5.15.3. Data description and analysis

The distribution of RD prevalence is skewed toward very low numbers. Of the 5,000 RD listed in Orphanet, only 105 have a prevalence ranging from 5 to 1 in 10 000 and 233 RD have a prevalence ranging between 1 in 10 000 and 1 in 100 000. Another 1 000 RD have probably a prevalence of around 1 per million, all the other ones (over 3 500 RD) affecting only a few patients worldwide, usually due to a single mutation segregating in family members. These figures have been extracted from literature and cannot be considered as well established. Nevertheless, they are the best information available to date. If accepted, this means that 350 RD affects 80% of the patients and 1,500 RD affect 95% of the patients. The estimated numbers have to be validated by data from RD patients’ registries.

Today, most rare diseases registries monitor a single disease or group of diseases. However, in order to evaluate the total burden of rare diseases on the population, it is necessary to establish area-based monitoring systems that would include all rare diseases. For that purpose, a special legislation was adopted in Italy in 2001 and a specific list of 2 138 specific rare diseases subject to systematic registration has been defined by law. Several regions of Italy (Piedmont, Lombardy, Tuscany, Veneto) have implemented population-based registries. The observed prevalence is 1 in 500 in the general population; this prevalence estimate is however rather conservative, since it is possible that some patients have not been recorded in the registry. A more extended prevalence estimate, which utilises hospital discharge records (HDRs), is 5 per 1 000 inhabitants with a confidence interval of 1-9. This estimation is lower than the prevalence figures typically presented in Europe. However, the estimates provided by the Italian registries, 5 per 1000, can only be considered as minimum estimates, since the registry system has several limitations. The main one is that not all rare diseases are included in the list. Rare tumours, for instance, are excluded, as well as cystic fibrosis. In addition, the health care system, both in Northern Italy and in other places, may produce both underestimation and latency.

Currently, there is no published report available regarding the contribution of RD to morbidity and mortality., A study was performed in 2001 (Drummond et al, 2007) on request by the French muscular dystrophy association (AFM) to assess the contribution of the 200 more frequent RD with a precise ICD code. This study demonstrated that 75% of these 200 RD affect children. In terms of incapacities, 66% of these RD are disabling and for 10% of studied diseases, the patients have no autonomy. In terms of vital risk, only 20% of the studied diseases do not affect life expectancy. For 39% of the diseases the life expectancy is rather short. An analysis of the death certificates in France between 1990 and 1997 revealed that these 200 RD contribute to 1.4% of total deaths, and in particular to 8.3% of deaths before the age of 1 year, to 9.6% of deaths between the age of 1 and 5 and to 12.5% of deaths between 5 and 15 years of age. In terms of hospitalisation, these 200 RD contributed to 1.3% of all hospitalisations during the year 1999 in France. These are the only data available to date.

The cost of treating RD and caring for patients has not been documented. The only available data concerns Orphan Drugs (OD), drugs developed for a rare condition. The European Commission's DG Enterprise and Industry DG has published an independent study on the price of orphan drugs (OD). The study, conducted by Alcimed, looks at the price of orphan drugs authorised in the EU and how these prices were set (ALCIMED, 2004). Several articles have been published which discuss the impact of the OD regulation and the economic burden of these new therapies (Drummond et al, 2007; Dear et al, 2006; Kesselman et al, 2006; Aronson, 2006; Haffner, 2006; Clarke, 2006; McCabe, 2005). Currently over 40 new orphan medicinal products are on the EU market following this regulation. They roughly contribute for 1% of the total pharmaceutical expenses in a country like France. Three times more OD are expected to reach the market in the next 10 years.

A survey, conducted by EURORDIS, has collected data on the access to orphan drugs in Europe (dates of national registries, prices, reasons for unavailability, level of reimbursement, population of patients treated etc.). The survey shows that access differs between countries and is very much delayed in general, a situation judged inequitable and unethical. The study stresses that “the 180 day legal delay for placing medicinal products on the market is not respected, and orphan drugs are made available in a timeframe and under conditions of access that are worse than those for other drugs, although they are intended for rare conditions where there are unmet medical needs”.

Most rare diseases are mendelian genetic disorders and all mendelian genetic disorders are rare as the causal mutations occur rarely and selection forces prevent their wide dissemination. For what concerns mendelian genetic disorders, the MIM catalogue lists 3,600 diseases for which the causal gene(s) is identified and 2,160 for which it remains still unknown. According to Orphanet 1,360 diseases can be diagnosed through a biological test in Europe (mostly molecular). This means that for most diseases, the diagnosis can only be established clinically, i.e. by expert clinicians. The vast majority of genetic diseases are inherited through a recessive mode. The parents are heterozygote for the mutation although healthy. Only 25% of their children carry the double mutation which causes the disease. The identification of at risk couples is hardly feasible. The fact that most genetic diseases mode of inheritance is recessive, implies that consanguinity plays a major role in providing a high likelihood for two people to carry the same recessive mutation, especially for very rare conditions. The consanguinity rate is very different from one population to another, depending on cultural habits. In some cultural groups, up to 25% of couples are first cousins. The prevalence of the recessively determined very rare diseases is therefore dependant on the composition of the population in terms of cultural groups and may vary in time.