EMA’s reflection paper on AI in the pharmaceutical lifecycle

September 22, 2023

AI, Artificial Intelligence, BDSG, benefit-risk ratio, CHMP, clinical trials, combination products, conditional marketing authorisations, CVMP, data integrity, data processing pipeline, data protection, data-driven regulation, discovery, early regulatory interaction, efficacy studies, ema, EMA Innovation Task Force, ethical aspects, GLP Data Integrity, GLP Principles to Computerised Systems, good pharmacovigilance practices, governance, HMA, human supervision, interactions with regulators, ITF, lifecycle, machine learning, MAH, manufacturing, marketing authorisation holders, ML, model architecture, non-clinical development, patient safety, Pharmacovigilance, post-authorisation phase, post-marketing surveillance studies for veterinary medicines, precision medicine, public consultation, quality risk management, Reflection paper, risk-based approach, safety studies, SAWP, scientific advice, Scientific Advice Working Party, SOPs, Standard Operating Procedures, Summary of product characteristics, technical aspects

by Giuliana Miglierini

The rapidly evolving role of artificial intelligence (AI) and its possible application in the pharmaceutical field led the European Medicines Agency (EMA) to publish a draft Reflection paper on the use of AI along the entire lifecycle of both human and veterinary medicines.

The Reflection paper summarises the current view on the possible use of AI and machine leaning (ML) technologies and is open to public consultation until 31 December 2023. Comments, together with the outcomes of the joint HMA/EMA workshop to be held on 20-21 November 2023, will support its finalisation, as well as the possible development of new guidance. The initiative aims to identify the aspects of AI/ML use that would fall within the remit of EMA or of the single National Competent Authorities (NCAs) in charge of the dossiers’ assessment.

The document is part of the effort to improve the European Medicines Regulatory Network’s capability in data-driven regulation set forth by the joint HMA-EMA Big Data Steering Group (BDSG), and it has been developed in coordination with EMA’s CHMP and CVMP committees.

“The use of artificial intelligence is rapidly developing in society and as regulators we see more and more applications in the field of medicines. AI brings exciting opportunities to generate new insights and improve processes. To embrace them fully, we will need to be prepared for the regulatory challenges presented by this quickly evolving ecosystem” said Jesper Kjær, Director of the Data Analytics Centre at the Danish Medicines Agency and co-chair of the BDSG.

“With this paper, we are opening a dialogue with developers, academics, and other regulators, to discuss ways forward, ensuring that the full potential of these innovations can be realised for the benefit of patients’ and animal health” added Peter Arlett, EMA’s Head of Data Analytics and Methods, co-chair of the BDSG.

The main contents of the Reflection paper

The Reflection paper addresses the use of AI/ML with a dedicated chapter for each one of the steps, part of the overall lifecycle of a medicinal product. The interactions with regulators are then explored, as well as the different technical aspects to be taken into consideration. The final chapters discuss the governance of AI/ML applications, the integrity, and ethical aspects to be considered and how to address data protection.

The increasing use of AI technologies is based on the wide availability of big amounts of data produced and captured in electronic format on a routine basis. This data can be analysed by machine learning algorithms to inform the training of other systems able to analyse data and take actions with some degree of autonomy in order to achieve specific goals. These latter systems are the truly intended AI algorithms, those use is under discussion also in the field of regulatory decision making.

The Reflection paper recalls how the diffusion of these new technologies carries with it also some new risks, due to the “exceptionally great numbers of trainable parameters arranged in non-transparent model architectures”. Measures should thus be taken to ensure the safety of patients and the integrity of data, as well as to avoid the integration of bias into AI/ML applications.

The contents of the Reflection paper may also refer to combinations between a medicinal pro-duct and AI/ML-including medical device, as in such occurrence EMA is involved in the assessment of the characteristics of the device.

In general terms, existing guidelines, best practices, and recommendations relative to model in-formed drug development and biostatistics also apply to AI/ML; the adjacent methodology guidelines which may be relevant to this instance are listed in the document. The Reflection paper warns readers about the differences between the human and veterinary regulatory domains, suggesting that another reflection document specific for veterinary may be developed in future.

A risk-based approach

The usual risk-based approach typical of pharmaceutical development should be used to identify risks throughout the entire AI/ML tool lifecycle, including regulatory impact. According to the Reflection paper, the level of risk may depend also on the context of use and the degree of influence the AI technology exerts.

Developers should always seek early regulatory interaction and scientific advice, especially in cases where the AI/ML system may impact on the benefit-risk ratio of the medicinal product un-der development. To this instance, the EMA Innovation Task Force (ITF) is responsible for pro-viding early interaction on experimental technology, while scientific advice and qualification of novel methodologies in medicines development is provided by the Scientific Advice Working Parties (SAWP) of the CHMP for human medicines and of the CVMP for the veterinary ones.

As for all other steps of pharmaceutical lifecycle, the final responsibility for the suitability and use made of AI/ML algorithms, as well as their compliance to ethical, technical, scientific, and regulatory standards (GxP standards) and to current EMA scientific guidelines falls under the Marketing Authorisation Holders (MAHs) or applicants.

According to the Reflection paper, risks referred to in the discovery step may be limited, but they may impact the final evidence presented for regulatory review, thus principles for non-clinical development should be followed. This second step may include, for example, AI/ML modelling approaches according to the 3R principles. Regulators would expect to receive Standard Operating Procedures (SOPs) for AI/ML applications in preclinical studies; advisory documents on Application of GLP Principles to Computerised Systems and GLP Data Integrity should be also considered where appropriate. A pre-specified analysis plan would be needed for preclinical data potentially relevant for the assessment of the benefit-risk balance.

In the field of clinical trials, ICH E6 and VICH GL9 on human and veterinary GCPs should also be applied to the use of AI/ML. In particular, regulators expect the full model architecture and description of the data processing pipeline would be made fully available for comprehensive assessment should a model be generated for clinical trial purposes, as they would be considered parts of the clinical trial data or trial protocol dossier.

From precision medicine to pharmacovigilance

Particular considerations may be needed for applications of AI/ML in precision medicine, to individualise treatment according to the patient’s characteristics. AI/ML application supporting indication or posology decisions should be referenced in the Summary of product characteristics and their assessment falls under medicines regulation, representing a high-risk use both from the patient and regulatory perspectives. Close human supervision is also expected for AI applications used to draft or translate product information documents.

Many are the possible applications of AI/ML in the manufacturing of medicinal products, where they should follow the usual quality risk management principles (ICH Q8, Q9 and Q10) to guarantee safety, quality, and data integrity. New recommendations are also expected from EMA.

In the post-authorisation phase, AI/ML tools can effectively support efficacy and safety studies and post-marketing surveillance studies for veterinary medicines, as well as pharmacovigilance activities. Good pharmacovigilance practices should always be respected, and the used model should be validated, monitored and documented under the responsibility of the MAH. For conditional marketing authorisations, AI/ML applications should be discussed within a regulatory procedure unless details are agreed already at time of authorisation.

EMA’s reflection paper on single-arm clinical trials

July 14, 2023

by Giuliana Miglierini

Single-arm clinical trials (SATs) are often the preferred study design in cases where target populations are very small, and it turns thus impossible to run a standard randomised clinical trial comprehensive of two patients’ arms. In single-arm trials, all recruited patients receive the experimental treatment, without the presence of a control arm. This means the observed effects of the investigational treatment are the sole source of evidence, without possibility to compare them with another available treatment or a placebo.

Rare diseases, including some rare cancers, are typically addressed by single-arm clinical trials. The so gained evidence is often submitted to regulatory authorities as pivotal evidence to demonstrate efficacy in a marketing authorisation application (MAAs). In order to improve single-arm study design and robustness of the collected data, the European Medicines Agency has published a Reflection paper, which is open to consultation until 30 September 2023. Comments will support the drafting of the final guideline, to be published in 2024.

The reflection paper represents the first guidance document produced at the international level to address issues and challenges typical of single-arm clinical trials. The document has been adopted by EMA’s CHMP committee with contributions from the CAT committee, the Methodology Working Party and the Oncology Working Party.

A choice that needs to be always justified

The choice to use SAT to produce the pivotal evidence to be submitted to regulatory authorities has to be always justified by sponsors, as it greatly deviates from the standard approach of double arms randomised clinical trials. The reflection paper suggests always seeking prior scientific advice to verify the acceptability of this type of study design with respect to the specific development programme.

EMA’s document focuses on the assessment of the efficacy of the treatment under study, but similar considerations are valid also to support the assessment of its safety; it can be applied also to SATs not intended to provide pivotal evidence. Trials in which only experimental arms are randomised, but without formal comparisons between the arms (i.e., platform trials) are also considered as SATs.

The direct consequence of the lack of randomisation is that SATs do not support a causal interpretation of the observed effect of the treatment. External data thus need to be used to estimate the average outcome for patients not being treated with the experimental drug.

The choice of the endpoints

The reflection paper addresses different items which should be considered in the planning and execution of a single-arm clinical trial, starting from the choice if the endpoints for the assessment of causal interpretation. According to ICH Q9, this should reflect the variable capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial.

The selection of the primary endpoint should take into consideration its validity, reliability and feasibility, as well was its ability to isolate the treatment effects. This is particularly critical, as SATs cannot exclude biases in the interpretation of results, and thus may lead to uncertainties in their effective acceptability. The reflection paper indicates the need to always discuss on clinical bases the possibility to accept a specific endpoint in a therapeutic area or in order to establish a clinically relevant treatment effect. Examples of some more common endpoints are also provided.

These include time-to-event endpoints (i.e., time to death, progression-free survival, etc.), which are considered not suited to be used in SATs as individual outcomes cannot often be attributed to the treatment. The determination of “time 0”, i.e., the starting point of being at risk for a specific endpoint, is also challenging, as well as the impact of the course of the disease on the selected endpoint.

Continuous endpoints measure changes the patient experience during the trial in comparison to baseline values. This type of endpoint may be affected by random fluctuation over time, systematic change due to the natural course of the disease or measurement errors, thus making it difficult to assign a causal attribution of treatment effect.

Binary endpoints refer to states of disease that cannot change without intervention, for example if life expectancy substantially exceeds that achievable without treatment. In such instances, binary endpoints are deemed acceptable to isolate treatment effect with sufficient certainty. Dichotomised endpoints similarly refer to pre-established thresholds, which are not possible to cross without treatment.

The patients population

A main challenge in single-arm clinical trials is represented by the limited number of patients available for recruitment. This reflects the external validity of study results, when transposed to the general population for routine treatment.

To this instance, assumptions made on the natural course of the disease are very important and must apply to the trial population, so to reflect the hypothetical control group. The reflection paper also mentions the possible bias deriving from selection mechanisms associated with prognosis and highlights the need to always specify and document the subject selection process to support the correct assessment of the benefit-risk balance.

Furthermore, the potential impact of unknown prognostic or predictive variables cannot be controlled in SATs, for example with reference to biomarker-selected populations or to the possible differentiation between subgroup heterogeneity.

External (extra-study) information is critical for the analysis and interpretation of SAT results; it should always be pre-specified in the study protocol, including the precise and a priori definition of control conditions.

The approach to statistical analysis

A specific chapter addresses the principles to be used for the statistical analysis of results. More particularly, if an SAT is intended to provide pivotal evidence, the level of the analysis should be the same as for confirmatory trials, according to ICH Q9.

It is thus important to define a priori a clear success criterion, to be justified on the basis of available external information. To this instance, the reflection paper underlines the high criticality of unplanned changes to the SAT study design once the experimentation had started, as amendments might be considered potentially data driven.

Methods to address multiplicity should also be pre-planned and adhered to in order to control the probability of false positive conclusions. Not less important is the predefinition of the primary analysis set, which should include all subjects that entered the SAT upon providing in-formed consent in order to avoid any bias. The reflection paper addresses the possible cases in which exclusion of some patients from the set is considered acceptable. The approach to avoid the occurrence of missing data is also described.

The pre-defined detailed statistical analysis plan should also be available before the start of the SAT, and it may be based both on the use of non-parametric or parametric statistical methods. The statistical analysis model used for estimation of the treatment effect should be fully pre-specified and justified. Critical points to be considered include the lack of calibration against a control and the distribution of the trial population in comparison to the target population. Sensitivity analyses should always be considered in order to support the robustness of the estimates resulting from the analysis of study results. The reflection paper also discusses how to approach the definition of the threshold values used to assess outcomes at the endpoint level.

EMA’s 3-year work plan for the Quality domain

July 7, 2023

Annex 11, Annex 15, Annex 16, Annex 4, Annex 5, assessor-inspector joint inspections, autogenous veterinary vaccines, Chapter 4, cooperative supervision, decentralised manufacturing, distant assessment, ema, EudraGMDP records, GMDP IWG, GMP Guide, GMP standards, guidance on data integrity, harmonised approaches, hybrid inspections, ICH Q12, ICH Q13, ICH Q7, ICH Q9, ICRMA, inspection capacity, inspections of the repositories system, International API programme, MAHs responsibilities. Nitrosamines LLE report, mutual recognition agreements. MRAs, new manufacturing technologies, novel veterinary medicinal products, PIC/S, reliance, scientific advice, security, sharing of information, sterile inspections, strategic goals, supply chain, supply chain dependance, tactical goals, traceability, Veterinary Regulation, work plan for the Quality domain

by Giuliana Miglierini

The European Medicines Agency has released the input notes made by the GMDP Inspectors Working Group (IWG) as for the drafting of the 3-year workplan for the Quality domain. The document, which reflects the objectives of the Network Strategy and Regulatory Science Strategy, addresses many aspects which may affect the overall efficiency of the pharmaceutical supply chain, both at the routine and specific level.

The document identifies a number of strategic goals aimed at improving the overall integrity and resilience of the pharmaceutical supply chain and the product quality, and to optimise the im-pact of new technologies. Description of the tactical goals follows, i.e., the projects and actions to be activated in order to reach the above-mentioned strategic objectives.

Improved traceability of the supply chain

Strategical goals include the enhancement of traceability, oversight and security for both the human and veterinary medicine supply chain. Four different actions are planned at the tactical level, starting from a better sharing of information regarding manufacturers, distributors, pro-ducts and their respective compliance. To this instance, actions to improve EudraGMDP records are expected.

Inspections of the repositories system should also be tackled by means of a liaison with the Ex-pert Group in inspectional procedures. The implementation of the new Veterinary Regulation should be addressed paying attention both to GDP for veterinary medicines and active substances. Improvement of the inspection capacity may benefit from the development of a specific training curriculum for GDP inspectors; to this instance, the IWG suggests a possible collaboration with PIC/S, through the EU4Health Joint Action 11 and the associated Work Programme 6.

Enhanced inspector capacity

Another strategic goal set forth by the GMDP IWG aims to improve inspector capacity building at EU and international level. To this regard, suggested actions include the support to the international API programme, comprehensive of the provisions of the new Veterinary Regulation related to API inspections and controls. Veterinary specific GMP guideline annexes 4 and 5 should be harmonised in collaboration with PIC/S. The collaboration should also include ongoing initiatives on inspection reliance, in order to better identify barriers preventing member states from accepting inspection results from other trusted authorities. PIC/S and the International Coalition of Medicines Regulatory Agencies (ICRMA) should also collaborate with the GMDP IWG to reach an agreement on shared definitions, best practices and harmonised approaches for distant assessment and hybrid inspections. The pilot programme for sterile inspections should be also finalised, with participation of all member states. Routine assessor-inspector joint inspections are suggested, as well as a training course specific to the new Annex 1.

The development of a harmonised, EU level guidance on data integrity is the tool identified by the GMDP IWG to reinforce responsibility of marketing authorisation holders (MAHs) for product quality. This goal may be achieved by adapting the current guidance published in the form of Q&As into Chapter 4 and Annex 11 of the GMP Guide, in collaboration with the WHO and PIC/S. A better attention on MAHs responsibilities and to the supervision of API manufacturers should also build upon the recommendations contained in EMA’s lessons learnt report (LLE) on Nitrosamines.

Critical manufacturing sites and new technologies

The review of long-term risks resulting from dependency on limited number of manufacturers and sites should support a better supply chain resilience. The review should be aimed to the identification of sites manufacturing a significant number of products or producing medical pro-ducts for a significant number of markets within the European economical area (EEA). The GMDP IWG also suggests performing cooperative supervision of these sites between member states and other strategic partners.

A better understanding of the possible implications resulting from the introduction of new manufacturing technologies has been also deemed important to regulate the new supply chains. To this instance, the indication of the IWG is to consider if a specific GMP annex would be re-quired in order to support the adoption of new and innovative technologies. As for decentralised manufacturing, this topic should also be evaluated in the GMP Guide to medicinal products other than advanced therapies.

Amendments to current guidelines

The document of the GMDP IWG details the specific guidelines that would need consideration in view of the proposed interventions.

Many actions are planned to achieve their objectives by the end of 2023. More specifically, the IWG expects to provide the EU Commission with the final text of the GMP for novel veterinary medicinal products and for autogenous veterinary vaccines. GMPs should be also revised to include Nitrosamines LLE recommendations to MAHs, so to ensure adequate quality agreements are in place with manufacturers.

The same deadline should apply to the development of specific training material on ICH Q9, addressing risk identification and risk management. This action would support EU members of the Expert Working Group (EWG) and should be coordinated with the dedicated PIC/S expert circle. A similar action is planned with respect to ICH Q12 on lifecycle management and ICH Q7 (GMP for active substances), as well as to other quality guidelines for veterinary medicines. The GMDP IWG is also expected to support the EWG in developing the new ICH Q13 guideline on continuous manufacturing.

Annex 15 on the Qualification and Validation may be revised by Q2 2024 in order to include considerations on new technology in facilities, products and processes, including also the possible extension of LLE recommendations to APIs.

The end of 2024 is the date indicated for the review of GMPs for advanced therapy medicinal products in order to include the new provisions of the revised Annex 1. The same deadline applies to the possible revision of Annex 16 on the certification by a Qualified Person and batch release, in order to provide further guidance on batch traceability according to LLE recommendations. The end of next year may see also the drafting of the final text of Annex 4 on the manufacture of veterinary medicinal products other than the immunological ones, based on comments received on the concept paper and the resulting draft text. A similar action is planned for Annex 5 on the manufacture of immunological veterinary medicinal products.

Chapter 4 (Documentation) and Annex 11 (Computerised systems) of the GMP Guide should be revised to assure data integrity in the context of GMP. The proposed deadline for these actions is Q1 2026.

Support to scientific advice and communication

A specific chapter of the GMDP IWG document is dedicated to actions deemed to support scientific advice activities. In this case too, target dates are provided for the completion of the different actions. These include the provision to the EU Commission of scientific advice on GMP standards to be included in the implementing act on GMP for veterinary medicinal products and active substances.

At the international level, the IWG plans to continue its efforts to reach a better convergence through existing mutual recognition platforms and programmes and to support the EU Commission to establish and maintain mutual recognition agreements. Collaborations with ICRMA, the EDQM, Chinese and Indian regulators should be also continued, as well as the dialogue with interested parties and stakeholders.

The new MHRA’s framework for clinical studies

May 26, 2023

ABPI, clinical development, clinical research dashboard, clinical trials, early scientific advice, independent review, innovative study designs, international collaborations, MHRA, notification scheme, patient centricity, patient recruitment, proportionate approach, public consultation, real-world evidence, reform, regulatory advice, regulatory and ethics reviews, regulatory flexibility, regulatory timelines, request for information, risk-based approach, summary of results, UK government, WHO public trial register

By Giuliana Miglierini

The repositioning of the United Kingdom as a global leader for clinical development of medicinal products can now benefit of the complete renewal of the framework regulating clinical studies run in the country. Announced in March 2023 by the Medicines and Healthcare products Regulatory Agency (MHRA), the new set of measures represents the deepest reform of the sector in the last 20 years. The new package is based upon results of the public consultation run in Q1 2022 in partnership with the Health Research Authority (HRA) and the Department of Health in Northern Ireland, which collected more than 2,000 responses.

As stated in the foreword of the final document, which details the government’s consideration of responses to individual questions, the main objective of the reform is for the UK to capitalise on the opportunity offered by the country’s new position in the global clinical trial landscape. Furthermore, it represents just the initial step of UK’s new regulatory approach, which may include for example a wider use of real-world evidence, novel analytics and data tools. International collaborations are also deemed important, e.g. with the FDA’s Project Orbis and the Access Consortium (Australia, Canada, Singapore and Switzerland) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals of Human Use.

“Our world-first Covid-19 approvals showed how important it is to ensure that regulation is flexible and agile. This overhaul of the clinical trials legislation will do just this – it will move us away from a one-size-fits-all approach to the regulation of clinical trials and help to streamline approvals by removing granular and duplicative regulatory requirements”, said MHRA Chief Science and Innovation Officer Marc Bailey.

According to the Health and Social Care Secretary Steve Barclay, the reform will make the UK more attractive for scientists and researchers. “These changes will help speed up clinical trials, without compromising on safety, and encourage the development of new and better medicines for patients. They come after the government announced additional funding of £10 million for the MHRA to accelerate the delivery of cutting-edge treatments including cancer vaccines”, he said.

The main goals of the reform

Patients are central to the UK’s reform of clinical trials. While efficacy and safety of new medicines under development remain the main target, great attention should be paid to reduce health disparities. To this instance, the MHRA announced the issuing of new guidance on how to ensure diversity of participants enrolled in trials, so to overcome imposed targets or arbitrary quotas. The improved attention to diversity would also support the delivery of trial results more adherent to the effective prevalence and clinical need across the population.

Flexibility and proportionality of the regulatory environment is another key objective of the reform. According to the final document, regulatory requirements should adapt to the current risk of the trial, and researcher should become subject to an overarching duty to consider proportionate approaches to clinical development.

Simplification of regulatory procedures is also expected, for example in the case of studies characterised by a risk similar to that of standard medical care. In this instance, regulatory review of the study protocol should not be needed anymore, substituted by simple “notification scheme” to enable approval.

As said, the attractiveness of the UK as a leading destination for international trials should be supported by streamlined and efficient application processes. This goal should include a new legislative action to integrate the regulatory and ethics reviews of clinical trial applications. Results from a pilot phase will be taken into consideration, as they proved possible to halve the approval times and cut the time from application to recruiting a first patient by 40 days.

All activities relating to clinical development should reflect the ICH Good Clinical Practice (GCP) principles for trial conduct. Regulatory timelines for approval are expected to compete at the international level, so to encourage sponsors to choose the UK as the preferred site to conduct multinational trials. According to the MHRA, the review of an application should take a maximum of 30 days in general, with a maximum of 10 calendar days for a decision to be granted once the regulator has received any final information. As for GCPs, compliance should also extend to service providers of electronic systems that may impact on patient safety.

Sponsors should also benefit from greater flexibility to respond to questions raised by regulators. In particular, the reform aims to amend the Request for Information (RFI) receipt, so that the sponsor has access to RFIs as they are ready rather than waiting for all requests to be made together.

The reform takes in consideration also the possible impact of incoming innovation, for example different types of trials and innovative study designs (e.g. decentralised trials). New guidance should be provided to set out specific details, thus avoiding any duplication. Guidance should be also provided on how to involve patients; family members or carers having a direct experience of the health problem in the design and conduct of a trial.

Transparency of the entire process should be supported by the compulsory registration of the trial in a World Health Organisation public register. A summary of results should also be published within 12 months of the end of the trial, and trial findings should be mandatory shared with trial participants.

Comments from the industry

“We welcome the MHRA and HRA’s commitment to work with our industry to codevelop new regulatory guidance and their pragmatic approach to patient & public involvement and trial diversity. We look forward to working with them to make the UK an attractive destination for clinical trials.”, said Richard Torbett, ABPI Chief Executive.

On 19 May, ABPI further commented from is blog the current situation of clinical development in the UK. According to the association representing the British pharmaceutical industry, enrolment to industry trials decreased by 44% between 2017 and 2021, while UK’s global ranking for phase III trials dropped to the 10th place (from the previous 4th). ABPI also reports revenues and cost savings to NHS England from life sciences companies of more than £10,000 for every patient recruited onto an industry clinical trial between 2016 and 2018.

In view of the release of the independent review commissioned by the government to former innovation minister Lord O’Shaughnessy, ABPI has identified three main steps necessary to support the international competitiveness of UK’s clinical trials sector.

Rapid and smooth regulatory procedures are at the first place, with the request not to delay from the 60 days target for combined regulatory and ethics review, comprehensive of the administrative processes of costing and contracting a clinical trial. Early scientific and regulatory advice and sufficient resources for the MHRA to clear the current backlogs and codevelop new regulatory guidance would be also important.

ABPI also highlights the often-experienced difficulty in recruiting a sufficient number of patients. The suggestion for the government is to take inspiration from UK’s leading position in early-phase (phase I) industry trials in order to improve investment in late-phase trial infrastructure. To this instance, health real-world data may prove important to support the search for eligible patients in a larger population.

According to the industrial representative, the UK is also lacking a nationwide clinical research dashboard to describe its performance in clinical research to global sponsors. This should include metrics on volume, speed, quality, impact, and innovation.

PIC/S new guidance documents for GDP inspectors

April 17, 2023

acceptable temperature limits, Aide-memoire, alarms, calibration, CAPAs, change control, cleaning procedures, complaints, computerised systems, contracts, delegation, Designated Responsible Persons, documentation management, environmental controls, expired/obsolete goods, falsified medicines, FEFO, GDP inspections, GDP inspectors, GDP training, general aspects, goods receipts, guidance document, key responsibilities, maintenance, Management review and monitoring, manufacturers, Mean Kinetic Temperature, on-site auditing, operations, outsourced activities, PE 011-1 wholesale distribution, periodic review, personnel, pest control procedures, PI 044-1, PIC/S, PIC/S GDP Guide, picking, Premises and Equipment, PS/ INF 22/2017, Q&As, QRM, qualification of customers, qualification of suppliers, quality agreements, Quality management, Quality systems, recalls, returns, risk assessment, security of the premises, segregation requirements, self-inspections, stock rotation, suspected falsified medical products, temperature conditions, temperature monitoring, temperature-sensitive products, transportation

By Giuliana Miglierini

Two new guidance documents for GDP inspectors have been issued by the Pharmaceutical Inspection Cooperation Scheme (PIC/S) Expert Circle on GDP, and are available on the PIC/S’ website.

The ‘AideMemoire on the Inspection of Good Distribution Practice for Medicinal Products in the Supply Chain’ (PI 0441) and a ‘Questions & Answers (Q&A) document regarding the PIC/S GDP Guide’ (PS/INF 22/2017) both entered into force on 1 February 2023.

Main contents of the AideMemoire

The AideMemoire aims to support GDP inspectors in the understanding the process of GDP inspections. The document is expected to be used for training and planning of inspections. Its adoption is voluntary, as the PIC/S GDP Guide for inspections is a legally nonbinding document unless it has been declared a legal standard in the jurisdiction of a PIC/S Participating Authority. The AideMemoire addresses inspections in wholesale distribution sites of entities holding a wholesale distribution licence according to national legislation (i.e. including importing, exporting, holding, or supplying distributors), as well as manufacturers performing any distribution activities. GDP inspections should be thorough and conducted under normal operating conditions.

The AideMemoire is organised in the form of 10 tables that could be used by inspectors as check lists of items to be investigated during inspections of manufacturers and wholesale distributors.

The first table addresses general aspects of GDP inspections, such as the accuracy of the Licence/ application in detailing relevant activities and products. Lists of prescription only medicines (POM), sales without prescription (P), or General sales list/Over the counter (GSL) products are some examples, together all other possible items that may be handled by wholesales distributors, including medical gases, products requiring storage at low temperature and controlled drugs according to national laws.

Preliminary activities also include the review of previous inspections and the assessment of corrective/preventative actions (CAPAs) outlined in the company response. Change should also be verified, namely in the case of high risk operations that may affect the risk profile of the organisation.

Table 2 lists items referred to Quality management. Inspectors should check, for example, the availability of procedures and logs for change control and deviation management. Quality Risk Management (QRM) principles should have been applied to outsourced activities, leading to the definition of specific activities falling under GDP rules, approval, auditing of suppliers, etc. An appropriate procedure should be available also for activities referring to Management review and monitoring and QRM.

Issues referring to personnel are discussed in table 3. An organisation chart and job descriptions should be available, the latter reflecting also key responsibilities and indication of Designated Responsible Persons. Inspectors should verify GDP training received by personnel, also with reference to specific aspects such as falsified medicines or temperaturesensitive products. Availability of a regular GDP training programme and training records should be checked. Personnel should have received specific training in SOPs relevant to their role, to be adequately assessed and documented. These should also include aspects relative to health, hygiene and clothing requirements.

The check list referred to Premises and Equipment is detailed in table 4. It includes among others items reflecting segregation requirements (e.g. identification, design and management of segregation areas) for hazardous or radioactive products, falsified medicines, products not authorised for the approved market, expired products, etc.

Cleaning and pest control procedures are also addressed in this section, as well as temperature and environmental controls and the appropriate monitoring of fridge or cold storage conditions. As for the equipment, inspectors should verify planned maintenance and calibration and their respective records. Alarms should also be checked, as well as computerised systems including validation, security and access restrictions. Appropriate qualification and validation procedures should be in place for all relevant equipment according to QRM principles, and risk assessment should be also available.

Table 5 lists all items referring to documentation management, including procedures and records. The qualification and approval of suppliers and customers according to QRM principles is addressed in Table 6, discussing Operations. This section also addresses the availability of goods receipts to be checked against purchase orders, including details of the temperature conditions during transportation and checks at receipt for products with special storage requirements or nonconforming products. Stock rotation according to the First Expiry First Out principle (FEFO) should be verified by inspectors, among items referred to storage. Aspects referring to the security of the premises also fall under this section, as well as the destruction of expired/ obsolete goods. Inspectors should address also picking operations, supply notes and records and procedures for import/export.

Table 7 refers to the management of complaints, returns, suspected falsified medical products and recalls, which should all be handled according to relevant procedures. Requirements and documentation to be verified for outsourced activities are listed in table 8. These include for example the availability of quality agreements, and contracts including clear responsibilities and audits schedules.

Procedures, plans and records referring to selfinspections are listed in table 9. Items to be verified by GDP inspectors include among others the selection of auditors, their training and independence, CAPAs implementation and verification. The last table addresses issues relative to transportation, including planning, outsourcing, temperature monitoring, GDP training of drivers, etc.

Q&As on PIC/S GDP Guide (PE 0111)

The second document published by PIC/S consists in a list of Questions & Answers specifically referred to the PIC/S GDP Guide (PE 0111). Contents are organised in the form of a table detailing the relevant chapter number and title, paragraph number, question and answer. The latter also make reference to other paragraphs of the GDP Guide to be considered. The sequence of topics is similar to that of the previously examined guidance document for inspectors.

Questions referred to Chapter 1 address issues referred to Quality management and Quality system, outsourced activities, management review and monitoring. Effectiveness of the QS, for example, may be measured by inspectors with reference to deviations and CAPA analysis or to the impact of QRM functions. Frequency of periodic review and responsibilities for ensuring GDP compliance of outsourced activities are also addressed.

Personnel and definition of responsibilities, including key positions and delegation, are detailed in Chapter 2, while Q&As referred to Premises and Equipment go deeper in contents of Chapter 3 (i.e. including the definition of “acceptable temperature limits” and use of Mean Kinetic Temperature for monitoring).

The following chapters and related Q&As address the proper management of Documentation (Ch. 4) and Operations (Ch. 5). The later details some aspects of suppliers and customers qualification, storage, picking. The management of complaints, returns and particular categories of medicinal products refers to Chapter 6. As for outsourced activities (Ch. 7), Q&As addresses onsite auditing, while selfinspections are treated in Chapter 8. Q&As referred to Transportation (Ch. 9), for example, refer to national legislations as for the need for the transportation company to hold a wholesaler licence.

Draft ICH M13A guideline on bioequivalence open for consultation

March 17, 2023

analysis of the parent drug, AUC, bioavailability, bioequivalence, biopharmaceutics classification system, biowaiver, capsules, chewable tablets, Cmax, comparative in vitro dissolution studies, comparator, comparator product labelling, data analysis, endogenous compounds, fasting and fed BE studies, fixed-dose combination products, granules, high-risk products, ICH E3, ICH E6, ICH M13A, ICH M13B, ICH M13C, ICH M9, immediate-release solid oral dosage forms, low solubility drug substances, multiple comparator products, multiple-dose studies, oral suspension, orally disintegrating tablets, parallel design, pharmacokinetic endpoint, pharmacokinetics bioequivalence studies, powders, primary metabolites, public consultation, randomised single-dose two-period two-sequence crossover studies, sampling, standardised fasting conditions, study design, study population, summary statistics, systemic circulation, tablets, test products, unadjusted measured drug concentrations

By Giuliana Miglierini

The draft ICH M13A harmonised guideline “Bioequivalence for immediate-release solid oral dosage forms” was endorsed by the International Council for Harmonisation on 20 December 2022 and is now open for consultation. Comments can be forwarded until 26 May 2023; publication of the final document is expected by May 2024.

The new guideline will then be implemented as a European guideline, replacing the current EMA guideline on the investigation of bioequivalence (BE) for oral dosage forms. The ICH M13A is the first of a planned series intended to address scientific and technical aspects of study design and data analysis, so to better support BE assessment both during development and post approval. The guideline covers immediate-release (IR) solid oral dosage forms delivering drugs to the systemic circulation (i.e. tablets, capsules, and granules/powders for oral suspension). Different approaches from those suggested in the guideline are possible, provided they are scientifically justified; applicants are thus encouraged to seek the advice of the relevant regulators in order to share a common approach to development.

Key concepts of the M13 series

The determination of bioequivalence to the originator is a fundamental step in the development of generic and biosimilar medicines. BE plays also an important role for some innovator products, as well as for post-approval changes of formulation and/or manufacturing process. BE is determined in terms of bioavailability of the products under comparison after administration, within predefined limits to ensure safety and efficacy. In vivo BE studies for certain orally administered IR solid oral dosage forms can be waived according to the ICH M9 guideline on Biopharmaceutics classification system (BCS)-based biowaiver, which has already superseded Appendix III of the EMA guideline.

The M13A guideline addresses study design containing multiple comparator products or test products, but not the acceptance of comparator products across different regulatory regions, as this greatly varies according to local legislations. The process of regulatory decision making based on BE is also excluded from the guideline.

The planned M13 series should also include the ICH M13B guideline, focused on biowaiver considerations for additional strengths not investigated in BE studies, and ICH M13C discussing data analysis and BE assessment for highly variable drugs, drugs with narrow therapeutic index, and complex BE study design. It should also address data analysis considerations, for example in the case of adaptive BE study design.

Pharmacokinetics (PK) bioequivalence studies and comparative in vitro dissolution studies are the main tools for BE determination for IR solid oral dosage forms with systemic action. These principles can be also applied to other non-orally administered drug products with immediate action (e.g., certain rectal, inhalation, and nasal drug products), provided BE may be derived from measures of systemic exposure.

The ICH E6 guideline on Good Clinical Practice should also be considered while conducting BE studies, in order to ensure the data integrity of all data generated in the trials.

The main contents of the ICH M13A

Chapter 2 of the ICH M13A guideline discusses the general principles to be used for the establishment of bioequivalence. These include the selection of the study population and the choice of the pharmacokinetic endpoint to be used in the BE studies. Healthy subjects should be the preferred choice, unless there are ethical concerns linked to the safety of the pharmaceutical products under assessment. In any case, inclusion and exclusion criteria should always be clearly reported in the study protocol. The main target of BE studies should be the detection of differences in the in vivo release characteristics between the products. Elements to be considered to select the study population are discussed in the draft guideline.

As for the study design, the recommended suggestion is for randomised, single-dose, two-period, two-sequence crossover studies comparing two formulations, as single-dose studies may better detect differences in the rate and extent of absorption. Multiple-dose studies may be conducted in patients should the single-dose design be not affordable for safety/tolerability or ethical reasons. A parallel design may be indicated for drugs with long elimination half-lives, requiring a prolonged washout period. Alternatives are also acceptable upon scientific justification.

The choice of the test product should be also discussed and justified, and it should be representative of the product to be marketed. As for the comparator, the selection of the batches to be used for BE studies should be based on assay content. The strength of the product to be used in the BE study depends on the dose proportionality in PK and solubility of the analyte.

The draft also indicates standardised fasting conditions should be the preferred choice to run BE studies, as they support a better discrimination between the PK profiles of the product and the comparator. Both fasting and fed BE studies should be conducted for high-risk products, due to their complex formulation design or manufacturing process that may impact differently on their in vivo performance, due to different gastrointestinal (GI) conditions. This is the case, for example, of low solubility drug substances formulated in the form of solid dispersions, microemulsions, lipid-based formulations, nanotechnologies, or other specialised technologies.

Analysis of the parent drug should be the preferred choice to demonstrated bioequivalence. Primary metabolites are considered acceptable in the case of pro-drugs which are rapidly eliminated. Stereoselective assays measuring individual enantiomers should be also considered while assessing chiral drugs.

Specific paragraphs address the setting up of sampling, the need to avoid occurrence of Cmax at the first post-dose sampling time point, the possibility to use truncated AUC for drugs with long half-life and considerations on early exposure.

How to analyse and present data

Specific sections of the guideline discuss how to present and report data obtained from BE studies. The study documentation should include the complete evidence of the protocol, conduct, and evaluation, and it should be written according to the ICH E3 guideline “Structure and content of clinical study reports”.

Unadjusted, measured drug concentrations in a suitable biological fluid should be always provided for both the product and the originator, for each subject participating in the study. Any deviations should be clearly identified. A suggested list of PK’s parameters to be tabulated for each subject-formulation combination is provided, together with summary statistics to be reported. Not less important is the statistical analysis performed on raw data. To this instance, the model of choice for the analysis should be pre-specified in the study protocol. Cmax and AUC(0-t) should be the preferred PK parameters to establish BE.

Chapter 3 discusses specific topics that may impact on the determination of BE. Among these is the presence of endogenous compounds identical to the drug under evaluation, thus requiring the determination of their baseline concentration in the biological fluids of interest. The draft guideline also specifies that both orally disintegrating tablets (ODTs) and chewable tablets should be administered in BE studies according to the comparator product labelling with regard to intake of water. The comparator product labelling should also represent the main reference for BE studies involving tablets, granules, and powders labelled as being only intended to be dispersed in a liquid before administration as an oral suspension. Considerations are also provided for fixed-dose combination products and the dependance of the drug solubility on pH.

EMA/EFSA joint report on human dietary exposure to residues of veterinary medicines, pesticides and feed additives

February 17, 2023

acceptable daily intake, acute reference dose, ADI, ARfD, assessment of dietary exposure, consumption data, ECHA, EFSA, ema, European Commission, exposure assessment methods, exposure limits, exposure studies, FACE, feed additives, Feed Additives Consumer Exposure, GECDE, Global Estimated Chronic Dietary Exposure, harmonised approach, HBGV, Health Based Guidance Values, high-level recommendations, human dietary exposure, IEDI, International Estimated Daily Intakes, JECFA, JMPR, Joint FAO/WHO Expert Committee on Food Additives, Joint Meeting on Pesticide Residues, joint report, legislative framework, marker residue, maximum residue limits, MRL, Pesticide Residue Intake Model, pesticides, PRIMo 4, recommendable harmonised methodology, Regulation (EU) 2022/1255, regulatory authorities, residue of concern, residues of veterinary medicines, risk assessments, RoC, substances with dual use, Theoretical Maximum Daily Intake, TMDI

By Giuliana Miglierini

The presence of residues of veterinary medicines, feed additives and pesticides in food of animal origin may pose exposure risks for human health. The topic has been historically approached under different perspectives according to the specific reference legislative framework and the respective authority involved in regulating and monitoring the products. The European Medicines Agency (EMA) and the European Food Safety Authority (EFSA) are among the main regulators involved in setting and verifying the legally binding maximum residue limits (MRLs) for chemical substances, together with the European Chemicals Agency (ECHA).

EMA and EFSA received in 2020 a mandate by the European Commission to work at the development of a harmonised approach to the assessment of dietary exposure to residues of veterinary medicines in food of animal origin. The comparison of the current situation run by the two agencies included only exposure assessment methods used in the regulatory areas, which are all based on traditional deterministic approaches. The resulting recommendations have recently been published in the form of a joint report.

EMA/EFSA experts focused on key concepts and features in order to provide a general agreement on the basic “building blocks” of a recommendable harmonised methodology, leaving the setting up of more detailed methodological aspects targeted to the different sectorial applications to a further phase of discussion. The document shall now be assessed by the European Commission and, if adopted, may request the implementation of specific action targeted to the different sectors to reach a better harmonisation. The Technical Report to be submitted to the Commission may also contain other elements to be considered.

Meanwhile, on 9 February 2023 the Commission implementing Regulation (EU) 2022/1255 designating antimicrobials or groups of antimicrobials reserved for treatment of certain infections in humans entered into force. The regulation lists a wide range of antibiotic, antiviral and antiprotozoal active substances. Those use is from now on excluded to treat animals, so to preserve their efficacy in humans. The measure is part of the broader approach against antimicrobial resistance, and it aims to promote a more prudent and responsible use of antimicrobial medicinal products in animals, including very strict rules on their veterinary prescription for prophylactic and metaphylactic use.

The main issues examined by the EMA/EFSA report

Sectorial legislations in the field of medicinal products (managed by EMA), food (EFSA) and chemicals (ECHA) may greatly differ from one another in the approach and methodologies chosen to define exposure limits and to run risk assessments referred to residues of veterinary medicinal products, feed additives, pesticides and biocides. This lack in harmonisation may lead to significantly different outcomes in the assessment of the same active substance, especially when it is characterised by a dual use for applications in different sectors.

There are several pieces of legislation in place aimed to guarantee a high level of protection of both human and animal health and the environment [Commission Regulation (EU) 2018/7829, Regulation (EC) No 1107/200910 and Commission Regulation (EC) No 429/2008], as well as sectorial legislations in the pharmaceutical, food, and feed additives fields that may diverge at the level of data requirements, purpose of the required studies, methodologies for exposure assessment, consumption models, etc.

In general terms, exposure studies are usually run using radiolabeling to trace the fate of a substance and to characterise its metabolites and their concentration in edible tissues/food commodities from target animals. The “residue of concern” (RoC) considered in the dietary exposure assessment is most commonly estimated assuming that metabolites have the same pharmacological/ toxicological potential as the parent compound. The difficulty of measuring the concentration of all compounds in residue monitoring often leads to the selection of a marker residue to be traced.

Health Based Guidance Values (HBGVs, or Reference Values) corresponds to the concentration of a chemical that may present hazards for the human, animal or environmental health; they are listed in the EFSA Open Food Tox Database, as well as in similar WHO and US-EPA databases.

HBGV, as well as acceptable daily intake (ADI) in case of chronic risk and the acute reference dose (ARfD) in case of acute risk, can be used in association with the estimated dietary exposure to the RoC to evaluate the risk of exposure.

The report initially discusses the different approaches and models currently in use by EMA, EFSA, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Joint Meeting on Pesticide Residues (JMPR). Reference is made to the alternative definitions for the establishment of residue limits related to veterinary medicinal products charactering the different sectorial legislation, as well as to methods to assess the related hazard.

The Theoretical Maximum Daily Intake model (TMDI, or diet-based approach), for example, is used by EMA to estimate the risk from life-long exposure to residues in food commodities from animals treated with veterinary medicinal products. This model has been already abandoned by JECFA and EFSA, that switched respectively to the Feed Additives Consumer Exposure (FACE) and Pesticide Residue Intake Model (PRIMo 4), as better suited to estimate age-dependent exposure scenarios based on individual food consumption data. The report also discusses the Global Estimated Chronic Dietary Exposure (GECDE) model, and the International Estimated Daily Intakes (IEDI) model. This last one is based on the WHO GEMS Food Cluster diets, estimating average per capita consumption figures based on international trade and production statistics of foods.

A further level of complexity in the assessment has to be considered for substances with dual uses, such as veterinary medicines and pesticides. In such instances, it is important to note that maximum residue limits/levels may vary for the same substance in the same animal commodity, as their concentration may differ in different tissues and/or organs (i.e., muscle, fat, liver, kidney, eggs, or milk). This may result in uncertainties at the level of the enforcement of the appropriate level and residue definition by different authorities.

The recommendations for future harmonization

The analysis and evaluation of the performance of the many available methods led EMA and EFSA to conclude that the observed differences in exposure assessment could be primarily attributed to the type and use of consumption and occurrence data. Other possible elements impacting on the obtained result may include the chosen calculation model and exposure model, the exposure to residues from multiple uses, and the use of commodity definitions and combined exposure from multiple species. Different timelines in the implementation of scientific innovation may have also contributed to the observed divergences.

The final goal of the exercise was to obtain a most realistic exposure assessment possible based on the available methodologies. The so identified “preferred methodology” focuses on data sources and models, includes also alternative proposals on a number of items, and it might represent the “blueprint” for a future harmonised methodology. EMA and EFSA’s recommendations pay particular attention to exposure assessment as the first step of a risk assessment; as for risk characterisation, no specific recommendations have been developed during this round of discussions.

EMA’s new Quality Innovation Expert Group (QIG)

December 16, 2022

(Co)-Rapporteur team, ATMPs, biological medicinal products, Biologics Working Party, biotechnological medicinal products, BWP, chemical medicinal products, CHMP peer reviewer, communication platforms, development, digital health, EMA’s Quality Domain, emerging technologies, entry point for developers, European regulatory network, GDMP Inspectors Working Group, GMDP inspections, guidance documents, harmonisation, horizontal scanning, ICH, ICMRA, innovative technologies, interconnected devices, IPRP, IWG, Listen and Learn platforms, manufacturing, Marcel Hoefnagel, marketing authorisation applications, medicinal products, novel materials, PICs, postauthorisation lifecycle changes, predictability, provisional mandate, QIG, quality and GMP requirements, quality assessment, quality control, Quality Innovation Expert Group, quality position papers, Quality Working Party, quality-related workshops, QWP, recommendations, regulatory decision making, regulatory measures, Regulatory science strategy to 2025, regulatory sciences, regulatory submissions, research driven agenda, routine manufacturing and control operations, scientific advice, training, wearables

by Giuliana Miglierini

Innovative approaches to the development manufacturing and quality control of medicines are becoming the new paradigm to be faced both from an industrial and regulatory perspective. Not only innovative technologies for delivery, such as mRNA vaccines, many novel materials as well as new types of interconnected devices, wearables and digital health approaches need a particular attention to ensure the European regulatory network will be able to intercept and address gaps in the current framework. An increased predictability for developers is the final target objective.

EMA’s answer to this need passed through the establishment, in September 2022, of the new Quality Innovation Expert Group (QIG). The Group will act also as a preferential location for exchange and interaction between regulators and other stakeholders, at the European and global level. QIG is part of the Quality Domain of EMA’s working party structure; all its activities will be aligned to EMA’s Regulatory science strategy to 2025.

QIG’s composition

The eight members of the Quality Innovation Expert Group have a background in chemical, biological quality assessment and Good Manufacturing Practice (GMP) inspections. They have been nominated from the list of European experts and adopted by the CHMP and CVMP. Other ad hoc experts may be recruited were needed.

The Chair of the new group is Marcel Hoefnagel (he will also become a member of the Domain Governance); other members include Giampiero Lorenti, Leticia Martinez-Peyrat, Christina Meissner, Silke Schül, Barbara Stubbe, René Thürmer, and Marcos Timon. Further members may be appointed in future, based upon workload considerations.

The members’ selection process aims to include in the QIG two experts for each of the following areas: quality assessment for chemical medicinal products, quality assessment for biological medicinal products and ATMPs, GMDP inspections. Membership will be reviewed every three years; the chair’s appointment may be renewed only once.

The current schedule described within QIG’s provisional mandate indicates a maximum of six meetings per year (one of which face-to-face), planned to fit with Biologics Working Party (BWP), Quality Working Party (QWP) and/or GDMP Inspectors Working Group (IWG) meetings. Ad hoc meetings can also be organised as required. QIG’s work plan shall also include topics and frequency of the “Listen and Learn” platforms, while interactions with the stakeholders should be accommodated as needed, as well as meeting with other international regulators.

The technical, scientific and administrative support to the QIG will be provided by the EMA Secretariat.

QIG’s provisional mandate

The provisional mandate and rules of procedure of the Quality Innovation Expert Group was published in November 2022. The complete 2023 work plan is also expected to be published.

The main goal of the new QIG is to facilitate the translation into practice of innovative pharmaceutical manufacturing approaches, with respect to all the different range of medicinal products (i.e. chemical, biological and/or biotechnological substances, advanced therapy medicinal products).

To achieve this very ambitious task, the QIG shall be involved in many different activities, starting from the identification of innovative manufacturing approaches for pharmaceuticals and of the regulatory challenges associated with them. To this instance, possible tools to be used include horizontal scanning of emerging technologies, followed by proposals of regulatory measures to address them in the form of developing position papers, Q&A documents, etc.

Translation of innovative technologies into regulatory submissions or manufacturing and control facilities may be supported through actions at the level of scientific advice, marketing authorisation applications, related post-authorisation lifecycle changes and routine manufacturing and control operations. This objective shall be supported by the interaction with other EMA’s structures, such as the BWP and QWP Working Parties, and IWG Working Group.

Harmonisation at the European level of the approach to be used by regulators for the quality assessment of submissions and GMP inspections also falls under QIG’s mandate to operate. Attention should be paid to the advancement of regulatory sciences, by mean of a research driven agenda aimed to increase the effectiveness and awareness of the European Union as a centre for innovation, and shared between the European regulatory network and the academia.

QIG’s representatives are expected to participate to various international regulatory fora (e.g. ICH, ICMRA, PICs, IPRP) to inform about the European position and to facilitate cross-regional convergence on open issues. Existing channels and confidentiality agreements may also be used to facilitate the dialogue between the Group and other international regulatory partners on product- specific or technology-specific topics. Outcomes from QIG’s activities will be reported to the Quality Domain Governance, EMA Committees and Working Parties as needed.

The main initial tasks

The provisional mandate lists the points to be addressed by QIG’s experts as the first tasks for new new-born group. Acting as an entry point for developers to discuss new approaches along the entire life cycle of innovative medicinal products is a main one, to be declined by QIG on technology only. Continuity with other dialogue pathways already put in place by EMA should be pursued through the participation of a QIG member to the primary assessment as part of the (Co)-Rapporteur team or alternatively, as CHMP peer reviewer.

Emerging technologies that might impact regulatory decision making in the medium to long term represent another QIG’s priority; their assessment may be performed also with engagement of ad hoc experts and academia.

QIG members may support the Quality Domain Governance with recommendations on the quality and GMP requirements of medicinal products (e.g. data requirements and expected regulatory impact of analytical technologies, control strategy approaches, devices, drug delivery systems, materials, manufacturing technologies and novel facility designs for active substances and finished products – including continuous manufacturing and decentralised manufacturing-, digitalisation). The implications for the regulatory and supervisory system of the implementation of innovative quality and manufacturing technologies may also be addressed.

The QIG group may contribute to the preparation, review and/or update of quality position papers and guidance documents, in collaboration with the BWP, QWP and/or GMDP IWG, as well as to the training and quality-related workshops for EU quality assessors and GMP inspectors. Harmonisation of efforts within the entire EMA’s and Heads of Medicines Agencies (HMA) structures shall be enabled by the interaction with EMA’s ITF/Innovation Office/SME Office and the HMA Innovation Office. Communication with the external stakeholders (including the industry, academia and regulators) shall be supported by the creation of a dedicated set of communication platforms.

A concept paper on the revision of Annex 11

November 18, 2022

AI, algorithms, Annex 11, Artificial Intelligence, audit trail review, backup, Cloud, Computerised System, Concept paper, CSA, ema, FDA, GMP, Good Manufacturing Practice, guideline, ICH Q9, machine learning, ML, Pharmaceutical Inspection Co-operation Scheme, PIC/S, qualification, Quality System Software, revision, validation

This concept paper addresses the need to update Annex 11, Computerised Systems, of the Good Manufacturing Practice (GMP) guideline. Annex 11 is common to the member states of the European Union (EU)/European Economic Area (EEA) as well as to the participating authorities of the Pharmaceutical Inspection Co-operation Scheme (PIC/S). The current version was issued in 2011 and does not give sufficient guidance within a number of areas. Since then, there has been extensive progress in the use of new technologies.

Reasons for the revision of Annex 11 include but are not limited to the following (in non-prioritised order):

The document should be updated to replace relevant parts of the Q&A on Annex 11 and the Q&A on Data Integrity on the EMA GMP website
An update of the document with regulatory expectations to ‘digital transformation’ and similar newer concepts will be considered
References should be made to ICH Q9
The meaning of the term ‘validation’ (and ‘qualification’), needs to be clarified
Guidelines should be included for classification of critical data and critical systems
Important expectations to backup processes are missing e.g. to what is covered by a backup, what types of backups are made, how often backups are made, how long backups are, retained, which media is used for backups, or where backups are kept
The concept and purpose of audit trail review is inadequately described
Guidelines for acceptable frequency of audit trail review should be provided
There is an urgent need for regulatory guidance and expectations to the use of artificial intelligence (AI) and machine learning (ML) models in critical GMP applications as industry is already implementing this technology
FDA has released a draft guidance on Computer Software Assurance for Production and Quality System Software (CSA). This guidance and any implication will be considered with regards to aspects of potential regulatory relevance for GMP Annex 11

The current Annex 11 does not give sufficient guidance within a number of areas already covered, and other areas, which are becoming increasingly important to GMP, are not covered at all. The revised text will expand the guidance given in the document and embrace the application of new technologies which have gained momentum since the release of the existing version.

If possible, the revised document will include guidelines for acceptance of AI/ML algorithms used in critical GMP applications. This is an area where regulatory guidance is highly needed as this is not covered by any existing regulatory guidance in the pharmaceutical industry and as pharma companies are already implementing such algorithms.

The draft concept paper approved by EMA GMP/GDP IWG (October 2022) and by PIC/S (November 2022) and released for a two-months consultation until 16 January 2023.

MDCG, a position paper on the capacity of notified bodies

October 14, 2022

administrative burden, appropriate surveillance, capacity of notified bodies, certification, coaching, common guidelines, compliance assessment, duplication of activities, Eudamed, first-time applicants, flexibility, Guidance, harmonisation, hybrid audits, in vitro diagnostics, internship activities, IVDR, legacy devices, limitations, machine-to-machine procedures, manufacturers, MDCG, MDR, medical devices, Medical Devices Coordination Group, national authorities, NBs, notified bodies, orphan devices, position paper, re-assessment, re-certification, regulatory framework, requirements, SMEs, structured dialogue, training

by Giuliana Miglierini

The lack of a suitable capacity of notified bodies (NBs) is one of the main issues still pending after the entry into force of the new Medical Device Regulation (MDR) (EU) 2017/745 and In Vitro Diagnostic Regulation (IVDR) (EU) 2017/746. The Medical Devices Coordination Group (MDCG) discussed some suggestions on how to address the problem within a position paper published in August 2022.

Even if the document does not represent an official guideline, it describes some critical points to be considered by manufacturers and notified bodies in order to face the great challenge of the re-certification of medical devices and in vitro diagnostics according to the new rules. Should this not occur in time, many products may exit the market at the end of the transition period, potentially leading to a supply crisis greatly impacting on the health of patients and the normal functioning of healthcare institutions.

The MDCG position paper answers the request of EU Health ministers advanced during the EPSCO Council meeting on 14 June 2022 to figure out some immediate measures to face the problem. The final goal of the document is to improve the efficiency in the application of the current regulatory framework, with no reduction of requirements to be fulfilled by manufacturers. Waivers from applicable conformity assessments procedures should be considered only in relation to an interest of public health, patient’s safety, or health.

The position paper consists of nineteen points addressing the issue under its different perspectives, the first eleven of which refer to the increase of notified bodies’ capacity. The MDCG calls on all stakeholders to collaborate in order to smoothly implement the suggested actions, a process that will be monitored by the MDCG itself.

How to increase the capacity of NBs

Hybrid audits should be the elective tool notified bodies may use where appropriate to timely and efficiently run conformity assessment. Duplication of activities should be also avoided. To this instance, the suggestion is to “develop a framework for leveraging evidence, or components thereof, from previous assessments” run according to previous Directives. A pre-condition to activate this possibility is that the previous assessment has been judged “valid and properly substantiated also with regard to the MDR/IVDR requirements and the device” by a duly qualified notified body personnel.

A flexible approach may also apply to the combination of audits for legacy devices and actions needed to guarantee their ‘appropriate surveillance’. Combined audits may be used particularly for legacy devices whose application for MDR/IVDR certification is under review by a NB, thus moving the focus more towards the assessment of compliance with the new rules. To this instance, the MDCG also announced the intention to produce a specific guidance on ‘appropriate surveillance’ under Article 110(3) IVDR and to update MDCG 2022-4.

Already existing guidance may also be reviewed to reduce the administrative burden for NBs, and remove limitations related to the scope of documentation not required by MDR/IVDR.

A fundamental piece of the new European infrastructure for medical devices and IVDs is represented by the centralised Eudamed database, which should be timely fed by NBs with all relevant information using machine-to-machine procedures. Double registrations should be avoided as much as possible.

New notified bodies are essential in order to increase capacity. To this instance, the MDCG suggests supporting training, coaching and internship activities for their personnel. The rationalisation of internal administrative procedures is also deemed important.

Time for re-assessment of NBs is undergoing a review by the European Commission, which is expected to result in the publication of new Delegated Acts. The proposal is to move from the current first re-assessment at three years after notification (and then every 4th year) to up to five years after notification, on the basis of a flexible approach. There are currently ten re-assessments planned in 2022, twelve in 2023 and 11 in 2024. According to the MDCG, the new timeframe for re-assessment would allow national designating authorities to free resources to assess new NBs, while existing ones could process higher numbers of first MDR/ IVDR certifications.

Assessment, designation and notification of conformity assessment bodies (including the European Commission) are also called to reduce their timeframes and improve the efficiency of their processes, keeping unaltered the requirements to be met. The possibility to add specific codes to the designation of NBs shall be also explored by the MDCG. The Group is also committed to prioritise some ongoing actions which may impact on NB’s capacity (i.e. revision of section III.6. of MDCG 2019-6 revision 3).

MDCG’s guidance documents should be seen as an aid “to apply the legal requirements in a harmonised way, providing possible solutions endorsed by the MDCG”. Nevertheless, demonstration of the compliance to requirements should always benefit of a certain flexibility. A reasonable time should also be granted to integrate the new guidance in the relevant systems and/ or to apply them, suggests the MDCG.

Suggestions for the manufacturers

Under the perspective of manufacturers of MDs and IVDs, costs to access NBs may play an important role, especially for small-and-medium companies (SMEs). The MDCG position paper recalls NBs to the obligation to make their standard fees publicly available, possibly in a way that might be easily compared. Specific access schemes should be also in place to make available some capacity to SMEs and other first-time applicants for conformity assessment.

Manufacturers should also refer to notice MDCG 2022-11 to ensure timely compliance with MDR requirements. IVDs should not left behind, even if this category of products benefits of one more year for the transition to new rules compered to medical devices.

Structured dialogue is the suggested tool to improve the collaboration between manufacturers and notified bodies along the entire process of conformity assessment aimed at regulatory procedures, should this approach turn to be useful in order to improve the overall efficiency and predictability.

A timely communication to manufacturers by mean of webinars, workshops, targeted feedback and informative sessions is also deemed important in order to allow for a better preparedness, with a particular attention to SMEs and first-time applicants. The MDCG also suggest NBs to develop common guidelines for manufacturers to assist them in the application phase, containing explicative examples of typical non-conformities and details on he preparation and content of technical documentation. National authorities and industry associations are called as well to contribute to the dissemination of relevant information across their stakeholders.

Specific guidance should be issued by the MDCG to support a simpler conformity assessment of some aspects of legacy and orphan devices denoted by a demonstrable track record of safety. The development of a specific definition of “orphan devices” is also planned.

An improved dialogue between NBs and medicines authorities, and cases where expedited review would be possible is also supported in order to speed up consultations on medical devices incorporating an ancillary medicinal substance and companion diagnostics.

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Regulatory Affairs Archives - European Industrial Pharmacists Group (EIPG)

EMA’s reflection paper on AI in the pharmaceutical lifecycle

EMA’s reflection paper on single-arm clinical trials

The new MHRA’s framework for clinical studies

PIC/S new guidance documents for GDP inspectors

Draft ICH M13A guideline on bioequivalence open for consultation

EMA/EFSA joint report on human dietary exposure to residues of veterinary medicines, pesticides and feed additives

MDCG, a position paper on the capacity of notified bodies

News from EIPG