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The risk of a biosimilar void in Europe


by Giuliana Miglierini The undergoing revision of the pharmaceutical legislation aims, among others, to redefine data protection to better support competitiveness of generics and biosimilars and to favour the timely access of patients to treatments. While the innovator pharma industry is Read more

The drug shortage situation - EIPG's point of view


by Maurizio Battistini The shortage of medicines has been a major concern in the countries of the European Union, and elsewhere, for more than 10 years, so much so that the Economic Community has devoted a great deal of effort Read more

EP’s draft position on Unitary SPC and SPC Regulation revision


by Giuliana Miglierini The Committee for Legal Affairs (JURI) of the European Parliament released the draft amendments to the Commission’s proposals aimed to establish a Unitary Supplementary Protection Certificate (SPC) (links to the document and to the procedure) and to Read more

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EMA’s reflection paper on AI in the pharmaceutical lifecycle

September 22, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.


The new MHRA’s framework for clinical studies

May 26, 2023 , , , , , , , , , , , , , , , , , , , , , , , ,

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.


IVD regulation in force: new MDCG guidelines and criticalities for innovation in diagnostics

June 10, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The new regulation on in vitro diagnostic medical devices (IVDR, Regulation (EU) 2017/746) entered into force on 26 May 2022. The new rules define a completely renewed framework for the development, validation and use of these important tools supporting the diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of a disease, in line with technological advances and progress in medical science. “Diagnostic medical devices are key for lifesaving and innovative healthcare solutions. Today we are marking a big step forward for the patients and the diagnostics industry in the EU. The COVID-19 pandemic has underlined the importance of accurate and safe diagnostics, and having stronger rules in place is a key element in ensuring this is the case for EU patients.”, said Stella Kyriakides, Commissioner for Health and Food Safety

The European Commission also published a Q&A document to facilitate the comprehension of the new framework.

The main contents of the IVDR

The risk-based approach for the classification and development of in vitro diagnostics is at the core of the IVDR. There are four different classes of IVDs: class A (low individual risk and low public health risk), class B (moderate individual risk and/or low public health risk), class C (high individual risk and/or moderate public health risk) and class D (high individual risk and high public health risk). The assessment of the quality, safety and performance of IVDs by independent notified bodies shall be based on more detailed and stringent rules. Higher-risk categories will also be subject to further assessment by newly created scientific bodies acting under the auspices of the European Commission, such as the expert panels and the network of EU reference laboratories. Twelve expert panels have been established up to now.

Each single IVD will be associated to a Unique Device Identifier (UDI), so to facilitate its traceability along the entire life cycle. The identifier will also serve to locate the relevant information about a diagnostic marketed in the EU within the European database of medical devices (EUDAMED), where also a summary of safety and performance will be publicly available for medium- and high-risk devices. The database will also contain information about all economic operators and provide a repository for the certificates issued by notified bodies.

The new regulation strengthened the framework for post-marketing surveillance of IVDs, asking for a closer coordination of the vigilance activities by all member countries. The IVDR also introduced reinforced rules on clinical evidence and performance evaluation, including an EU-wide coordinated procedure for authorising multi-centre performance studies, and a specific regime for devices manufactured and used in the same health institution (in-house devices).

Difficulties in the timely implementation of the (EU) 2017/746 regulation may still be possible due to the lack of a sufficient number of notified bodies, as only seven have been designated up to now, established in only four countries (Germany, France, the Netherlands and Slovakia), while eleven other applications were pending in May 2022. To solve this issue, Regulation (EU) 2022/112 was adopted. A transition period up to May 2025 applies to devices that require a notified body certificate already under the previous Directive (around 8%, vs about 80% according to the IVDR); other classes of IVDs benefit of different transition periods (May 2025 for class D, May 2026 for class C and May 2027 for class B and A sterile).

Q&As on the interface with the Clinical Trial regulation and UDI

The Medical Devices Coordination Group (MDCG) published a Q&A document (MDCG 2022-10) to provide guidance on the interface between Regulation (EU) 536/2014 on clinical trials for medicinal products for human use (CTR) and the IVDR.

The guideline addresses the requirements for assays used in clinical trials, that may include IVDs carrying a CE mark for the intended purpose, IVDs developed in-house and devices for performance studies. Only the devices falling on the definition of an IVD with regards to their intended purpose are subject to the IVD legislation. The guideline also provides suggestions on assays likely to be considered IVDs, as they are used for medical management decisions of trial subjects within the trial.

Another Q&A guideline (MDCG 2022-7) provides clarifications on how to apply the Unique Device Identification system to both medical devices and in vitro diagnostics.

Topics covered by the document include the need for a new UDI-DI assignment in case the number of items in a device package changes or for single-use reprocessed devices, the requirement for economic operators to maintain a registry of all UDIs of the devices which they have supplied or with which they have been supplied, or the requirement of a new UDI-DI for substance-based medical devices, in case of formula quantity changes or additional claims.

The MDCG also addressed the assignment and use of the Basic UDI-DI and the determination of the ‘grouping’ for design or manufacturing characteristics, including the case of devices comprising a patient and a physician facing module, and the contents of the Declaration of Conformity (DoC). Labelling is also addressed, as well as rules for systems and procedure packs (SPPs) and configurable devices, as well as those applying to retail point of sale, promotional packs and marketing related samples.

The impact of the IVDR on innovation

The issues linked to the IVDR implementation and their impact on innovation and diagnostic laboratories, including the development and use of in-house devices, have been analysed by the BioMed Alliance In Vitro Diagnostics Task Force, and published in HemaSphere.

The Task Force identified two main challenges to be faced by the academic diagnostic sector. The first one impacts on the possibility to use in-house IVDs, based on the demonstration that no equivalent CE-IVD kit is present on the market or when the specific needs cannot be met at the appropriate level of performance by an equivalent CE-IVD. The strict exemptions applying to in-house IVDs (e.g. prohibition of transferring to other legal entities, compliance with EN ISO 15189 and justification of use, etc.) may impact also on the potential for innovation in the diagnostic sector.

The second challenge refers to the not so clearly defined boundaries between CE marked-IVDs, modified CE-IVDs, Research Use Only (RUO) tests, and in-house IVDs. The Task Force recalls the immediate applicability of the General Safety and Performance Requirements specified in Annex I of the IVDR, as they have not been included in the approved amendment of the implementation timeline.

Furthermore, only tests meeting economic viability may in the future be transferred from the academia to the industry, while rare or complex tests would probably remain excluded. According to the paper, the cost of diagnostics shall likely increase, and the academa should carefully consider how to support further research into rare or complex diagnostics in order to ensure their availability to patients.

Following the results of a survey among medical societies on current diagnostic practices, several suggestions are made to better support the implementation of the IVDR, namely by mean of the availability of diagnostic equivalents of the European Reference Networks for rare diseases and a concerted action involving all stakeholders. A joint biomarker-to-test pipeline between the IVD industry and research/academic labs would also be useful to facilitate the initial development and local application of innovative diagnostics within healthcare institutions or diagnostic reference networks with specific expertise, to then transfer them to manufacturers above a certain production volume.


Artificial intelligence in medicine regulation

August 20, 2021 , , , , , , , , , , , ,

The International Coalition of Medicines Regulatory Authorities (ICMRA) sets out recommendations to help regulators to address the challenges that the use of artificial intelligence (AI) poses for global medicines regulation, in a report published on 16 August 2021.

AI includes various technologies (such as statistical models, diverse algorithms and self-modifying systems) that are increasingly being applied across all stages of a medicine’s lifecycle: from preclinical development to clinical trial data recording and analysis, to pharmacovigilance and clinical use optimisation. This range of applications brings with it regulatory challenges, including the transparency of algorithms and their meaning, as well as the risks of AI failures and the wider impact these would have on AI uptake in medicine development and patients’ health.

The report identifies key issues linked to the regulation of future therapies using AI and makes specific recommendations for regulators and stakeholders involved in medicine development to foster the uptake of AI. Some of the main findings and recommendations include:

  • Regulators may need to apply a risk-based approach to assessing and regulating AI, which could be informed through exchange and collaboration in ICMRA;
  • Sponsors, developers and pharmaceutical companies should establish strengthened governance structures to oversee algorithms and AI deployments that are closely linked to the benefit/risk of a medicinal product;
  • Regulatory guidelines for AI development, validation and use with medicinal products should be developed in areas such as data provenance, reliability, transparency and understandability, pharmacovigilance, and real-world monitoring of patient functioning.

The report is based on a horizon-scanning exercise in AI, conducted by the ICMRA Informal Network for Innovation working group and led by EMA. The goal of this network is to identify challenging topics for medicine regulators, to explore the suitability of existing regulatory frameworks and to develop recommendations to adapt regulatory systems in order to facilitate safe and timely access to innovative medicines.

The implementation of the recommendations will be discussed by ICMRA members in the coming months.

Source: EMA