clinical trials Archives - European Industrial Pharmacists Group (EIPG)

Generative AI in drug development


by Giuliana Miglierini Generative AI is perhaps the more advanced form of artificial intelligence available today, as it is able to create new contents (texts, images, audio, video, objects, etc) based on data used to train it. Applications of generative Read more

PGEU annual medicine shortages report


by Giuliana Miglierini The situation of medicine shortages is getting worse, with many countries which in 2023 experienced more issues than the previous years, according to the PGEU annual report on medicine shortages. Community pharmacists are on the front line Read more

EMA’s pilot scheme for academic and non-profit development of ATMPs


by Giuliana Miglierini Advanced therapy medicinal products (ATMPs) are often developed by academic and non-profit organisations, because of their high level expertise in the biotechnological techniques that underpin many new therapeutic approaches. On the other hand, these organisations often lack Read more


The new MHRA’s framework for clinical studies

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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.


ICMRA report on best practices against antimicrobial resistance

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by Giuliana Miglierini

Antimicrobial resistance (AMR) is the consequence of mutations that allow microbes to survive pharmacological treatment. Resistant strains can often be tackled only by a limited number of therapeutic options: according to a systematic analysis published in The Lancet, an estimated 1.27 million deaths occurred in 2019 due to unresponsiveness to available medicines.

As a part of its effort against AMR, the International Coalition of Medicines Regulatory Authorities (ICMRA) has published a report discussing successful regulatory and non-regulatory best practices in the field of AMR.

The report was drafted by ICMRA’s Work Group led by Health Canada, and inclusive also of the European Medicines Agency, UK’s MHRA, and regulators from Japan, Argentina, Nigeria, Saudi Arabia and Sweden. For each of the nine case studies, Annex 2 presents a table summarising the problem under examination, the proposed solution, results and consequent recommendations.

Regulatory flexibility

The US’ Biomedical Advanced Research and Development Authority (BARDA) focused on innovative approaches to developing supporting data packages required for regulatory review of certain non-traditional therapies. Public-private partnerships are the preferred vehicle to manage R&D projects and to reach regulatory approval by the FDA. The main targets for BARDA are new antimicrobials to treat antibiotic-resistant secondary bacterial infections and bioterrorism infections. Selected proposals shall lead to the development of candidate medical countermeasures (MCMs), based on a regulatory master plan inclusive of a tentative schedule for regulatory milestones. Partners may also benefit from BARDA’s expertise in the field of animal studies, flexible manufacturing and clinical study design. A Memorandum of Understanding was also signed with the FDA to provide a coordinated framework for the development of MCMs.

Antimicrobials for veterinary use

Antimicrobials for veterinary use include some products for human use. It is thus important to act in the animal sector to limit the selection pressure for the development and spread of resistant pathogens in both animals and humans.

The project led by Health Canada in collaboration with the Public Health Agency of Canada (PHAC) focused on the implementation of the Veterinary Antimicrobial Sales Reporting (VASR) system, aimed to collect data on the total quantity of antimicrobials sold or compounded by animal species. The activation of the system in 2018 followed some changes to Canada’s Food and Drugs Regulation (FDR): manufacturers and importers have to report annual sales of medically important antimicrobials intended for veterinary use based on active ingredients listed in List A. The acquired data are collected and screened by the Veterinary Drugs Directorate and validated and analysed by PHAC’s CIPARS.

Regulatory agilities during the Covid-19 pandemic

Regulatory flexibility has been one of the main tools used to respond to the Covid-19 pandemic. Health Canada’s main goal was to expedite the regulatory review of health products without compromising their safety, efficacy and quality standards. A temporary regulatory pathway was introduced in September 2020 by a Interim Order, and new transition measures were approved in September 2021 to allow the review, authorisation and oversight of Covid-19 medicines under the FDR. A procurement strategy for Covid vaccines, treatments and diagnostics was also adopted by the Government, based on advanced purchasing agreements with different companies. Another Interim Order allowed the activation of a temporary regulatory pathway to facilitate clinical trials of candidate Covid-19 products. Flexibilities to Drug Establishment Licensing (DEL) and GMPs were also introduced, and collaborations with other international regulatory bodies activated (including the EMA open pilot).

Non-prescription availability of antibiotics

UK’s MHRA focused on the case of tyrothricin-containing lozenges, a combination product available for sale at pharmacies since 1968, and that underwent a restriction of prescribing in 2018, following a NHS’s guidance advising prescriptions for the treatment of acute sore throats should not be routinely offered in primary care. The UK’s Commission on Human Medicine considered MHRA’s request of advice on the feasibility to remove the product from the market. As a result, the MHRA interacted with the Marketing authorisation holder to verify the possibility of a reformulation to exclude the antibiotic active ingredient. The action of impacted also on the education of the wider public towards the responsible use of antibiotics.

Reimbursement models for novel antimicrobials

The Public Health Agency of Sweden addressed the issue of antimicrobial market failure. Not all the few available antibiotics launched during the last decade are accessible in all European countries, due in some instances to unfavourable sales prospects. A pilot project was launched in 2018 to test a new, partially delinked reimbursement model based on a minimum annual guaranteed revenue at nation level for the pharmaceutical company (on the basis of estimated clinical needs). Security of supply of antibiotics within 24 hours and a security stock located in Sweden were the requests to interested companies.

Selective antibiograms to inform antimicrobial choice

The choice of the most appropriate antimicrobial is usually based on an antibiogram, a laboratory test used to evaluate the susceptibility and resistance profile of bacterial isolates to various antimicrobial active ingredients. The Swedish Medical Products Agency (SMPA) focused on the use and selective reporting of antibiograms of urinary cultures for Enterobacteriaceae from patients with symptoms of cystitis. The analysis included six different antibiotics for men and five for women, since the fluoroquinolone ciprofloxacin is no longer recommended to treat cystitis in women. This selective reporting allowed to decrease fluoroquinolone prescriptions of 46% in 15 years.

Feedback on prescriber data

SMPA also provided some feedback to prescribers on their antibiotic prescribing practices. The tool was implemented at the national, regional, local and also individual level, in order to raise knowledge and information, and influence prescription habits. Prescribers’ data at a high resolution level (prescriber identifying codes) are used to elaborate relevant trends. Statistics on antibiotic use at regional and national level are freely accessible at the National Board of Health and Welfare website.

Common infections in outpatient care

The Sweden’s Rainbow Pamphlet provides treatment recommendations for common infections in outpatient care. The initiative was launched in 2010 by the Swedish Strategic Programme for the Rational Use of Antimicrobial Agents and Surveillance of Resistance (STRAMA); it can be accessed in paper form or through the STRAMA mobile application. The use of the Rainbow pamphlet has been supported also by communication campaigns targeted both to healthcare professionals and the public.

Methods for monitoring AMR in the environment

The monitoring of antibiotics’ diffusion in the environment is relevant with respect to the One- Health approach, which focuses on the harmonised surveillance across human, veterinary and food sectors.

The SMPA launched two projects aimed to better identify indicators to be used for the monitoring of antibiotic resistance in the environment: EMBARK (Establishing a Monitoring Baseline for Antimicrobial Resistance in Key environments) and Antibiotikasmart Sverige (Antibiotic Smart Sweden). The current main gaps in knowledge include the abundance and prevalence of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) occurring naturally. Furthermore, antimicrobials may enter the environment at different points along the lifecycle of human and veterinary medical products, with processes still to be fully clarified.


ACT EU’s Workplan 2022-2026

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by Giuliana Miglierini

The implementation phase of the Accelerating Clinical Trials in the EU (ACT EU) initiative, launched in January 2022 by the European Commission, started with the publication of the2022-2026 Workplan jointly drafted by the Commission, the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA).

The final target is to renew how clinical trials are designed and managed, so to improve the attractiveness of Europe for clinical research and the integration of results in the current practice of the European health system.

The 2022-2026 Workplan details the actions and deliverables planned according to the ten priorities identified by ACT EU. The drafting of the document took as primary reference also the recommendations of the European Medicines Regulatory Network (EMRN) strategy to 2025 and the European Commission’s Pharmaceutical Strategy for Europe.

Steps towards the full implementation of the CTR

The first priority of action should see the completion by the end of 2022 of the mapping of already existing initiatives within the EMRN and ethics infrastructure. This exercise represents a fundamental step to achieve a detailed picture of the current clinical trials regulatory landscape, characterised by the presence of various expert groups working in different areas.

The results of the mapping will form the basis to plan and implement a new strategy for the governance of the entire framework governing clinical trials, including the clarification of roles and responsibilities to the Network and its stakeholders. The expected outcome is the rationalisation and better coordination of the work done by different expert groups and working parties, as reflected by a new regulatory network responsibility assignment (RACI) matrix. The analysis and setting up of the new framework should start from the core governance bodies (Clinical Trials Coordination and Advisory Group (CTAG), Clinical Trials Coordination Group (CTCG), Commission Expert Group on Clinical Trials (CTEG) and Good Clinical Practice Inspectors Working Group (GCP IWG)), to then extend to other parts of the Network further.

The full implementation of the Clinical Trials regulation (Reg. (EU) 536/2014) by mean of the launch of monthly KPIs tracking of the planned activities is another key action. A survey to identify issues for sponsors and the consequent implementation of a process to prioritise and solve them are planned for the second half of 2022. The beginning of 2023 should see the launch of a scheme to better support large multinational clinical trials, particularly those run in the academic setting. One year later, at the beginning of 2024, a one-stop shop to support academic sponsors should also be launched.

An important action for the success of ACT EU should see the creation of a multi-stakeholder platform (MSP) to enable the interaction and regular dialogue of the many different stakeholders working in the field of clinical trials under different perspectives, both at the European and member state level. The platform should be launched by Q2 2023, with the first events run under its umbrella planned for Q3 and is expected to help in the identification of key advances in clinical trial methods, technology, and science.

Methodological updates in clinical trials

Another key step in the renewal of the European framework for clinical trials is linked to the updating of the ICH E6(R2) guideline on “Good Clinical Practice” (GCP). A targeted multi-stakeholder workshop on this theme is planned for Q1 2023, while the resulting changes should be implemented in EU guidance documents by Q3 2023. New GCPs should take into better consideration the emerging designs for clinical trials and the availability of new sources for data and are expected to “provide flexibility when appropriate to facilitate the use of technological innovations in clinical trials”. This action also includes the development of a communication and change management strategy to support the transition to the revised GCP guideline, and the updating of other relevant EU guidelines impacted by the change.

The opportunity to introduce innovative clinical trial designs and methodologies shall be addressed starting from decentralised clinical trials (DCT), with the publication of a DCT recommendation paper by the end of 2022. A workshop on complex clinical trials should be also organized to discuss issues linked to study design, such us umbrella trials and basket trials or master protocols. New technologies may support innovative approaches to the recruitment of eligible study participants and new ways to capture data during clinical trials. The publication of key methodologies guidance is an expected deliverable, together with a improved link between innovation and scientific advice.

A new EU clinical trials data analytics strategy is expected to be published by the end of 2022, while the first half of next year should see the development of a publicly accessible EU clinical trials dashboard and a workshop to identify topics of common interest for researchers, policy makers, and funders. These activities are targeted to fully exploit the opportunities offered by data analytics, so to identify complex trends from the large base of data about clinical trials collected by the EMRN. The existence of multiple data sources is a main barrier currently affecting the possibility to access, process and interpret these data.

Another priority is to plan and launch a targeted communication campaign to engage all enablers of clinical trials, including data protection experts, academia, SMEs, funders, Health Technology Assessment (HTA) bodies and healthcare professionals. Up to 2024, this action will also support sponsors in remembering the importance of training linked to the application of the CTR and the mandatory use of the Clinical Trials Information System (CTIS). All other communication needs across all priority actions will also be handled under this action.

Scientific advice, safety monitoring and harmonised training

The current framework sees the involvement of different actors who interact with sponsors at different stages of product development to provide them with scientific advice. A simplification of the overall process should be pursued by grouping of key actors in clinical trials scientific advice in the EU, “with the aim of critically analysing the existing landscape in line with stakeholder needs”. The Workplan indicates several pilot phases should be run to identify the better way to address this topic, which should benefit especially academic or SMEs sponsors that may have less experience of regulatory processes. Planned activities include a enhanced intra-network information exchange, the running of a survey among stakeholders and the operation of a first pilot phase by Q4 2024, to then optimise and expand the advice process upon results.

The establishment of clinical trial safety monitoring is another central theme of action, that should see member states involved in a coordinated work-sharing assessment. Key activities should include the identification of safe CT KPIs by the end of 2022 and a review of IT functionalities for safety, and it will be run in strict connection with the EU4Health Joint Action Safety Assessment Cooperation and Facilitated Conduct of Clinical Trials (SAFE CT). Training of safety assessors and the development of a harmonised curriculum thereof shall be also considered, as well as the alignment of safety procedures for emerging safety issues potentially impacting clinical trials.

The development of a training curriculum informed by regulatory experience should support the creation of a renewed educational ‘ecosystem’ characterised by bidirectional exchanges to enable training on clinical trials. This action is target mainly to better engage universities and SMEs, and it should include also training provided by actors other than the regulatory network.


Revision of the PIC/S GMP Guide: Annex 13 and Annex 16

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by Giuliana Miglierini

The entry into force of EU Regulation 536/2014 “Clinical trials”, at the end of January, resulted in the parallel updating of some international guidelines. In particular, a new version of the GMP Guide PE016 was published by PIC/S (Pharmaceutical Inspection Co-operation Scheme) on 1st February 2022. The revision included Annex 13 on the manufacturing of Investigational Medicinal Products (IMPs), and the new Annex 16 on the certification and batch release to be performed by Authorised Persons (AP) (click here to access all PIC/S guidance related to GMP). The revision of PIC/s guidelines is aimed to reflect the last changes occurred in the corresponding EMA documents, so to maintain the alignment between the two regulatory references (as established by the cooperation agreement between EMA and PIC/S). PIC/S has invited all non- EEA Participating Authorities and applicants to transpose the new Annexes 13 and 16 into their own GMP Guides.

The new Annex 16

Annex 16 represents a completely new addition to the PIC/S GMP guide; the EU Annex 16 (part of the EU GMP Guide) was initially considered to be too EU-specific and difficult to transpose for PIC/S purposes. Following a consultation in 2017, PIC/S Participating Authorities agreed to make an attempt to transpose EU Annex 16, as the adaptation may support a better harmonisation of GMP standards at the international level.

Annex 16 refers to both human and veterinary medicinal products which are subject to the PIC/S Participating Authority or are made for export. Furthermore, the Annex applies to investigational medicinal products for human use, “subject to any difference in the legal provisions and more specific guidance published by PIC/S Participating Authorities under national law”. With reference to imported medicinal products, each PIC/S Participating Authority may independently and voluntary decide whether to adopt the guidance as a legally-binding standard.

Certain types of medicinal products (e.g. blood and immunological products) are not addressed by the Annex, as they are regulated by national laws and fall under the competences of National authorities; to this instance, Annex 16 applies to the certification process performed by the AP and to the subsequent release of the batches.

The marketing authorisation holder (MAH) remains the sole responsible for the safety, quality and efficacy of the marketed products. Authorised Persons are required to check each single batch to verify compliance to national and GMP requirements, as well as to those detailed within the marketing authorisation (MA). After certification by the AP, batches of finished products can be transferred to saleable stock and/or export. Specific and documented agreements are needed should this require transfer to a site different from the certification’s one. Authorised Persons should be clearly identifiable, with reference to any quality defect leading to investigation or batch recall. APs certifying the release of the finished product are responsible for verifying the conditions of storage and transport for the batch and the sample, if sent separately, and of all testing required upon importation (including sampling, where needed).

A formal Quality Risk Management (QRM) process is required when sampling is performed at a manufacturing site located in another jurisdiction; Annex 16 provides detailed guidance on the elements to be considered in this exercise. Documentation of the continuous training received by the AP in charge of certification and batch release should be always available, with specific reference to the product type, production processes, technical advances and changes to GMP.

Annex 16 provides detailed guidance on how to conduct the process of certification of each batch of finished product, independently of the number of sites involved. With reference to specific manufacturing or control steps performed at different sites, their respective AP has to provide confirmation of the performed activities, sharing responsibilities with the AP in charge of the final batch release.

The certification process should take into consideration the entire supply chain of both the active substance and the finished product, including manufacturing sites of the starting and packaging materials. The AP responsible for certification should be able to access results of the audits performed at the sites involved, in order to check the consistency of all activities with those described in the MA and within GMPs. Audits run by third parties should reflect requirements set forth in Chapter 7 of the PIC/S GMP Guide.

In particular, suppliers of active substances should comply with GMP and GDP requirements relating to the supply of the active ingredient used to the finished product manufacturing. Excipients should also fulfil GMP requirements, and be possibly manufactured and supplied in accordance with the PI 045-1 guideline. Specific guidance may also apply for other types of products, i.e. biological active substances and medicinal products for human use or radiopharmaceuticals. Annex 16 provides templates for the confirmation letters to be used for the partial manufacturing of a medicinal product and for the content of Batch Certificates.

The revision of Annex 13

Annex 13 has been revised in order to reflect the contents of the new EU Regulation n. 536/2014 on clinical trials, which will replace EU Annex 13. PIC/S Annex 13 discusses the manufacturing of Investigational Medicinal Products (IMP), apart from the reconstitution phase, which is not considered to be part of the process. Provisions set forth by Annex 13 should be taken into consideration with reference to the re-labelling or re-packaging of IMPs and to the preparation of radiopharmaceuticals used as diagnostic investigational medicinal products, occurring in hospitals, health centres or clinics and performed by pharmacists or other persons legally authorised in the country concerned.

All activities should refer to an appropriate Pharmaceutical Quality System to be in place, according to requirements set forth in Chapter 1 of Part 1 of the PIC/S GMP Guide.

 The characteristics of IMPs may intrinsically evolve along the development process, as new data become available that may require changes to, for example, the formulation or the dosage form. This has to be reflected into the respective product specifications and manufacturing instructions, that should also evolve in parallel and be fully traceable and documented. Annex 13 indicates that all deviations should be registered and investigated, and preventive and corrective actions put in place. The new Annex provides detailed guidance on the different items to be considered within the product specification file, as well as for the proper management of personnel, premises and equipment.

All the documentation generated during the clinical development phases should fulfil requirements specified by the PIC/S GMP Guide, Part I, Chapter 4. To this instance, relevant documentation includes specifications and instructions, orders, manufacturing formulae and processing instructions, packaging instructions and batch records. Detailed guidance is provided also for production, including packaging materials and manufacturing operations, the modification of comparator products, blinding operations, and the packaging and labelling of the IMP. Annex 13 also offers guidance on how to perform quality control and batch release, and how to address outsourced operations, complaints and recalls and or the destruction of batches of IMP products.


ACT EU: the EU’s vision for the future of clinical trials

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by Giuliana Miglierini

Just few days before the entry into force of the new Clinical Trials Regulation and of the Clinical Trials Information System (CTIS) on 31 January 2022, a new initiative has been announced to completely renew the European framework governing how clinical trials are designed and run. The strategic document ACT EU (Accelerating Clinical Trials in the EU) has been jointly developed by the European Commission, the European Medicines Agency (EMA), the Heads of Medicines Agencies (HMA) and national regulators with the aim to strengthen the European Union as a leading “focal point” for clinical research at the international level.

ACT EU shall support the achievement of the goals established by the European Pharmaceutical Strategy and the European medicines agencies network strategy (EMANS) to 2025. The initiative will be co-led by the European Commission, EMA and HMA; the proposed governance shall find inspiration on the model already in use by the Clinical Trials Information System, with an EUCTR Coordination Group with an adapted mandate and composition. The individual domains which form the overall matrix will be coordinated by the relevant functions available within the network. The formal public communication phase on ACT EU will start after the official endorsement of the initiative by HMA and EMA.

Six objectives and ten priorities of action for 2022-2023

The ACT EU strategy identifies six different goals for the future of European clinical research. Its leading role shall be optimised through a unified European position on clinical trials at the international level, a better ethical oversight and integration of ethics committees into the clinical trial and medicines regulatory lifecycle. Large-scale multinational clinical trials with broader geographical scope shall be incentivised, while reducing the administrative burden for sponsors and investigators.

A special attention will be paid to the generation of decisional evidence for unmet medical needs, rare diseases, and on vaccines and therapeutics for public health crises and pandemics. A truly high level and coordinated scientific advice is indicated as an important element in order to support the trial and marketing authorisation processes. The strategy confirms the need to adopt new patient-oriented medicines development and delivery models with pro-active engagement of all the stakeholders. The availability of an improved capacity both at the development and regulatory level is also deemed important to achieve the goals of the initiative.

These challenging objectives shall be pursued in years 2022-2023 through the activation of a set of ten specific priority lines of action. An initial exercise to map already existing initiatives within the European medicines regulatory network (EMRN) will be run, that will represent the basis for the consequent development of a governance rationalisation strategy. This might include, for example, the alignment of different expert groups and working parties in the EMRN and ethics infrastructure.

The smooth implementation of the Clinical Trials Regulation shall be monitored using a set of Key Performance Indicators (KPI), still to be developed; the modernisation of the good clinical practices (GCPs) should occur under specific ICH’s guidance. The attractiveness of Europe for larger, multinational trials should specifically address studies run in the academic setting. Furthermore, the academics and non-profit organisations may also play a leading role in the analysis of data arising from clinical trials.

Further actions will include the availability of a multi-stakeholder platform, including patients, and the engagement in the initiative of all enablers by mean of a targeted communication campaign. A tighter coordination of different aspects relevant to the planning of new clinical trials, i.e. the scientific advice on the trial approval and the design of the study, has been also announced. The increasing use of artificial intelligence and/or machine learning technologies in the clinical domain and issues pertaining complex and decentralised trials, as well as the interface between the In Vitro Diagnostics Regulation (IVDR) and the Clinical Trials Regulation will benefit of new targeted methodological guidelines.

As for safety monitoring of clinical trials, the priority is to start its integration into a pre- and post-marketing safety monitoring framework. At the educational level, the competences needed to face this challenging scenario for the future of clinical trials in the EU will require the activation of specific training curricula, inclusive of modules on drug development and regulatory science with links to universities and SMEs.

Four principles to guide all actions

The complexity of the ACT EU initiative will require also the development of a new approach to make available the resources needed to smoothly run all the planned activities, possibly including the exploitation of the expertise external to the European medicines regulatory network. The strategy indicates the intention to adopt a collaborative and integrative approach, so to achieve a large research impact in the EU.

To this instance, the four principles “Do, Require, Influence, Support” have been identified to guide the execution and coordination of the projects, the requirement of specific guidance to address the expectations on applicants/developers/researchers, the availability of key publications and leadership to support the transformation phase at all levels (including patient, the academic, etc.), and stakeholders interactions suited to support all the above mentioned objectives.

The initial mapping of existing activities should also led to the identification of the budget needed for meetings, inclusive also of the activities relative to stakeholder engagement, training, and communication. Any other activities falling outside the optimisation of the already existing ones would be self-funded by the respective organisations (EC/NCA/EMA).

Comments from EFPIA

According to EFPIA, the announcement of ACT EU represents the beginning of an exciting new phase for clinical research in Europe. The industrial association highlights that the innovative design of many clinical trials, especially the complex ones, requires an increased efficiency.


Steps towards the final approval of the IP action plan

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By Giuliana Miglierini

The end of 2021 may see the final approval of many pieces of the new legislative framework announced in November 2020 by the European Commission. An important piece of this puzzle is represented by the IP Action Plan, governing the protection of intellectual property (IP); a step forward in this direction is represented by the resolution of 11 November 2021 on the Own-initiative report of the European Parliament.

The final text licensed in single reading is the result of the examination of the initial draft report – issued in May 2020 by the Committee for Legal Affairs, rapporteur Marion Walsmann – by several other Committees (IMCO, DEVE, CULT, AGRI).

The main points of the resolution

The resolution recognises the importance for the European economy of a balanced protection and enforcement of intellectual property rights (IPR). In years 2012-2016, the knowledge-intensive industries generated almost 30% of all jobs and almost 45% of total economic activity (in terms of Gross Domestic Product, GDP) in the EU; the IPR-intensive industries account for 93% of total EU exports of goods.

Europe’s recovery and resilience capacity is also highly impacted, as demonstrated by the pandemic when shortages of certain medicinal products and vaccines occurred. The EU Parliament acknowledges the role played by intellectual property in increasing the overall value of companies,especially the small-and-medium size ones (SMEs).

A current limitation to IP protection in Europe is represented by the still fragmented situation across different member states, which often leads to parallel national validation procedures and litigation for European patents. To this instance, the Parliament suggests the establishment of an IP coordinator at European level, to harmonise the approach to EU IP policy and enhance cooperation between the different bodies involved in the process (i.e. national IP authorities, Commission Directorates-General, EPO, EUIPO, WIPO, etc).

The Parliament also recognised the role IP plays in the pharmaceutical sector, where the availability of incentives greatly favours the development of new and innovative treatments. The resolution asks the Commission to support the innovative potential of European companies “on the basis of a comprehensive IP regime”, so to guarantee effective protection for R&D investments and favour fair returns through licensing. The availability of open technology standards has been valued as an important competitive element on the wider, global scenario.

Many different types of incentives are suggested by the Parliament’s resolution as useful to support micro-enterprises and SMEs in filing and managing their intellectual property, including IP vouchers, IP Scan and other Commission and EUIPO initiatives to support simple registration procedures and low administrative fees. The newly created European IP Information Centre may represents a fundamental reference point to increase knowledge in the field. The Parliament also suggests to introducing an EU-level utility model protection, not yet available, as a possible fast and low-cost protection tool to protect technical inventions.

Unitary patents and improved market competition

Still missing members states are urged to adhere to the enhanced cooperation scheme for the creation of a Unitary Patent Protection (UPP) and to ratify the Protocol to the Agreement on a Unified Patent Court on provisional application (PPA). The activation of this unique Court in charge of the examination of litigations would allow for a more efficient process and for lowering legal costs and improving legal certainty.

Fragmentation remains an issue also with respect to Supplementary Protection Certificates (SPCs): to this instance, the resolution asks the Commission to issue guidelines for member states and to provide a legislative proposal based on an exhaustive impact assessment. A major criticality to be solved is represented by the unitary patent not providing a unique SPC title valid across the EU; the own-initiative report also suggests the extension of the EPO’s mandate, so that examination of SPC applications could be carried out on the basis of unified rules.

Other important points needing attention to improve the presence of generic and biosimilar medicines in the EU are the abuse of divisional patent applications and patent linkage, which should also see an intervention by the Commission. The Parliament also opened the possibility of a revision of the Bolar exemption, which allows clinical trials on patented products needed to reach marketing authorisation of a generic or biosimilar version not to be regarded as infringements of patent rights or SPCs. This may also support the immediate market entry after the expiration of patent rights and SPCs. The Commission is called also to ensure the effectiveness and better coordination of compulsory licensing in order to provide access to medicines needed in case of health emergencies.

The resolution also addresses the theme of standard essential patents, which currently often leads to litigations, and it calls for the revision of the 20-years old system for design protection. Transparency on results obtained from publicly funded R&D is also recommended. The Parliament suggests artificial intelligence (AI) and blockchain technologies may play an important role in tackling counterfeiting practices and guarantee traceability of goods, as they may contribute to a better enforcement of intellectual property rights along the whole supply chain. The Commission should also work to establish clearer criteria for the protection of inventions created by the AI, without human intervention.

Comments from the industry

The European Parliament has clearly voted for a strong and fair IP system by underlining the importance of timely generic and biosimilar medicine competition. The misuse of divisional patents, the need to enlarge the scope of bolar to include API and all regulatory and administrative steps, and the long overdue ban anti-competitive patent linkage are well known problems that the Commission should address in the IP Action Plan. The Parliament has voted; the Commission must act.”, said Adrian van den Hoven, Director General at Medicines for Europe.

A major point in the implementation of the new European policies is represented by the review the Commission is going to conduct in 2024 to assess the effective achievement of goals of the SPC manufacturing waiver, which entered into force in July 2019 and is expected to start producing effects in the second half of 2022.

Many of the themes discussed in the Parliament’s resolution were debated during a webinar organized by Medicines for Europe, with the participation of representatives from the European Commission and the European Patent Office.

EFPIA, representing the innovator pharmaceutical industry, focused its attention on the impact of past EU Free Trade Agreements (FTAs) on drug spending, timing of countries’ access to new medicines after global launch, investments overall and in pharmaceuticals, and clinical trial participation. A report by IQVIA published in the Federation’s website addresses the impact of IP protection on these elements. Results confirm the central role of the pharmaceutical sector as the most R&D intensive industry in the world, with R&D spending averaging over 15% of revenue. A strong IP protection framework available at the level of EU FTAs favours the attractiveness for investments in the EU and its FTA partner countries. According to the report, an expanded IP protection appears not to be linked to the generation of a higher pharmaceutical spending; drugs’ share of healthcare spending is claimed to stay flat or fall after an FTA, and prices for medicines to rise more slowly than the level of inflation. A stronger IP index, adds IQVIA, is also correlated with increased clinical trial activity in a country, bringing both clinical and economic benefits.


Commission establishes portfolio of 10 most promising treatments for Covid-19

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by Giuliana Miglierini

The second phase in the development of new medicines to treat Covid-19 – a part of the EU Strategy on Covid-19 Therapeutics launched in May 2021 – has reached a cornerstone with the announcement made by the European Commission of a first portfolio list of ten potential Covid-19 therapeutic candidates likely to be authorised by the European Medicines Agency (EMA). The only medicine authorised up to now at EU-level to treat Covid-19 is remdesivir.

The choice of the molecules to be included in the list was based on independent scientific advice by an expert group, and it is aimed to offer new treatment opportunities for patients affected by the disease in a way complementary to the preventive action of the already available vaccines. The strategy shall contribute to the achievement of the European Health Union, and it has been modelled on the example of the EU Vaccines Strategy.

Once available in the European market, the new medicines are expected to contribute to the reduction of hospitalisations and deaths from Covid-19. “We have already signed four joint procurement contracts for different Covid-19 treatments and we stand ready to negotiate more. Our goal is to authorise at least three therapeutics in the coming weeks and possibly two more by the end of the year and help Member States gain access to them as soon as possible.”, said the Commissioner for Health and Food Safety, Stella Kyriakides.

Three different categories of therapeutics

The initial list of ten candidates includes three different categories of therapeutics, and it may evolve in future according to the emerging of new scientific evidence.

Antiviral monoclonal antibodies have been identified as the most efficacious approach to be used in the earliest stages of infection. This category includes the following medicinal products under development:

  • Ronapreve, a combination of two monocolonal antibodies casirivimab and imdevimab from Regeneron Pharmaceuticals and Roche.
  • Xevudy (sotrovimab) from Vir Biotechnology and GlaxoSmithKline.
  • Evusheld, a combination of two monoclonal antibodies tixagevimab and cilgavimab from Astra-Zeneca.

The second category refers to oral antivirals, in this case too for early treatment; it includes the following candidates:

  • Molnupiravir from Ridgeback Biotherapeutics and MSD.
  • PF-07321332 from Pfizer.
  • AT-527 from Atea Pharmaceuticals and Roche.

Hospitalised patients may also benefit from the use of immunomodulators; four different possible candidates have been selected within this category:

  • Actemra (tocilizumab) from Roche Holding.
  • Kineret (anakinra) from Swedish Orphan Biovitrum.
  • Olumiant (baricitinib) from Eli Lilly.
  • Lenzilumab from Humanigen.

The scrutiny and selection of the most promising therapeutic options took into consideration 82 different molecules in late-stage clinical development. The analysis assumed that different types of products are needed for different patient populations and at different stages and severity of the disease. This scrutiny exercise was completely separate from the standard scientific assessment of the regulatory dossiers submitted for the candidates, that will be performed by EMA in order to issue the recommendation for final marketing authorisation by the EU Commission.

Steps towards the approval of the selected candidates

As announced by Commissioner Stella Kyriakides, half of the selected candidate therapeutics may reach approval by EMA by the end of 2021. These include products for which the rolling review is already ongoing or that have applied for marketing authorisation to the European Medicines Agency. Pre-requisite for the approval is the final demonstration of their quality, safety, and efficacy; there is still the possibility some of the products in the list shall not be authorized should the scientific evidence provided to EMA be considered not enough robust to meet the regulatory requirements.

Four other candidates are still in early phase of development and have already received scientific advice from the Agency; their rolling review shall begin as soon as enough clinical data will be available. The further development of these products will benefit by an innovation booster to support development activities.

As said, this is just a first list of promising therapeutics to treat Covid-19; some other approaches are expected to be identified as a consequence of the activation of several new initiatives by the EU Commission. Among these are the setting up of the interactive mapping platform for promising therapeutics which represents one of the first targets of action for the newly created Health Emergency Preparedness and Response Authority (HERA) (we wrote about this in October’s newsletter). The Commission also announced the activation within few weeks of the HERA website, where contact details and practical guidance for interested companies shall be found.

A pan-European matchmaking event for therapeutics industrial production has been also announced; this effort will focus on the development of new and repurposed Covid-19 therapeutics and it is aimed to mobilise the EU’s pharmaceutical manufacturing capacity.

The criteria used to select the candidate therapeutics

The European Commission published also a Q&A note to better explain the process that led to the selection of the ten promising therapeutics to be included in the list.

The portfolio of the selected products (authorised and under development) has been established by the expert sub-group on Covid-19 therapeutics (part of the expert group on SARS-CoV-2 variants) upon request of the Commission. The criteria used to run the analysis were approved by Member States in the Human Pharmaceutical Committee.

They include the evaluation of the pharmacological rationale on the basis of the available evidence of the potential role played by the single medicinal product in the treatment of Covid-19, its stage of development and availability of relevant data from clinical trials, the absence of (new) major identified safety issues, and the ability to answer to unmet clinical need and/or bring therapeutic added value. For some product categories, the efficacy against new SARSCoV-2 variants has been also evaluated.

Other points included in the assessment refer to the route of administration, treatment regimen, and formulation, and the company’s intention to access EMA’s early stage scientific advice procedures. The analysis run by the expert group did not focused on more industrial aspects, i.e. manufacturing, production volumes, prices and access conditions; these will be part of the considerations made by the Commission in order to activate its support instruments.

As for the three different categories of selected products, antiviral monoclonal antibodies are intended to mimic the action of natural antibodies generated by the immune system against coronavirus. They can exert both a curative and a preventive action against the infection, in particular in the earliest stages of the disease. They are usually administered by injection.

Oral antivirals are small molecules aimed to block the activity and replication of the virus. These too are early interventions targeted to prevent damage in tissues and organs and offer the advantage of administration as tablets or capsules, thus favouring compliance. Other plus identified by the expert group are a higher resistance to variants, and the therapeutic action maintained also in vaccinated patients.

Immunomodulators aim to regulate the excessive reaction of the immune systems against the virus, thus preventing the risk of hospitalisation. They represent a symptomatic treatment option for patients at severe stage of progression of the disease despite vaccination and antiviral therapy.


A new role for EMA and a pilot project for the repurposing of medicines

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by Giuliana Miglierini

A draft agreement was reached at the end of October between the Council of the European Union and the European Parliament to reinforce the mandate of the European Medicines Agency (EMA) with reference to crisis preparedness and management for medicinal products and medical devices. “EU-level preparation and coordination are two essential ingredients to fight future health crises. Thanks to this deal we are adding an essential new building block to upgrade the EU’s health architecture. It will allow the EU’s Medicines Agency to make sure we have the medicines needed to deal with public health emergencies”, said Janez Poklukar, the Slovenian minister for health.

The revision of EMA mandate is part of the broader activities announced by the EU Commission in November 2020 to achieve the European Health Union; these also include the reinforcement of the European Centre for Disease Prevention and Control and a draft law on cross-border health threats. The establishment of the new Health Emergency Preparedness and Response Authority (HERA), announced in September 2021, is also part of the package. The draft agreement shall now be endorsed both by the Council and the Parliament before entering into force.

Three new key targets for EMA

The draft agreement reached by the Council and Parliament negotiators focuses on three main areas. The first one refers to the definition of a major event and how to recognise it: these shall be events likely to pose a serious risk to public health in relation to medicinal products, as acknowledged by a positive opinion from the Medicines Shortages Steering Group, and which may trigger specific actions such as the adoption of a list of critical medicinal products to fight the health threat.

Solid funding from the Union budget shall be also provided to EMA in order to support the work of the new steering groups, task force, working parties and expert panels. The availability of provisions for adequate data protection is important to guarantee the full compliance to the GDPR regulation and other EU data protection rules, and the safe transfer of personal data relevant to EMA’s activities (e.g. data from clinical trials).

EMA shall play an improved role in the monitoring and management of shortages of medicines and medical devices, a critical activity for the availability of the products needed during public health emergencies. Other points of the agreement include the timely development of high-quality, safe and efficacious medicinal products, and the creation of a new EMA’s structure specific for expert panels in charge of the assessment of high-risk medical devices and of essential advice on crisis preparedness and management.

How to tackle shortages of medicines

According to the EU Parliament, two “shortages steering groups” (for medicines and medical devices, respectively) shall be created by EMA; if needed, these groups may also include expert advice from relevant stakeholders (e.g. patients and medical professionals, marketing authorization holders, wholesale distributors, etc.).

Parliament negotiators highlighted the importance to achieve a high transparency of the process, including avoidance of interests related to industry sectors for members of the two groups; summaries of the proceedings and recommendations shall be also made publicly available.

A European Shortages Monitoring Platform shall be created by EMA to facilitate the collection of information on shortages, supply and demand of medicinal products; a public webpage with information on shortages of critical medicines and medical devices shall be also made available.

As already occurred during the Covid pandemic, future public health emergencies may boost the development of new medicines and medical devices. Sponsors of clinical trials conducted during health emergencies will be required to make the study protocol publicly available in the EU clinical trials register at the start of the trial, as well as a summary of the results. Following the granting of the marketing authorisation, EMA will also publish product information with details of the conditions of use and clinical data received (e.g. anonymised personal data and no commercially confidential information).

With this agreement, Parliament makes both the Agency and all actors in the supply chain more transparent, involving them more in the process and fostering synergies between EU agencies. Moreover, we pave the way to promoting clinical trials for the development of vaccines and treatments, boosting transparency on those issues. In short, more transparency, more participation, more coordination, more effective monitoring and more prevention”, said Rapporteur Nicolás González Casares (S&D, ES).

EMA’s pilot project for the repurposing of medicines

The repurposing of already approved and marketed medicines is another key action put in place to ensure improved response capacity in case of future health emergencies.

A new pilot project to support the repurposing of off-patent medicines has been launched by EMA and the Heads of Medicines Agencies (HMA), with special focus on not-for-profit organisations and the academia as the main actors to carry out research activities needed to support the regulatory submission for the new indication. The initiative follows the outcomes reached by the European Commission’s Expert Group on Safe and Timely Access to Medicines for Patients (STAMP).

Interested sponsors may access EMA’s specific scientific advice upon submission of the drug repurposing submission form to the e-mail address [email protected] by 28 February 2022. More information is available in a Question-and-Answer document. The pilot will last until scientific advice for the selected repurposing candidate projects; filing of an application by a pharmaceutical company for the new indication is another target. Final results of the project will be published by EMA.

Comments from the industry

The European Federation of Pharmaceutical Industry Associations (EFPIA) welcomed the proposed framework for the repurposing of authorised medicines. “This pilot launch comes at a timely moment to test whether a streamlined and more transparent regulatory pathway for repurposing of off-patent established products increases the chances of including existing scientific evidence into regulatory assessment. One of the goals of the pilot is to raise awareness regarding the standards required for regulatory-ready evidence on the road to further increase availability of authorised therapeutic use”, said the chair of EFPIA’s Regulatory Strategy Committee Alan Morrison.

Innovation on existing, well-known molecules through repurposing can deliver huge benefits for patients, according to Medicines for Europe. The Association of the generic and biosimilar industry supports the pilot project as a way to generate robust data packages and to translate research into access for patients. A sustainable innovation ecosystem for off-patent medicine is the expected final outcome, possibly including also reformulation of existing medicines, new strengths or adaptation for specific patient groups (i.e. paediatric populations). “These investments must also be recognised in pricing and reimbursement policies to make access a reality for all patients”, writes Medicines for Europe.


IMP manufacturing in the era of the clinical trial regulation 536/14

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The next EIPG’s and PIER’s webinar to be held on Thursday 18th November 2021 (17.00 CET) will be chaired and the subject introduced by Irene Gonzales-Conde, Board Member of AEFI (Spanish Association of Industrial Pharmacists).

The main speaker, Luciano Gambini has spent most of his working life in global R&D quality assurance, setting up internal policies for the quality of Investigational Medicinal Products (IMPs). He is the coordinator of the AFI (Italian Association of Industrial Pharmacists) working group on manufacture of IMPs.

There has been extensive debate about the Clinical Trial Regulation which finally enters into force on 31st January 2022. However, little has been discussed about manufacture of the IMPs. The aim of this webinar is to raise questions and provide preliminary answers to any differences between the current and new manufacturing and labelling requirements.

This is an event for members of EIPG member organisations. Contact your national association EIPG representative for further information.