We all want safe and effective medicines to reach patients as soon as possible, but as we know, drug development, market authorization and payer assessment are all slow sections of a long and drawn out journey for a drug. But what if patients could have access to medicines not just months earlier, but potentially 8 years earlier? This is exactly what the European Medicines Agency (EMA) have in mind, as they lead a broad and diverse group of key stakeholders towards a root-and-branch upheaval of current practice. Adaptive Licensing (AL) (earlier known as adaptive pathways; AP), an ambitious and evolving new initiative which incorporates Real World Evidence (RWE): clinical data collected outside of a conventional randomized controlled trial. AL reforms the existing regulatory approach.
In March 2014 EMA launched a pilot project to explore the adaptive pathways approach, a scientific concept of medicines development and data generation intended for medicines that address patients’ unmet medical needs. AL seeks to balance timely access for patients who are likely to benefit most from the medicine with the need to provide adequate evolving information on the benefits and risks of the medicine itself. AL is not a new route of approval for medicines. It makes use of existing approval tools, in particular conditional marketing authorization, which has been in operation in the European Union (EU) since 2006. It also builds on the experience gained with strengthened post-marketing monitoring tools introduced by the 2012 pharmacovigilance legislation (e.g., post-authorization studies and patient registries). The adaptive pathways concept is not meant to be applicable to all medicines, but only to medicines that are likely to offer help for a patient population with an unmet medical need, and where the criteria for adaptive pathways apply.
Notwithstanding the classic randomized controlled clinical trials (RCTs) are Gold Standard for the regulatory approval of new technologies, their inherent generation of efficacy and safety data, are not always utilizable in the daily context. Items such as ‘homogenous populations without other diseases than the one explored in the study’, ‘placebo comparator, not the standard treatment or other active comparator’, and ‘high adherence,’ are just to nominate some points, which are far from the regular use of a medication on the part of patients and healthcare professionals. Even though currently, in parallel with clinical studies, collection programs of observational information are more and more generated, the available evidence is limited and onerous in case of necessity of large volumes; at least by means of clinical studies. This can be overcome with the help of real-world data.
RWE refers to the planned and systematic recollection of the data generated outside the clinical studies. Adaptive approaches link decision making to an evolving evidence base, parts of which are frequently seen as being derived from analyses of observational data gathered from sources such as electronic medical records, registries or administrative databases. Acceptance of such evidence is an important issue- regulatory authorities and payers are currently prepared to accept observational data to support manufacturers’ efficacy/effectiveness claims only in limited circumstances. In the pilot project, the concept of RWE was expressly intended as wide ranging, encompassing different types of observational research that may be utilized to supplement randomized clinical trials. This was to encourage the submission of different approaches, not all of which could be foreseen at the conceptual stage, with the intent to highlight possibilities, needs and maximize the learning potential.
RWE data collection within AL has the potential to improve our understanding of disease processes, epidemiological factors, and difficult issues such as adherence, which will in turn allow RCTs to become more efficient. Additionally, for many subpopulations, the life span approach to licensing and coverage and learning from real-world experience as advocated by adaptive pathways will become the only viable access route to new treatments in future. Additionally, in-depth knowledge of the natural history of diseases, existing baseline data, as well as other epidemiology aspects gleaned from existing databases or emerging large data networks and reanalysis of past trials helps to make RCTs more efficient and identify surrogate endpoints, and may increasingly obviate the need for concurrent control groups, e.g., in rare diseases. This knowledge and data can also be leveraged for the post-initial licensing evidence generation foreseen under AL, by providing a reference point against which the real-world performance of a treatment can be assessed.
Further important steps towards enabling AL are currently being taken. Regulators have just begun to explicitly address and communicate “uncertainty” in their templates for benefit–risk assessment. A growing number of regulators and payer (or HTA) organizations involve patients in their decision-making processes. This can be considered as a pertinent analogy for the history of bringing new drugs to market.