ema Archives - Page 2 of 4 - European Industrial Pharmacists Group (EIPG)

Home  /  EMA’s recommendations to prevent medicines shortages  /  ema

A new member within EIPG


The European Industrial Pharmacists Group (EIPG) is pleased to announce the Romanian Association (AFFI) as its newest member following the annual General Assembly of EIPG in Rome (20th-21st April 2024). Commenting on the continued growth of EIPG’s membership, EIPG President Read more

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

•••

EMA’s recommendations to prevent medicines shortages

June 9, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.


EMA, new features for the PRIority Medicines (PRIME) scheme

May 19, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

Based on the review of results obtained in the first five years of implementation of the PRIority Medicines (PRIME) scheme, the European Medicines Agency has launched a set of new features to further enhance the support to developers of new medicinal products in areas of unmet medical needs (see the revised guidance for applicants seeking access to PRIME scheme).

The guideline complements contents of other documents, i.e. EMA’s Guidance on accelerated assessment, the guidance on the preparation of the PRIME kick-off meeting and submission readiness meeting, the one specific for applicants seeking scientific advice and protocol assistance, and the toolbox guidance for robust CMC data packages.

The new set of measures to speed up approval

The major goal of the PRIME scheme, introduced by EMA in 2016, is to accelerate the regulatory pathway for new medicines seeking approval and that may have a high impact on severe conditions currently lacking treatment options. The scheme aims to facilitate the generation of robust data packages supporting the compliance to regulatory requirements for all aspects of development and production of a new medicine.

A critical aspect to ensure efficiency of this process is the ability to build a constructive and continuous dialogue between regulators and sponsors, fundamental for the continuous monitoring of development activities. To this regard, EMA will establish a new roadmap for each PRI-ME development, that will parallel and complement the already existing product development tracker. The combination of the two should allow the optimisation of early scientific advice and regulatory support provided by EMA committees. It should also facilitate the prompt identification of critical aspects and emerging issues in the development, requiring further discussion between regulators and sponsors to positively solve them.

Should issues occur with a specific programme that has already received comprehensive initial advice, EMA is now entitled to provide expedited scientific advice specifically for PRIME developments. The new approach will be tested in a one-year pilot project started in March 2023. Requests of expedited scientific advice have to meet some criteria: the request is a follow-up advice, subsequent to the initial scientific advice procedure; it refers to issues with a specific, well-defined scope; and its urgency has to be justified, in comparison to standard scientific ad-vice timelines. The PRIME Scientific Coordinator is the first point of contact for sponsors to discuss these requests, which have to be submitted via IRIS, as well as all other issues referred to the PRIME scheme.

The pilot phase also includes the new roadmap and tracker to replace the previous PRIME annual update for any products that have not yet been discussed in a Kick-off meeting. Contents of both the roadmap and development tracker are detailed in the updated guidance.

Submission readiness meetings are the third new measure introduced by EMA. The meetings will serve as the final checking point to assess the status of development, with respect to the implementation of the regulatory advice previously provided by the Agency, and the resulting data package intended to support the MA application. Mature plans for post-marketing evidence generation should also be presented, as needed. Applicants are expected to start organise the submission readiness meeting approx. 15 months prior to the intended MAA submission date; the meetings should occur approx. 9-12 months prior the same date. Confirmation of eligibility to accelerated assessment should be checked 2-3 months before submission of the MA application.

Key features of PRIME scheme

At the end of 2022, the PRIME scheme supported the development and final recommendation for approval for 26 medicines. Sponsor can voluntarily file an application to access the scheme, providing evidence the eligibility criteria are met, in particular with reference to a potential major public health interest. These include conditions for which there is an unmet medical need in prevention, diagnosis or treatment, a new therapeutic method is introduced providing significant benefit over the existing ones or bringing a major therapeutic advantage to patients in a given indication.

The PRIME scheme articulates its support through different actions along the planned pathway. Depending on the type of medicinal product under development, the early appointment of a Rapporteur from the Committee for Medicinal Products for Human Use (CHMP) or the Committee for Advanced Therapies (CAT) allows for the discussion of all preparatory aspects of the ap-plication from both a technical and scientific perspective. Opinions may be also provided by other relevant EMA’s Committees and Working Parties, as needed.

Sponsors can also benefit from an initial Kick-off meeting with all the above-mentioned regulators and experts, to obtain preliminary guidance on the overall development plan. Key development steps subject to future scientific advice and the recommended regulatory strategy should be addressed during this meeting.

Special provisions are set forth to facilitate access to the PRIME scheme for SMEs and academic applicants. Upon demonstration of proof of principle, these may be granted Early Entry PRIME status, allowing for introductory meetings to raise awareness on regulatory requirements, and provide early advice on the overall development plan and relevant milestones. The requested proof of principle should be based on compelling non-clinical data in a relevant model providing early evidence of promising activity, and first-in-human studies indicating adequate exposure for the desired pharmacotherapeutic effects and tolerability.

Advice on the generation of proof of concept data is also provided at this stage by the EMA pro-duct team, and it must be fulfilled in order to confirm transition to full PRIME eligibility. In this instance, appointment of the CHMP/CAT Rapporteur is also activated.

The main steps of the procedure

Upon a first checking of acceptability of the application and related documentation, a Scientific Advice Working Party (SAWP) reviewer and a EMA scientific officer are appointed (plus a CAT reviewer in case of advanced-therapy products), and sponsors are informed of the start of the procedure and expected timelines. The SAWP committee should provide its comments to the reports by day 30, followed by final adoption by CHMP by day 40. A flowchart describing the criteria to determine eligibility is reported in Annex 1 of the guideline. The opinion of the CHMP is followed by the issuing of a letter detailing the reasons for the positive/negative decision. The outcomes of the CHMP meetings including discussions of PRIME developments are published as part of the highlights on the monthly adopted recommendations.

The confirmation of eligibility to the centralised procedure triggers the appointment of the CHMP Rapporteur, according to the specific procedure. A letter of intent to submit an MAA (approximately 6-7 months prior to submission of the MAA) is also requested.

In the case of SMEs accessing Early Entry PRIME, the appointment of the Rapporteur follows the generation of data confirming eligibility at proof of concept stage. SMEs or academic applicants also benefit from a full fee waiver for scientific advice or follow-up requests.

The Kick-off meeting is usually scheduled around 3-4 months after granting of the PRIME eligibility; submission of relevant background information and a detailed regulatory roadmap is requested to applicants in order to prepare the meeting.


Webinar: Pharmacovigilance as a specialization and the role of the Pharmacovigilance Risk Assessment Committee (PRAC)

May 8, 2023 , , , , , , , , , , , ,

EIPG webinar

Next EIPG webinar is to be held on Wednesday 31st of May 2023 at 17.00 CEST (16.00 BST) in conjunction with PIER and University College Cork. Sofia Trantza, a pharmacist with long experience as a Qualified Person for Pharmacovigilance in the Pharmaceutical Industry, currently representing Greece at the European Medicines Agency (EMA) as a member of the Pharmacovigilance Risk Assessment Committee (PRAC) will present the role and the procedures of the latter as a European body responsible for providing recommendations to EMA on any questions relating to pharmacovigilance activities in respect of medicinal products for human use.

According to the World Health Organization (WHO) pharmacovigilance (PV) is defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. During the pandemic, this science went more popular than ever, and many people got familiarized with it. A very important role at the activities of this speciliazation plays the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA).

Webinar attendees will gain understanding of:

  1. What is pharmacovigilance and what it represents for the public health.
  2. The process of reporting adverse reactions at national and at European level.
  3. The main activities and procedures in this discipline.
  4. The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA).
  5. The role and the responsibilities of PRAC Committee.
  6. The processes that PRAC is engaged in and how the work of this Committee is reflected in these processes.

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


The Windsor Framework

March 3, 2023 , , , , , , , , , , ,

On 27 February 2023, UK Prime Minister Rishi Sunak and the European Commission President Ursula von der Leyen announced that agreement had been reached on changes to the operation of the Protocol on Ireland/Northern Ireland.

The Protocol has been in effect since 1 January 2021 requiring that all goods coming into Northern Ireland from Great Britain comply with EU regulations. The UK Government and EU Commission have both made proposals in relation to the operation of the Protocol over the last two years. One approach adopted by the UK Government was to introduce the Northern Ireland Protocol Bill on 13 June 2022 providing UK with power to make further changes to it. In response to the Bill being introduced, the European Commission announced it was proceeding with legal action against the UK. Since then, negotiations between the UK Government and the European Commission increased in intensity and this led to the announcement of the agreement called “Windsor Framework”. Part of the new Windsor Framework is a political declaration published by both parties which confirms that the UK Government will not be proceeding with the Northern Ireland Protocol Bill and that the European Commission will halt its legal proceedings relating to the Protocol against the UK.

The Framework (This publication is available at www.gov.uk/official-documents)

The original Protocol applied all EU rules and authorisation requirements for medicines, notwithstanding that medicine supply is an essential state function. This meant that for novel medicines, including innovative cancer drugs, it was the EMA, not the MHRA, which approved medicines for the Northern Ireland market. This failed to recognise or accommodate for the fact that the overwhelming flow of medicines to Northern Ireland is from Great Britain, with medicines provided for the UK market as a whole.

The EU made a series of changes to its rules last year to address some of these issues, addressing regulatory requirements which prevented medicines flows and supporting the MHRAs continued ability to authorise generic drugs under a single licence for the whole UK. This, combined with the UKs own Northern Ireland Medicines Authorisation Route (NIMAR), has ensured that medicines have continued to flow uninterrupted into Northern Ireland. But these arrangements were not a complete solution for the long-term and did not address the EMAs role in licensing novel medicines, leaving Northern Ireland exposed to divergence as UK and EU rules changed into the future.

This uncertainty, as well as the requirement for Northern Ireland drugs to meet various EU labelling requirements, risked discontinuations if firms were unwilling to maintain two sets of labels and packs for Great Britain and Northern Ireland. This was not a sustainable way forward and has been addressed by this deal.

Under the agreement, both UK and EU have listened to the needs of industry and the healthcare sector and secured an unprecedented settlement that provides a comprehensive carve-out from EU rules: fully safeguarding the supply of medicines from Great Britain into Northern Ireland, and once again asserting the primacy of UK regulation.

As a result, it will be for the MHRA to approve all drugs for the whole UK market. This will enable all types of medicines to be supplied in single packs, within UK supply chains, with a single licence for the whole UK. This will provide a long-term, durable basis for medicines supplies into Northern Ireland.

  • Specifically, the whole of the Falsified Medicines Directive has been disapplied for medicines supplied to Northern Ireland, ending the unnecessary situation in which – even with grace periods – wholesalers and pharmacies in Northern Ireland were expected to keep barcode scanners to check individual labels.
  • And for the provision of innovative drugs to patients, Northern Ireland will be reintegrated back into a UK-only regulatory environment, with the European Medicines Agency removed from having any role.
  • This responds to the overwhelming calls from industry for stability and certainty, and can give reassurance to patients and clinicians in Northern Ireland well into the future.

At the same time, the agreement safeguards frictionless access to the EU market for world-leading Northern Ireland pharmaceutical and medical technology firms. This pragmatic dual-regulatory system protects business, patients and healthcare services, and reflects that it is an essential state function to maintain and oversee the supply of medicines within the whole United Kingdom.

Proposal for a Regulation (This publication is available at EU commision website here)

The European Commission has published a proposal for a Regulation that in essence carves-out medicinal products destined for the UK internal market from the EU pharmaceutical rules. Article 4(1) of the proposed Regulation provides that centrally-authorised products cannot be placed on the market in Northern Ireland. Such medicines may be placed on the market in Northern Ireland if all the following conditions are met:

  • the competent authorities of the UK have authorised the placing on the market of the product in accordance with the law of the UK and under the terms of the authorisation granted by the competent authorities of the UK;
  • the medicinal product concerned shall bear an individual label which shall be attached to the packaging of the medicinal product in a conspicuous place in such a way as to be easily visible, clearly legible, and indelible; it shall not be in any way be hidden, obscured, detracted from, or interrupted by any other written or pictorial matter or any other intervening material. it shall state the following words: “UK only”.
  • the UK shall provide the European Commission with written guarantees that the placing on the market of the medicinal products does not increase the risk to public health in the internal market and that those medicinal products will not be moved to a Member State.

.

Sources:


HERA reports on stockpiling of antimicrobials

February 24, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

The European Health Emergency Preparedness and Response Authority (HERA) has published the two final reports, prepared by McKinsey Solutions for the European Commission, describing respectively the results obtained during the first and second phases of the antimicrobial resistance (AMR) feasibility study on stockpiling.

Antibiotic resistance represents a major threat for human health, as many active substances are losing efficacy towards many bacterial species. The first report (deliverables D1–D5) focuses on the mapping exercise run during the project and aimed to assessing the current situation, identifying vulnerabilities, and reviewing the stockpiling systems currently available in the EU and at the global level.

The second report (deliverables D6-D7) discusses the vulnerabilities identified in the previous phase and the potential tools and solutions to address them, including the assessment of available options for stockpiling of antimicrobials at EU level.

Mapping of the current situation

According to the first report, 32 classes of antibiotics were identified as critical with respect to the need to ensure continued access to patients in order to offer sufficient therapeutic and prophylactic options against systemic bacterial infections.

The analysis proceeded further to identify narrower sets of antibiotics most useful to treat infections due to common pathogens with acquired antibiotic resistance: a first subset of 20 substances was indicated as specially relevant as first- or last-line/reserve therapies against AMR pathogens, and from this a shorter sublist of 13 was identified as last-line/reserve therapies for severe and potentially lethal infections.

The report did not identified any critical market withdrawal of antibiotic substances from the EU market, even though some criticalities may occur in some member states. Alternatives with better efficacy and/or safety profiles are still available on the market for the six substances identified as fully withdrawn.

According to the report, stockpiling at the EU level might not have a direct impact on the mitigation of market-driven trends. Improved monitoring of potentially critical future withdrawals would be needed to enable early detection of shortages and establishment of counteractions.

Innovation in the field of new antibiotics is still largely insufficient, with only six substances currently in phase 3 clinical development. These might prove useful especially as the ultimate reserve line of therapy after exhaustion of the currently available therapeutic options. The report suggests that, upon reaching approval, these innovative substances could be considered for future stockpiling or incentives to facilitate launch in the EU.

The analysis of supply chain vulnerabilities aimed to identify higher priority antibiotics as possible candidates for stockpiling. The report highlights that the analysis was “significantly limited by a lack of outside-in transparency”. Potential single points of failure and/or past disruptions in most supply chains were identified for the 32 critical antimicrobial classes, but the lack of capacity data made the in-depth analysis particularly difficult.

Six representative sets of antibiotic substances were assessed, for five of which less than 25% of API manufacturing occurs in the EU. Similar trends have been also observed for the remaining 26 classes. The supply of critical intermediates (i.e., 6-APA and 7-ACA) appears particularly worrying and may potentially lead to a future shortage of that specific antibiotic/class in the case of a shock. HERA report warns against the possible risks related to potential vulnerability to trade disruptions and unforeseen geopolitical shocks, which may lead to a significant shortage in case of failure of just a single manufacturing site, independent of its location.

The feasibility study also mapped the already existing or planned stockpiling systems, so to use this information to better design the new, EU-level stockpiling system. Four different levels were identified, ranging from the EU’s and member states’ systems to multilateral and/or international NGO stockpiles, stockpiles/inventories in the commercial value chain, and extra-EU national stockpiles.

At the EU and EFTA national level, 13 countries reported a national stockpile that includes antimicrobials, even if greatly differing as for the chosen model. The rescEU system was identified at the EU level as the most relevant mechanism potentially useful to complement and/or integrate with a publicly managed physical stockpile of antibiotics.

The Stop TB Partnership’s Global Drug Facility (GDF) was identified as one of the international models of interest, together with the US Strategic National Stockpile (SNS). The GDF includes more than 2,000 partners and acts as the largest purchaser and supplier of medicines to treat tuberculosis in the public sector globally. The suggestion is for HERA and the European Commission to collaborate with the GDF in case of a TB-related demand spike. The SNS may represent a significant example of how to address many of the criticalities highlighted by the report.

How to better address stockpiling of antibiotics

The second report builds on the above-mentioned observations to go deeper in analysing from different perspectives and targets the possible approaches to the stockpiling of antibiotics. The indication is for HERA to consider using existing initiatives (e.g., rescEU, the EU’s Joint Procurement Agreement and the Emergency Response Coordination Centre) and to work closely with EU member states and other EU agencies (i.e., EMA and the ECDC).

An important warning was also made: stockpiling is just “a short-term mechanism. It does not alter the fundamental market environment. It can only represent one part of any answer to the challenges faced by health agencies including HERA, whether AMR-related or otherwise”.

A sudden and unpredictable surge in demand and an interruption to supply are the two archetypes analysed to better identify how to address stockpiling.

More than 30 potential demand scenarios were considered, leading to the identification of one high priority stockpiling candidate (higher demand for anti-mycobacterial medicines due to a surge of imported tuberculosis cases) and other three important, but not yet prioritised scenarios. These include stockpiling against the accidental or deliberate release of a bacterial pathogen, treating bacterial super-infections due to a viral pandemic, and the potential rapid spread of an AMR pathogen in the current European context.

Stockpiling for supply chain disruptions was also assessed, leading to the conclusion that alternative products are available as substitutes in the great majority of cases. A point of attention is represented by cross-class substitution, that might provoke different side effects for different groups of patients and could represent a potential factor for the promotion of AMR. More complex treatment procedures (e.g., i.m. vs oral administration), higher costs for healthcare systems and organisational issues for providers should also be considered.

Virtual stockpiling to be managed through the new European Shortages Monitoring Platform (ESMP) or the existing European Medicines Verification System (EMVS) would increase transparency of the system. A mandate or incentives to support private sector physical stockpiling was considered as the most feasible option available. Efforts should be made by the EU Commission to better characterise the relationships between the economic sustainability of limited generics productions (e.g. oral formulations for paediatric use of narrow-spectrum genericised penicillins) and the risk of shortages.

Five lines of possible action

The second report identifies five possible lines for future action aimed to strengthen the antibiotic supply chain and improve the stockpiling feasibility. At first instance, it would be important to improve transparency and reporting, so to better enable the availability of targeted preparedness and response measures.

This might include the harmonisation and extension of mandatory reporting of medicine shortages across the EU, the possibility for HERA to access regulatory data from agencies and information from marketing authorisation holders on supply chain setup and inventories in the case of a healthcare emergency situation, the implementation of an opt-out mechanism from stockpiling obligations at final product level, and the introduction of a general extension of reporting requirements for the supply chain of antibiotic products sold in the EU.

The second line of possible action addresses how to lower wastage in existing private and public inventories and stockpiles. Available options include regulatory measures and limited financial support for drug stability studies or for packaging options able to maintain product quality over longer periods of time.

Facilitation and regulatory support for mutual recognition of national level approvals for antibiotics might help to improve the flexibility of existing inventories and stockpiles, so as to better mitigate the shortages occurring in some member states.

Other two complementary approaches have been identified as potentially useful to improve the supply chain resilience of the EU antibiotics market. On one hand, diversified and in-market antibiotic manufacturing capacities and capabilities could be supported by targeted incentives and investments. On the other, the maintenance of reserve/convertible manufacturing capacity for hard-to-make substances might be also supported, so to better face the need to rapidly compensate the increased requests from patients should disruptions occur.


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

February 17, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

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

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

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

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

The main issues examined by the EMA/EFSA report

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

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

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

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

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

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

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

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

The recommendations for future harmonization

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

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


ICMRA report on best practices against antimicrobial resistance

December 9, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.


Comments to the draft ICH guidelines Q2(R2) and ICH Q14

November 25, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The public consultation on the two draft guidelines ICH Q2(R2) on the validation of analytical procedures and ICH Q14 on analytical procedure development closed at the end of July 2022.The European Medicines Agency published in August two documents summarising comments received (ICH Q2(R2) and ICH Q14).

Many industrial organisations contributed to the consultation with their point of view on the two draft guidelines. In the next phase of the procedure (step 3 of the ICH process), comments will be reviewed by the ICH Q2(R2)/ICH Q14 Expert Working Group (EWG). We summarise for readers some of the main comments received from industrial stakeholders. A webinar organised byEIPG on the implications and opportunities of the revision of ICHQ2 and the ICHQ14 was presented by Dr Phil Borman, Senior Fellow & Director Product Quality at GSK on 15thJune 2022 (recording and slides are available at the webinars page of EIPG’s website).

Key principles from the EIPG’s webinar

During the webinar, Dr Borman gave a comprehensive picture of the process of Analytical Quality by Design (QbD). The systematic approach to method development starts with the identification of the predefined objectives (Analytical Target Profile, ATP). The understanding and control of the analytical procedure are at the core of the process, and they should be pursued according to principles of ICH Q8. Analytical QbD covers both the drug product (ICH Q8) and the active ingredient (Q11). This means that a similar framework to ICH Q8 and Q11 can be applied also for analytical procedures. The ATP is made up of the sum of performance characteristics, precision, range (including sensitivity), and bias/accuracy.

According to ICH Q2(R1), published in 1994, the objective of validation of an analytical procedure is to demonstrate its suitability for the intended scope. Revision of both guidelines started in 2019, based on a Concept paper published in 2018. ICH Q2(R2) covers the validation of the analytical protocols and reports, while ICH Q14 refers to the development of the analytical procedure and its lifecycle management.

Key features of the new drafts include the fact that no additional expectations / mandated requirements for pharmaceutical analytical scientists are present, the possible use of “enhanced approaches” and the clear link between performance characteristics and their related criteria and the validation study. The Q2(R2) guideline shall apply to both small molecules and biologics and includes the possibility to use prior knowledge (e.g., from development or previous validation) as a part of the validation exercise. Assay for the determination of robustness can be conducted, for example, during development. Other key features highlighted by Dr Borman include the possible use of Platform analytical procedures to reduce the number of validation tests and the possibility to use any type of calibration model (including multivariate calibration).

The expected benefits refer to the possibility to reduce the existing burden associated with post-approval changes to analytical procedures and the use of Established Conditions.

As Dr Borman explained, the ATP could form the basis of a Post Approval Change Management Protocol (PACMP), thus favouring the reporting of changes between technologies at a lower reporting category. A more performance driven and flexible approach to validation is expected following the entry into force of the new ICH Q2(R2) guideline. The selection of validation tests shall be based on the concrete objective of the analytical procedure.

Comments to ICH Q2(R2)

The overview of comments relative to the draft ICH Q2(R2) published by EMA consists of a 72-page document, divided into a first section containing general comments and a second focused on specific comments.

APIC, representing manufacturers of active ingredients and API intermediates, focused on the fact that “uncertainty is not part of the validation whereas it has a reality in practice and part of the discussion between laboratories”. The measurement of uncertainty is also considered linked to the Total analytical error (TAE), a concept that would not be adequately addressed in the guideline.

EFPIA, on behalf of the biopharmaceutical industry, asked for a better connection between the two guidelines ICH Q2 and Q14, starting from the alignment of the respective titles. Improved consistency in the use of some terms was also suggested (e.g. ‘performance criteria’). Improved clarity and greater flexibility should be applied to the concept of working and reportable ranges. The association also asked to provide more examples for multivariate analytical procedures using different models to facilitate the understanding of their validation and lifecycle management.

Medicines for Europe, representing manufacturers of generic and biosimilars, asked to provide a more specific methodology for reportable range validation. The association requested some clarification about the possibility of using the minimal requirements of the performance characteristics for the addendum method validation strategy.

The European Association of Nuclear Medicine (EANM) focused its intervention of radiopharmaceuticals, a class of substances that should be considered a special case and therefore be excluded from the scope of the guidance. The request assumes that other approaches different that those discussed may be applicable and “acceptable with appropriate science-based justification”. The same request also applies to the draft ICH Q14 guideline. The EANM contribution also highlighted aspects specific to radiopharmaceuticals that should be considered, including the strength of the radioactivity content, the unavailability of radioactive standards of the active substance, and the need of specific techniques for radioactivity determination. The suggestion is to refer to the specific guideline on the validation of analytical methods for radiopharmaceuticals jointly developed by the EANM and the EDQM.

According to the International Society for Pharmaceutical Engineering (ISPE), there are many sections of the draft Q2(R2) guideline that may pose challenges due to lack of alignment and fragmentation of contents. A revision of the structure is thus suggested, together with the harmonisation of terms with those listed in the Glossary. ISPE also highlighted the opportunity to better clarify the distinction between validation elements and recommended data applicable to multivariate analytical procedures vs traditional analytical methods.

The ECA Foundation/European QP Association reported a very critical position on the two draft guidelines, clearly stating that ICH Q2 and Q14 should integrate with one another. According to ECA, the corresponding US guideline “USP <1220> is far superior”. Many of the points reported above with respect to the general section of the overview are discussed in more deep detail within the part of the document listing specific comments.

Comments to ICH Q14

The same structure of the document also applies to the 54-page overview summarising the results of the consultation on ICH Q14 guideline.

According to the Plasma Protein Therapeutics Association (PPTA), representing manufacturers of plasma-derived and recombinant analog therapies, the draft would be too focused on chemical methods, with just a residual attention to biological methods.

APIC asked for improved discussion of the capability (and uncertainty) of the method of analysis, a fundamental parameter to assess its appropriateness for the intended use within the defined specification range. According to the association, more specific reference should be made in relation to development data that can be/cannot be used as validation data.

ISPE suggested adopting a more detailed title for the guideline; something similar has also been suggested by EFPIA. ISPE also addressed the issue of reproducibility, that may be influenced by external factors across multiple laboratories. Multivariate analysis is also discussed, suggesting adopting additional requirements for the multivariate elements while maintaining the same approach to other analytical procedures.

EFPIA would prefer to avoid the use of the term “minimal” in favour of other expressions denoted by a less negative connotation (e.g., traditional, suitable/historic, classical, fit for purpose) with reference to the validation approach. The availability of training case studies is considered important to support the alignment between industry and regulatory agencies on expectations for regulatory change management, especially with reference to multivariate models. EFPIA asked that the paragraph discussing the relationship between ICH Q2 and Q14 should not address what should be submitted to regulatory agencies. Discussion of OMICS methods used in quality control of complex biological products should be included in the annexes.

ISPE asked to avoid reference to geographic regions, as the final goal is to reach harmonisation. A clearer statement of the scope would be advisable (a possible example is provided), as well as a better linkage to the ICH Q12 guideline on pharmaceutical product lifecycle management.

Specific comments include the suggestion of the PPTA to define all acronyms at first use in text and to include them in the Glossary. According to Medicines for Europe, it would be advisable to add characterisational assays (other than release/stability) for biosimilars. Furthermore, the scope of the guideline should focus on the risk assessment and availability of the analytical knowledge needed to select the most appropriate method for a specific application. Activities deemed to the submission of the regulatory CTD dossier should remain confined to the complementaryQ2 guideline.


A concept paper on the revision of Annex 11

November 18, 2022 , , , , , , , , , , , , , , , , , , , , , , ,

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

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

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

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

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

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


Real-world evidence for regulatory decision-making

September 23, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

Digitalisation is rapidly advancing also in the regulatory field, as a tool to improve the efficiency and accuracy of processes used for the generation and use of data to inform the regulatory decision-making. To this instance, real-world data (RWD) on the use of a certain medicine by the general population are increasingly important to monitor the impact in terms of health benefits, adverse events and costs for healthcare systems.

The trend is confirmed by the publication of a joint statement by the International Coalition of Medicines Regulatory Authorities (ICMRA) addressing the use of real-world data and real-world evidence (RWE) in the development, authorisation and monitoring of medicines to support regulatory decision-making. The document has been endorsed by the European Medicines Agency (EMA), which also published the third workplan developed by its Big Data Steering Group to set key actions to be delivered in the period 2022–2025.

The debate on real-world evidence for regulatory decision making was also stimulated by an ISPE’s position paper released in 2020, and by papers published in the scientific literature (see here a recent review).

ICMRA’s joint statement on real-world evidence

The joint statement is the final result of a ICMRA workshop on real-world evidence co-organised with EMA, the US FDA and Health Canada in June 2022, that saw the participation of representatives from more than 40 countries. Heterogeneous data sources across different geographic areas and different levels of quality, as well as various processes for data sharing and access of the data, were among the main open issues identified during the meeting. Four different areas of collaboration have been identified, representing the focus of further discussion by international regulators in order to implement concrete actions to address criticalities.

The first area addresses the harmonisation of RWD and RWE terminologies. This exercise is deemed essential in order to share common operational definitions of RWD and RWE, characterized by a clear scope and level of granularity (e.g., pertaining to RCTs and observational studies).

Already existing guidance, such as the ICH M14 on “General principles on planning and designing pharmacoepidemiological studies that utilize real-world data for safety assessment of a medicine”, may represent useful tools to support these activities.

The convergence on RWD and RWE guidance and best practice should include the development of common principles for RWD quality. Metadata are an essential feature, as they enable the characterisation and discoverability of RWD. Other targets include the definition of suitable scenarios where RWE may contribute to regulatory decision-making, and the setting up of templates for study protocols/reports that can be used in multiple regulatory jurisdictions.

Readiness shall be pursued by strengthening the international regulatory collaboration on RWE. The rapid creation of expert groups on specific topics of interest and an improved collaboration on governance and processes aimed to support the efficient conduct of RWD studies in different countries are key actions in this area.

Transparency should be the common denominator underlying all the above-mentioned activities. It should be tackled through the definition and use of common principles and practices for the systematic registration of pre-specified study protocols and study results in publicly available registries. Publication of study results in open-source, peer-reviewed journals is also expected.

The 2022-2025 workplan on Big Data use for public health

In parallel with the publication of ICMRA’s joint statement, EMA released the Big Data Workplan 2022-2025, jointly developed with the Heads of Medicines Agencies (HMA). The joint workplan represents the expansion towards the operative phase of the priority recommendations for regulators on the best approaches to use and generate data developed in 2020 by the former Big Data Task Force. The document refers mainly to medicines for human use, even if it includes some information on veterinary medicines.

Big data are the key element to be considered in order to achieve the overall objectives seen above, as they enable the extensive analysis of information available on medicinal products subject to regulatory scrutiny. According to the Big Data Steering Group, the increased evidence arising from big data analysis may accelerate medicine development, improve treatment outcomes and facilitate earlier patient access to new treatments.

The workplan details ten different priory areas and the respective recommendations for action, and it provides the expected timelines for their implementation.

Central to the overall planned system is the Data Analysis and Real-World Interrogation Network (DARWIN EU), a federated network to enable access and analysis of real-world data. After the establishment of the DARWIN EU Coordination Centre and the activation of the first studies in 2022, new activities shall focus on the support to the European Health Data Space (EHDS) and the collaboration with the European Centre for Disease Prevention and Control (ECDC), HTA bodies and payers.

The joint action Towards A European Health Data Space (TEHDAS) shall facilitate the engagement with stakeholders, a critical point to ensure the quality of data. The release of a first version of a data quality framework for the EU Regulatory Network is expected in late 2022. An agreement on metadata to describe and identify RWD sets shall also be supported by the publication of a good practice guide on metadata and a public catalogue of European RWD. Release of new analytics tools and a review of the utility of eHealth data and social media data are also part of actions targeted to data discoverability.

The reinforcement of skills of all stakeholders involved in the process of RWD and RWE generation, analysis and use is also essential to guarantee the success of the new approach. EMA and HMA aim to develop agreed training curricula on biostatistics, pharmacoepidemiology and data science, including the availability of selected modules open to patients, healthcare professionals and academics. A curriculum on genomics data shall also be adopted.

The results of pilot studies on the use of RWE by EMA scientific committees will be released in next years, with a final report and a portfolio of RWE use cases to support uptake of RWE by the ERMN expected in 2025.

More in detail, a proof-of-concept pilot assessing access to individual patient data from clinical trials (raw data) in the scientific assessment of medicines is planned for Q4 2022. The final reflection paper on artificial intelligence (AI) for use in regulatory processes shall be published in Q3 2023, while 2024 should focus on a pilot on data analysis for CMC data.

All the above-mentioned activities shall be supported by new guidance issued by the new EMA Methodologies Working Party, while expert advice will be strengthened through the European Specialised Expert Communities (ESEC), initially focusing on AI & RWE.

The governance of the process shall benefit by a review of the mandates of the Big Date Steering Group and EU Network Data Board expected for late 2022. Target actions aimed to strengthen the framework for ethics in data analysis will also be explored. Activities at the level of the international framework of regulators shall include among others the evaluation of the clinical trial conceptual model under the ICH M11.

An annual Big Data stakeholder forum is also planned, complemented by topic specific meetings and workshops and biannual industry meetings. In the veterinary field, the workplan includes the implementation of the EU Veterinary Big Data strategy adopted in 2022. Among the main deliverable are a catalogue of veterinary data sources, finalisation of the system on antimicrobials sale and use data, and the evolution of training curricula.


« Previous   1 2 3 4   Next »