognized rare conditions. istration. Hence, unlike the WHO list of essential medi- Te second approach to developing the essential rare cines, this list of RD drugs is not stratifed nor prioritized disease medicines list was to start with the World Health on the basis of various criteria that could afect feasibility Organization Model List of Essential Medicines—21st of adoption. list, 2019 [13] and the WHO Model List of Essential Tis list is intended to be the initial iteration of a “liv- Medicines for Children—7th list, 2019 [14] to extract all ing document”, to be revised and updated periodically. essential medicines that were indicated for the treatment Te list is not based on defnitive criteria for inclusion of rare diseases. Tis exercise identifed 26 medicines nor is it the product of an expert consensus process. It on the FDA, EMA, and/or China NMPA lists that were is not intended to be comprehensive but is proposed to also on the WHO essential medicines lists; however, the the rare disease community for consideration and uptake Gahl et al.

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