Generating evidence from expanded access use of rare disease medicines: challenges and recommendations 229 11 ♠ controlled trial (N=229), data from 558 patients treated under compassionate use were considered in support of the indication. In the case of cholic acid, a treatment for patients suffering from various rare genetic disorders in bile acid metabolism, all evidence came from expanded access. The FDA and EMA evaluated data from 2 expanded access programs (N=63, N=22) to support the marketing authorization.The EMA approved cholic acid under exceptional circumstances, because 'the applicant was unable to provide comprehensive data on the efficacy and safety of the medicine under normal conditions of use. This can happen because the condition to be treated is rare or because collection of full information is not possible or is unethical.'4 In the 39 cases where expanded access programs were included in the ‘pivotal efficacy section’ of regulatory submissions for rare disease medicines, 58% of all patients were treated under expanded access pathways.33 Expanded access data can also be used to obtain special regulatory designations: in 2014, the FDA granted ‘breakthrough designation’ to uridine triacetate based on published case studies and expanded access data.34 This highlights the role of expanded access in regulatory decision making in rare diseases. Use of expanded access data in health technology assessments As expanded access programs may provide the first source of evidence on the treatment use of investigational medicine in non-trial populations, various countries have explicitly combined expanded access with evidence generation or reimbursement schemes, such as l’Accèss Précoce in France, the DRUG Access Protocol in the Netherlands and the Early Access to Medicines Scheme (EAMS) in the UK.3,9,35,36 In the United Kingdom (UK), drug approval is followed by a separate appraisal of cost-effectiveness compared to existing treatment options. Twenty-one percent of the health technology assessments conducted for the National Health Service in the last decade have relied in part on expanded access data.11 We here highlight ipilimumab, a treatment for advanced, previously treated, unresectable skin cancer, which was approved in 2011 based on a trial involving 676 patients. For ipilimumab, the number of vials of drug needed is based on patient weight. As only 55 patients from the UK participated in the pivotal trial, the addition of expanded access patients helped the reimbursement agency obtain a better estimate of vial usage in the realworld patient population in their jurisdiction. At the reimbursement stage, data were pooled from 258 UK patients receiving ipilimumab through an expanded access program (using 1.19 vials of 50 mg on average) to supplement the data from the pivotal regulatory trial (using 1.51 vials of 50 mg on average). In this particular case, including data from expanded access led to a decrease in mean cost estimates. 4 https://www.ema.europa.eu/en/medicines/human/EPAR/orphacol
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