Essential list of medicinal products for rare diseases: recommendations from the IRDiRC Rare Disease Treatment Access Working Group.

BACKGROUND: Treatments are often unavailable for rare disease patients, especially in low-and-middle-income countries. Reasons for this include lack of financial 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 first 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-inflammatory, endocrine, pulmonary, and immunologic, plus a miscellaneous 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

A significant unmet need for individuals living with rare diseases is access to beneficial therapies, even those that are approved by major regulatory bodies and are considered as standards of care by experts throughout the world. This issue is especially apparent in low-and-middle-income countries (LMICs) [1] but also affects a substantial proportion of eligible patients in high-income jurisdictions. Of course, this inequity in access applies not only to rare disease drugs but also therapies for common, chronic diseases [2]. However, the disparity is even greater for rare disease treatments [3]. Moreover, while there are international initiatives and programs to make available therapies for conditions affecting large patient populations, such as diabetes, HIV and cancer, there has been little action to improve access to drugs for those suffering from rare conditions [4].

To stimulate a broad response to this unmet need, the International Rare Diseases Research Consortium (IRDiRC) established the Rare Disease Treatment Access Working Group (RDTAWG) with three aims: (1) To improve standards of care for RD patients by promoting access to approved medicines; (2) To initiate research into the barriers to accessing RD drugs, especially in LMICs; and (3) To define opportunities to address those barriers.

This paper is the first of a three-part series with special focus on lack of access to orphan and rare disease drugs in LMICs and also inequitable access in high-income countries. This first paper presents a curated list of medicines considered to be essential for rare disorders and already approved by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and/or China’s National Medical Products Administration (NMPA). The second paper will discuss the barriers to access stratified by types of therapy, characteristics of rare disease populations, and key country parameters such as investment in health, health system capabilities, and rare disease priorities. That paper will also review some existing mechanisms for providing therapeutic access for rare and non-rare conditions. The third paper will consider strategies for improving access directed toward barriers identified along the patient pathway, in general and specific to rare conditions.

Methods

The IRDiRC RDTAWG developed a list of essential medicinal products for rare conditions; the list was not intended to include all medicines used to treat rare diseases but those that could be considered as essential based on approvals by key regulatory agencies in the USA, the European Union (EU) and China for the treatment of rare conditions. Two approaches were used to compile the list. The first approach was to start with databases of medicinal products with designated orphan status or marketing authorizations for rare disease indications. The initial references were the USA FDA Orphan Drug Product Designation database for products approved in the USA [5], the Orphanet list of medicinal products for rare diseases in Europe (2020) [6], and the EMA database of approved products and designations [7]. All drugs with orphan designations and FDA approval were extracted and a list was created, arranged by rare condition usage, generic (medicinal) name, and regulatory approval status. Medicinal products for rare diseases that have European Union marketing authorizations (with or without orphan drug designation) were then collated by using the Orphanet and EMA databases. To round out the list, China’s first published Rare Diseases Catalog [8, 9] of 121 rare diseases/disease types and China’s Lists of Novel Drugs Approved in Other Jurisdictions with Urgent Clinical Needs [10-12] were consulted to develop a list of medicines that were approved for the treatment of recognized rare conditions.

The second approach to developing the essential rare disease medicines list was to start with the World Health Organization Model List of Essential Medicines—21st list, 2019 [13] and the WHO Model List of Essential Medicines for Children—7th list, 2019 [14] to extract all essential medicines that were indicated for the treatment of rare diseases. This exercise identified 26 medicines on the FDA, EMA, and/or China NMPA lists that were also on the WHO essential medicines lists; however, the WHO indication was often not for a rare disease but a more common condition. Some key exceptions are medicines for treating hemophilia, cystic fibrosis, Marfan syndrome, Prader–Willi syndrome, myasthenia gravis, and sickle cell disease.

It is important to note that this collated list does not include any rare cancer drugs. Given the large number and the uniqueness, rare cancers deserve a separate list [15]. The European Joint Action on Rare Cancers initiated this work by conducting a survey for health professionals leading to the identification of 68 essential medicines for the treatment of pediatric malignancies according to best standards [16].

The core WG collated the initial list of medicinal products by eliminating duplicates and combining medicines that were ostensibly versions of a single drug therapy. While strict inclusion and exclusion criteria were not employed in compiling the RD drug list, all the entries were required to be approved by a major regulatory agency. In addition, all were recognized by the authors and the consultant group to have a reasonable risk/benefit ratio and to represent accepted treatments for the diseases under consideration. Drugs were excluded if they had orphan designation but lacked approval, if approval was withdrawn, or if the drug was known to have unacceptable side effects. Some medications in Table 1 are indicated for common disorders but are also treatments for rare subsets of the disorder (e.g., pediatric ulcerative colitis).

Table 1

List of essential medicinal products for rare diseases

	Condition	Drug	Approvals	WHO
Metabolic
	Aminoacid Disorders
	Urea cycle disorders	Benzoate and phenylacetate	FDA
		Sodium phenylbutyrate	FDA, EMA
	N-acetylglutamate synthetase deficiency	Carglumic acid	FDA, EMA
	Homocystinuria	Betaine	FDA, EMA
	Hyperphenylalaninemia	Sapropterin	FDA, EMA, NMPA
	Tetrahydrobiopterin deficiency	Sapropterin	FDA, EMA, NMPA
	Phenylketonuria	Pegvaliase	FDA, EMA
	Tyrosinemia type 1	Nitisinone	FDA, EMA
	Alkaptonuria	Nitisinone	EMA
	Lysosomal Storage Diseases
	Gaucher disease	Miglustat	FDA, EMA, NMPA
		Eliglustat	FDA, EMA
		Velaglucerase alfa	FDA, EMA
		Imiglucerase	FDA, EMA, NMPA
		Taliglucerase	FDA, EMA
	Fabry disease (alphagalactosidase A deficiency)	Agalsidase beta	EMA, NMPA
		Agalsidase alfa	EMA, NMPA
		Migalastat	FDA, EMA
	Lysosomal acid lipase deficiency, Wolman disease, Cholesteryl ester storage disease	Sebelipase alfa	FDA, EMA
	Pompe disease	Alglucosidase alfa	FDA, EMA, NMPA
	Alpha mannosidosis	Velmanase alfa	EMA
	Mucopolysaccharidosis I (Iduronidase deficiency)	Laronidase	EMA, NMPA
	Hunter syndrome (Mucopolysaccharidosis II)	Idursulfase	FDA, EMA, NMPA
	Mucopolysaccharidosis IV (Morquio A syndrome)	Elosulfase alfa	FDA, EMA, NMPA
	Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome)	Galsulfase	EMA
	Mucopolysaccharidosis VII (Sly syndrome)	Vestronidase alfa	FDA, EMA
	Neuronal ceroid lipofuscinosis type 2	Cerliponase alfa	FDA, EMA
	Nephropathic cystinosis	Cysteamine	FDA, EMA
		Cysteamine (enteric coated)	FDA, EMA
		Cysteamine hydrochloride eyedrops	FDA, EMA
	Cholesterol, Lipid, Fatty Acid Disorders
	Homozygous familial hypercholesterolemia	Evolocumab	FDA, EMA, NMPA
		Rosuvastatin calcium	FDA, NMPA
		Lomitapide	FDA, EMA
	Cholesterol and bile acid synthesis defects	Cholic acid	FDA, EMA, NMPA
	Cerebrotendinous xanthomatosis	Chenodeoxycholic acid	EMA
	Familial chylomicronemia syndrome	Volanesorsen	EMA
	Congenital or hereditary chronic cholestasis	Tocofersolan	EMA
	Other Metabolic Disorders
	Pediatric onset hypophosphatasia	Asfotase alfa	FDA, EMA
	Hypophosphatemic rickets (x-Linked)	Burosumab-twza	FDA, EMA
	Hyperphosphatemia in renal failure	Calcium acetate	FDA
	Osteogenesis imperfecta	Alendronate	NMPA
	Scurvy	Ascorbic acid	FDA	WHO
	Metabolic acidosis	Thiamine	EMA	WHO
		Trisodium citrate	EMA
	Genetic carnitine deficiency	Levocarnitine	FDA, NMPA
	Fatty acid oxidation disorders	Triheptanoin	FDA
	Acyl Coenzyme A dehydrogenase deficiency	Riboflavin	EMA	WHO
	Hereditary orotic aciduria	Uridine triacetate	FDA
	Prevention of uric acid nephrolithiasis	Potassium citrate	FDA
	Prevention of cystine nephrolithiasis (cystinuria)	Tiopronin	FDA
	Wilson disease	Penicillamine	NMPA	WHO
		Trientine HCl	FDA, EMA
		Zinc acetate	FDA, EMA
	Cobalamin defects	Hydroxocobalamin	FDA	WHO
Neurologic
	General
	Transthyretin amyloidosis	Inotersen	FDA, EMA
		Tafamidis	FDA, EMA
		Patisiran sodium	FDA, EMA
	Multiple Sclerosis	Teriflunomide	EMA, NMPA
		Fingolimod HCl	EMA, NMPA
		Siponimod	NMPA
	Parkinson Disease (Young and Early-onset)	Rasagiline	EMA, NMPA
		Selegiline	FDA, EMA, NMPA
		Pramipexole	EMA, NMPA
		Carbidopa/Levodopa	FDA, EMA	WHO
	Narcolepsy with cataplexy	Pitolisant	FDA, EMA
		Sodium oxybate	FDA, EMA
	Huntington Disease	Deutetrabenazine	NMPA
		Tetrabenazine	FDA, EMA
	Dystonia, Spasticity	Baclofen	FDA
	Tuberous Sclerosis Complex	Everolimus	FDA, EMA
	Spina bifida (prevention)	Folic acid	EMA	WHO
	Biotinidase deficiency	Biotin	NMPA
	Epilepsy
	Infantile spasms	Vigabatrin	FDA, EMA
	Lennox-Gastaut syndrome	Rufinamide	FDA, EMA
		Cannabidiol	FDA, EMA
	Severe myoclonic epilepsy in infancy (Dravet syndrome)	Stiripentol	FDA, EMA
	Status epilepticus	Midazolam	FDA	WHO
	Juvenile myoclonic epilepsy, Generalized epilepsy	Levetiracetam	EMA
	Complex and rare disease epilepsy	Clobazam	FDA
		Lamotrigine	FDA	WHO
		Topiramate	FDA
	Neuromuscular Diseases
	Amyotrophic lateral sclerosis	Gabapentin	FDA
		Riluzole	FDA, EMA, NMPA
		Radicava	NMPA
	Myasthenia gravis	Pyridostigmine Bromide	NMPA	WHO
	Lambert-Eaton myasthenic syndrome	Amifampridine	EMA
	Non-dystrophic myotonic disorders	Mexiletine hcl	EMA
	5q Spinal Muscular Atrophy	Nusinersen sodium	FDA, EMA, NMPA
Hematologic
	Coagulation Defects
	Hemophilia A (Factor VIII deficiency)	Octocog alpha	EMA
		Rurioctocog alfa pegol	EMA
		Lonoctocog alfa	EMA
		Emicizumab	FDA, EMA, NMPA
		Damoctocog alfa pegol	EMA
		Turoctocog alpha	EMA
		Simoctocog alfa	EMA
		Moroctocog alpha	EMA
		Desmopressin acetate	FDA, EMA	WHO
		Recombinant Factor VIII	EMA, NMPA
		Efmoroctocog alfa	EMA
	von Willebrand disease	Factor VIII/ von Willebrand factor	EMA
		Vonicog alfa	EMA
	Hemophilia B (Factor IX deficiency)	Eftrenonacog alfa	EMA
		Albutrepenonacog alfa	EMA
		Nonacog alpha	EMA
		Human coagulation factor IX	EMA	WHO
		Nonacog beta pegol	EMA
		Nonacog gamma	EMA
		Recombinant Factor IX	EMA, NMPA
	Hemophilia (Factor VII deficiency)	Eptacog alpha (activated)	EMA
		Recombinant Factor VIIa	EMA
	Factor X deficiency	Human coagulation factor X	EMA
	Factor XIII A-subunit deficiency	Catridecacog	EMA
	Protein C deficiency	Human protein c	EMA
	Anemias
	Sickle cell anemia	Hydroxyurea	FDA
	Anemia of end-stage renal disease	Epoetin alfa	FDA	WHO
	Idiopathic thrombocytopenic purpura, Aplastic anemia	Eltrombopag	FDA, EMA
	Beta thalassemia major	Deferasirox	FDA, EMA, NMPA
	Other Hematologic Disorders
	Congenital and acquired methemoglobinemia	Methylene blue injection	FDA
	Acute intermittent porphyria	Hemin	FDA
	Erythropoietic protoporphyria	Afamelanotide	FDA, EMA
	Multicentric Castleman’s disease	Siltuximab	FDA, EMA
	Essential thrombocythemia	Anagrelide hydrochloride	FDA, EMA
	Paroxysmal nocturnal hemoglobinuria	Ravulizumab	FDA, EMA
	Severe congenital neutropenia	Macapegfilgrastim	NMPA
	Conditioning for hematopoietic stem cell transplant	Busulfan	FDA, EMA
		Thiotepa	FDA, EMA
	Iron overload	Deferiprone	FDA, EMA
	Acquired thrombotic thrombocytopenic purpura	Caplacizumab	FDA, EMA
	Immune (idiopathic) thrombocytopenic purpura	Romiplostim	FDA, EMA
	Polycythemia vera	Ropeginterferon alfa-2b	EMA
		Ruxolitinib	FDA, EMA
	Agammaglobulinemia	Immunoglobulin infusion	NMPA
Inflammatory
	Rheumatoid Arthritis
	Juvenile rheumatoid arthritis	Methotrexate	FDA, EMA	WHO
		Etanercept	FDA, EMA
		Methylprednisolone	EMA	WHO
		Adalimumab	FDA
		Infliximab	FDA
		Tocilizumab	FDA, EMA
		Abatacept	EMA
		Golimumab	FDA, EMA
	Gastrointestinal Inflammation
	Pediatric Crohn's disease	Adalimumab	FDA
		Infliximab	FDA
	Pediatric ulcerative colitis	Mesalamine	FDA
		5-aminosalicylic acid	FDA
		Adalimumab	FDA
		Infliximab	FDA
	Primary biliary cholangitis	Obeticholic acid	FDA, EMA
	Hereditary chronic cholestasis	Tocofersolan	EMA
	Angioedema
	Hereditary angioedema	C1 inhibitor(human)	EMA
		Icatibant acetate	FDA, EMA
		Lanadelumab	FDA, EMA, NMPA
		Danazol	NMPA
		Tranexamic acid	FDA, NMPA	WHO
	Angioedema due to C1 esterase inhibitor deficiency	C1-esterase-inhibitor, human	FDA
		Conestat alfa	EMA
	Other Inflammatory Disorders
	Multiple sclerosis, Behcet's disease, Familial Mediterranean fever	Colchicine	FDA, NMPA
	Dermatomyositis, Atypical hemolytic uremic syndrome, Neuromyelitis Optica, Paroxysmal nocturnal hemoglobinuria, Myasthenia gravis	Eculizumab	FDA, EMA, NMPA
	Anti-neutrophil vasculitis, Wegener’s granulomatosis, Churg-Strauss Syndrome	Rituximab	FDA	WHO
	Familial Mediterranean fever, Cryopyrin fevers	Canakinumab	FDA, EMA, NMPA
	Still's disease, Systemic juvenile arthritis	IL-1 Receptor antagonist anakinra	FDA, EMA
	Neurotrophic keratitis	Cenegermin	FDA, EMA
	Vernal keratoconjunctivitis	Ciclosporin	EMA	WHO
	Non-infectious uveitis	Dexamethasone	FDA, EMA	WHO
	Cryopyrin-associated periodic syndromes	Rilonacept	FDA, EMA
Endocrine
	Growth hormone deficiency in children	Somatropin for injection	FDA, EMA
	Acromegaly	Octreotide	FDA
		Lanreotide	FDA
		Pegvisomant	FDA, EMA
		Pasireotide	FDA, EMA
	Endogenous Cushing’s syndrome	Osilodrostat	FDA, EMA
		Ketoconazole	EMA
	Adrenal insufficiency	Hydrocortisone	FDA, EMA, NMPA	WHO
	Idiopathic Hypogonadotropic Hypogonadism	Human chorionic gonadotropin	EMA, NMPA
		Gonadotropin-releasing hormone	EMA, NMPA
	Primary insulin-like growth factor-1 deficiency	Mecasermin	FDA, EMA
	Paget's disease (osteitis deformans)	Calcitonin-human for injection	FDA
	Hypoparathyroidism	Parathyroid hormone	FDA, EMA
	Non-24-h sleep–wake disorder	Tasimelteon	FDA, EMA
	Leptin deficiency in lipodystrophy patients	Metreleptin	FDA, EMA
	Familial partial lipodystrophy	Metreleptin	EMA
Pulmonary
	Pulmonary arterial hypertension	Macitentan	FDA, EMA, NMPA
		Tadalafil	FDA, EMA
		Ambrisentan	FDA, EMA, NMPA
		Nitric oxide	FDA, EMA
		Sildenafil	EMA, NMPA
		Bosentan monohydrate	FDA, EMA, NMPA
		Selexipag	FDA, EMA, NMPA
		Iloprost	FDA, EMA, NMPA
		Parenteral treprostinil	FDA, EMA, NMPA
		Riociguat	FDA, EMA, NMPA
	Cystic fibrosis	Mannitol	FDA, EMA	WHO
		Ivacaftor	FDA, EMA
		Tezacaftor/ivacaftor	FDA, EMA
		Tobramycin	FDA, EMA
		Aztreonam	FDA, EMA
		Colistimethate sodium	EMA
		Lumacaftor / ivacaftor	FDA, EMA
		Levofloxacin	EMA	WHO
	Idiopathic Pulmonary Fibrosis	Pirfenidone	FDA, EMA
		Nintedanib	FDA, EMA, NMPA
	Primary apnea of premature newborns	Caffeine citrate	FDA, EMA	WHO
	Lymphangioleiomyomatosis, Tuberous sclerosis	Sirolimus	FDA, EMA
Immunologic
	Severe combined immunodeficiency, Adenosine deaminase deficiency	Pegademase bovine	FDA
		CD34 + cells transduced with ADA cDNA	EMA
	Chronic granulomatous disease	Interferon gamma 1-b	FDA
Miscellaneous
	Mastocytosis	Cromolyn sodium	FDA
	Ventricular tachycardia	Amiodarone	FDA	WHO
	Limbal stem cell deficiency	Autologous human corneal stem cells	EMA
	Inherited retinal dystrophy	Voretigene neparvovec	FDA, EMA
	Short bowel syndrome	Teduglutide	FDA, EMA
	Hepatic veno-occlusive disease, Sinusoidal obstruction	Defibrotide	FDA, EMA
	Autosomal dominant polycystic kidney disease	Tolvaptan	FDA, EMA
	Patent ductus arteriosus	Ibuprofen	FDA, EMA	WHO
	Anthracycline extravasation	Dexrazoxane	FDA, EMA

List of 204 essential medicinal products for rare diseases with marketing authorization extracted from the FDA database and/or EMA database and/or Chinas’s Rare Diseases Catalog

The goal of the RDTAWG for this first stage of work was identified as the creation of a list of RD medicines that, based on orphan designation and approval or marketing authorization, were efficacious, safe and having a significant impact on the quality and/or duration of life. In some cases, they could be considered standards of care based on widespread and long-term use; however, no attempt was made to categorize the drugs according to life-saving, curative, or beneficial properties.

Moreover, while it was desirable that the medicines on the list could be managed across a variety of countries at different stages of health system development, there was no detailed assessment on the basis of cost-effectiveness, complexity of management, or requirements for administration. Hence, unlike the WHO list of essential medicines, this list of RD drugs is not stratified nor prioritized on the basis of various criteria that could affect feasibility of adoption.

This list is intended to be the initial iteration of a “living document”, to be revised and updated periodically. The list is not based on definitive criteria for inclusion nor is it the product of an expert consensus process. It is not intended to be comprehensive but is proposed to the rare disease community for consideration and uptake as well as a starting point or guide for jurisdictions to set policies on provision of rare disease medicines to their populations.

The compiled list was sent to a group of rare disease specialists (as listed in Acknowledgments) with instructions to review those medications within their area(s) of expertise and, specifically, to eliminate duplicate or redundant medicines, remove drugs considered inappropriate or ineffective, add other drugs that should be on the list, and provide comments as appropriate. Feedback was discussed by all members of the core RDTAWG to arrive at a consensus whether to accept recommendations, or not, to arrive at a final collated list.

Results

The Table 1 presents the current working list of essential rare disease medicines with different versions of a medication listed separately where appropriate. The list is organized into seven disease categories: metabolic, neurologic, hematologic, anti-inflammatory, endocrine, pulmonary, and immunologic, plus a miscellaneous category. Moreover, some diseases cluster together in groups (e.g. Wolman disease and Cholesteryl ester storage disease cluster in the group of Lysosomal acid lipase deficiency). However, in identifying the total number of diseases, these diseases are counted individually and not as a single cluster. Within each category, drugs are listed by subgroupings and specific conditions, with multiple indications where appropriate. The third column gives the agencies that approved the drug; the fourth column notes drugs that are on the WHO Model List of Essential Medicines (21st edition). Some of the drugs have indications beyond those listed in the table. The drugs are not coded in terms of priority, therapeutic strength or equivalence, need for specialized diagnosis or care, or any restrictions (cf. WHO Model List of Essential Medicines). The greatest number of drugs is in the metabolic disease category, but various neurological diseases are extensively represented.

Table 2 provides a summary on the total number of listed diseases, the number of diseases per category, the number of total medicinal products, the number of drugs and biologics, the number of medicinal products per disease category, the number of medicinal products treating more than one disease, and the number of medicinal products approved in each jurisdiction. A total of 134 diseases are listed; among these, the largest category consists of metabolic conditions (n = 40), followed by hematologic conditions (n = 24), inflammatory (n = 23), neurologic (n = 20), endocrine (n = 11), miscellaneous (n = 9), pulmonary (n = 5) and immunologic (n = 2).

Table 2

Number of diseases and medicinal products per category

	Number
Diseases
Total	134
Metabolic/inborn errors	40
Neurologic	20
Hematologic	24
Inflammatory	23
Endocrine	11
Pulmonary	5
Immunologic	2
Miscellaneous	9
Medicinal products
Total medicinal products (MP)	204
Drugs	125
Biologics	79
MP for metobolic diseases	51
MP for neurologic diseases	34
MP for hematologic diseases	43
MP for inflammatory diseases	28
MP for endocrine diseases	15
MP for pulmonary diseases	22
MP for immunologic diseases	3
MP for miscellaneous	9
MP used to treat multiple diseases	6
MP approved by the FDA	139
MP approved by the EMA	160
MP approved by the NMPA	51
MP on the WHO list of essential medicines (2019)	25

Summary of the total number of listed diseases, the number of diseases per category, the number of total medicinal products, the number of drugs and biologics, the number of medicinal products per disease category, the number of medicinal products treating multiple diseases, and the number of medicinal products approved in each jurisdiction

Additionally, as noted in Table 2, the list includes 204 drugs, of which 125 are chemical drugs and 79 are classified as biologics, which also includes recombinant proteins, polyclonal and monoclonal antibodies, and cell and nucleic acid therapies. There are six drugs that treat more than one disease (Additional file 1).

Discussion

Individuals with rare diseases encounter many challenges along the path to appropriate care and treatment. The first obstacle for many is obtaining an accurate diagnosis, which often takes more than 5 years [17]. For many, the next hurdle involves finding expert care and treatment, which can vary depending upon many factors including geographic location and socioeconomic status. In fact, researchers have noted profound disparities across the globe in access to rare disease medicines, with significant impact on health outcomes and quality of life [18, 19]. In 2006, Stolk et al. [20] called for inclusion of RD drugs as essential medicines, but this has not occurred.

Many of the drugs in our RD drug list are not included in the WHO Model List of Essential Medicines.

We note that not all of the drugs on our list are approved across all jurisdictions, and a few with regulatory approval and/or marketing authorization are not indicated for the specified rare disease(s), even if they are recognized as a standard of care or appropriate. Based upon such a lack of indication, some health systems may choose to deny reimbursement even if the drug is inexpensive, genericized and in distribution. This problem affects patients in high-income as well as low-and-middle income countries. Therefore, it is important to take a broader contextual approach to understand the challenges rare disease patients are facing and address them collectively and systematically. Moreover, some of the drugs listed in Table 1 are applicable to only a fraction of the patients who have the associated disease. Ivacaftor for certain genetic subtypes of cystic fibrosis is one example.

Approximately one-third of all persons worldwide, including those in low-income but also middle-income countries, do not have access to essential medicines, specifically drugs, vaccines, and diagnostics for communicable, noncommunicable, social-behavioral illnesses, and emerging environmentally induced diseases [1]. The cause of the problem, like the cause of the diseases, is multifactorial and requires not only multidisciplinary and multisectoral approaches but integrated, holistic innovative solutions. Barriers at the individual level include the lack of health literacy, awareness of therapies, and advocacy capacity. Healthcare professionals similarly may lack awareness of appropriate medicines, knowledge to use effectively, and capacity to advocate for access. Major impediments at the systems level include lack of lower cost alternatives (generics and biosimilars) as well as the lack of regulatory, clinical and infrastructure capacity to make complex innovative therapies available and to deliver them to patients [21]. For example, depending of the type of therapies (chemical drug/biologic/gene or cell therapy), countries or jurisdictions may have to consider the feasibility of establishing and maintaining manufacturing and delivery chains relative to their local capacities. In addition, while nations may be criticized for limited national commitment to healthcare and insufficient investment in universal health coverage, criticism may also be levied on industry for the lack of transparency and high pricing that compromise a nation’s ability to deliver optimal healthcare; this critique is punctuated by the WHO resolution on disclosure of drug prices [22].

Many of the aforementioned challenges (especially regulatory expertise and clinical capacity) have a disproportionate impact on rare disease drugs and patients, but there are additional barriers. Some are grounded in “high evidential uncertainty” in extending clinical trial data to real-world outcomes. This is highly problematic in countries that apply “traditional” health technology assessment (HTA) or value-based assessment (VBA) methodology to RD therapies compared to those jurisdictions that use supplemental processes with greater flexibilities that treat RD treatments differently [23].

How could this list of RD medicines be used? A potential pathway is one based on EMA’s EU-Medicines4all (EUM4all) procedure. EMA established EUM4all to provide expert reviews on benefits and risks of medicines that would be used outside the EU, with emphasis on LMICs [24]. Subsequent analysis found that 138 regulatory approvals had been granted in 90 different countries worldwide for six medicines based on EUM4all opinions, with acknowledged great public health impact.

The EUM4all initiative dealt with a broad range of medicines with high impact in LMICs, but we propose that the procedure could profitably be applied to RD medicines. This paper is intended to elicit suggestions and call for collaborations on how to modify, disseminate, and use the list of medicines in the Table 1. Specifically, the RDTAWG seeks input from RD advocacy groups, healthcare providers, pharmaceutical companies, and government agencies. Subsequent actions include a conference to bring together key stakeholders to elaborate on the list, identify barriers and opportunities for application and collaborate on next steps. The ultimate goal is to enhance access to appropriate medicines for all rare disease patients throughout the world.

Conclusions

The limited number of approved therapeutic options, combined with the unavailability of existing treatments, significantly impair the life of rare disease patients in LMICs. While many countries have recently developed policies and regulations for rare diseases and orphan drugs, access to treatment remains variable among LMICs. With the vision of leaving no one behind, the IRDiRC RDTAWG used the FDA, EMA and China NMPA databases to extract approved drugs and create the first list of 204 essential medicinal products for rare diseases. The list was organized into seven disease categories, excluding rare cancers and rare infectious diseases. The ultimate goal of this list is to further stimulate interactions among patient organizations, health care providers, industry and government agencies to improve standards of care for rare diseases by promoting access to treatments.

Additional file 1. Used to complement the information provided in Table 2. Individual diseases (and not cluster of diseases) are listed by alphabetic order for each category. Medicinal products are filtered by alphabetic order and listed for each disease category. The 6 medicinal products used to treat multiple diseases and the 79 biologics are listed.