The first book on rare diseases was published in 1581 under the title Medicinalium observationum exempla rara, recognita et aucta accessere et alia quaedam, quorum elenchum pagina post praefationem exhibit.
The principal author was Rembert Dodoens, and co-authors were Valesco de Tarenta, Alexander Benedictus, Antonio Benivieni, Maternus Cholinus, Mathias Cornax, Achilles Pirmin Gasser and Gilles de Hertoghe.1 The book lists 189 rare diseases in the 16th century, such as aneurisma, calculus in vesica (bladder stone), catalepsis (seizure), diabetes, dysenteria, gemini pueri (twins), lapides in vessica fellis (gall stones), mania cum melancholia affinitatem habet (mania with melancholia), scorbutus, tetanos, vermis in vesica (worms in the bladder) and vomitus sanguinis (vomiting blood).
These were all macroscopic (‘de visu et de manu’) or organoleptic observations, as they preceded Antonie Van Leeuwenhoek’s development and use of the microscope in cell- and microbiology.
For pharmacological treatment, Dodoens referred to his own Cruydenboeck (Book of Herbs, Mechelen/Belgium, 1554) with ‘Plaetse, Tijt, Naem, Natuere, Kracht ende Werckinghe’ (growing place and time, name, identification, pharmacological activity) of 942 plants. Procedures for the production of his ‘orphan drugs’ from plant material were given at the end of some monographs. Besides being the first publication on rare diseases, this was also a very early attempt to share best practices between eight physicians about the diagnosis and treatment of rare disorders.
Through the ages
Over the last 500 years at least, there has always been interest on the part of the medical and pharmaceutical professions in the diagnosis and treatment of disorders that have a low prevalence. Lifestyle changes (scorbutus/vitamin C; dysenteria/better quality of drinking water) and vaccinations (tetanos/Clostridium) have almost eliminated some, and a better understanding of the diseases has led to prevention and better therapies.
Diagnostic procedures have changed tremendously over time. Compounding medications following standard operating procedures (SOPs) and good manufacturing practice is still practised today but most of the medicinal products for the prevention, diagnosis and treatment of a limited number of rare diseases are now commercially available.
Today 129 orphan drugs are authorised by the European Medicines Agency (EMA) for the diagnosis, prevention and treatment of chronically debilitating or life-threatening diseases having a prevalence of not more than 5 in 10,000 of the general population.2 Once they are approved for marketing in the EU, orphan drugs benefit from the incentive of ten years of market exclusivity in all EU Member States. Reimbursement, however, is left to the decision of the different Member States, which gives rise to several ethical and social concerns.3 Medical devices and in vitro diagnostics (for example, ‘companion diagnostics’) are standards of care for rare disease patients. A new EU directive is scheduled for release in the first half of 2017.
Off-label use of a medicinal product entails the intentional use for any indication, population, dosage, administration route, or treatment duration other than that approved by a country’s authority. For the most part, off-label use of medicinal products is not underpinned by rigorous clinical and non-clinical trials necessary to confirm quality, efficacy and safety. Off-label use of medicinal products is quite common in rare diseases in the absence of an on-label treatment,4 and because of the limited number of patients.
The risks associated with off-label use makes the sharing of data between different health professionals very important. In the literature, there is a tendency to report only positive results with off-label use and efforts should be made to share both adverse and positive events linked to the off-label use.5 Also medical devices are used off-label mainly in the surgical treatment of rare disorders.6 Besides off-label use, unlicensed medications are often compounded when there is no appropriate dose or administration route available (especially for children).
The sharing of SOPs can help to improve the quality and stability of the compounded pharmaceutical. Import of medicinal products that have no authorisation in the patient’s state can also be necessary. The cross-border healthcare directive (2011/24/EU) is laying down measures to facilitate the recognition of medical prescriptions issued in other Member States.
When there is no on-label or off-label medication, pharmacists compound medicinal products for the prevention, diagnosis and treatment of rare disorders. Ordering primary ingredients for this compounding can be a challenge when there is no monograph in any national or international pharmacopoeia (such as for diphenylcyclopropenone (alopecia totalis) and bi-myconase (congenital sucrase isomaltase deficiency)). SOPs to obtain the best possible pharmaceutical product must be shared between the compounding pharmacists.7
Examples of compounded orphan drugs include sodium benzoate injections (congenital hyperammonaemia), primaquine diphosphate capsules (Plasmodium vivax), cysteamine eyedrops (ocular cystinosis), carmustine ointment (lymphoma), capsaicin nasal spray (idiopathic rhinitis) and LevoArginine oral solution (citrulinaemia). Some EU Member States have ‘specials’ regulations to produce unlicensed medications when there is no registered pharmaceutical product.
The European Commission is now installing European reference networks8 for rare diseases to serve as European research and knowledge centres, updating and contributing to the latest scientific findings to ensure the availability of subsequent treatment.9 Pharmacists should contribute to this initiative as experts in prevention and dispensing of medicinal products and devices and the EU cross-border healthcare directive will be very helpful.
Today orphan drugs are mostly high-cost drugs10 but their budget impact is rather low due to the limited number of patients. As the authorisation of orphan drugs is a European regulation, pricing and reimbursement is different in every EU Member State. A common European health technology assessment recommendation could help to reimburse correctly orphan medicinal products in the different EU Member States.
Joint procurement of orphan drugs as proposed by the Austrian, Belgian and Dutch Ministers of Health will be instrumental in negotiating prices with pharmaceutical companies, exchange information, share registers and coordinate evaluation methods. Recommendations to stop useless treatment can be based on the evidence collected here. Generics of orphan drugs (for example, imatinib and sildenafil) are rather limited and biosimilars are not marketed yet.
Social media and mailing lists play a major role these days in the sharing of information on many subjects such as orphan drugs and rare diseases. Several Facebook, Reddit and Twitter accounts (@RareDiseases, @CheckOrphan, @eurordis, @RareDR, @RareConnect, @DoomsMarc) share daily information on the treatment of diseases with a low prevalence.
Several websites contain valuable information on orphan medicinal products in Europe such as Orphanet (www.orpha.net/consor/cgi-bin/index.php), the EMA (www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp), Eurordis (www.eurordis.org/) and Hospital Pharmacy Europe (www.hospitalpharmacyeurope.com/).
Sharing of information about the diagnosis, prevention and treatment of diseases with a low prevalence is key for better care. Hospital pharmacists have a key role to play and must contribute to aspects such as dispensing, production and pharmacovigilance of orphan drugs.
- A rare disease is defined by the European Union as one that affects less than 5 in 10,000 of the general population.
- The first book on rare diseases was published in 1581 and documented nearly 200 diseases of low prevalence.
- Sharing of information about the diagnosis, prevention and treatment of rare diseases is key for providing better care.
- As the authorisation of orphan drugs is a European regulation, pricing and reimbursement can be different in every EU Member State.
- Hospital pharmacists have a key role to play and must contribute to aspects such as dispensing, production and pharmacovigilance of orphan drugs.
- Dooms M. Rare diseases and orphan drugs: 500 years ago. Orphanet J Rare Dis 2015;10:161. https://ojrd.biomedcentral.com/articles/10.1186/s13023-015-0353-3 (accessed December 2016).
- European Medicines Agency. Orphan designation. www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp&mid=WC0b01ac05800240ce (accessed December 2016).
- Pinxten W et al. A fair share for the orphans: ethical guidelines for a fair distribution of resources within the bounds of the 10-year-old European Drug Regulation. J Med Ethics 2012:38:148–53.
- Dooms M, Cassiman D, Simoens S. Off-label use of orphan medicinal products: a Belgian qualitative study. Orphanet J Rare Dis 2016:11:144. https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0507-y (accessed December 2016).
- European Medicines Agency. Access to EudraVigilance data. www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000674.jsp (accessed December 2016).
- Dooms M. Orphan devices: yesterday is history, tomorrow is mystery: towards a European orphan device directive? Orphanet J Rare Dis 2016;11:22. https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0393-3 (accessed December 2016).
- International Society of Pharmaceutical Compounding. www.isphc.org/ (accessed December 2016).
- European Commission. European networks of reference for rare diseases. http://ec.europa.eu/health/rare_diseases/european_reference_networks/erf/index_en.htm (accessed December 2016)
- Hollak CE et al. Position statement on the role of healthcare professionals, patient organizations and industry in European reference networks. Orphanet J Rare Dis 2016;11(7). https://ojrd.biomedcentral.com/articles/10.1186/s13023-016-0383-5 (accessed December 2016).
- Simoens S et al. Cost-effectiveness assessment of orphan drugs: a scientific and political conundrum. Health Econ Health Policy 2013;11:1–3.