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EMA, new features for the PRIority Medicines (PRIME) scheme


By Giuliana Miglierini Based on the review of results obtained in the first five years of implementation of the PRIority Medicines (PRIME) scheme, the European Medicines Agency has launched a set of new features to further enhance the support to Read more

The proposals of the EU Commission for the revision of the IP legislation


By Giuliana Miglierini In parallel to the new pharmaceutical legislation, on 27 April 2023 the EU Commission issued the proposal for the new framework protecting intellectual property (IP). The reform package impacts on the pharmaceutical industry, as it contains proposals Read more

Webinar: Pharmacovigilance as a specialization and the role of the Pharmacovigilance Risk Assessment Committee (PRAC)


EIPG webinar Next EIPG webinar is to be held on Wednesday 31st of May 2023 at 17.00 CEST (16.00 BST) in conjunction with PIER and University College Cork. Sofia Trantza, a pharmacist with long experience as a Qualified Person for Pharmacovigilance Read more

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Real-world evidence for regulatory decision-making

September 23, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

Digitalisation is rapidly advancing also in the regulatory field, as a tool to improve the efficiency and accuracy of processes used for the generation and use of data to inform the regulatory decision-making. To this instance, real-world data (RWD) on the use of a certain medicine by the general population are increasingly important to monitor the impact in terms of health benefits, adverse events and costs for healthcare systems.

The trend is confirmed by the publication of a joint statement by the International Coalition of Medicines Regulatory Authorities (ICMRA) addressing the use of real-world data and real-world evidence (RWE) in the development, authorisation and monitoring of medicines to support regulatory decision-making. The document has been endorsed by the European Medicines Agency (EMA), which also published the third workplan developed by its Big Data Steering Group to set key actions to be delivered in the period 2022–2025.

The debate on real-world evidence for regulatory decision making was also stimulated by an ISPE’s position paper released in 2020, and by papers published in the scientific literature (see here a recent review).

ICMRA’s joint statement on real-world evidence

The joint statement is the final result of a ICMRA workshop on real-world evidence co-organised with EMA, the US FDA and Health Canada in June 2022, that saw the participation of representatives from more than 40 countries. Heterogeneous data sources across different geographic areas and different levels of quality, as well as various processes for data sharing and access of the data, were among the main open issues identified during the meeting. Four different areas of collaboration have been identified, representing the focus of further discussion by international regulators in order to implement concrete actions to address criticalities.

The first area addresses the harmonisation of RWD and RWE terminologies. This exercise is deemed essential in order to share common operational definitions of RWD and RWE, characterized by a clear scope and level of granularity (e.g., pertaining to RCTs and observational studies).

Already existing guidance, such as the ICH M14 on “General principles on planning and designing pharmacoepidemiological studies that utilize real-world data for safety assessment of a medicine”, may represent useful tools to support these activities.

The convergence on RWD and RWE guidance and best practice should include the development of common principles for RWD quality. Metadata are an essential feature, as they enable the characterisation and discoverability of RWD. Other targets include the definition of suitable scenarios where RWE may contribute to regulatory decision-making, and the setting up of templates for study protocols/reports that can be used in multiple regulatory jurisdictions.

Readiness shall be pursued by strengthening the international regulatory collaboration on RWE. The rapid creation of expert groups on specific topics of interest and an improved collaboration on governance and processes aimed to support the efficient conduct of RWD studies in different countries are key actions in this area.

Transparency should be the common denominator underlying all the above-mentioned activities. It should be tackled through the definition and use of common principles and practices for the systematic registration of pre-specified study protocols and study results in publicly available registries. Publication of study results in open-source, peer-reviewed journals is also expected.

The 2022-2025 workplan on Big Data use for public health

In parallel with the publication of ICMRA’s joint statement, EMA released the Big Data Workplan 2022-2025, jointly developed with the Heads of Medicines Agencies (HMA). The joint workplan represents the expansion towards the operative phase of the priority recommendations for regulators on the best approaches to use and generate data developed in 2020 by the former Big Data Task Force. The document refers mainly to medicines for human use, even if it includes some information on veterinary medicines.

Big data are the key element to be considered in order to achieve the overall objectives seen above, as they enable the extensive analysis of information available on medicinal products subject to regulatory scrutiny. According to the Big Data Steering Group, the increased evidence arising from big data analysis may accelerate medicine development, improve treatment outcomes and facilitate earlier patient access to new treatments.

The workplan details ten different priory areas and the respective recommendations for action, and it provides the expected timelines for their implementation.

Central to the overall planned system is the Data Analysis and Real-World Interrogation Network (DARWIN EU), a federated network to enable access and analysis of real-world data. After the establishment of the DARWIN EU Coordination Centre and the activation of the first studies in 2022, new activities shall focus on the support to the European Health Data Space (EHDS) and the collaboration with the European Centre for Disease Prevention and Control (ECDC), HTA bodies and payers.

The joint action Towards A European Health Data Space (TEHDAS) shall facilitate the engagement with stakeholders, a critical point to ensure the quality of data. The release of a first version of a data quality framework for the EU Regulatory Network is expected in late 2022. An agreement on metadata to describe and identify RWD sets shall also be supported by the publication of a good practice guide on metadata and a public catalogue of European RWD. Release of new analytics tools and a review of the utility of eHealth data and social media data are also part of actions targeted to data discoverability.

The reinforcement of skills of all stakeholders involved in the process of RWD and RWE generation, analysis and use is also essential to guarantee the success of the new approach. EMA and HMA aim to develop agreed training curricula on biostatistics, pharmacoepidemiology and data science, including the availability of selected modules open to patients, healthcare professionals and academics. A curriculum on genomics data shall also be adopted.

The results of pilot studies on the use of RWE by EMA scientific committees will be released in next years, with a final report and a portfolio of RWE use cases to support uptake of RWE by the ERMN expected in 2025.

More in detail, a proof-of-concept pilot assessing access to individual patient data from clinical trials (raw data) in the scientific assessment of medicines is planned for Q4 2022. The final reflection paper on artificial intelligence (AI) for use in regulatory processes shall be published in Q3 2023, while 2024 should focus on a pilot on data analysis for CMC data.

All the above-mentioned activities shall be supported by new guidance issued by the new EMA Methodologies Working Party, while expert advice will be strengthened through the European Specialised Expert Communities (ESEC), initially focusing on AI & RWE.

The governance of the process shall benefit by a review of the mandates of the Big Date Steering Group and EU Network Data Board expected for late 2022. Target actions aimed to strengthen the framework for ethics in data analysis will also be explored. Activities at the level of the international framework of regulators shall include among others the evaluation of the clinical trial conceptual model under the ICH M11.

An annual Big Data stakeholder forum is also planned, complemented by topic specific meetings and workshops and biannual industry meetings. In the veterinary field, the workplan includes the implementation of the EU Veterinary Big Data strategy adopted in 2022. Among the main deliverable are a catalogue of veterinary data sources, finalisation of the system on antimicrobials sale and use data, and the evolution of training curricula.


ICMRA, two pilot programmes to optimise regulatory assessment and inspections

July 22, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

New flexible modalities for the management of regulatory procedures are becoming progressively accepted even for routine activities, upon the experience built during the pandemic. Efforts are ongoing at the global level in order to better harmonise the new approaches. To this instance, the International Coalition of Medicines Regulatory Authorities (ICMRA) has launched two pilot programmes focused, respectively, on the collaborative assessments of chemistry, manufacturing and control (CMC) and Post-Approval Change (PAC) submissions and related regulatory actions and on hybrid inspections.

Each programme is expected to last 1-1.5 years and should see the involvement of at least two regulatory regions, each one conducting three assessments or collaborative hybrid inspections. Recommendations resulting from the pilots shall be published in 2023, representing the basis of an initial common framework for collaborative assessment and hybrid inspections. The initiative follows the results of a workshop organised by ICMRA in July 2021, during which emerged the need for more convergence and reliance across regulatory authorities in order to support the timely supply of critical medicines.

ICRMA has invited industrial sponsors to participate to the initiative, with particular reference to those planning to file an application for a new product or for post approval changes of already approved products to more than one regulatory agency. All details and the procedure for application are available at this link.

Therapeutics which may be object of the submission include both small molecules and biological products. The submission may refer to products for the treatment of Covid-19, other medically necessary/critical medicines or products granted for access to fast-track procedures such as the Breakthrough (US), PRIME (EU) or Sakigake (JP) schemes.

Interested sponsors are required to check with the involved facility’s management to ensure readiness for inspection and possibility to host a collaborative hybrid inspection, with a particular attention to the availability of suitable IT infrastructures and interpretation services, and the possibility to coordinate at least two inspectorates across different time-zones.

Applications are open since 15 June 2022 and have to be forwarded using the EudraLink secure file transfer application provided by EMA. After a rolling review of the applications, starting of the first pilot is scheduled for September 2022.

The general objectives

The main goals of the initiative include the definition of best practices and standards in the quality assessment of CMC-related post-approval changes and collaborative hybrid inspections. A single list of questions to the sponsor or manufacturer should also be delivered, and answers be shared with the participating quality assessors and inspectors.

The exercise should lead to the identification of misalignments and potential areas of harmonization across participating regulatory regions. An improved convergence and collaboration among regulators in specific data expectations and assessment approaches for the assessment of manufacturing facilities for Pre-Approval and Pre-License Applications (PAIs & PLIs) and reviewing PACs and PAC Management Protocols may also be supported by the analysis of the data acquired during the two programmes.

Hybrid inspections

Hybrid inspections are based on the collaboration of at least two different National Regulatory Authorities (NRAs), one of which in charge of the on-site inspection activities, the second acting as a remote inspectorate. The respective tasks shall be coordinated and run using virtual technologies, so to enable real-time collaboration in the inspection activities, which should target facilities and products of interest for multiple regulatory agencies (see more details here and here).

The pilot is expected to reduce the need of multiple inspections or facility assessments and to support the identification of the best virtual platforms and information technology (i.e., video) to facilitate concurrent on-site inspection and distant assessment. Focus on the development of a common framework to accommodate time zone differences between the facility location and the distant inspectorates is also expected.

Best practices to prepare and conduct the hybrid inspection are another important outcome, as both the on-site and distant inspectorates needs to obtain from the activities all the information needed to run their respective assessments.

In the critical field of GMP expectations, a possible target of the pilot may be represented by how the inspection is reported and how deficiencies are classified by different regulators. Aligned reports and protocols may also support the sharing of information with other interested ICRMA inspectorates. In any case, each participating authority remains the sole responsible for the evaluation of the outcomes of the inspection and the enforcement of any consequent action, according to its own reference legal framework.

A final protocol describing how to execute a hybrid inspection is a main expected outcome of the fist pilot, to be then applied by the Working Group to evaluate at least 3-5 facilities with at least two regulatory agencies involved in the hybrid assessment.

Collaborative assessment

The second pilot aims to run collaborative quality assessment for a minimum of three different applications and a minimum of three regulatory agencies involved each time. The initial phase of the pilot should see a limited number of regulatory agencies (3-5) participating to the project, on the basis of specific confidentiality agreements.

Sponsors participating to the pilot shall submit a single application for the proposed CMC changes for assessment by multiple regulatory authorities; the initial focus is expected to be on post-approval change management protocols (PACMPs; chapter 4 of ICH Q12) for Covid-19 therapeutics. More in detail, participating regulatory agencies will agree on the procedure to be used for the collaborative assessment. They are expected to share and discuss in advance any information request or comment, prior to the interaction with the applicant. Any participating authority can maintain its independence to issue information requests, but in any case, the so obtained answers shall be shared with other NRAs and assessed on the basis of a common approach, so to avoid the need of multiple independent lists of clarification seeking comments.

The project also aims to achieve a single regulatory decision regarding the joint assessment (see more details here and here).

More specifically, priorities to be addressed should include for example the evaluation of information or data on specifications, stability, and/or PACMP that support site changes or additions.

As for the hybrid inspections, expected outcomes are represented by the identification of the best practices and standards in the quality assessment of post approval changes, including PACMPs, and of potential areas for alignment or harmonisation across regions.

A forum of discussion should be also created in order to facilitate convergence on the basis of such best practices. Each evaluation should lead to the preparation of lessons-learned summaries to share the acquired knowledge; new quality assessment guidance and standards might also be proposed, where appropriate.


ICMRA published a Reflection paper on remote inspections

January 21, 2022 , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

Remote inspections have become a widely used approach since the last two years to ensure the oversight of the compliance of pharmaceutical productions to regulatory requirements, as the prolonged lockdown periods determined by the pandemic made very difficult the maintenance of the regular schedule for on-site inspections.

A Reflection paper on the so gathered experience has been recently published by the International Coalition of Medicines Regulatory Authorities (ICMRA); the document addresses from the point of view of regulatory authorities the many issues encountered to establish appropriate modalities to interact at distance with the industrial counterparts by mean of digital technologies and suggests the best practices for the future. The analysis focused especially on remote GCP and GMP inspections.

The Reflection paper was drafted by a working group chaired by the UK MHRA and inclusive of representatives from the US FDA, EMA, Health Canada, Swiss-medic, HPRA Ireland, AEMPS Spain, ANSM France, PEI Germany, MHLW/PMDA Japan, TGA Australia, ANVISA Brazil, HSA Singapore, WHO and Saudi FDA.

The lack of a uniform definitions and approaches

Each national competent authority adopted during the pandemic its own approach to remote inspections, evaluating this type of opportunity on a case-by-case basis, making use of established quality risk management principles and tools to reach their decision (par. 3 of the Reflection paper enlists the more widely used parameters for risk assessment and management).Among the factors entering this preliminary evaluation are the regulatory compliance history of the inspectee, the scope of the inspection (pre-approval, routine or for cause), and the inherent risk associated with the activities conducted by the site, the types of products and the need for the product.

The term used to identify the at distance interaction with the company to be inspected also assumed a quite wide variability; “distant assessment”, “remote evaluation”, “desktop assessment” or “remote assessment” are other frequent declinations used to define oversight procedures run by using digital technologies, both at the national and international level.

The choice of the specific term to identify this sort of practice depends upon many different factors, including the type of inspection and of the involved facilities, and the local national legal frameworks governing inspections as well as protection of personal data. The specific areas or sites to be included in the official review of activities, documents, facilities, records, etc. have proved also highly variable, as they may include not only the manufacturing site, but also investigator sites of a clinical trial, the sponsor’s and/or contract research organisation’s (CRO’s) facilities, or any other establishments deemed appropriate by the regulatory authority running the inspection.

Should the preliminary risk assessment had discouraged the possibility to conduct a remote inspection, the on-site inspections were usually postponed until the termination of lockdown measures in the interested countries. Hybrid or collaborative inspections represent another opportunity used to handle critical cases: the first ones involve the assessment or inspection to be conducted using a mix of remote and on-site activities, the second see two or more regulatory authorities collaborating to perform a conjunct inspection of a specific site.

According to the Reflection paper, it thus appears highly unlikely that a unique and fully harmonized approach to remote inspections in all scenarios might be developed for the future. “While the ICMRA group have found remote inspections an enabling tool to maintain at least a minimal regulatory oversight during the pandemic, it is not the view of the group that remote inspections would fully replace an on-site inspection programme”, states the document.

The main issues encountered

The possibility to conduct inspections, evaluations or assessments at a distance/virtually is based on the implicit availability of a robust IT and communication infrastructure; this has proved a fundamental requirement to smoothly share and review all the relevant documentation and ensure access from remote to systems and plants. Virtual tours of the manufacturing facilities are a typical example, for which the availability of solid “hardware and software that can provide an appropriate field of vision, clarity and stabilisation of the picture, while simultaneously facilitating conversation between the inspector and tour host” is essential to enable the real-time transmission of images and sounds captured by the in charge on-site staff by mean of smart devices or more advanced systems as smart-glasses.

In international inspections, the difference in time-zone and the availability of real-time, online translation services have also proved critical in many instances, especially if parallel sessions of discussion were needed. The possibility for inspectors to access on-line the relevant documentation requires the availability of the inspected company to provide credentials to enter in a read-only mode its proprietary document management systems and repositories. To this instance, confidentiality issues often led many companies to provide access to IT systems by mean of a specifically appointed member of the staff, in charge of accessing in real-time the systems and made available all the documentation as indicated by the inspectors.

The main areas of attention

The Reflection paper identifies four different areas for which remote assessment/inspection proved to be particularly useful during the pandemic period.

In the case of virtual tours, the indication coming from ICRMA experts is to limit the use of prerecorded video tours only in exceptional circumstances, and never for inspection of high-risk activities, as the inspector may not be in the right conditions to effectively verify all details needed to evaluate the suitability of the facility.

“Direct access to documentation by inspectors is an expectation, electronically or otherwise, whether the inspection is on-site or remote”, states the Reflection paper. The alternative intervention of site staff may be acceptable, but it should not negatively impact the results of the assessment. Furthermore, this modality may also prove quite time consuming for both the inspector and the inspected company. ICRMA also supports the possibility for regulators to access documentation after the closure meeting, and upon the formal closure of the inspection, in order to facilitate the drafting of the report or to clarify a deficiency already raised.

GCP and GMP inspections

Specific issues for both GCP and GMP inspections are addressed in two dedicated chapters of ICRMA’s Reflection paper.

“It should be noted that within the EU remote inspections at investigator sites are not considered to be feasible”, writes ICRMA. The motivation has to be found mainly in the need to avoid any further impact on the clinical sites during an health emergency like the pandemic, andin the issues posed by local frameworks for data protection. The Reflections paper provides a list of clinical areas not suitable for remote inspection.

As for GMP inspections, not all regulatory authorities adopted the same approach during the pandemic; in general terms, this sort of practice has been judged acceptable by ICRMA to handle emergency situations with restrictions to travels in place, but it cannot fully substitute onsite inspections of manufacturing sites. More specifically, the experience of the past two years shows that remote inspection proved unfeasible for sites requiring detailed observation, as those performing aseptic manufacturing or handling potent active ingredients with low Permitted Daily Exposure.