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Page 10 of 15 Zanello et al. Rare Dis Orphan Drugs J 2023;2:9 https://dx.doi.org/10.20517/rdodj.2023.04

Off-label considerations
As mentioned in the previous section, most of the respondents considered the granting of a Marketing
Authorization as one of the main aims of their repurposing approach. However, this is not the case for all
developers. For some, the success will be determined by the use of the repurposed drug clinically,
recommended use and inclusion in well-accepted consensus treatment guidelines, and its acceptance for
payment by payers. Further development could then be conducted via an observational study to track its use
in the real world instead of an open-label clinical trial.

Considering that generic drugs targeting key pathways are likely to be efficacious in treating a variety of
diseases, it was reported that with the appropriate pairing of drugs and untreated or undertreated diseases,
drug manufacturers, health care systems, and patients stand to greatly benefit from the identification of
repurposing of these medications. This model may not only provide a faster, simpler pathway to providing
new therapies for underserved populations, but avoids the cost and time of developing and producing novel
therapies.

This point should be balanced by the fact that off-label use is considered very differently depending on the
country/region of the world, and such use lacks the advantages of regulatory review on the benefits and
risks with formal pharmacovigilance oversight. In some places, it is not authorized by law; in some others,
there is widespread access to the (generic) drug off-label at a relatively low cost (of note: when the drug is
off-patent, it is more likely that the price will be kept low); in some others, off-label is tolerated but
[25]
sometimes not reimbursed . In addition, it might also bring fewer opportunities to monitor safety issues
and more uncertainty for patients who are then at risk of a withdrawal from the market of the drug for
reasons related to the licensed indication, leaving them with no alternative.

DISCUSSION
The over 6,000 rare diseases affect about 300-350 million people worldwide. Low disease prevalence,
heterogeneous patient populations, the limited natural history of the diseases and high research and
development costs are among the factors limiting the emergence of new therapeutic options for rare disease
patients. Altogether, less than 6% of rare diseases have approved treatments, and therefore, drug
repurposing must be supported and valued as an approach to address the unmet needs of rare disease
patients. This paper aimed to provide drug developers with a framework for creating a sustainable approach
to drug repurposing, helping researchers avoid recurrent pitfalls and increasing the chance of seeing
medicines repurposed into new orphan indications. Through the Task Force, we have derived ten key
success factors which can be considered and applied consistently by developers using repurposing
approaches. Based on these ten items, the Task Force group has drawn up three main cross-cutting
actionable recommendations: awareness raising, funding allocation, and operational implementation.

What is needed for sustainable approaches in drug repurposing in terms of awareness raising?
Some efforts are required in order to disentangle concerns arising around repurposing. First, there is a need
for clarification of what is intended by the term “repurposing” itself. In this respect, the recent manuscript
from Asker-Hagelberg et al. brings a welcome precision to the definition of repurposing: “Medicine
repurposing is the process of identifying and substantiating a new use for an existing medicine/active substance
outside the scope of the original indications as well as the process of allowing a medicinal product to broaden
its position in a relevant market (excluding the extension of an authorised indication to those of a new age
group or to another genetic mutation)”. The latter part of the sentence clarifies which extensions of
indications are to be considered as repurposing and which ones are not .
[25]