In the interest of patients with a rare disorder, but also of other stakeholders, better understanding of the effect of the market exclusivity incentive on follow-on OMP development for a rare disorder for which an approved OMP exists is warranted. The objective of this study was to determine whether the market exclusivity incentive of the EU Orphan Drug Regulation results in a market monopoly, as argued by Roos et al. , or that absence of follow-on OMPs is a matter of time or market size, as claimed by Tambuyzer . First, the impact of various market-, product- and disease-related characteristics on follow-on OMP development in the EU was determined. Comparison of rare disorders with a first approved OMP and at least one follow-on OMP ('Follow-on' group) with rare disorders with a first approved OMP and no follow-on OMP ('no Follow-on group') revealed disease prevalence, turnover of the first OMP, disease class, disease-specific scientific output and age of onset as predictors of follow-on OMP development. Although it was not possible to perform a multivariate analysis and to test whether any of the aforementioned characteristics were mutually related, it is suspected that some level of mutual relationship may exist. Heemstra et al. showed that scientific output for oncologic rare disorders in general is higher than for other rare disorders, which suggests some degree of mutual relationship between disease class and scientific output . Also, the prevalence of a rare disorder and turnover of the first OMP may to some extent be mutually related. Despite the possibility of mutual relationships, our findings are in line with several studies that focused on characteristics that play a driving role in the orphan drug development process [20, 23–25].
The lower likelihood on follow-on OMP development for rare childhood disorders is most likely a natural consequence of the general reluctance of the pharmaceutical industry to invest in the development of specific therapies for a population that is small in number and fragmented into several age groups with often unique requirements [26, 27]. To stimulate paediatric drug development in the EU Regulation (EC) No 1901/2006 on medicinal products for paediatric use came into force in January 2007 . Through a number of regulatory and economic incentives, including extension of the market exclusivity period from ten to twelve years for OMPs intended for a paediatric indication, the legislation intends to have a positive impact on paediatric drug development, although risks and pitfalls remain . Conducting clinical trials for rare indications, especially very rare ones, remains difficult due to a number of well-known practical limitations (e.g. lack of proper diagnosis, finding enough patients, geographical distribution of patient population) . Successful drug development requires thorough disease knowledge, such as its etiology and pathophysiology . The latter explains our finding that, next to initiation of an orphan drug development program , the level of disease-specific scientific output increases the likelihood on follow-on OMP development. It also explains our observation that for rare oncologic diseases the likelihood on follow-on OMP development is higher than for other ICD disease classes. Considerable public and private expenditure on research and a high-level of transnational research infrastructure have resulted in oncology having the highest scientific output in the area of rare diseases [31, 32]. Consequently, oncology represents an attractive indication for the pharmaceutical sector [33, 34], resulting in the highest number of first and follow-on OMPs in development as well as approved . Because of its dynamic and divergent nature, biomedical research can result in several competing hypotheses on the possible causes of diseases, and several promising targets and therapeutical approaches . This makes biomedical research an extremely complex process to manage, and as a result translation of disease knowledge into (follow-on) OMP development requires time.
In contrast to the claim by Roos et al. that the market exclusivity incentive basically creates a market monopoly that in their view allows manufacturers to charge 'exorbitant' prices for orphan drugs , we found that turnover of the first OMP in fact increases the likelihood on follow-on OMP development. The presence of an approved OMP for a rare disorder is a clear indication that development and marketing of a therapy for that specific rare disorder is attainable. However, the mere presence of an approved OMP for a rare disorder is not sufficient; a certain level of profitability is apparently an important prerequisite for the initiation or continuation of the development of a follow-on OMP.
Our finding that prevalence of a rare disease is associated with an increased likelihood on follow-on OMP development provides corroborative evidence for an element in Tambuyzer's hypothesis that if an approved OMP is currently the only product on the market, this can be explained because the market is too small to attract competition . Acemoglu and Linn more generally revealed that an increase in the potential market size for a drug category correlates with an increase in the number of new drugs in that category . The importance of prevalence of a rare disease, which can be regarded as a surrogate marker for market size, was already confirmed in other stages of the orphan drug development process. Heemstra et al. showed that prevalence is a predictor for the translation of rare disorder research into the initiation of an orphan drug development program . Yin reported that "the US Orphan Drug Act has led to a significant and sustained increase in new trials" among more prevalent rare diseases, but not for less prevalent rare diseases .
Tambuyzer's hypothesis is further supported by our finding that in the EU all manufacturers of follow-on OMPs upon approval of the first OMP for the same rare disorder decided to continue development of their product, except for one. Only a substantial level of discontinuation of follow-on OMP development would have indicated the existence of a market monopoly. Discontinuation of several follow-on OMPs was found, however, reasons for discontinuation were related to conducting clinical trials, focus on another more promising indication, registration failure and lack of funding. Apparently, discontinuation of follow-on OMPs is not directly associated with market approval of a first OMP for the same rare disorder, but rather due to safety-, efficacy-, or economic-related factors similar to the majority of regular drug development discontinuation . Interestingly, we found that 15 of the 120 follow-on OMPs (12.5%) subsequently obtained a marketing authorization in the EU between the start of the legislation and April 2010. This is considerably higher than the 45 of 528 orphan designations (8.5%) that were approved in the EU between the start of the legislation and 2007 . One explanation for this observation could be that the majority of follow-on OMPs is in development by large pharmaceutical firms (data not shown), whereas most orphan designated products are being developed by Small and Medium-sized Enterprises (SMEs) . In general, SMEs have less experience in (orphan) drug development, which was reported by Heemstra et al. as an important predictor for OMP approval .
Finally, we found that sponsors that continue development of a follow-on OMP in the EU predominantly assume that their product has an improved efficacy compared to the first OMP. Establishing the assumption of significant benefit based on an improved safety and/or major contribution to patient care may be either more difficult for or less attractive to manufacturers of follow-on OMPs. The EMA guideline on significant benefit mentions that "a theoretical risk with an authorized product cannot be compared with a theoretical lack of risk with the product under development" . However, most applications for an orphan designation by a sponsor are done in the late preclinical or early clinical testing stage, which doesn't include extensive human safety testing. Moreover, serious adverse events with authorized orphan medicinal products have been limited until now ; only sitaxentan was voluntarily withdrawn from the market by Pfizer in 2010 due to new information on two cases of fatal liver injury . The reason for the limited number of follow-on OMPs with significant benefit based on an assumption of a major contribution to patient care may be best explained by a current lack of interest by the pharmaceutical industry. Increased patient involvement and demand may result in shifting focus to novel innovative drug delivery systems that will allow more selective, more precise, less frequent dosing of the orphan medicinal product [40, 41].