Adaptive pathways gathers momentum
It allows for the approval of medicines in restricted patient groups where there is an unmet clinical need, which would then be approved for wider indications and larger patients groups as subsequent clinical efficacy and safety data is gathered. It also includes conditional approval at an earlier stage under conditions of acknowledged uncertainty, with iterative phases of post-approval data gathering to reduce the level of uncertainty1.
The EMA launched the first phase in March 2014 and began to accept applications for participation in the adaptive pathways (AP) pilot program. The purpose of the pilot according to the EMA is to “provide a framework for open and informal dialogue between stakeholders, allowing them to explore different options in a ‘safe harbour’ environment and to consider detailed technical and scientific questions based on concrete examples” 2. The aim, then, is not to evaluate data, rather to provide advice to the applicant on the proposed development pathway and assist in their preparation of a submission. Discussions will be between the “coalition of the willing” including companies, academia, regulators, Health Technology Assessment bodies (HTAs) and patient representatives.
After a slow start and few applications, the AP project is gathering momentum. By December 2014 the EMA held teleconferences with 7 of the 34 applicants. This phase closed in February 2015 and six medicines were selected for second phase ‘in depth’ face to face discussions3.
Why is change necessary?
There is a clear need to move away from the binary nature of drug regulation. The current model of licensing is too rigid where pre-authorisation and post-authorisation is separated by what EMA senior medical officer, Hans-Georg Eichler, describes as a “magic moment” of marketing approval4.
As a result the regulatory landscape seems to be shifting and the EMA is attempting to confront this “evidence vs access” problem, with regulatory processes such as compassionate use and conditional approval. The FDA has also instituted an accelerated approval program and Japan has established its own version of conditional authorisation4. There is now an effort to find the right balance between shorter approval times for promising medicines in unmet therapeutic areas and ensuring there is sufficient information on the safety and potential benefits of a particular medicine.
Adaptive licensing would be a further evolution of the system and will replace the dichotomy of pre and post approval with staggered, tightly monitored, but quicker and more cost-effective market entry. Rather than holding back a product until it can be shown to be safe in a broad population, adaptive licensing allows for a limited early approval which can be expanded over time.
How will it work?
The name of the project changed from adaptive licensing to adaptive pathways because the term “licensing” created a false impression that a new regulatory tool was being established. Instead, its intention is to create earlier dialogue to shorten the pathway of product development to patient access.
There are many scenarios in which AP could be useful. For example, organising clinical trials with sufficient statistical power can prove very challenging for some rare diseases. In this situation, an initial approval may be granted based on studies where the statistical significance is greater than the conventional significance level (P < 0.05). ‘Full approval’ would be granted later on, when enough evidence is gathered to achieve the conventional significance level5.
Another example is to grant an initial license based on surrogate endpoints which are considered likely to predict a real clinical outcome, and conduct further studies subsequently to confirm the effect on the relevant clinical end point.
In these examples, an early, and possibly conditional, approval is obtained and the level of uncertainty is then gradually reduced by pre-agreed obligations to gather post-approval safety and efficacy data. When uncertainty is satisfactorily reduced by obtaining the relevant data, a ‘full’ approval can be issued. An article published in Clinical Pharmacology and Therapeutics makes a prescient point that risk and uncertainty, although often conflated in public debate, are very different concepts. AP allows the acceptance of greater uncertainty, not increased risk, and any positive decision is subject to a “balance of probabilities with continuous monitoring”. Encouraging patients and health authorities to accept greater uncertainty must not be confused with a lack of scientific rigor4.
Pros and Cons
There are some clear benefits associated with the AP licensing model, which suggests it is a reasonable alternative to the current system. It will provide quicker access to medicines for patients, allow for quicker approval, and it may reduce development costs for industry by allowing decisions on a drugs viability to be made at an earlier stage, sparing unnecessary late-stage costs.
However, whilst the pilot program has made impressive progress, there are still several challenges and unanswered questions. Firstly, regulators must show some imaginative flexibility in order to create new incentives for developers. Companies rely on market exclusivity periods after approval in order to generate revenue. If AP is to succeed, market exclusivity periods may need to be restructured.
Moreover, for some countries, decisions on reimbursements for medicines is made by public bodies (e.g. Medicare in the US and NICE in the UK). It will be important to include payers in early stage discussions with the regulators to agree on a development plan which satisfies both. Currently, an absence of communication between these parties has resulted in rejections for reimbursement because payers believe they can’t square the benefit with the cost.
Finally, regulators face a complicated challenge to ensure drug developers stand by their commitments to continue gathering safety and efficacy data after ‘initial approval’. This problem can be foreseen based on examples from the US, as described by Jerry Avorn in The New England Journal of Medicine, in which he observes the FDA lacks the authority to instruct companies to conduct post-licensing studies of suspected safety problems. Over 50% of the studies requested had not been started, were behind schedule or had been prematurely halted6. If the EMA is to grant an initial approval, the conditions for doing so must be crystal clear because the appropriate action to take if a company refuses to conduct such studies is clear as mud. Revoke the licenses and the health of patients could be severely jeopardised, or brush it under the carpet and undermine the entire model. If AP is to be a realistic alternative to the current licensing system, these issues must be resolved.
The current approval process is tried and tested but it is also does much to discourage drug development and prevent timely access of medicines. Adaptive Pathways represents a bold attempt by the EMA to revolutionise the way in which medicines are licensed in Europe. It is clear that such a transformation will not be without considerable challenges, but the pilot program is progressing nicely and may well confirm AP as a viable model for drug approval. Change is long overdue. It is crucial that drug regulation does not strangle development, but is used as a safety mechanism which can release medicines to patients in need.
Written by Oliver O’Connell, Regulatory Affairs Assistant
European Medicines Agency. Adaptive Pathways. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000601.jsp (accessed 12/05/2015).
European Medicines Agency. Pilot Project on adaptive licensing. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/03/WC500163409.pdf (accessed 12/05/2015)
European Medicines Agency. Adaptive pathways to patients: report on the initial experience of the pilot project. http://www.ema.europa.eu/docs/en_GB/document_library/Report/2014/12/WC500179560.pdf(accessed 13/05/2015).
Eichler HG, et al. From Adaptive Licensing to Adaptive Pathways: Delivering a Flexible Life-Span Approach to Bring New Drugs to Patients. Clin Pharmacol Ther. 2015;97(3):234-246.
Eichler HG, et al. Adaptive Licensing: Taking the Next Step in the Evolution of Drug Approval. Clin pharmacol ther. 2012;91(3):426-437.
- Avorn J. Paying for drug approvals – Who’s Using Whom? N Engl J Med. 2007;356:1697-1700.