real-world evidence Archives - European Industrial Pharmacists Group (EIPG)

The EU Parliament voted its position on the Unitary SPC


by Giuliana Miglierini The intersecting pathways of revision of the pharmaceutical and intellectual property legislations recently marked the adoption of the EU Parliament’s position on the new unitary Supplementary Protection Certificate (SPC) system, parallel to the recast of the current Read more

Reform of pharma legislation: the debate on regulatory data protection


by Giuliana Miglierini As the definition of the final contents of many new pieces of the overall revision of the pharmaceutical legislation is approaching, many voices commented the possible impact the new scheme for regulatory data protection (RDP) may have Read more

Environmental sustainability: the EIPG perspective


Piero Iamartino Although the impact of medicines on the environment has been highlighted since the 70s of the last century with the emergence of the first reports of pollution in surface waters, it is only since the beginning of the 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.


Review of the pharmaceutical legislation, the proposals of the industrial associations

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By Giuliana Miglierini

The Staff Working Document on “Vulnerabilities of the global supply chains of medicines” published by the European Commission on 17 October 2022 identified several issues related to the current, often difficult situation experienced by pharmaceutical supply chains. Among these are the increasing complexity and specialisation, challenges linked to the production process and technologies, the lack of geographical diversification and other dependencies, the need to unlock the potential of data to improve supply and demand predictability, and a perceived regulatory complexity.

The same issues have been widely debated under different perspectives during recent months as a possible contribution to the current revision of the pharmaceutical legislation, a major goal of the EU Commission’s Pharmaceutical Strategy for Europe together with the New Industrial Strategy for Europe.

The structured dialogue with stakeholders has been the tool chosen to facilitate the interaction and exchange of opinions in order to optimise the development and implementation of the new pieces of legislation. We resume some of the latest proposals arising from the main industrial associations on how to better achieve this very challenging objective.

EFPIA proposals for action

In November 2022, the European Federation of Pharmaceutical Industry Associations published a report to illustrate its proposals for action to tackle shortages of medicines and to improve the efficiency and robustness of the supply chain.

Five key principles form the basis of nine operative proposals. A standard definition of a shortage and an interoperable IT European monitoring/notification system would be needed in order to build a harmonised EU prevention and mitigation system. Epidemiological data are deemed essential to better analyse patient demand, so to improve transparency in the overall supply chain by means of the European Medicines Verification System (EMVS). Targeted shortage prevention plans (SPP) should be developed to prevent the risk of shortages for critical products and to manage safety stocks on a risk-based approach. Regulatory mitigation measures for shortages would also be of help in improving flexibility. At the global level, the maintenance of global open supply chains should be the goal, supported by the strong existing EU manufacturing and R&D footprint, and where appropriate, targeted incentives for the diversification of supply chains.

The current revision of EU pharmaceutical legislation is a golden opportunity to reverse the trends of the last 25 years. It is our once-in-a-generation chance to reinvent the regulatory framework to ensure we have a modern approach that matches our ambition to be a hub of medical innovation”, writes EFPIA’s director general Nathalie Moll in a recent post, published on the association’s website.

In its Regulatory roadmap to Innovation of January 2023, EFPIA focused on how to achieve a more agile and streamlined regulatory framework, so to shorten the period needed for approval of a new active substance (currently 426 days, vs 244 days in the USA, 306 in Canada, 313 in Japan or 315 in Australia). Innovative approaches to clinical trials, including complex clinical trials (CCTs) and decentralised trials (DCTs), and the development of clear guidance on the use and regulatory acceptance of real-world data (RWD) and real-world evidence (RWE) are among the eight areas of possible immediate actions identified by EFPIA.

A dynamic regulatory assessment pathway based on early and iterative dialogue on data, international data standards and technology, and cloud-based submission modalities would support EMA and HTAs in accepting iterative data generation as part of the evaluation procedures.

As for drug-device combinations and in-vitro diagnostics, EFPIA suggests adopting an integrated EU pathway for the assessment, including the possibility for parallel advice with Notified Bodies. A clearer definition of unmet medical need would also be needed, as well as the full digitalisation of regulatory processes. A common definition of shortage coupled to the setting up of a European reporting system (possibly the already existing EMVS) would support the collection of real-time information and activation of alerts. Epidemiological data should be elaborated and released by the European Centre for Disease Control (ECDC).

The Variation Regulation is also under review by the EU Commission. EFPIA’s proposal is to incorporate the considerations for pharmaceutical product lifecycle management set forth by the ICH Q12 guideline, and to develop a vaccine-specific annex to the Variation guideline.

EFPIA also identified four areas requiring legislative change to accelerate pharmaceutical innovation in Europe. These include the possibility to redesign EMA’s committee structure in order to speed up the efficiency of regulatory assessment and decision-making process from EMA approval to EC decision.

Expedited regulatory pathways (ERP) are still of limited use in the EU, according to EFPIA. The suggestion is to embed the PRIME scheme in the new legislation to ensure its optimal use and allocation of sufficient resources. The creation of a new legal category for drug-device combination products, to be regulated as medicinal products, would also accelerate the approval of this increasingly important type of therapeutic option.

The transition from paper leaflets to electronic product information (ePI) should be also supported within the new pharmaceutical legislation, while considering the still present difficulties that may be experienced by elders and people not having access to computers or mobile devices. A new, centralised ePI repository/database would also be needed.

Medicines for Europe, focus on access and prevention of shortages

The 2022 of Medicines for Europe (MfE), representing the generic, biosimilar and value-added medicines industry, focused its lobbying activities mainly on access to medicines and prevention/ mitigation of shortages.

The economic and geopolitical crisis highly impacted the sector, which suffers strict price caps requirements in market policies. In a recent letter to the EU institutions, Medicines for Europe highlights the possible link between the shortages of amoxicillin and amoxiclav antibiotics and the low pricing and procurement policies in place in many EU member states.

There are significant risks of more medicine shortages in 2023”, writes the association, which may be tackled by concrete policy reforms and industry commitments.

The economic model for generic medicines in Europe is identified as the structural root cause of shortages, requiring manufacturers to run their plants at the maximum capacity in order to “remain profitable as GMP rules require continuous investment in manufacturing plant upgrades”. This leaves little space to accommodate requests for increased production in order to face shortages. Other measures that, for MfE, impacted on the consolidation of supply chains and generic markets include the requests set forth by the Falsified medicines directive, as well as the Brexit, the Covid emergency and the current war scenarios.

The letter also identifies some possible short- and medium-term measures useful to mitigate the risk of shortages and improve the efficiency of the generic’s supply chains.

The first ones include the request for more regulatory flexibility for packaging, to facilitate the distribution of the available products in different member states. Clearer thresholds for nitrosamines and the need to avoid new regulations that may have a disproportionate impact on low margin medicines are also suggested. A better dialogue on immediate measures to tackle the cost of inflation on generic medicines would also be beneficial, says MfE, which also agrees on the need to better estimate demand surges on the basis of available data and epidemiological analysis.

The association of the generic and biosimilar industry shares also the importance of a rapid digitalisation of the medicines regulatory network in order to fully exploit the potential of big data. On the medium-term (2025), this may prove important to achieve objective related to the implementation of the ePI, the reduction of variations, the management of API sources, the harmonisation of packs and a better handling of requirements at national level.

Suggested actions at the legislative level include the introduction of legal guidance on the implementation of the criteria established by the Public Procurement Directive. The Transparency Directive may take example from Canada, where prices for generics varies according to the variation of the demand. A Medicine Security Act might represent the legislative tool to support investments in manufacturing diversification and greener technologies.

MfE also highlights some threats resulting from political choices such as national stockpiling requirements, that can increase costs and reduce cross-country solidarity. A preferred approach would be that of the European strategic reserve concept, based on rolling reserves. The real usefulness of joint procurement should also be better evaluated, especially with reference to OTC and other medicines directly dispensed by community pharmacies.

A note published in November 2022 focused on the still greatly unused potential of value-added medicines, a sector which according to MfE may benefit by a re-evaluation of the current innovation model, leading to a increased attention to the entire lifecycle of a medicine and on off-patent molecules. The request to the EU Commission is to fully acknowledge value added medicines in the EU pharmaceutical legislation as a separate group of medicines, with its own dedicated regulatory pathway and proportionate data exclusivity incentives.

The vision of the ATMP sector

The vision of the advanced therapies (ATMPs) sector, represented by the Alliance for Regenerative Medice (ARM), was illustrated in an event held in November 2022 at the European Parliament.

The declining competitiveness of the EU and how to ensure patients’ access to transformative treatments have been subjects of the debate. Many of the newly approved treatments fall under the ATMP categories of medicinal products (cell and gene therapies, tissue therapies), that according to ARM would require a better suited policy and regulatory framework to fully exploit their potential. “The same policies and approaches that brought us yesterday’s biomedical innovation simply will not work for the cell and gene therapies of today and tomorrow. The EU has led before — and can lead once again — but the time to act is now.” said Timothy D. Hunt, chief executive officer of ARM.

According to data by ARM, the number of ongoing industry clinical trials in Europe involving ATMPs is increasing very slowly (just 2% at the end of June 2022). More in detail, only one phase 1 study was initiated in Europe in the first half of 2022, says the association, and the region accounted for just 11% of new trials involving ATMPs and started in the same period. Many EU’s approved advanced therapies are also suffering, with 23 ATMPs withdrawn from the market. The reduced interest of the sector towards Europe is also acknowledged by the declining number of developers headquarters (-2% vs the previous five years): a trend opposite to that of North America and, especially, the Asia-Pacific region



A new joint work plan to 2023 for EMA and EUnetHTA 21

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by Giuliana Miglierini

The new Regulation (EU) 2021/228 on Health Technology Assessment (HTA) will assume full validity in January 2025, at the end of the 3-year transition period. To this instance, it is time to define the actions needed to establish the new framework for HTA in the field of medicinal products.

A central point of the new approach is represented by joint scientific consultations (JSCs) to be carried out in coordination between the European Medicines Agency (EMA) and the bodies entitled of HTA at the level of single member states.

After the termination of the European Network for Health Technology Assessment (EUnetHTA) initiative, in 2021, the new consortium EUnetHTA 21 has been created grouping thirteen HTA agencies from The Netherlands, Spain, Italy, Austria, Germany, France, Portugal, Belgium, Ireland, Hungary and Norway. EUnetHTA 21 signed a contract service in 2021 with the Health and Digital Executive Agency (HaDEA) for the provision of joint health technology assessment up to September 2023.

On this basis, EMA and EUnetHTA 21 have now published a joint work plan of the activities to be put in place until 2023; the initiative represents the continuation of the EUnetHTA Joint Actions, started in 2010 and concluded in May 2021.

The document identifies the priority areas of future collaboration between regulators and HTA bodies at European level, with the final goal to “improve efficiency and quality of processes, whilst respecting the respective remits of different decision makers, and ensure mutual understanding and dialogue on evidence needs”.

The transition to the new legislative framework shall be based on a flexible approach to the different tasks; the work plan includes both methodological and operative actions, and it will be monitored in close cooperation with the EU Commission. Progresses will be discussed during the four bilateral meetings planned until September 2023.

Under the new framework, high priority HTA activities related to the service contract will be delivered by EUnetHTA 21. Other voluntary activities can be actioned through individual HTA bodies from a European (EU/EEA) member state that expressed their interest to participate. Should this be the case, the work plan clarifies that the position is that of the individual HTA body, not of EUnetHTA 21. A public consultation on deliverables part of the EUnetHTA’s mandate is also planned.

Actions in support of JSCs

Joint scientific consultations are the core of the new approach to HTA, aimed to generate a robust evidence relative to the entire life cycle of medicinal products, including the post-licensing and launch.

The work plan establishes a new European process of “parallel joint scientific consultation” involving both HTA bodies and EMA, that will take the place of the current procedures of parallel scientific advice, parallel consultation and early dialogue. This action shall make available a single assessment process, reflecting both regulatory and HTA’s needs.

Interested parties can apply to access the EMA/EUnetHTA parallel JSC procedure; a joint guidance on how to apply and the dates of EMA’s Scientific Advice Working Party (SAWP) meetings are available at the dedicated page of the Agency’s website, together with the template of the parallel consultation briefing document and submission deadlines. The joint guideline also provides details for applicants on how to respond to a EUnetHTA 21 open call for joint scientific consultation.

Exchange of information

The setting up of the JSC procedure includes the optimisation of the use of registries to facilitate post-licensing evidence generation (PLEG) and/or launch evidence to support decision making. To this instance, and depending on the specific products selected during the JSC, advice may be provided on requirements for data collection and analysis of disease registries in the context of development plans, or for qualification of registries in disease areas of particular mutual interest (including advanced therapies, ATMPs).

This exchange of information between EMA and EUnetHTA 21 may lead to discussions in order to monitor progress in the identification of PLEG. Under this action, a voluntary pilot might be activated to explore the feasibility of earlier engagement with an HTA agency during regulatory assessment, including evidence sharing and managing of uncertainties. A main outcome of this area of cooperation shall see the initial drafting of the rules for the exchange of information on the preparation and update of joint clinical assessment of medicinal products.

Capturing patient relevant data and information

The ability to generate patient relevant data and information is key to support the process of decision making. The joint work plan aims to develop new methodologies to improve reliance of patient relevant data. To this instance, the cooperation with EUnetHTA is expected to contribute to EMA’s initiative to establish an EU network of experts on Patient Reported Outcomes (PROs). The work plan also includes voluntary actions focused on the discussion and exchange of relevant data in bilateral meetings, in parallel with the development of the respective guidelines, and a workshop on patient experience data planned in June 2022.

The work plan shall also favour a better engagement of patients and healthcare professionals in areas of mutual interest. To this regard, EMA and EUnetHTA 21 will share their best practices as for compensation for expert participation and how to incorporate the input received in regulatory and HTA deliverables.

Preparedness for future challenges

The need to better understand challenges arising from the development of innovative treatments will benefit the sharing of horizon scanning activities between EMA and EUnetHTA 21. This may include, on a voluntary basis, joint discussions on data requirements and preparative measures relative to high-impact innovative medicines for patients with high unmet needs. Other voluntary activities by individual HTA bodies may focus on the optimisation of regulatory assessment reports in order to facilitate the uptake of their outcomes as part of the HTA process. Sharing of experience and guidance on the optimisation of information on subpopulations (e.g. labelling and EPARs) may also be considered, as well as the improvement of Orphan Medicines Assessment Reports (OMARs). Under the methodological perspective needed to make real-world evidence more available, a main goal of the plan shall achieve HTA representation in the advisory board of Darwin EU, the Data Analysis and Real World Interrogation Network established and coordinated by EMA to provide timely and reliable evidence on the use, safety and effectiveness of medicines for human use from real-world healthcare databases across the EU.

Other voluntary activities in this area may include multi-stakeholder discussions aimed to optimise the design, quality and utilisation of disease registries and the training on new guidance on registry-based studies. Joint methodological work may be also carried out to identify key concepts supporting the acceptance of extrapolation and/or evidence transfer, and to share best practices and experiences in the field of the integrated assessment of companion diagnostics, or other diagnostics for targeting therapeutics not directly related to the use of specific medicines.