Rhetoric and Realism Colliding on EU Discussions of Drug Repurposing

Repurposing of medicines is back on the EU agenda, with the COVID-19 pandemic providing a boost to the long-running arguments for identifying new uses for approved or investigational products outside the scope of their original medical indication. The issue was given new prominence during the summer by Slovenia, the country holding the presidency of the EU health council until the end of 2021. The Slovenian health minister brought together regulators and health officials from across Europe for something of a première in terms of EU discussions on the topic. And it supported the play with a lengthy reflection paper developed in concert with the World Health Organization, ambitiously entitled ‘Repurposing of medicines in oncology–the underrated champion of sustainable innovation.’ The aim was to give sharper focus and new impetus for a more general discussion of repurposing that has been underway among EU health officials for several years now, without reaching any clear conclusions.

The Slovenian starting point is that new technology and new approaches can revolutionize what has been seen traditionally as a predominantly non-commercial and even artisanal approach to drug development. It stresses in its background paper that repurposing previously has moved on from its earlier reliance on an ad hoc discovery process, and can now build on organized, systematic, data-driven approaches to identify suitable candidates, facilitated by the use of big data and artificial intelligence. The focus is on cancer, but the overall argument is that repurposing can deliver innovation in terms of new treatments that resolve unaddressed health needs, and often in shorter timeframes than de novo development.

This chimes conveniently with the EU push during 2021 for repurposing of treatments specifically to counter COVID-19, and also gains strength from the widely-publicized success of the RECOVERY trial in identifying valuable therapeutics for COVID-19 patients–notably dexamethasone. As the paper says, “The lack of effective therapies for the SARS-CoV-2 pathogen highlighted the need to find treatments that can be applied quickly to reduce mortality and morbidity. Repurposing was identified as one main strategy to provide a fast and cost-efficient approach to this purpose.”

But the argument relies too, on more familiar arguments–that repurposing can offer lower costs of development and lower risk of failure–as well as pointing out that many products are already commonly used off-label in cancer treatment, particularly for patients who have no alternative options. “Establishing rigorous scientific evidence and repurposing the vast arsenal of existing approved medicines with established safety profiles may be an attractive strategy to offer more effective treatment options to patients with cancer,” says Slovenia.

The paper also assembles a range of specific points in defense of its thesis, collectively amounting to an appeal for a radical review of the current business and regulatory models of drug development. Most of the arguments are linked to easing conditions for the non-commercial activity that still constitutes much of the repurposing of off-patent medicines, particularly for cancer treatment. Slovenia sees potential for addressing areas that are not attractive for the pharmaceutical industry, such as rare cancers (which it estimates as accounting for a fifth of new cases in Europe). It depicts “traditional models of collecting clinical evidence” as sub-optimal for repurposing, “owing to the high costs involved and the applicability of established pharmaceutical development and testing paradigms,” notably for combination therapies.

The paper perceives particular handicaps in the persistent reliance on the good will of industrial partners. As it observes, only the marketing authorization holder of a given medicine can currently apply for an extension or variation of its marketing authorization. Consequently, even if non-commercial clinical trials confirm the efficacy of a repurposed drug, patient access to these treatments depends on the willingness of a pharmaceutical company to obtain authorization for the new indication and to take responsibility for its risk management–something that experience to date shows has not often been forthcoming. “Returns on investment for repurposed off-patent medicines are expected to be low or nil, and pharmaceutical developers are rarely interested in pursuing repurposing opportunities, even when clinical evidence is made readily available by other stakeholders,” it remarks glumly. In addition, the existing EU legislation that might help in promoting off-patent drug repurposing (such as on data exclusivity or orphan designation) “do not offer the usual level of incentives for the industry compared to alternative investments, and they are underused.”

The paper also reflects a keen awareness of the current debates in the EU–and elsewhere–over the cost of medicines, liberally citing references from official international organizations to the “exorbitant” price of cancer medicines or “market failure” endangering patients’ access through “very high and unsustainable price levels.”

In the best tradition of European problem statements, the Slovenian initiative also contains a range of potential solutions, particularly aimed at assisting non-commercial repurposing. They are rather glibly listed as “reducing the risk of failure by improving the selection of candidates, facilitating generation of clinical evidence, streamlining regulated processes, amending restrictive legislation, improving collaboration and coordination between stakeholders and ensuring adequate funding.” Unexceptionable ambitions–but requiring rather more than enunciation to realize them.

Wide support can be assumed for the proposals for early scientific advice and regulatory assistance throughout the process to ease the generation of evidence, and “exploring the potential for greater reliance on real-world data, data networks, adaptive platform trials and innovative trial designs” finds an echo in much current EU debate. The concept of reducing fees for repurposing of financially unattractive medicines can be seen as consonant with the current approach of easing regulatory barriers for smaller firms or orphan products. But simply citing “artificial intelligence and use of big data” may be considered a little thin as a way of improving selection of candidates. And most strikingly, perhaps, many in industry will bristle at the suggestion of over-riding current rules that permit marketing authorization holders as sole arbiters of applications for authorization of new indications for their products. This proposal is not, many will say, the solution to “removing barriers for non-commercial champions.”