The evolution towards new digital models to run clinical R&D requires all stakeholders, including the pharmaceutical industry, clinical centres and regulators, to optimise their interactions in order to streamline from the beginning the optimal planning of all activities. EMA recently published two scientific articles addressing different aspects of early interaction, with the aim to improve evidence generation and speed up the approval process. The Agency also released an updated version of the Q&A documentQualification of digital technology-based methodologies to support approval of medicinal products”.

The importance of post-approval evidence generation

Real-word data (RWD) coming from the post-approval use of a new medical product are very important to assess its performance and safety in the general population. Post-licencing evidence generation (PLEG) is discussed in the article published in the British Journal of Clinical Pharmacology, under the perspective of early advice activation to optimise PLEG plans, which need to be submitted to EMA together with the marketing authorisation application (MAA).

Post-approval RWD should be generated in a reasonable, not too long time length, as they are used to inform decisions by both the regulatory authorities (also in the US and Japan) and the value proposition evaluation run by health technology assessment (HTA) bodies. Despite the availability of various scientific advice tools, this instrument is not yet broadly used by Marketing Authorisation Holders (MAHs) for the planning  of their PLEG activities. These are utmost important to clarify the uncertainties left behind from the pre-approval development, as they may help identifying emerging points requiring attention. PLEG data come not only by new trials (randomised or not, observational, interventional, pragmatic, etc), but also from electronic healthcare records and other medico-administrative documentation, as well as from smart devices (wearables, smartphones, etc.). 

Post-authorisation safety studies (PASS) or post-authorisation safety efficacy studies (PAES) are possible examples of PLEG requests coming from the regulators; MAHs are free to develop their own initiatives, including the use of data from temporary authorisation of use programmes or early access to medicines schemes.

The article provides a discussion of the rationale for PLEG studies according to the perspective typical of the different stakeholders, i.e. regulatory authorities, HTA bodies or National Immunisation Technical Advisory Groups (NITAGs) for vaccines. Evidence sufficient to determine the risk–benefit profile has to be available to reach approval, for example; this evidence can be then complemented with PLEG data, according to an impact-based hierarchic approach led by post-approval data specifically requested in order to confirm efficacy and safety (e.g. in the case of conditional or exceptional marketing authorisations). 

The evidence acquired by EMA in the period 2012-2016 shows that data from phase 2/3 studies are mainly related to conditional MAs’ PLEGs requests, while evidence on long-term real-world safety and efficacy and disease epidemiology more relates to exceptional circumstances authorisations. The resulting evidence was included in the product information in 72% of requests reaching the fixed milestones. “Notably, all conditionally authorised products had imposed obligations to collect additional data of between 1 and 4 activities”, write the authors. Analysis of centrally approved products in the period 2005–2013 shows the use of a registry has been imposed by EMA in 4% of non orphan and 29% of orphan medicinal products, and in 12% of conditional MAs and 67% of exceptional circumstances approvals, respectively. The primary objective of such registries was to track safety data (53% of cases). 

Several forms of early advice are available and are discussed in the paper, with the possibility to activate actions with single regulators or, for example, in parallel between regulatory and HTA bodies, or EU-US bodies. The potential benefit for patients is the main criteria the EUnetHTA Early Dialogue Working Party uses to select products for consolidated parallel consultations. Sharing of best practices, qualification of data sources and methods and monitoring of PLEG’s impact in different geographic regions are among EMA’s suggestions to correctly approach these procedures. 

How to support the use of digital technologies

Digitalisation is a reality in the way clinical studies are being conducted; for example, it plays an essential role in the generation of RWD or in the continuous monitoring of pato-physiological parameters. The second paper from EMA was published in Nature Reviews Drug Discovery and addresses how the Agency could support the development of reliable digital tools, able to provide data characterised by a quality level sufficient to meet regulatory needs. This tools can be classified under the regulatory point of view as medical devices or medicinal products depending from their principal mode of action (alone or in combination with a medicine)

EMA has recently activated a new voluntary procedure for the qualification of novel methodologies, which can be used to establish their regulatory acceptability. The experience gained so far suggests developers to seek early advice, so to optimise the use of digital technologies with respect to the goals established in the benefit-risk evaluation. EMA, on its side, can better and timely set the multidisciplinary team needed to assess the technologies and their outputs, identifying the optimal interaction channel and guiding the development targets for data generation and acquisition. 

Early tests aimed to gain proof-of-concept on the applicability of a certain digital technology should be followed by a validation phase aimed to gain pivotal data to be used in the marketing authorisation application (MAA). 

All questions for advice on the digital technology posed to EMA should fall within the Agency’s remit, suggests the article. In particular, the expected benefits compared to traditional methods should be clearly explained, together with the interest, contest of use and identification of a clinically meaningful change. Developers should document the reliability, accuracy and repeatability of the technology, according to principles of design control and medical device regulations. Just high-level information is requested in relation to technical parameters that do not impact on the assessment of the benefit-risk ratio for the medicinal product. 

The MAA should also contain a risk assessment of the impact any changes introduced to the final digital technology element during development would exert on the validity of the generated clinical data; this exercise should be run according to ICH guidelines Q8, Q9, Q10 and Q12. Whenever applicable, digital technologies have to fulfil relevant legislations for medical devices and in vitro diagnostic, as well as the the GDPR regulation on the protection of personal data. CE marks for medical devices are not needed during development, but are necessary at the time of marketing.