The European Medicines Agency (EMA) on Wednesday published a final report on its experience from its adaptive pathways pilot project, noting that a few aspects of the program need to be further improved and refined moving forward.
Though the vast majority of applications for the pilot were rejected, EMA said that moving forward, the agency needs to further integrate the patient voice into the program and refine the definition of methodologically sound strategies for collecting real-world evidence to support the assessment of both efficacy and effectiveness, as well as to bring together more organizations responsible for making decisions on drug pricing and reimbursement.
Drug developers interested in engaging in the adaptive pathways approach can still submit a proposal to EMA, and an updated guidance document published Wednesday outlines the steps to follow.
“EMA will further explore adaptive pathways in the context of its parallel advice with HTA bodies, which provides a framework to include additional stakeholders (e.g., patients and, if relevant, payers),” the agency said in a statement.
First announced in March 2014, EMA’s pilot program, which has now ended, sought to accelerate access to drugs for patients with the most pressing medical needs, and though the pilot was not a new route for marketing authorization, it sought to make use of existing regulatory tools. Following a drug’s approval for a narrow indication, additional clinical and real-world data were expected to be used in the pilot to gauge if the treatment is actually as effective as expected.
Though the use of real-world data from the pilot has so far been a learning experience, EMA noted that the pilot showed that adaptive pathways can bring multiple stakeholders together, including regulators, health technology assessment (HTA) bodies, health professionals and patients.
As part of the pilot, EMA invited companies to submit ongoing drug development programs that met the following criteria: 1. An iterative development plan, meaning that evidence can be acquired step-wise to either expand the target population from an initial approval in the population with high(est) medical need; or to progressively reduce uncertainty with additional data collection after an initial (conditional) marketing authorisation based on surrogate endpoints, early time points, or a smaller population sample; 2. The involvement of HTAs and other downstream stakeholders, with proposals for how the demands of these stakeholders can be met; 3. Real-world data used as a complement to randomized controlled clinical trials.
During the pilot, EMA received 62 applications, 20 were accepted for a Stage I meeting, which is a short meeting with regulators intended to improve the understanding of the concept and the design of the proposal, while 18 proposals were selected for Stage II, and of these seven progressed, one to formal scientific advice and six to parallel regulatory-HTA scientific advice (including two in oncology, two in hematology, one anti-infective and one cardiovascular drug).
“The majority of the proposals received were considered not suitable for adaptive pathways, and the companies were advised to pursue traditional development routes,” EMA said.
As far as the real-world data, EMA said that all of the 18 proposals accepted to Stage II of the pilot included plans for the use of such data to supplement randomized clinical trials, with a plan that went beyond the traditional use of a registry to investigate safety aspects, including:
- Use of existing disease registries to identify natural history of a disease, current standard of care, resource utilization and adherence to treatment
- Single arm studies for rare diseases compared with outcomes and time-points inferred from disease registries
- Open label salvage studies in patients with no therapeutic options remaining, with the purpose of obtaining an expansion of the indication
- Collection of efficacy and safety data from early access/compassionate use programs to supplement randomized controlled trials in small populations
- Post-authorization drug registries for effectiveness, long-term outcomes, drug utilization, Patient Reported Outcomes (PROs), time to treatment failure, diagnosis confirmation;
In May, nine professors from Oxford, Cambridge, the London School of Hygiene and Tropical Medicine, the French National Academy of Medicine, Royal College of Physicians, Toronto-based York University, as well as others from Barcelona, Italy and Copenhagen raised some serious questions with respect to the assumptions made by EMA in developing the pilot, which EMA Executive Director Guido Rasi and senior medical officer Hans-Georg Eichler responded to.
Of those participating, at least four companies went public with their acceptance into the pilot, including Bluebird Bio, which said in May 2015 that it planned to seek conditional approval for its gene therapy LentiGlobin BB305 to treat beta-thalassemia major (and which EMA said in Wednesday’s report that “an initial conditional approval route is foreseen in the EU”); the biotech company Immunocore said in September 2015 it also planned to seek conditional approval for its lead biologic IMCgp100 for the treatment of patients with metastatic uveal melanoma, a rare and fatal disease with few available treatment options; in August 2015, Pluristem Therapeutics, said it was using EMA's guidance in the pilot to develop a cell-therapy product that targets a subgroup of patients with critical limb ischemia; and F2G, a UK-based antifungal drug company, said in November 2015 that its antifungal product had been accepted to participate in the pilot.
And though EMA did not go into the specific companies, it said that small and medium-sized enterprises (SMEs) accounted for 23% of the initial applications submitted to the pilot (14/62). And of these, four products were selected for a Stage I meeting, representing 20% of the total selected for this phase. And about half of the products invited for a Stage I meeting were developed by biotechnology companies, three of them being spin-offs from academic and research institutions.
In terms of HTA involvement, EMA said that a number of different groups participated including:
- AEMPS (Agencia Española de Medicamentos y Productos Sanitarios, Spain)
- AIFA (Agenzia Italiana del Farmaco, Italy)
- G-Ba (Gemeinsame Bundesausschuss, Germany)
- HAS (Haute Autorité de Santé,France)
- HVB (Hauptverband der Österreichischen Sozialversicherungsträger, Austria)
- NICE (National Institute for Health and Care Excellence, UK)
- NoMA (Statens legemiddelverk / Norwegian Medicines Agency, Norway)
- TLV(Tandvårds- och läkemedelsförmånsverket , Sweden)
- ZINL (Zorginstituut Nederland, The Netherlands).
Patient representatives participated in four (out of 18) Stage II meetings and EMA said the issues where input was needed included: balancing unmet medical needs with accelerating development to safeguard patients’ safety, relevance of endpoints, development of PROs, risk management and prescription control discussions.
EMA says that drug developers interested in following the adaptive pathways approach should submit a proposal to EMA. An updated guidance document published Wednesday outlines the steps to follow.
“Future adaptive pathways discussions, including proposals already submitted, will be incorporated in the existing operational platform of a parallel regulatory-HTA scientific advice, with the inclusion of other stakeholders (patients, interested HTAs and, if relevant, payers will also be invited) which are relevant decision makers for the specific issues under discussion,” EMA said. “This will provide a more structured, sustainable and tested framework, and may increase the availability of relevant expertise from all stakeholders. An additional presubmission meeting (two for SMEs) will be granted as compared to the parallel regulatory-HTA scientific advice.”
The European Federation of Pharmaceutical Industries and Associations (EFPIA) said in a statement that the “challenges to creating methodologically sound strategies of real-world evidence collection are clear. These include: data not always generated to the same standards, and therefore not comparable; e-health systems not always compatible between hospitals or countries; patients not having a single, electronic health record that stores data in one place; and data being collected for different purposes, which can’t always be linked together, with the added problem that regulation sometimes stops data transfer between systems.”
And to gather more views and proposals from its stakeholders on the adaptive pathways approach, the agency will run a workshop on 8 December 2016.
EFPIA Director General Richard Bergström added: "Prior to the December workshop EFPIA will carry out its own evaluation of members' experience. But we can already now say that we agree with the EMA that new methodologies are needed for better patient involvement in the choice of development strategies. There is also an immediate need to agree standards and approaches to use real world evidence in addition to randomised clinical trials. Combination therapies, and medicines for children and in multi-morbid elderly patients are often better studied in real-life than in RCTs. The involvement of payers in early dialogue is already under way but must be scaled-up and broadened to involve more countries.”
Final report on the adaptive pathways pilot
Guidance for companies considering the adaptive pathways approach