Over the past decades its popularity has increased, especially amongst academics. In 2010, there were only 57 publications on drug repurposing. By 2024, this number has increased to over 2300 publications, reflecting the increased interest and activity in the field of drug repurposing.
Strategic questions
One of the key benefits of drug repurposing is its potential to be faster and more cost-effective than de-novo drug development (Remedi4All). Moreover, it is an area where academic researchers have proven to have considerable expertise.
Over the past years, Orfenix has supported the development of multiple academic drug repurposing projects. Through this work, we have identified recurring strategic questions that play a crucial role in academic drug repurposing. In this insight, we will explore one of the most frequently encountered strategic decisions in academic drug repurposing:
“Should I use an existing (generic) medicinal product, or is it better to develop a new medicinal product for the repurposed indication?”
Before we answer this question, it is important to note that no drug repurposing development is the same and in the end all these developments will require tailored approaches. In general terms however, here is our generalised answers to this question.
On-label vs Off-label
When progressing to the clinical phase of drug repurposing with a medicinal product of which the formulation and route of administration remains equal in the new indication, one of the most common questions to answer is whether the research in the new indication can and/or should be performed with an existing (generic) medicinal product or whether it is more beneficial to develop a new medicinal product. The first step is to define the end goal: Are you aiming for a new on-label indication with marketing authorisation, or will the medicinal product be used through off-label prescription.
Both routes generally lead to patient access to the repurposed medicinal product. However, it is important to note that the conditions for off-label use vary across countries. Furthermore, patients treated with off-label medicinal products often receive information leaflets that are not tailored to their specific condition. Both routes however remain a viable option for drug repurposing in an academic setting, both requiring different (strategic) decisions along the way.
Licensed medicinal products – a marketing authorisation
First, it is important to understand the requirements for licensed medicinal products. To obtain marketing authorisation in Europe, applicants must comply with the requirements outlined in Directive 2001/83/EC. The authorisation of medicines builds on three key criteria, namely quality, safety and efficacy, to ensure that medicinal products administered to patients are of suitable quality and provide a positive benefit-risk balance.
When applying for marketing authorisation, applicants must provide documentation showing that the medicinal product is of suitable quality. To be able to do so, applicants need to be able control the quality and therefore need to be involved in the production process. In practice, this means the applicant must either produce the medicinal product in-house or contract a manufacturer to do so. In both scenarios, the applicant maintains control over the medicinal product and its quality data.
On-label drug repurposing
An ‘on-label’ repurposed product refers to a medicinal product that has obtained a marketing authorisation for a new indication: the repurposed indication. In line with a new marketing authorisation, to obtain an authorisation for a repurposed indication, the applicant needs to provide data to support the quality, safety and efficacy in the new indication.
For an on-label repurposing, it is important that the collected safety and efficacy data are linked to the quality data of the medicinal product. Generally, this means that the clinical trials must be conducted using the medicinal product that will be used in the application for marketing authorisation, or there must be a clear bridge between the trial data and the medicinal product’s quality data.
In practice, this means there are two options to develop an on-label repurposed medicinal product:
- Collaborate closely with an existing marketing authorisation holder and add the new safety and efficacy data on the new indication to the existing marketing authorisation (Type II variation)
- Develop a new, de-novo medicinal product and link the quality data to the new safety and efficacy data. Request a new marketing authorisation for the new indication.
When on-label prescription is the goal, researchers therefore need to decide on which medicinal product to use in their clinical studies at the beginning of the clinical development. For an on-label repurposed medicinal product either de-novo development or a close collaboration with an existing marketing authorisation holder is necessary.
Off label drug repurposing
In cases where no licensed medicinal product is available for a specific indication, doctors may prescribe medicinal products ‘off label’, provided they comply with national regulations. While the conditions for off-label use vary per country, researchers will need to establish a robust body of safety and efficacy data, similar to what would be required for a marketing authorisation application. This data enables prescribers to carefully weigh the risks and benefits before considering an off-label treatment.
Unlike on-label repurposing, there is no requirement to link the collected safety and efficacy data to the quality data of a specific medicinal product. As a result, when the goal is off-label prescription, researchers generally have the flexibility to use any licensed product for their studies.
Off label prescription
The conditions for off-label prescriptions vary per country. In the Netherlands the conditions for off-label prescription are set out by the Health and Youth Care Inspectorate (IGJ):
- The physician must follow the treatment guideline of the professional group. This includes current scientific and clinical insights.
- Is the treatment guideline still under development? Then the physician must consult with the pharmacist about prescribing the medicine off-label. Only then can the pharmacist dispense this medicine.
- The physician must determine whether another acceptable treatment is possible with a medicine that is registered for the specific complaints.
- The physician carefully weighs up any risks and the benefits of the off-label medicine.
- The physician must inform the patient that he is being prescribed an off-label treatment. The patient must also agree to this treatment.
- The prescribing physician must consult with the primary physician before prescribing off-label.
Source: https://www.igj.nl/publicaties/standpunten/2018/01/13/off-label-voorschrijven
The future: proposed new European legislation
In 2023 the European Commission adopted a proposal for a new Directive and Regulation, aimed at revising and replacing the existing general pharmaceutical legislation. Although both the Directive and Regulation are still under revision and far from adopted, the current version include an interesting addition relevant to the choice between de novo development and the use of an existing licensed medicinal product.
Under Article 48 of the draft regulation, it will be possible for entities – without being the Marketing Authorisation Holder – to submit “substantive non-clinical or clinical evidence for a new therapeutic indication that is expected to fulfil an unmet medical need” to the European Medicine Agency. In practice this could mean that research conducted for a new indication, as described hereabove in the ‘off-label repurposing’ section, could still lead to an ‘on-label’ repurposed product. This change could significantly impact the strategic decision in choosing which product to use for research in drug repurposing.
Draft Regulation: Article 48
Scientific opinion on data submitted from not-for-profit entities for repurposing of authorised medicinal products.
- An entity not engaged in an economic activity (‘not-for-profit entity’) may submit to the Agency or to a competent authority of the Member State substantive non-clinical or clinical evidence for a new therapeutic indication that is expected to fulfil an unmet medical need. The Agency may, at the request of a Member State, the Commission, or on its own initiative and on the basis of all available evidence make a scientific evaluation of the benefit–risk of the use of a medicinal product with a new therapeutic indication that concerns an unmet medical need. The opinion of the Agency shall be made publicly available and the competent authorities of the Member States shall be informed.
- In cases where the opinion is favourable, marketing authorisation holders of the medicinal products concerned shall submit a variation to update the product information with the new therapeutic indication.
- Article 81(2), point (c) of [revised Directive 2001/83/EC] shall not apply for variations under this Article.
Conclusion
Choosing between using an existing (generic) medicinal product or developing a new medicinal product remains a decision that must be made on a case-by-case basis. It is important to determine early in the process whether the goal is to develop a licensed, on-label repurposed product or to pursue off-label prescription.
For on-label repurposing, establishing clear a link between the safety efficacy data and the medicinal product’s quality data is essential. In contrast, for off-label use, this connection is less critical, and the focus should be on collecting robust safety and efficacy data using an available licensed product.
With the introduction of new European legislation, it may soon become possible to follow an off-label research route and still obtain an on-label indication. However, only time will reveal whether these regulatory changes will be implemented and how they will influence drug repurposing in the future.
