The aim of the study was to assess clinical and regulatory variables that could influence the P&R decisions of ODs authorised in Spain.
From 2006 to 2021, 111 ODs had been granted marketing authorisation by the AEMPS, representing 86.7% of the total of ODs approved at the European level. However, only 51.4% (n = 57) of these ODs received P&R approval in Spain, 27% were rejected and 21.6% were undergoing the P&R decision process. This highlights that with the same evidence triggering EMA approval with or without conditions, the timing and level of access to ODs could vary across countries determined by differences in national criteria used for medicines assessments and P&R decisions .
Regarding evaluation timelines, the mean time from Spanish marketing authorisation to P&R decision after the inclusion of the TPR in 2013 was 18.2 months. P&R evaluation timelines have been slightly reduced since the inclusion of TPRs by an average of less than 1 month. This could be due to the fact that the performance of the TPR requires time. In addition, evaluation timelines could have been affected by the COVID pandemic over the last two years. Other reports that assessed the access to orphan medicines in Spain until December 2021 have reported similar findings in terms of estimated regulatory timelines during the P&R process, thus reinforcing the validity of the data presented in this study [29, 30].
Regression analysis showed that a positive TPR conclusion was key in the P&R decision in Spain. This is consistent with a previous study, where the association between a positive TPR and reimbursement of new ODs has been shown . In addition, regression analysis has also shown that ODs whose evaluation is subject to less uncertainty, i.e. ODs without a conditional authorization by the EMA and without a PASS study, would be more likely to be reimbursed. Therefore, with respect to the findings discussed above, variables related to safety and efficacy have shown an impact on the likelihood of reimbursement. The study showed that traditional evaluation criteria were the main drivers in the P&R decision. A recent report by the Spanish Ministry of Health highlighted that clinical uncertainty (translated into financial uncertainty) actually increases the complexity in P&R decision-making . Although the price of the ODs was not included in the analysis, we considered would be a key variable to explain reimbursement status, however, further studies would be needed to corroborate it. The prices for ODs may be higher, as it is difficult to recover the costs of innovation. Thus, ODs are unlikely to reach the standard cost-effectiveness thresholds [5, 32, 33]. However, many ODs are often reimbursed despite having incremental cost-effective ratios (ICERs) that are much higher than the willingness to pay (WTP). This suggests that, in practice, alternative approaches might be considered in ODs for P&R decisions, as the incorporation of new financing schemes reflected in the resolutions (e.g. expenditure cap, pharmacological protocols) .
Previous reports at national and international level have described similar findings on the identified ODs, their P&R status, and regulatory times to P&R decisions (e.g. aeLmhu report "Access to ODs in Spain”, Spanish Ministry of Health report "The evolution of the financing and pricing of ODs in the NHS”, and the “Waiting to Access Innovative Therapies (WAIT)” report performed by IQVIA) [29,30,31]. However, the main differentiating aspect of the present study is the assessment of the impact of TPR on P&R evaluation timelines and the assessment of clinical and regulatory variables that could be relevant in the P&R process of ODs in Spain.
Another finding to highlight from the regression analysis is that the absence of therapeutic alternatives does not seem to be associated with the P&R approval of an OD in Spain despite being a P&R criterion as established in article 92 of Royal Decree Law 1/2015 of 24 July. This could be due to the limitation of sample size, as despite having collected all available and published data, we still have a small sample size to be able to identify significant differences for some criteria in a multivariate analysis.
In addition, there are some variables, such as the authorisation under exceptional circumstances by EMA or the inclusion in the Valtermed registry in Spain, which have not been included in the study because the sample size is too small. In Spain, there are only 9 ODs approved under exceptional circumstances and with P&R resolution, and 11 ODs included to the Valtermed registry.
The study results have reflected the importance of the TPR prepared by the REvalMed NHS network in the reimbursement decision. However, unlike its name suggests, the final positioning of the drug is only established once the price has been negotiated with the DGCBF. Accordingly, the positioning of the drug is, among other factors, determined by its price. In addition, as stated in the above-mentioned report by Spanish Ministry of Health, clinical benefit uncertainty and price proposed by the MAH were highlighted as the main drivers to deny the P&R by the CIPM . This would have been a determinant variable to have contributed to our analysis, but such information is not publicly available because official listed prices in the available databases do not reflect the reimbursement price agreed between the Ministry of Health and the MAH. Confidential prices would be around 40% of the list price, but they do not always follow the same pattern . In addition, the reimbursed price depends on other variables such as the requested price, the price of other similar treatment alternatives and the medicine price in other EU reference countries, which are also not public and, therefore, not controllable.
Among the methodological limitations of the study, several assumptions were made. For those ODs appraised before the introduction of the TPR, it was assumed that reimbursed ODs had a positive TPR opinion. However, rejected ODs were assigned a questionable opinion of the TPR as opposed to the EMA's efficacy and safety assessment. Thus, we could include the maximum number of observations, with respect to the sample, in the analysis.
As the data cut-off point was December 2021, the number of observations to compare evaluation timelines before and after the introduction of REvalMed NHS in 2020 was not large enough (n = 9). Future analysis could assess the impact of the new procedure on evaluation timelines and reimbursement decisions.
As mentioned, economic criteria influencing the P&R decisions, such as the price of the OD and budget impact, have not been included in the statistical analysis, as the available official public prices do not reflect the reimbursement price. In addition, the study could have omitted alternative criteria considered by evaluators.
Other limitations come from the potential interaction between some of the explanatory variables. For instance, it could be assumed that ultra-rare diseases will present a limited arsenal of therapeutic alternatives. However, the objective of the model was to provide a construct of variables that could shed some light on P&R decisions in Spain. Considering the criteria established in Spain for the reimbursement of new drugs , it would be advisable to increase transparency regarding how these criteria are measured and assessed for decision-making  related to the value of a new drug.