Chapter 11 232 generation. Access inequality The current set-up of expanded access, in which individual EU member states retain full freedom to regulate these programs within their borders, forces companies to navigate a complex array of pathways that are often only accessible in local languages. Pharmaceutical companies without local presence or sufficient resources may prefer to provide access in countries with easier access pathways, raising issues of patient access equity. The cost of expanded access creates further complications.Although manufacturers mainly provide treatment free-of-charge, France is willing to pay for treatment under expanded access, Italy has reimbursement options for expanded access in rare diseases, and the US allows the sponsor to recover the direct costs (e.g., manufacturing, shipment) from private or government payers. Most other countries prohibit paying for unlicensed medicine, or even charge the manufacturer for setting up an expanded access program. Belgium charges €19,835 to set-up a compassionate use program, and participation in the UK EAMS scheme comes at a fee7 of £25,643.52 These costs may discourage pharmaceutical companies from participating in expanded access programs, negatively impacting patient access. Ethical implications Providing treatment without collecting relevant data deprives future patients of the benefit of known outcomes and denies the patient the opportunity to altruistically contribute to generalizable knowledge. Prohibiting the use and collection of data could reduce manufacturers’ willingness to provide expanded access, affecting even those countries that allow or encourage such reliance. Furthermore, expanded access is non-randomized and unblinded, which can lead to confounding.40,41 There are no guidelines on the quality assurance of data collection in expanded access – Good Clinical Practice is mandated by the EMA only for interventional trials.53 Regulators or ethics committees should therefore ensure that expanded access does not undermine enrolment in traditional clinical trials adequate to generate high-quality evidence. The recent US convalescent plasma expanded access program for SARS-CoV-2 showed that this fear is not unfounded. Over 105,717 patients were enrolled in this program before trials where fully enrolled or completed.54 Although a first analysis of these single-arm data hinted at beneficial treatment effects, randomized trials later did not confirm that convalescent plasma improved outcomes in inpatient care.17,55 7 https://www.gov.uk/guidance/apply-for-the-early-access-to-medicines-scheme-eams#fees
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