A Brief Summary of the new fast-track European procedure by Simon Ruini, Director of PhD London
The Adaptive Licensing Pilot Project was launched by the EMA on 19 March 2014. This summary addresses some frequently asked questions and clarifies the terms of engagement and expected outputs for prospective applicants.
1. What is Adaptive Licensing and what does AL seek to achieve?
Adaptive Licensing (AL) is a prospectively planned, adaptive approach to bringing medicines to patients, and is intended to maximise the positive impact of new medicines on public health by balancing the need for timely patient access with the importance of providing adequate, evolving information on a medicine’s benefits and risks. The AL approach is based on a prospectively designed development plan which is the subject of an early dialogue with stakeholders (regulatory authorities, patients’ organisations, HTA bodies). The development plan would generally foresee an initial authorisation of a medicine, granted on the basis of the demonstration of a positive benefit/risk balance at the time of authorisation, most likely in a restricted patient population, possibly on basis of surrogate endpoints. This would be followed by iterative phases of evidence-gathering, including real world data, and the adaptation of the marketing authorisation to extend the access to the medicine to broader patient populations while gradually refining the knowledge of the benefit-risk balance during the post-authorisation phase.
2. What is the objective of the AL pilot project?
The AL pilot project seeks to examine whether ‘adaptive’ approaches to medicine development and authorisation offer advantages in terms of achieving the best balance between the need for timely patient access with the importance of providing adequate, evolving information on a medicine’s benefits and risks.
The confidential discussions intend to promote free exploration of the strengths and weaknesses of all options for development, assessment, authorisation, reimbursement, monitoring, and utilisation pathways in a confidential manner. The discussions should serve to guide the applicant through the next regulatory steps.
An aim of the pilot is to promote and establish early dialogue and not to pre-assess suitability of data that are already available for an early approval. Some submissions have been made to the pilot requesting early approval on the basis of available data without particular consideration of post- authorisation work, iterative changes to the product authorisation, HTA engagement or use of real- world data. Such submissions are not considered suitable for the pilot discussions. This does not preclude the suitability of such proposals for further dialogue with CHMP through SA/PA procedures or submission of a MAA.
3. What are the criteria for selection?
The following criteria are prioritised in evaluating the plausibility and feasibility of an Adaptive Licensing approach:
1. An iterative development pathway, most likely in terms of gradual expansion of the target patient population, alongside a gradual reduction of any uncertainties in benefits and risks associated with the initial authorisation decision.
2. Real-world monitoring, data collection and use, as a complement to RCT data, in subsequent regulatory decision making. This is assisted by good definition of the target population (e.g through restricted indication), and additional risk minimisation measures that promote the likelihood of real-world data collection.
3. Ability to engage HTAs and other stakeholders in multiple discussions along the development pathway and with proposals for how the demands of these stakeholders can be met.
In addition to the criteria set out above, high unmet medical need is an important feature since this opens the possibility to use a wider set of regulatory tools and may justify a higher degree of uncertainty at the time of initial authorisation.
4. When should I apply for the Adaptive Licensing Pilot?
There is flexibility as long as the indication and development plan fit the AL concept: the applicant may find that a different timing may offer the opportunity to better support the plausibility of the plan to demonstrate a positive benefit/risk in the initial, restricted population, without loss of equipoise. The type, extent and timing of data to be generated will depend on the product characteristics, the disease, and the chosen development pathway. The type of Marketing Authorisation obtained (full, conditional, under exceptional circumstances), including any potential restrictions or conditions, will depend on the level of evidence ultimately obtained.
5. Are the adaptive licensing discussions an in depth scientific discussion replacing Scientific Advice?
No. Scientific Advice / Protocol Assistance procedures remain the appropriate forum for detailed discussions concerning regulatory standards for a medicine development program. The AL pilot project is an opportunity for enhanced and prospective brainstorming interactions in a confidential environment with regulators and other downstream stakeholders (HTA, patients) prior to a formal regulatory interaction steps.
6. Are AL discussions confidential?
Yes. The only information to be disclosed pro-actively will be of a descriptive nature, e.g. the overall number of medicinal products discussed, the number of Orphan medicines, SMEs, ATMPs and the therapeutic area (not the proposed indication).
7. Is Adaptive Licensing based on a new regulatory framework?
AL uses the regulatory processes within the existing EU legal framework. Therefore, only existing regulatory tools will be used, including scientific advice (with participation of HTA bodies and/or payers and/or other stakeholders), centralised compassionate use assessment, the “standard” marketing authorisation, conditional marketing authorisation, marketing authorisation under exceptional circumstances, and other provisions of the pharmacovigilance legislation including risk management plans, patient registries, etc. Data protection and other relevant legal provisions remain unchanged.
8. What happens in practice in AL?
As the aim of AL is timely access to new treatments for patients, the Agency takes the view that all decision makers who ultimately influence patient access should ideally be involved in the pilot discussions; this includes HTA bodies that inform reimbursement decisions and, where applicable, organisations issuing clinical treatment guidelines, and patient organisations.
For paediatric aspects, and should the development require the demonstration of Significant Benefit in the framework of Orphan Medicinal Products, it is advisable that discussions start in the initial proposal.
It is a high-level early dialogue led by the SAWP chair and assigned coordinators to review the plausibility of the development plan and guide to the next –more formal – regulatory steps. Given the nature of this discussion, the timelines for involvement of downstream stakeholders may be shorter than for other EMA procedures (e.g. parallel EMA/HTA advice) which require in-depth review.
The output of the teleconference is a list of comments, similar to the one that results from an SA pre-submission meeting. The document is signed by Spiros Vamvakas, Head of Scientific Advice, and includes, as an attachment, the minutes of HTA and other stakeholder discussion commented upon by those participants for accuracy. It is the responsibility of to the sponsor to decide on how to take this feedback forward into their clinical development. If needed, depending on the outcome and content of the initial discussion, further confidential discussions with the Applicant and relevant experts can take place prior to a formal regulatory step.
An HTA/SA parallel advice, shaped by this initial discussion, is expected to be the next regulatory step. Stakeholders to be involved in the procedure should be identified by the Applicant.
The interaction process can be repeated several times prior to follow-up scientific/regulatory advice or submission of the marketing authorisation application.