Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Adaptive Licensing – A new approach in medicinal product authorisation ***

Dr. Katja Jennißen (Abschlußjahr: 2014)

Summary
Language: English
The pharmaceutical industry has been confronted with a considerable decline in research and development (R&D) efficiency during the last years. In parallel, there is a high unmet medical need in several therapeutic areas and patients often do not have timely access to new medicinal products (MPs) due to long development processes. Thus, calls for regulatory changes to support pharmaceutical innovation and timely access for patients to new MPs have been put forward. One concept that has been proposed as a potential approach to solve the problem of the decline in R&D productivity and the unmet medical need in a variety of therapeutic areas is Adaptive Licensing (AL).
Under the traditional, binary MP licensing approach, the life cycle of a MP is divided into two distinct phases – the pre- and the post-approval period – separated by the granting of the marketing authorisation (MA). In contrast, the basic principle of AL is the idea that evidence generation in MP development is a continuum and, thus, MP licensing should follow a stepwise approach characterised by continuous learning and progressive reduction of uncertainty about a MP. Therefore, in an AL setting, the traditional key event of receiving a single MA that raises the status of a new pharmacological therapy from "experimental" to "safe and efficacious" would be replaced by multiple regulatory assessment and authorisation steps. Initially, administration of a new MP authorised under AL would be restricted in accordance with the current level of knowledge, for example, to a certain patient population with the highest medical need for the MP, and would be extended during subsequent authorisation steps based on the continuous generation of evidence.
However, in order for AL to be a successful approach a variety of prerequisites would have to be fulfilled including an increased acceptability of uncertainty about a MP by all stakeholders, the prevention of off-label use, a truly continuous, robust and reliable generation of knowledge during the product’s life cycle as well as an intensive communication and collaboration between sponsors, regulators and Health Technology Assessment (HTA) bodies starting early and continuing throughout MP development.
Currently, there is a variety of regulatory mechanisms in place that would facilitate the implementation of AL, for example, by allowing for a continuous knowledge generation (possibility to impose PASSs or PAESs), a controlled distribution to prevent off-label use and minimise risks associated with a MP (legal status of the MP, MA subject to certain conditions, PAMs, RMP, additional risk minimisation measures, etc.), a staggered approval process (conditional MA) and iterative rounds of regulatory assessment (PSURs, renewal of the MA) as well as an early communication between sponsors, regulators and HTA bodies (parallel Scientific Advice).
However, there are several outstanding issues and gaps in the current regulatory and legal framework that counteract the implementation of more comprehensive AL approaches. This includes the limited flexibility of current licensing schemes defined by the current MP legislation, the restricted applicability of the existing staggered approval pathway (conditional MA), the fact that the establishment of a tripartite communication and collaboration between sponsors, regulators and HTA bodies is still in progress, the limitations of robust data generation following the granting of an initial MA, the limited generation of revenues in early licensing stages given the limited number of patients initially eligible to the new MP as well as a potential lack of  acceptance of increased uncertainty about a MP or the whole AL concept by all stakeholders.
Therefore, the current MP legislation does not constitute an appropriate legal basis for the implementation of more comprehensive AL approaches. However, current provisions might certainly allow for the initiation of pilot projects following a less comprehensive AL approach. Insights gained from these pilot projects might serve as a valuable source of information on the implications of utilising AL as well as the extent of legislative changes required for a successful implementation of AL.
Ultimately, a broad implementation of more comprehensive AL approaches would most likely require an extensive revision of the current MP legislation aiming at the introduction of a variety of new provisions and regulatory mechanisms, e.g. a new legal basis for multiple steps of  iterative regulatory assessment and MP authorisation at flexible intervals, new ways of communication to ensure awareness and understanding of a certain level of acknowledged uncertainty about a MP, novel reward and data exclusivity provisions to support pharmaceutical innovation, additional mechanisms to prevent off-label use, etc.
Moreover, substantial efforts are still required in order to establish a close collaboration between sponsors, regulators and HTA bodies as a standard feature in MP development – with an enhanced level of bindingness of the advice provided. Furthermore, an attempt to harmonise European HTA / reimbursement requirements for MPs would be highly desirable. In parallel, a regular communication and collaboration between international competent authorities and HTA bodies aiming at a common interpretation and implementation of the AL concept in order to facilitate the generation of global development programmes would be a preferable path forward.
Taken together, although there is a variety of obstacles to the implementation of more comprehensive AL approaches, the AL concept seems to be a promising approach to provide patients with the highest medical need, thus, potentially willing to accept a higher level of uncertainty about a MP, with early access to new MPs. Moreover, AL would support pharmaceutical innovation and counteract the decline in R&D efficiency by reducing the risk of late-stage failure and, therefore, the costs of MP development by facilitating an early and intensive collaboration between sponsors, regulators and HTA bodies. However, AL alone will probably not suffice to overcome the crisis in pharmaceutical R&D efficiency.
Pages: 62