TABLE 2.

Identified hurdles in the three cases of drug repurposing for rare diseases. CTLA-4 HIS: cytotoxic T-lymphocyte antigen four haploinsufficiency. PXE: pseudoxanthoma elasticum. NDM: Non-dystrophic myotonia.

	Hurdles	Abatacept CTLA-4 HIS	Etidronate PXE	Mexiletine NDM
Healthcare professionals involved in drug repurposing	1. Lack of knowledge of and alignment with the regulatory and reimbursement frameworks	Obtaining reimbursement is challenging and time-consuming	No incentive for clinicians to engage in regulatory activities	—
	2. Off-label use is not a major concern if sufficiently supported by scientific evidence. This slows down evidence development	Consensus amongst doctors based upon pathophysiological mechanisms	Unavailability hampers clinical use and scientific development	Has been used off-label since the 1980s
Private sector	3. Private actors do not invest because of uncertain regulatory and reimbursement outcomes	Viable business case not likely due to patent expiration	—	—
	4. Failure to register an old drug for a fair price, resulting in commercialization as a high priced orphan drug	—	—	Price increase as a result of monopoly position
Payers	5. Hesitant to pay for off-label use, when scientific evidence is limited	Reimbursement only on case-by-case basis	—	—
Regulators	6. Regulatory frameworks not fully adapted for repurposing, both in terms of processes and data/evidence requirements	Case studies not eligible for regulatory purposes	Investigator-initiated trial not eligible for regulatory purposes	—
	7. Regulators are not used to other types of applicants than industry, e.g. academics, doctors, public-private partnerships	—	No appropriate guidance or timing of interaction	—