The European Medicines Agency (EMA) recently announced that it has selected six drugs to move forward in its adaptive pathways (formerly adaptive licensing) pilot program.
In March 2014 EMA announced it would be launching an adaptive pathways pilot program that would seek to accelerate patient access to drugs intended to treat serious unmet medical needs. The adaptive pathways program would allow drugs to receive approval for use with a narrow indication or in a “well-defined patient subgroup,” before using post-approval and real-world data to broaden the indication.
EMA said it sees its adaptive pathways pilot as “an opportunity for early brainstorming discussion among all relevant stakeholders, including regulators, companies Health Technology Assessment bodies (HTAs) and patient representatives, to explore ways to optimize development pathways and potentially accelerate patients’ access to medicines.”
For more about EMA's adaptive pathways pilot program, please see our March 2014 article, "EMA Unveils new Adaptive Licensing Initiative, Meant to Provide Earlier Niche Approvals."
First Stages and Next Steps
Stage I of the pilot calls for the submission of applications to take part in the program. By early December, EMA received 34 applications which included six advanced-therapy medicines, 12 orphan products and 14 anticancer medicines. Out of these products, 10 were selected for Stage I discussions, and from those discussions six products were chosen to move forward for Stage II meetings which will consist of in-depth discussion(s) with stakeholders. EMA will continue to accept Stage I submissions until 28 February 2015, at which point the agency will only consider submissions of “very well developed proposals” that are eligible to go directly to Stage II discussions.
Following the Stage II in-depth discussions and the completion of a parallel formal Scientific Advice/HTA advice procedure on at least six products, the EMA will conduct an evaluation of the “impact and usefulness” of the adaptive pathways program.
Faster Access around the World
Regulators in other jurisdictions have acknowledged the need for faster approval for therapies that address unmet medical needs. The US Food and Drug Administration (FDA) has offered a pathway known as accelerated approval since 1992 which allows for drugs to be approved based on a surrogate endpoint(s). Companies are required to conduct what FDA calls phase 4 confirmatory trials to confirm the clinical benefit of the surrogate (or intermediate clinical) endpoint.
EMA currently allows for conditional marketing authorizations to be granted based on early clinical trials data. A company receiving conditional marketing authorization for one of its products must conduct ongoing or additional studies to demonstrate the product’s benefits, and may be given additional requirements to collect pharmacovigilance data. Conditional marketing authorizations are considered valid for one year and can be renewed annually.
Other countries, in addition to having broad-based adaptive pathways, also target specific types of therapies for accelerated approvals. In Japan, for example, a 2013 amendment to the Pharmaceuticals and Medical Devices Law created a new pathway for faster approval of regenerative medicine products. This pathway will allow regenerative medicine products whose safety can be demonstrated to be marketed under certain conditions for a fixed term once they have received a positive opinion. The conditions of approval in this case could include marketing restrictions, specific post-marketing surveillance and/or follow up studies.
The Case for Adaptive Licensing
A group of researchers consisting of individuals from regulatory authorities, HTA bodies, patient groups and industry headed by Hans-Georg Eichler, senior medical officer at EMA, recently published a paper in the journal Clinical Pharmacology & Therapeutics that spells out the case in favor of moving to adaptive licensing.
Eichler’s group argues that the adaptive licensing model can provide faster access to new treatments. “The approach considers simultaneously the patients’ situation and the potential efficacy and safety of the treatment under study," they wrote.
The researchers make clear that adaptive licensing “is not about changing the benefit-risk trade-offs […] the expected benefits should outweigh the expected risks for a defined patient population – anything else is unethical.” Even so, faster approvals based on incomplete data would come with greater degree of uncertainty. The researchers here make the case that the degree of uncertainty about a product approved this way would be reduced through additional studies and the collection of real-world data.
The researchers also point to the fact that “almost every disease or clinical indication consists of multiple sub-populations,” wherein specific subpopulations may respond better to a treatment or be more tolerant of uncertainty than others.
Hurdles and Challenges
Eichler’s group also points out that the adoption of adaptive licensing will likely be gradual and “evolutionary rather than disruptive.” The researchers acknowledge that there are a number of issues and challenges that would need to be resolved for the concept to function.
One such hurdle would be getting buy-in from payers and HTA bodies to ensure access to products approved in this manner. Additionally, there are a number of “legal, logistic, and scientific pre-conditions” that must be in place for the adaptive licensing concept to work, they said.
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