regulatory flexibility Archives - European Industrial Pharmacists Group (EIPG)

The risk of a biosimilar void in Europe


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

The drug shortage situation - EIPG's point of view


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

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


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

EMA’s recommendations to prevent medicines shortages

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By Giuliana Miglierini

Continuity of medicinal product supply is still representing a key issue for European countries. The HMA/EMA Task Force on the Availability of Authorised Medicines for Human and Veterinary Use has published a new guidance document in the form of recommendations for the industry on best practices to be adopted to prevent shortages of human medicines.

The recommendations are targeted at marketing authorisation holders (MAHs), wholesalers, distributors and manufacturers. The specific role of each actor is detailed, and highlights are provided on how to optimally approach the prevention and mitigation of shortages. The document refers to the harmonised definition of shortage agreed by EMA and HMA, i.e. “A shortage of a medicinal product for human or veterinary use occurs when supply does not meet demand at a national level“.

Different players for different roles

The pharmaceutical supply chain is characterised by many different actors, each of which plays a specific role in the development, manufacturing and distribution of medicinal products.

Marketing authorisation holders are the ultimate responsible for the monitoring of all activities needed to timely produce and distribute their products. This means MAHs should oversight the entire supply chain, from suppliers of active ingredients (APIs) to end users, in order to continually align demand with supply, evaluate the actual impact of a shortage, and establish the more suitable prevention or mitigation strategies. According to the guidance, reference should be made to the “ISPE Drug shortages prevention plan – Holistic view from root cause to prevention” in order to build a suitable quality culture integrated into product lifecycle; compliance to ICH Q10 is also recommended.

Manufacturers include both APIs suppliers and producers of the medicinal product, which should possess a in depth knowledge of their processes and issues that may impact on product availability. This is even more true for contract manufacturing organisations (CMOs), as a problem with their manufacturing capacity may impact many different customers. Wholesale distributors have general visibility of stock levels and product flow and can identify early signals of a potential medicine shortage. They are subject to national laws as for their obligations to ensure continuity of supply to patients.

As for institutions, national competent authorities (NCAs) are responsible for the coordination of the response to a shortage by means of regulatory tools and strategies. Existing regulatory flexibility can be used, while NCAs cannot intervene in pricing, sourcing, and clinical practice. NCAs are also responsible to communicate actual shortages from their websites.

EMA’s responsibilities relate to shortages of centrally authorised products and coordination of the EU response to supply issues due to major events or public health emergencies. The Agency is also responsible for the publication of a public catalogue for shortages assessed by the CHMP and/or PRAC committees, and for the publication of information on critical shortages monitored at EU level.

National health service providers are responsible for the setting up of policy and operational aspects needed to guarantee the timely access to medicines (i.e. reimbursement schemes, purchasing arrangements, clinical guidelines, etc.). In case of a shortage, they are called to indicate available alternatives, and to issue specific clinical guidance for healthcare professionals if needed.

The overall sustainability and accountability of health systems is the major goal for national Ministries of Health, to be tackled by mean of legislative initiatives. End users include healthcare professionals responsible for appropriate prescribing and for the identification of available alternatives in the case of a shortage affecting their patients. Timely information to patients, in particular for specific diseases, may be provided by patients representative groups, which may also collect feedback on the impact of shortages for patients.

Ten recommendations to prevent shortages

The guidance highlights the importance to notify as soon as possible to NCAs any potential or actual shortage, in order to timely face the increased demand for alternative product suppliers. To this instance, MAHs and wholesalers are in the best position to monitor available stocks and report at early stages about possible issues.

An improved transparency would be needed as for the provided shortage information, to avoid patients’ concerns and the consequent risk of stockpiling and to avoid duplication of efforts. To this instance, MAHs are called to provide all available information requested by the notification form, including also multi-country information (e.g. related to API suppliers).

MAHs should also have a shortage prevention plan in place, addressing the entire life cycle of the specific product from sourcing of raw materials to manufacturing capacity and distribution. Wholesale distributors are also called to develop similar plans focusing on their specific role. Prevention plans should include an analysis of vulnerabilities and risks of interruption of supply, the assessment of the robustness of the supply chain arrangements and controls as well as of the need of revalidation, and the availability of a medicine shortage risk register to identify products of clinical importance by therapeutic use and availability of alternatives.

MAHs and wholesalers should also have a shortage management plan to be activated in case of issues with the availability of a certain product. To this instance, the capacity of available alternative manufacturing sites is critical, including CMOs which should always be kept timely informed by MAHs. A possible approach suggested by the guidance sees the development of a dashboard to continuously monitor signals for potential supply disruption. Procedures to identify true shortage points would also be needed to overcome the current limitation of the automated order systems.

The punctual implementation of Pharmaceutical Quality System according to ICH Q10 and ICH Q12 is also deemed fundamental to prevent any delay related to regulatory procedures that may impact on product availability. Product quality reviews (PQRs) are suggested as a possible tool to capture appropriate data and trends for continuous improvement.

The overall resilience of the supply chain should be supported by the justification of the adoption of the just-in-time supply model, particularly when limited alternatives are available. MAHs and wholesalers should guarantee the availability of suitable contingency stocks to face any unexpected delay.

Sub-optimal communication among different stakeholders should be also addressed by means of an improved cooperation, including a two-way communication system extending also to potential or actual shortages. Critical points of attention are identified in the intra-company communication between different departments, those between local MAH representatives and manufacturer, and the availability of information on stock levels to entities entitled to supply medicines to the public via ordering portals. Specific criteria for communication, together with the description of key processes and supply chain maps should be developed by each stakeholder.

Stockpiling is another critical practice to be avoided in order to ensure the fair and timely distribution of medicines. To this instance, healthcare professionals are called not to order or dispense more stock than normal in case of shortage, while MAH stock allocation practices between different countries should also take into account the clinical need of patients, and not just economic factors. Parallel trade should be also avoided as far as possible. NCAs should duly justify any decision to limit this practice, while companies should seek advice from their relevant authorities of the exporting country in case of critical shortages.


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.


The EU Commission proposal of the new pharmaceutical legislation

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By Giuliana Miglierini

After a five-months delay, the European Commission has announced on 26 April 2023 its proposal for the revision of the European pharmaceutical legislation. The package is comprehensive of a Directive governing authorisations and other regulatory procedures, and a Regulation focused on central authorisation procedures. A Council Recommendation on antimicrobial resistance is also included. The entire reform package shall now undergo the scrutiny of both the European Parliament and Council in order to gain final approval and adoption.

In this first article, we will resume the main features of this highly complex reform, leaving to following posts a more detailed discussion of the single lines of intervention.

The experienced delays acknowledge of the many difficulties encountered by the Commission in reaching a balance between forces representing different perspectives within the pharmaceutical sector. Among the main areas of debate was the exclusivity protection: an issue not yet re-solved, judging from the first reactions from industrial associations, and that should be addressed during the incoming negotiations at the EU Parliament and Council.

A single market for medicines

Central to the entire reform package is the creation of a single European market for medicines, aimed to facilitate the fair and rapid access to patients of all member states. Regulatory procedures for approval of generic and biosimilar medicines should be simplified. Patients are also expected to benefit from more innovative medicines, thanks to a wide array of incentives, and from the repurposing of products already on the market.

Patient centricity should also address rare diseases and new therapeutic options for paediatric patients, including the creation of a EU network of representatives of patients associations, academics, developers and investigators. Patient representatives should be appointed to the EMA Committees, and thus involved in the approval of new medicines. A more extensive use of electronic Product Information is expected to facilitate access to updated information, while reducing costs for manufacturers.

A greater transparency on public funding for R&D should better support price negotiations with national authorities, so to make medicines more affordable to patients.

The long lasting issue of medicines shortages should be tackled from different perspectives. Pharmaceutical companies should be responsible for the emission of earlier warnings on shortages and withdrawals, and for the establishment of prevention plans. European authorities should create a list of critical medicines, to be used to identify supply chain vulnerabilities and improve security of supply. National and central competent authorities are called to a better monitoring of shortages, while EMA should play a stronger guiding role on security of supply.

The One Health approach should inspire actions to improve the environmental sustainability of medicines. From this perspective, the proposed reform includes a strengthened environmental risk assessment for all medicines, including those already on the market. Actions to improve environmentally friendly production technologies and to reduce the release of drugs into the environment are also considered.

Actions supporting innovation

The reform package completely redesigns the duration of regulatory protection, reducing the standard length to 8 years (6 years of data protection + 2 years of market protection), but offering a wide range of incentives to reach a cumulative maximum of up to 12 years of protection. The true novelty is the 2-year incentive for companies launching a new product in all EU markets at the same time. Other incentives are targeted to unmet medical needs (6 months), comparative clinical trials (6 months), and for a new indication to treat another disease (1 year).

The standard market exclusivity should reach 9 years for medicines for rare diseases. In this case too, a wide range of incentives may extend protection to up to 13 years.

The Transferable data exclusivity voucher is the tool identified to support the development of new antimicrobial medicines: the voucher would be transferred to another of the company’s products, extending its protection by 1 year. The Commission plans to issue no more than 10 vouchers over a 15 year period, under strict conditions, so to limit the impact of the measure on healthcare systems. Reshoring of pharmaceutical productions and EU’s strategic autonomy are not included in the reform. A number of other actions are ongoing to support specific lines of intervention, i.e. the EU FAB flexible manufacturing network of vaccines producers, HERA’s Joint Industrial Cooperation Forum on vulnerabilities along the supply chain, and the Important Project of Common European Interest on Health to allocate state aid to support for innovative EU projects.

A more flexible regulatory framework

A higher regulatory flexibility should support fast approval of medicines. Regulatory assessment for centralised procedures should shorten to 180 days (from the current 210); the time should be reduced further to 150 days for products needed for health emergencies.

Simplification of procedures will include full electronic submission of applications. Rolling re-views and temporary emergency marketing authorisations at the EU level for public health emergencies will fully enter the set of available procedures. Simplification should also include the abolishing of the marketing authorisation renewal in most cases.

A reform of EMA’s Committees is also envisaged: only the Committee for Human medicinal pro-ducts (CHMP) and the Safety Committee (PRAC) should continue to exist, while the orphan, paediatric and ATMP committees would be abolished.

Generic and biosimilar medicines shall also benefit from simpler rules for approval, while regulatory sandboxes are the tool to support testing of particularly new and innovative therapies. These may also benefit of additional early scientific advice and regulatory support by EMA, particularly for unmet needs. Dedicated pathways are also planned to support repurposing, especially for SMEs and not-for-profit organisations.

Clinical development may be improved thanks to a wider use of adaptive clinical trials, real world evidence and health data. The reform is also expected to make easier the interaction with other relevant healthcare frameworks, e.g. for medical devices and health technology assessment.

The first comments from interested parties

A very negative opinion on the proposed reform has been issued by the European Federation of Pharmaceutical Industrial Associations (EFPIA), representing the innovator industry.

Unfortunately, today’s proposal manages to undermine research and development in Europe while failing to address access to medicines for patients”, said EFPIA’s Director General Nathalie Moll. The main point of criticism is the 2-year incentive for the contemporary launch of a new medicine in all 27 member states, that for EFPIA would represent an impossible target for companies. According to President Hubertus von Baumbach, “the ‘net’ impact of policies set out across these proposals, in their current form, puts European competitiveness at risk: overall, it weakens the attractiveness for investment in innovation and hampers European science, research and development”. A comprehensive competitiveness checks on the impact of the revised pharmaceutical legislation is EFPIA’s request.

The Association also published a series of reports supporting its vision on the availability of new medicines throughout Europe, as its first action to stimulate the debate in view of the assessment of the proposal by the EU Council and Parliament.

We strongly support the proposal’s intention to stop the well documented patent games manship and evergreening and the adaptation of incentives to necessary equity of access across the EU. Moreover, there should not be an accumulation of regulatory incentives that would extend the regulatory data protection period beyond the existing system (8 years) which is already the longest in the world. Regarding AMR, the Commission proposal for a reserve fund is the correct alternative to transferable vouchers and most efficient policy to protect against future risks”, wrote in a note Medicines for Europe, representing the generic, biosimilar and value added medicines industry. “The central role of the off-patent medicines industry for the patient is clearly reflected in the intentions of the draft legislation. We are still lacking an industrial strategy to strengthen the European off- patent sector and improve open strategic autonomy in health”, said Medicines for Europe President Elisabeth Stampa.

EuropaBio, on behalf of the biotech sector, welcomed the provisions improving the EU’s regulatory framework and promoting novel technologies. In this case too, the main concern is the proposed new set of incentives, that according to EuropaBio may undermine the predictability and stability of the European landscape for innovation. “It is essential that EU policies meaningfully improve patient access to medicines across the EU without undermining the EU’s attractiveness for life science investments”, said EuropaBio Healthcare Public Affairs Director Vlad Olteanu.

AESGP supports the revision of the EU pharmaceutical legislation in principle. While we welcome the regulatory simplifications introduced by the revision, we are voicing some concerns on behalf of non-prescription medicines manufacturers that may have unintended negative consequences”, said Jurate Svarcaite, AESGP Director General. The Association resumed its worries in a statement published in its site.

These include the proposed two new prescription criteria for antimicrobial products and medicines containing an active substance which may have an environmental impact. As for incentives, according to AESGP a longer data exclusivity period (3 years instead of 1) should be considered in cases where new, pivotal evidence is generated, for switching from prescription to non-prescription status. Other points of concern refer to how environmental risks for medicines are to be assessed. “Decisions to minimise the environmental impact should always lead to proportional risk mitigation measures and never interfere with clinical priorities and benefit/ risk assessments that ensure EU citizens get access to the healthcare products they need”, wrote AESGP.

Improvement to the Commission’s proposal would also be needed with regard to the adoption of electronic Product Information, where a phased and harmonised approach to digitalisation is suggested. A better definition of real-world evidence/data would also be needed. As for shortages, mitigation measures should be proportionate and aimed at the critical medicines that do not have alternatives and have concentrated supply chains. AESGP supports the extension of the proposed approach to Risk Management Plans exemption also to medicinal products of well-established use, as for generics and biosimilars.

We appreciate the proposals aimed at streamlining and digitalising regulatory procedures, yet we are concerned that other provisions will undermine R&D, innovation, and EU competitiveness. These will be especially detrimental to the small and mid-sized innovative companies that Eucope represents. The proposal introduces more risk and unpredictability into the system while reducing incentives for innovation and investment, which will negatively impact patient access”, wrote the association in its comments to the proposal of reform.

The Commission’s revision includes troubling proposals, such as the introduction of (High) Unmet Medical Need, which risk reducing the EU’s global competitiveness in life sciences, thereby limiting the development and availability of innovative therapies”, said Eucope Secretary General Alexander Natz.


Current inspection trends and new approaches to the monitoring of post-inspection activities

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by Giuliana Miglierini

The European Federation of Pharmaceutical Industries and Associations (EFPIA) has published its Annual Regulatory GMP/GDP Inspection Survey 2021, highlighting the more recent trends in inspections and how the pandemic affected this critical verification process of pharmaceutical productions. Meanwhile, UK’s regulatory authority MHRA launched the Compliance Monitor Process pilot, aimed to use eligible consultants as Compliance Monitors to supervise companies in the delivery of actions identified in the Compliance Protocol agreed with the regulatory authority.

Main trends in inspections

The main effect of the lockdowns has been the implementation of new ways to run inspections. The recommendation resulting from EFPIA’s report is now for virtual tools combined with onsite presence; to this instance, data gathered in 2021 show that the two modalities of inspection have a similar duration (2.9 days for on-site inspections vs 2.8 days for virtual ones). The report also indicates there is still a backlog of inspections due in 2020, the critical period of the pandemic; suggestions to manage expiring GMP/GDP/ISO-certificates include a one-year prolongation of current certificates, a dedicated communication process between the industry and regulators in the case of issues with the registration in third countries, and a planning of inspections based on the quality history of the site.

Domestic inspections confirming the trend observed since 2016, are almost double of the number of foreign inspections. These last ones focused in 2021 on only 23 countries, compared to the 44 countries visited by inspectors in 2017. EU’s countries were the most visited ones, with some 350 inspections reported vs the 150 of US, confirming the importance of European pharmaceutical manufacturing. According to the report, 2021 saw an increased attention to GDP inspections, while the percentage of sites with no inspections remains stable for six years.

A new mix of inspection tools

The use of new tools, additional to physical on-site presence, has now become a routine possibility accepted by many regulatory authorities. Many different approaches have been tested during the pandemic, including different inspections tools. Different combinations of tools cannot be considered to be equivalent, according to EFPIA. In general, a mixture of physical presence, document review and virtual presence flanked by the sharing of experience, collaboration and reliance is deemed suitable to confirm compliance and capability while supporting a risk-based efficiency.

Data show that the number of virtual inspections was higher in 2020 compared to 2021; the last year saw an increase of on-site presence vs 2020 and a mixture of virtual and on-site inspections. According to the report, only seven European countries have experience with the implementation of virtual inspection tools (Germany, Denmark, Finland, Ireland, Italy, Poland and Sweden). As a consequence, the impact of mixed virtual and on-site domestic inspections in 2021 was lower in EU member states that, for example, in the US, Brazil, Russia and Singapore.

There is still space for improvement

EFPIA’s survey presents the respective advantages and disadvantages of on-site inspections vs virtual tools. The implementation of the new modalities is far from being accomplished, the process is still on the learning curve, says the document.

While the remote, virtual interaction allows for a greater flexibility of the inspection process, it may result stressful for some people; furthermore, it impacts on the way work is organised, as it needs a flexible schedule and time to prepare for the next day meetings. Also, the style of communication changes to become less natural and more focused. Overall, virtual inspections appear to be more efficient when performed in real-time, as it would be for on-site inspections. While being less costly, due to avoiding extensive travelling, virtual inspections require a careful preparation, including the availability of a suitable IT infrastructure and connectivity. Documents are also often required in advance of the meetings to be shared with regulators.

How to further improve inspections

According to EFPIA, the future of inspections calls for improved collaboration and reliance in order to increase the knowledge shared by the different inspectorates and overcome the limits intrinsic to self-dependency. The expected final outcome of the new approach to inspections is an improvement in the decision-making process. Inspection frequency may be set every 1 to 5 years on the basis of a risk-based evaluation.

Collaboration, reliance and delegation appear to be the new mantras to guide the actions of regulators: the focus suggested by EFPIA is on inspections run by domestic authorities, coupled to the implementation of Mutual Recognition Agreements (MRA) to avoid duplication of efforts. According to the report, it would be needed to harmonise the scope of existing MRAs and to establish new ones between the EU and PIC/S participating authorities (e.g. Argentina, Brazil, South Korea, Turkey and UK). The European legislation should be also updated to include the concept of listed third countries, as already in place for the importation of active substances under the provisions of the Falsified Medicines directive.

The report also suggests a qualitative tool that would fulfil the legal requirements for “inspections” and may prove useful to support inspection planning on the basis of the knowledge of the GMP compliance history of the site, the footprint history of critical and major deficiencies and the type of inspection to be run. These elements lead to the identification of the hazards to be considered, including the intrinsic risk and the compliance-related one. The final output of the tool takes the form of a risk-ranking quality metric, to be used to establish the frequency of inspection for a certain site and the number and level of expertise of the required inspectors, as well as the scope, depth and duration of routine inspections.

All these items may form the basis for the drafting of a GMP inspection “Reliance Assessment Report”, which would also include the statement about the name of the hosting national competent authority and the basis on which country reliance has been established. Such a document may be then used to support regulatory decisions. According to EFPIA, the suggested approach would benefit of a better knowledge of the site inspected by the local NCA, a better insight in the local culture and less barriers to the interaction, with optimisation of resources. A better transparency of the inspection process is also expected, as a non-compliant site may negatively impact on the reputation of local inspectorates. Identified pre-requisites to allow the implementation of such an approach are the availability of high-quality standards at the local level and the evaluation of national regulatory systems by and independent body (e.g. PIC/S or the WHO Global Benchmarking Tool).

UK’s pilot of a Compliance Monitor Process

A new approach that may represent a first example towards the new paradigm of collaboration and reliance has been undertaken in the UK, where the Medicines and Healthcare products Regulatory Agency (MHRA) launched in April 2022 a pilot project focused on the Compliance Monitor (CM) Process (see more here and here). The pilot is part of MHRA’s delivery plan 2021-2023 and will focus on the CM supervision process for appropriate GMP and GDP Inspection Action Group (IAG) cases.

According to the MHRA, the new process would allow companies to concentrate on the delivery of the required improvements without the need to use resources to manage MHRA supervision inspections to assess compliance remediation activities. On the regulatory side, the MHRA should be able to concentrate on the delivery of the routine risk-based inspection programme. The risk-based approach to supervision and monitoring is also expected to limit the number of potential shortages of supply.

The CM process is based on the figure of eligible consultants acting as Compliance Monitors (CM) in charge of working with the company to deliver the remediation actions identified in a Compliance Protocol (CP) agreed with the MHRA. The supervision by the CMs is expected to contribute to lower the need of on-site inspections with respect to the current process managed by the IAG. The CP also includes the transmission to MHRA of high-level updates at fixed intervals of time, which should include only exceptions to the agreed timelines or significant related compliance issues which were identified. Once completed the CP protocol, the CM informs the regulatory authority that the company is ready for inspection, so that the MHRA can verify onsite the possibility of its removal from IAG oversight.

CMs will be selected by the involved company from a dedicated register and accepted as suitable for that case by the MHRA. At least five years’ experience in independent audits of GMP/ GDP companies is needed to be eligible as CM. Furthermore, not having been personally the subject of MHRA regulatory action and/or significant adverse findings in the previous three years,  a suitable CV and the completion of a MHRA training as CM. All details on requirements for the CM role and application are available at the dedicated page of the MHRA website.

Suitability criteria to act as a CM for the specific case include as a minimum a sufficient experience of the dosage form manufactured, testing activities being performed, or distribution activity being carried out and a written confirmation of absence of Conflict of Interest. These criteria will be assessed by the company selecting the CM.

BIA’s view of the reliance in the UK medicines regulatory framework

The UK’s BioIndustry Association (BIA) contributed to the debate on the reliance in the UK medicines regulatory framework with a Reflection Paper. According to BIA, the MHRA has a well recognised status and history as a valued contributor to the global regulatory ecosystem and a point of reference for the regulatory decision-making which should be preserved also in the future.

BIA recalls the role played by the MHRA in the development of the concept of regulatory reliance at the EU level, as a way to support the agile management of resources and simultaneously focusing on core and innovative national activities across all stages in the product lifecycle. The central concept sees regulators from one country to rely on the decision and assessments of trusted authorities from another country in order to speed up the timeline of regulatory procedures. At the end of the process, each regulator remains fully responsible and accountable for all its decisions.

BIA also highlights the contribution of reliance to the advancement of good regulatory practices and international networks of regulators, so to better allocate resources potentially taking into account also the respective fields of specialisation. The proposal is for a list of accepted reference regulatory authorities as a way to recognise the evolution of partnerships over time. Examples of recognition pathways already active in the UK are the EC Decision Reliance Procedure (ECDRP) and international work-sharing through the Access Consortium and Project Orbis, through which the MHRA may act as the reference regulatory agency in many procedures.

BIA also warns about the risks of a sudden interruption at the end of 2022 of the reliance pathway, that would have a highly disruptive impact on companies and patients.


EMA’s consultation on draft Q&As on remote certification of batches by QP

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by Giuliana Miglierini

The last two years saw the implementation of a high degree of regulatory flexibility as a mean to respond to the many challenges posed by the travel bans consequent to the pandemic. After this “experimental” phase, regulatory authorities are now considering the possibility to allow the routine implementation of some remote procedures in the field of pharmaceutical production.

It is the case of the remote certification/confirmation of batches by the Qualified Person (QP): after the publication of a draft guideline in the form of Q&As (EMA/INS/169000/2022), the European Medicines Agency (EMA) has launched a short public consultation which will remain open up to 13 June 2022. Comments may be sent by email.

The guideline offers EMA’s point of view on the requirements for the physical attendance at the authorised manufacturing site applying to QPs in order to routinely run the remote certification of batches, outside emergency situations. The document has been drafted by the GMDP Inspectors Working Group; it is composed of four questions and their relative answers and it addresses some considerations arising from the experience gained on the application of the guidelines for human and veterinary medicines issued during the pandemic. These last ones were elaborated in cooperation between the European Commission, the Coordination group for Mutual recognition and Decentralised procedures – human (“CMDh”), the Inspectors Working Group, the Coordination group for Mutual recognition and Decentralised procedures – veterinary (“CMDv”) and EMA.

The Agency also warns that the contents proposed by new Q&As’ guideline may be subject to any other interpretation by the European Court of Justice, which is the ultimate responsible for the interpretation of the EU legislation.

The contents of the Q&As

The routine remote certification or confirmation of batches may in future apply to the activities carried out by the QPs within the EU and European Economic Area (EEA), with reference to manufactured or imported human and veterinary medicinal products and investigational medicinal products.

The first answer clarifies that it could be possible for the QP to routinely run remote batch certification or confirmation only if this type of practice is accepted by the relevant national competent authority (NCA) of the member state where the authorised site is located. To this instance, it should be noted that some NCAs may request some specific requirements to authorise the routine remote certification procedure, for example with reference to the location of the QPs.

Should the remote certification be allowed on a routine basis, specific requirements should be met in order to validate this practice, starting from its full compliance to the EU legislation and EU GMP guidelines.

The answer to question 2 specifies that all activities should take place in an EU/EEA country, and that the time spent by the QP at the authorised site should be commensurate with the risks related to the processes” hereby taking place. To this instance, it is of paramount importance the ability to demonstrate that the QP acting from remote has maintained full knowledge of the products, manufacturing processes and pharmaceutical quality system (PQS) involved in the remote certification/confirmation of batches. That also means that the QP should be highly reliant on the PQS of the authorised site, and this would be only possible by spending an adequate time on-site to verify the adequacy of the PQS with respect to the processes of interest. The pharmaceutical quality system should also include details of all the procedures used for the routine remote certification/confirmation of batches. The possible use of this type of remote procedure by the QP should be also clearly mentioned in the technical agreement governing the relationship between the authorisation holder and the QP, which should also specify all cases requiring the presence on-site of the QP. A robust IT infrastructure should be in place to guarantee the remote access of the QP to all the relevant documentation in the electronic format needed to achieve bath certification/confirmation, according to the provisions described in Annex 16 to the GMPs (Certification by a Qualified Person and Batch Release). To this instance, presence on-site should be always considered to solve issues that cannot properly be addressed from remote. The demonstration of the presence on-site of the QP falls under the responsibility of the Manufacturing/Importers Authorisation (MIA) holders.

These are also responsible to make available to the QPs all the hardware and software needed to guarantee the remote access to the relevant documentation (e.g. manufacturing executions systems, electronic batch records system, laboratory information systems etc.) as well as batch registers. All IT systems used for remote batch release should comply with the requirements of Annex 11 to the GMP (Computerised Systems).

On the same basis, it should be possible for NCAs to contemporaneously access for inspection all documentation and batch registers involved in routine remote certification/confirmation at the authorised site of batch release. MIA holders should also guarantee the QP is the only allowed person to access the batch certification/confirmation function and batch register, that the transferred data are complete and unchanged, and that an adequate system for electronic signatures is in place.

Question 3 simply clarifies that some members states may have some specific requirements about the country of residence of the QP, for example it should be the same where the authorised site involved in the remote certification procedure is located.

The last question discusses technical requirements linked to IT-security and data integrity for remote access, a type of procedure presenting a higher intrinsic risk in comparison to the same activities carried on-site. Here again, the main reference is Annex 11; all equipment and software used for remote certification of batches should always reflect the current technological developments.

Among the suggestions made by the Q&A draft guideline is the precise identification of all hardware transferred off-site to the QP, that should be inventoried and kept updated. Hard disks should be encrypted, and ports not required, disabled.

Attention should also be paid to the configuration of any virtual private network (VPN) used by the QP to improve the security of the connection to the IT infrastructure of the authorised site and to prevent unauthorised accesses. Authentication should be based on recognised industry standards (e.g. two-factor or multifactor authentication, with automatic date of expiry). The transfer of data should be secured by strong transport encryption protocols; assignment of individual privileges and technical controls falls under the responsibility of the MIA holder


A study on medicines shortages from the European Commission

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by Giuliana Miglierini

The study on medicines shortages commissioned in March 2020 by the European Commission upon request of the European Parliament and Council has been published; the document, prepared by a consortium led by Technopolis, suggests 16 possible policy measures – both legislative and not-legislative – that the Commission may consider while drafting a new legislative proposal to govern the issue, expected to be announced at the end of 2022.

According to the current EU pharmaceutical legislation (Directive 2001/83/EC), marketing authorization holders (MAHs) have to submit – two months before the temporary or permanent interruption of supply of a certain medicinal product – a pre-notification to the relevant national competent authorities (NCAs) (Article 23a, a part in the case of exceptional circumstances).

The mandate to continue supply to cover the needs of patients, and respective responsibilities of MAHs and wholesale distributors are established by Article 81 of the same directive.

The new study will support some of the achievements set forth in the Pharmaceutical Strategy; another action undertaken to reduce the impact of shortages in the EU is represented by the EU Executive Steering Group on Shortages of Medicines Caused by Major Events, an initiative set up in March 2020 with the contribution of the Commission, EMA and member states.

The Commission study on shortages by Technopolis confirms that current market framework conditions for off-patent medicines play against supply resilience – said Rebecca Guntern, President ad-interim of Medicines for Europe, commenting the release of the study –. As long as healthcare systems only focus on the cheapest possible price for off-patent medicines and do not reward investments to ensure robust supply chains, the only option for companies is to be the cheapest or to leave the market.

The main outcomes of the study

The study on shortages focused its attention on medicines for human use marketed in the EU/ EEA in the period 2004-2020. The main objectives of the exercise include the identification of shortages’ root causes and specific characteristics, the assessment of the adequacy of the current framework (at EU and national level) and of possible solutions to address the problem.

Data from the shortages registries kept by national competent authorities (NCAs) of 22 EU’s countries was only available for years 2007-2020. Commercial data on pharmaceutical sales from IQVIA MIDAS was also used, and extensive consultation with stakeholders was run under different formats.

Central to the 16 recommendations highlighted in the study is the establishment of a centralized and harmonised EU-wide definition of medicine shortages, as well as of harmonised reporting criteria. The latter should aim to collect sufficiently detailed information on key parameters (e.g. product details, MAH, details on the shortage and impact).

Different definitions, systems for notifications and type of information requested are currently in use in the various member states; even the definition of “shortage” agreed in 2019 by EMA and HMA was not considered by stakeholders adequate to differentiate between critical and non-critical shortages. According to the report, this fragmented situation doesn’t allow for the sharing of data and comparative analysis between countries, thus resulting in the overall inefficiency of the system.

Attention should be paid also to the creation of a EU-wide list of medicines subject to critical shortages; specific policies and regulations may be developed on this basis to improve their availability. Medicines typically experiencing shortages are older, off-patent and generics drugs with low profit margins; the main therapeutic areas involved include pain, hypertension, infections and oncology.

The creation of dialogue platforms at the national level is also envisaged, where to exchange the point of view of different supply chain stakeholders (including patients and healthcare providers). The study highlights the high burden shortages create on pharmacists and physicians looking for the best possible treatment alternative for their patients. A possible way to address this issue would see the availability of information about alternative medicines in shortage databases. In many cases, this type of occurrence is referred just to some countries within the EU, thus suggesting inequitable distribution and access rather than global supply issues may play a major role in shortages.

Understanding the root causes

Limited reporting is a key point to be solved in order to improve the understanding of root causes of shortages. According to the study, a reductionist approach to reporting is often used; this makes fully evident just acute causes (e.g. a problem at the production site), but leaves unattended more systemic issues (e.g. consolidation of manufacturing, resulting in a very limited number of production sites) and market-related factors (e.g. single-winner procurement practices).

Quality and manufacturing issues account for approx. half of all cases of shortages, suggest the report; among commercial reasons are market withdrawals and unexpected increases in demand. The information available for the analysis was judged insufficient to exactly asses the potential risks linked to outsourcing of manufacturing activities (including the production of APIs) and parallel distribution.

The proposed recommendations ask for greater transparency of industry supply quotas as well as parallel traders’ and wholesalers’ transactions. Suppliers should establish adequate shortage prevention and mitigation plans; legal obligations for MAHs and wholesalers are suggested in order to maintain a safety stock of (unfinished) products for medicines of major therapeutic interest at EU-level.

A new legislation to tackle shortages

The provisions set forth by Articles 23a and 81 of the Directive have been transposed differently into the single national legislations, often well before the establishment of the shortages registries. Several EU’s countries have acted on their own to strengthen the system, for example establishing mandatory reporting on stock levels and export restrictions. Nevertheless, according to the study available data are not sufficient to draw final conclusions on the costs and efficacy of stock keeping obligations on the level of (notified) shortages in the countries where they were introduced.

A more pro-active approach to the management of medicines shortages by MAHs and distributors may be supported by the availability of a EU-wide and uniform legislation governing financial sanctions to be applied if notification requirements and/or supply responsibilities are not met. Other suggestions include the adoption of common principles for the introduction of national restrictions on intra-EU trade, and the availability of greater flexibilities for emergency imports of specific products in case of market withdrawals and other critical shortages. As for procurement, the study indicates the opportunity to address public procurement tenders also considering the incorporation of requirements for more diversified, multiple tenderers and thereby supply sources.

From a regulatory perspective, the document highlights the opportunity to reduce costs and simplify administrative procedures for the submission of post-approval changes. The availability of an accelerated mutual recognition procedure (MRP) within the EU is also suggested, together with a more efficient use of the Repeat Use Procedure. Improved flexibility should be a target also with respect to the EU-wide regulation governing medicines packaging and labelling, so to allow for the use of digital leaflets and multi-country/multi-language packaging and labelling.