Referred to by various terms (staggered approval, managed entry, progressive authorisation), “adaptive licensing” is a departure from the traditional approach to authorising new medicinal products. Under the current system, the initial grant of a marketing authorisation (MA) tends to be regarded as a “magic moment”, at which point the medicine is suddenly held to be safe and efficacious. The “adaptive licensing” (AL) approach embraces the reality that, due to restricted patient exposure during clinical trials, it is often not until the post-marketing phase that information on the benefit-risk profile of the product as used “in real life” is obtained, and that there are certain situations in which a degree of acknowledged uncertainty over the benefit-risk profile of a product at the time of initial MA may be acceptable to regulators, patients and payers alike. Given this, medicines regulators have been discussing developing the concept of AL, namely, a prospectively planned, flexible approach to licensing whereby an initial, limited MA is granted (often for a “niche” indication / restricted patient population) based on limited data. Prospectively planned extensions of the MA, following iterative phases of data gathering and regulatory evaluation, follow. The hope is that, as well as providing patients with timely access to new medicines for treating serious conditions with unmet medical needs, AL will also help to address the fact that the number of newly approved drugs per year has remained flat in recent years (as increasing demands in terms of the amount of up-front data required to bring a new drug to market necessitates increased investment to match the scale, duration and complexity of clinical trials required). The AL approach will allow products onto the market based on smaller scale trials in limited indication(s) / patient population(s).
For now, the AL approach is founded on various existing mechanisms (discussed below) which are already in place to ensure that the regulatory framework is able to promote the assessment and approval of medicines to treat currently unmet medicinal needs, making them available to patients as soon as possible. AL seeks to balance timely access to new authorised treatments with the need to have enough data for a robust risk/benefit profile assessment. In the European Medicine Agency’s “Road Map to 2015”, it is emphasised that “AL should not lead to reducing evidentiary requirements for first-time marketing authorisation”.
The European Medicines Agency (EMA) has now announced that it is seeking candidate medicines to enter a pilot scheme to investigate the application of the AL approach in the context of medicines currently in development. Although already much debated, this is the first formal step by EU regulators towards introducing a specific AL approach to getting selected products onto the market.
From the current licensing framework to AL
The current medicines regulatory framework does recognise that MA applicants will not always be able to produce full dossiers of robust clinical data at the time of MA application. In the interests of making authorised products available to patients in need, the legislation already provides for mechanisms to address this issue, allowing authorisation in a variety of special circumstances where there is sufficient justification. For example, a “conditional” MA (valid for one year and renewable) may be granted where there is scientific data to demonstrate a positive benefit-risk profile for the medicinal product (pending confirmation) but the clinical part of the dossier is incomplete. The product must meet certain criteria. Specific obligations (with a timetable for completion of further studies) are attached to the MA and the aim is to convert the authorisation to a “normal” MA in due course, depending on the outcome of those studies. An “exceptional circumstances” authorisation also provides a route to MA (again with specific obligations attached and based on annual reassessment of the benefit-risk profile), but in situations where it is unlikely that a full data package will ever be obtained (where the indication is very rare, where comprehensive information cannot be provided “in the present state of scientific knowledge” or where it is contrary to generally accepted principles of medical ethics to collect such information).
Pre-authorisation “compassionate use” schemes and the increasing emphasis on post-authorisation pharmacovigilance through follow-on trials, patient registries, risk minimisation plans and other schemes, also illustrate a shift in thinking away from the traditional binary unapproved / approved paradigm towards viewing the initial authorisation of a product more as just a formal step in a progressively managed product development and monitoring programme.
For the time being, AL will use the regulatory approaches available within the existing framework (including scientific advice, centralised compassionate use and the other mechanisms described above, particularly conditional marketing authorisation and risk management plans). However, some stakeholders see this new approach as possibly transforming the licensing landscape to become the standard approach to authorising new medicines; it may well be that legislative changes (strengthening these existing mechanisms and addressing other issues) will be required for full implementation to succeed.
The EMA’s AL pilot scheme and beyond
In seeking candidates for its pilot scheme, the EMA has asked industry to identify suitable experimental medicines currently in the early stages of clinical development (normally prior to the initiation of confirmatory studies i.e. during or prior to phase II, although this can be considered case-by-case). Significant coordination and buy-in among all stakeholders will be needed to make AL work well, so the pilot scheme will involve all those with a role in determining patient access, including health technology assessment bodies, organisations issuing clinical treatment guidelines and patient organisations. The informal discussions will take place in a “safe harbour” environment to allow for open discussion of the pros and cons of all options in confidence, without commitment from either side; the rules of engagement are currently being developed.
Under AL, the aim is to adapt the MA as information on the benefits and risks of the product evolves and undergoes regulatory assessment. AL may not be applied to all drugs in the same manner; a product for use in treating a serious or life-threatening illness where there is an unmet medical need and promise of high added clinical value for patients may require considerably less data for an initial authorisation than would be required for a new product to treat a disease for which there is already a range of treatments. The specifics of the pathway are likely to vary on a case-by-case basis and to differ from one product to another and from one therapeutic area to another. This pilot scheme aims to assess how future AL pathways might be designed for different products and indications, as well as highlighting any potential problems that might arise. For a fully developed AL framework to succeed, regulators may need new authorities to allow them to implement wide use of restrictions on the terms of the MA and prescribing surveillance.
The possibility of a means of reducing the overall costs of developing new products, by allowing better informed decisions on product viability to be made earlier in the development process, should be attractive to industry, although it is likely that a number of issues will need to be addressed if AL is to succeed; for example, the current reward and incentive structures are designed to work in the context of the traditional “all-population” authorisation and promotion approach and these may need to be re-examined. The EMA notes that the European Commission will examine the legal and policy aspects of AL as the scheme progresses.