Chapter 5 94 DISCUSSION Having analyzed all available approval documentation, we observe that expanded access programs can provide information on clinical efficacy that impacts regulatory decision making. Furthermore, we find that sponsors and regulators increasingly include RWD from expanded access programs in the efficacy profile of an approval package. The indications of these approvals are characterized by their orphan designation and high unmet medical need, a specific group of conditions. Although the use of RWD may seem a novel application, our study shows that in the case of expanded access, RWD was already used before the year 2000. The expanded access programs propelled by AIDS activism already led to the use of RWD: in 1996, for abacavir (FDA) or 1997 for stavudine (EMA): both compounds are used in the management of HIV. The specific circumstances in which RWD can complement or even substitute RCTs are in line with the motivations behind the use of RWD from expanded access programs.25–27 One of these conditions arises when randomization is unethical, for example due to a large unmet medical need.25 By design, this prerequisite is also a criterion of expanded access: expanded access programs are only for patients in dire need of unapproved treatments. A second situation occurs when further randomized controlled research is infeasible, e.g., when patient populations are small due to low disease incidence.26 Our study shows that indeed, orphan designations characterize RWD use from expanded access. As the rising interest in personalized medicine results in sample sizes becoming even smaller, data from expanded access may become increasingly important. Although in most cases data collected from expanded access programs complements data from conventional clinical trials, in four approvals in our research expanded access data was the sole source of evidence. The absence of other approved therapies, the rarity of the condition and the large observed treatment effect formed the extraordinary circumstances that led to the approval without evidence from (randomized) clinical trials. In particular conditions it may be challenging to collect data in conventional highly controlled settings and therefore collection of RWD from expanded access programs may be crucial. Interestingly, there is no guidance on the collection and analysis of data within expanded access programs. This seems rather odd, as our results show that RWD have been used over a period of time, there is an increasing demand of patients and physicians for pre-approval access to investigational treatments and recently, pharmaceutical industry demanded such guidance.28 Some European countries prohibit the collection of data in an expanded access setting stating that 'no other data except pharmacovigilance data can be gathered which will only be used for the evaluation of the UMN (red: Unmet Medical Need/expanded access) program'.29 Well-designed data collection in clinical trials should be considered a prerequisite for scientifically sound
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