On-Label or Off-Label? Overcoming Regulatory and Financial Barriers to Bring Repurposed Medicines to Cancer Patients

Abstract

Repurposing of medicines has gained a lot of interest from the research community in recent years as it could offer safe, timely, and affordable new treatment options for cancer patients with high unmet needs. Increasingly, questions arise on how new uses will be translated into clinical practice, especially in case of marketed medicinal products that are out of basic patent or regulatory protection. The aim of this study was to portray the regulatory framework relevant for making repurposed medicines available to cancer patients in Europe and propose specific policy recommendations to address the current regulatory and financial barriers. We outlined two routes relevant to the clinical adoption of a repurposed medicine. First, a new indication can be approved, and thus brought on-label, via the marketing authorization procedures established in European and national legislation. Such procedures initiate a detailed and independent assessment of the quality and the benefit-risk balance of a medicinal product in a specific indication, benefiting both prescribers and patients as it reassures them that the scientific evidence is robust. However, the process of marketing authorization for new therapeutic indications entails a high administrative burden and significant costs while the return-on-investment for the pharmaceutical industry is expected to be low or absent for medicines that are out of basic patent and regulatory protection. Moreover, most of the repurposing research is conducted by independent or academic researchers who do not have the expertise or resources to get involved in regulatory procedures. A second option is to prescribe a medicine off-label for the new indication, which is managed at the national level in Europe. While off-label use could provide timely access to treatments for patients with urgent medical needs, it also entails important safety, liability and financial risks for patients, physicians, and society at large. In view of that, we recommend finding solutions to facilitate bringing new uses on-label, for example by developing a collaborative framework between not-for-profit and academic organizations, pharmaceutical industry, health technology assessment bodies, payers, and regulators.

Repurposed agents in the Alzheimer’s disease drug development pipeline

“…Some steps in the development process might be repeated to account for these contingencies. Repurposed agents are often generic and have limitations on intellectual property rights that compromise attracting investments that could propel their development [ 20 ].…”

New Mechanisms to Fund Independent Clinical Trials for Repurposing Off-Patent or Generic Medicines

“…Yet, revenues for off-patent and generic medicines are not expected to increase substantially after adding a new therapeutic indication since payers are unlikely to agree to pay a higher price for an existing medicine, which is often already prescribed off-label for the new indication. Moreover, new uses for off-patent or generic medicines are particularly di cult to protect from generic competition (17). As a result, pharmaceutical companies rarely pursue new indications after expiry of basic patent and/or regulatory protection, especially for inexpensive small-molecule medicines (5).…”

“…Finally, some interviewees proposed the idea of creating commercial interest for developing new uses for off-patent or generic medicines by "changing the rules of the game", for example by providing additional IP or regulatory protection, introducing prize or reward funds (e.g., the health impact fund (106)), offering tax incentives or exploring indication-based pricing mechanisms. This idea of introducing new incentives to increase the industry's willingness to invest in repurposing off-patent or generic medicines was discussed in more detail elsewhere (17,107), but will likely not be sustainable on the long term.…”

“…A major bene t is that the pharmacokinetic, pharmacodynamic and toxicity pro les of approved medicines are well-known, so the new use can more easily be translated into Phase II/III clinical trials (11)(12)(13)(14). Off-patent and generic medicines are widely available and relatively cheap owing to generic competition, which facilitates clinical research and enables timely and affordable access for patients by prescribing the medicines off-label (15)(16)(17). However, return on investment (ROI) is expected to be low or absent in this last scenario due to a lack of economic incentives (5,6).…”

The Regulatory Challenges for Drug Repurposing During the Covid-19 Pandemic: The Italian Experience

“…The main advantages of drug repurposing over de novo medicine research are the faster and potentially cheaper development and the reduced risk of failure due to safety concerns (Bertolini et al, 2015;Pushpakom et al, 2019;Verbaanderd et al, 2019). Therefore, the regulatory authorities were rapidly overwhelmed by requests for clinical trials and compassionate use program approval.…”