EU Focus Archives - European Industrial Pharmacists Group (EIPG)

Lessons learnt to transition from Horizon 2020 to the new FP10


by Giuliana Miglierini The European Commission published the ex post evaluation of Horizon 2020 (H2020), the FP8 framework programme for research and innovation (R&I) run in years 2014-2020. The report identifies several areas of possible improvement, which may be taken into Read more

Approvals and flops in drug development in 2023


by Giuliana Miglierini Approvals and flops in drug development in 2023 The European Medicines Agency published its annual highlights, showing 77 medicines were recommended for marketing authorisation, and just 3 received a negative opinion (withdrawals were 19). In 2023 some highly expected Read more

Webinar: Oral Colon Drug Delivery - Design Strategies


EIPG webinar Next EIPG webinar is to be held on Wednesday 21st of February 2024 at 17.00 CET (16.00 GMT) in conjunction with PIER and University College Cork. Anastasia Foppoli, will discuss on the various approaches and the general aspects Read more

The risk of a biosimilar void in Europe

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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 claiming the proposed reform would reduce the attractiveness of Europe for R&D activities, a recent report from Iqvia analysed the status of biosimilar competition. According to the document, not all biological medicines experiencing loss of exclusivity (LoE) in the next decade would automatically face competition by the corresponding biosimilars. This would result in the creation of a “biosimilar void” on the market, with many originators losing protection without seeing the parallel development of their biosimilar versions.

Competition is not guaranteed

Biosimilar competition is not necessarily guaranteed, and emerging dynamics pose a risk to conventional notions of medicines lifecycles, states the report since its very beginning. The analysis refers to biological medicines that will lose protection in the period 2023-2032.

Despite the approx. 8-fold expected increase in LoE opportunity by value between 2012 and 2032 (from €4.4 billion to €32.2 bln, as result of loss of exclusivity for 110 biological medicines), data show a declining trend for years 2021-2023 (€4.3 bln). According to Iqvia, more than a half (55%) of biologics with LoE in the period 2023-2027 might experience the lack of a biosimilar in development.

The report highlights five areas of common perception to be addressed to better define the issue. The increasing complexity of many biological medicines coupled to new barriers to entry is one of the factors making the development of biosimilars interesting only for products referred to originators with large market shares. According to Iqvia, 27% of the 26 high-sales products that will reach loss of exclusivity by the end of 2032 do not have yet a biosimilar candidate in development in Europe (vs 45% at the global level), corresponding to a potential loss of approx. €8 bln market opportunity. The number of biosimilar candidates in the pipeline for high-sales biologics is also expected to decrease from 2027 onwards.

Regulatory hurdles, therapeutic classes, and disease indication are expected to play a greater role in guiding decisions on biosimilar development, indicates the report. The attractiveness of the European market should also be considered. Oncology will remain the more interesting area, with 44% of all candidates in early to late development for LoE events occurring between 2023 and 2027. Immunology and ophthalmology are other therapeutic areas that might experience growing competition.

The current barriers to biosimilar development

According to Iqvia, the main constraints limiting the decision on biosimilars development are represented by cost and time. In the oncology area, for example, high costs have to be considered to purchase the reference comparator biologic medicine, and large patients populations are required to demonstrate relevant clinical endpoints. New therapeutic classes, i.e., PD-L1/PD-1 inhibitors, may also pose challenges for the design of pharmacokinetic and equivalence studies. From the manufacturing perspective, the increasing use of antibody-drug conjugates (ADC) would result in new barriers to entry.

According to Iqvia, the least attractive products for biosimilars development are those with less than €500 million annual sales in Europe. The report shows 93% of these products might fail to see biosimilar competition, compared to 27% of high-sales medicines. This negative trend would result in a “biosimilar void” corresponding to approx. €15 bln in lost savings. Iqvia also identified some exceptions that might experience a niche development, on the basis of specific technological and manufacturing know-how, platforms and market access excellence.

Another factor to be considered is reimbursement rate, that the report identifies in 51% for low-sales biologics with no biosimilar pipeline (approx. 30% lower than for products with a biosimilar pipeline). The management of the intellectual property referred to the originator should be also taken into consideration.

Orphan and one-off medicines

Despite the growing number of new biologics reaching marketing authorisation as orphan medicines, according to Iqvia biosimilar development is undergoing by now for only one product (eculizumab). No other orphan biologics are expected to face biosimilar competition in future, as annual sales of the 39 orphan medicines currently on the market are too low (approx. €105 mln).

A major factor limiting the development of biosimilars for orphan medicines is linked to the fact many of these therapies fall in the antibody-drug conjugates (ADC) and cell- or gene-therapies (ATMPs) categories (wave 3 biologics). This implies many challenges from the development and manufacturing point of view, higher upfront investments and a more complex setup for analytical and clinical testing.

According to Iqvia, there are currently 16 non-orphan biosimilar candidates under development, corresponding to wave 3 biologics. A limiting factor for this pipeline is identified in the still present fragmentation of the European regulatory system, e.g., reimbursement policies, incentives, and clinical standards. ATMPs, also referred to as one-off therapies, represent a particular case, being relatively young on the market. This leads to no expectation of LoE events in the next five years. The trend would then change, with some 10 products losing protection by 2040, but it should be considered together with the parallel declining of the number of eligible patients, as many of them might have been already treated with the one-off originator medicine.

Shifting standards of care

Another factor analysed by Iqvia is the impact on biosimilars development of the possible changes in the current standards of care, for example resulting from the availability of new and more user-friendly formulations of the originator (i.e., subcutaneous vs intravenous injections). The availability of second- and third generation versions of the original biologic should be considered as another factor limiting the possible market share of a biosimilar of the first-generation product. The picture is indeed furthermore complicated, as another frequent possibility, especially in the oncology area, sees the development of combination therapies based on the use of two or more biologics. As already said, some of them might be very costly (i.e. monoclonal antibodies and PD-1 inhibitors), and require a larger study population to demonstrate equivalence of the add-off effect.

The proposed solutions to fill the biosimilar void

The Iqvia report proposes several possible solutions to overcome the expected biosimilar void, starting from horizon scanning activities aimed at early identification of upcoming LoE events in order to prevent contractions in biosimilar development. Horizon scanning may also support market entry and granting of incentives based on demand. The development of biosimilars of orphan medicines might benefit of a default waiver of comparative efficacy studies, a suggested measure that according to Iqvia would not compromise the demonstration of biosimilarity. Improvements at the regulatory level might also help to streamline development, together with global convergence of regulatory guidance. Iqvia also suggests the adoption of clear regulatory pathways to incentivise the development of the next-generation, one-off biosimilar gene- and cellular treatments. Access might be improved by optimisation of market conditions, with incentives for clinicians combined with the introduction of prescription targets. New tender models would also be needed to favour multi-winner procurement practices.


The hearings at the ENVI committee on the revision of pharmaceutical legislation

by Giuliana Miglierini

As a part of the ongoing process of revision of the pharmaceutical legislation, the Committee on Environment, Public Health and Food Safety (ENVI) of the European Parliament hold a public hearing on 20 September 2023 with the EU Commission’s representative Mr Florian Schmidt (DG Santé). We summarise the main contents of the hearing.

The proposals of the Commission

The proposed package is comprehensive of a new Regulation introducing specific measures for innovative medicines, new rules on how to manage shortages and a new framework for the governance of the European Medicines Agency (EMA). The new Directive redefines pathways for regulatory authorisation and incentives for the development of various types of products. The third part of the package is the Council Recommendation on antimicrobial resistance (AMR).

As highlighted by Florian Schmidt, the proposed reform is characterised by six key political objectives, starting from the creation of a Single European market of medicines, claimed to represent a key factor to improve access to new medicines especially in the smaller Member States.

The Commission also aimed to improve the availability of critical medicines, acting on the long-lasting issue of shortages and security of supply, while addressing the sustainability of healthcare systems.

The global competitiveness of the European pharmaceutical sector would be supported by a more flexible regulatory framework, while the compulsory Environmental Risk Assessment (ERA) would improve the environmental sustainability of medical products. Last, but not least, is the fighting of antimicrobial resistance.

Main comments from ENVI rapporteurs

The hearing saw the intervention of the two rapporteurs of the EU Parliament (Pernille Weiss and Tiemo Wölken) and of several members of the ENVI Committee involved in the discussions on the proposals. The general objectives of the Commission are shared by Parliament, but some elements requiring optimisation emerged during the hearing.

As indicated by Rapporteur Pernille Weiss (Denmark), the ambitious target of improved access to a greater number of medicines for all EU citizens would require also a similar pricing structure and access across Member States. It would be important to ensure a fair playfield, as the pharma legislative package is expected to exert effects on EU competitiveness and access.

According to Ms. Weiss, the actual level of protection a new medicinal product might achieve would be dependent on how IP protection is regulated in different Member States. Pricing structure is also a matter falling under national competences. On this basis, the objective to guarantee access to medicines at lower prices to all Europeans should be considered vs the need to guarantee appropriate data protection. Without a national module on data protection, said Ms. Weiss, it would be very difficult to manage the system, and a realistic approach would be advisable.

Mr. Tiemo Wölken (Germany) supported the removal of the traditional one-fits-for-all approach, in favour of the modulation of regulatory protection. According to the Rapporteur, it would be a mistake to think that more R&D would be only generated with longer protection. Instead, a compulsory reinvestment of a certain percentage of turnover in R&D would be advisable in order to benefit from EU protection. This provision would help stopping the migration of companies towards China or India, despite they may had already experienced a very high level of protection in the EU.

Mr. Wölken was also not convinced the Transferable Exclusivity Voucher (TEV) would be the appropriate form of incentive to support research in new antimicrobials, as a great number of these activities are run by small and medium-sized companies (SMEs). The TEV would benefit big pharma players that would acquire the vouchers. According to the Rapporteur, this might lead to a sort of blockbuster scenario, delaying access of generics to market. TEVs would also not guarantee safety of supply: the Rapporteur mentioned the need of a new wording to be introduced in the text to guarantee the availability of antibiotics in the EU market, should the voucher be maintained in the final form of the proposal.

Finally, Mr. Wölken welcomed the provisions aimed to prevent and mitigate shortages and to ensure safety of supply of critical medicines. To this instance, he mentioned the transparency of marketing authorisation referred to production and the supply of medicines as key factors companies should be made accountable for.

Main comments from other ENVI members

MEP Tomislav Sokol (Croatia) highlighted the need to bring back innovation to the EU. Identified issues in the Commission’s proposals refer to a better balance between incentives for R&I, and the need to find the real value and access to new therapies. More in particular, incentives should focus in areas of major gaps, but for many companies their modulation may pose problems as they might have not enough capacity to serve all Member States.

Mr. Sokol proposed to better define these aspects so to improve the certainty and predictability for companies. He added some areas in rare diseases and paediatric medicines would need more incentives, while regulatory sandboxes can present opportunities for testing promising products.

According to MEP Monika Bénová (Slovakia), it would be very important to improve access to affordable medicines in small European countries by acting on rules on competitiveness, transparency and healthcare expenditure.

Ms. Bénová added it would be positive to have a shorter regulatory process, but not at the expense of safety and pharmacovigilance.

She also asked the Commission what the planned actions in the field of AMR are. Monika Bénová said the high profits pharma companies made in the last few years should be used for public health, and not only as a profit tool, especially during emergencies or pandemics. A goal that should be supported by new rules for better transparency in public procurement.

French MEP Catherine Amalric said a balanced framework would be needed to safeguard all interested parties. Support to research and innovation is essential in order to compete on the global scenario, but it would be important to avoid unrequested delays to investments and development.

According to Ms. Amalric, it would be also advisable to adapt to technological changes. Activities should be planned on all scales, from SMEs to big companies, while maintaining the autonomy and authority of the EU in the field of medicines. To this instance, more rapid procedures and a stronger role for EMA were suggested, among others.

It would be also advisable to have harmonised good practices in the field of pharmacovigilance. The digital revolution should be taken in mind, as well as the Green Deal: to this instance, Catherine Amalric supported the approach of the Critical Medicines Act.

According to MEP Frédérique Ries (Belgium), the proposals of the Commission may create a worrying hierarchy between rare diseases and medicines for very important needs. She said the Expert Group for incentives for orphan diseases proposed a much more pragmatic framework for prioritisation, asking the Commission if it was considered.

The participation of patients in the marketing authorisation procedures should be also approached from a pragmatic point of view, she added. As for access, Ms. Ries said active European support would be needed as for joint purchasing, something that would turn important for medicines entering the PRIME programme.

According to MEP Tilly Metz (Luxembourg), the balance between incentives and access is yet not optimal, as it is mainly focused on IP protection. New solutions are needed, including a greater emphasis on conditions for access and public subsidies independently from the form they assume.

Ms. Metz also indicated that the authorisation pathway for medicines for unmet medical needs appears too vague, thus potentially leading to some confusion. Available options should be better clarified, while in the field of antibiotics long-term solutions would be needed. Tilly Metz said TEVs would not represent the needed solution, as it would highly impact healthcare systems without solving the issue of access. Ms. Metz mentioned also the impact assessment of incentives targeted to R&D in the field of antibiotics, an area where would be advisable not to look only to solutions that please the industry. A European Fund for R&D in antimicrobials would be needed instead.

Furthermore, comparative studies should be always included, while their reference to the incentives scheme only would not represent the correct approach. Speaking on behalf of an absent MEP, Tilly Metz mentioned an issue with the Directive due to the non-inclusion of manufacturing in the Environmental Risk Assessment. It would be advisable to look at all the lifecycle of environmental risk, she suggested, as it was proposed in the first draft of the Commission.

MEP Joanna Kopcinśka (Poland) said Europe is still dealing with shortages of raw materials, something that also impacts access to medicines in different countries. It would be important to ensure a fair market in all the EU, by means of legal tools that would smooth out differences between countries.

Ms. Kopcinśka rejected the hypothesis of restrictions on marketing authorisations linked to environmental considerations, as this would be detrimental for patients. As for safety, the Directive would present some crucial aspects referring to active substances, especially in the case raw materials are manufactured outside the EU. It would thus be needed to include a clear definition of critical medicines, and the new methodology should be based among others on the therapeutic importance of critical medicines.

Speaking on behalf of an absent MEP, Ms. Kopcinśka said in the field of rare diseases is often difficult to reach a number of patients sufficient to test new substances. Innovation is key, and research should be of interest for investors in the EU.

MEP Peter Liese (Germany) strongly supported the TEV system, as according to him no other better proposal emerged in the past ten years. On the other hand, Mr. Liese judged not good enough the proposal on innovation, as six months’ incentives would not be sufficient.

The reply of the Commission

The hearing closed with the reply of Mr Florian Schmidt, who was happy to see sharing of the general objectives by MEPs even if not of all the proposed solutions. Mr. Schmidt mentioned the importance of SMEs and the specific measures planned to support them in the pre-authorisation phase and modelisation.

The Commission tested the different options available to model incentives, he added; the final choice was based on the ambition not to burden more on national systems, and the will to achieve a broader and earlier access for patients.

As for the voucher system, the Commission planned very closed conditions aimed at allowing for the issuing of no more than 10 TEVs in 15 years. According to Mr. Schmidt, this should improve the predictability of the system and the calculation of effects on healthcare systems.

He also mentioned the introduction of some new requirements in the Paediatric Investigational Plan in order to close some current loopholes in paediatric research. The Commission made no shortcuts on safety while reviewing the regulatory framework, he added, for example for the first time it was introduced the possibility to kick out the system for immature applications.

As for the proposed hierarchy of standard rare diseases and medicines for high unmet medical needs, according to Mr. Schmidt there was no intention in considering medicines for standard rare diseases less important. He also reassured MEPs on the involvement of patients in regulatory discussions and on ERA, that would not represent any risk for compliant companies.


Insights to the Industrial Pharmacist role for the future

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A concept paper from EIPG Advisory Group on Competencies vol.2, 2023

This paper is an update of the previous EIPG paper and intends to raise awareness of the changing requirements of the professional profile of Industrial Pharmacists for Pharmacists at any stage of their career who intend to pursue careers in the Pharmaceutical Industry and those involved in the education of Pharmacists to update the education provided accordingly.

This paper is aimed at Pharmacists at all stages of their careers, including Pharmacy students, early career Pharmacists and Pharmacists working in a sector other than the Pharmaceutical Industry. The considerations presented are based on the collective expertise of the group. Therefore, this paper should be consulted as a starting point and is not a complete discussion of Pharmacist knowledge, competencies and skills nor a comprehensive overview of the Pharmaceutical Industry.

The EIPG with responsibility for the Pharmaceutical World, decided to continue the Project of the Advisory Group of Competencies. They used as a baseline document the first version of the position paper from 2020, in order to update the missing or outdated areas in the Pharmaceutical Industry. By examining some new trends and evolutions in drug science and technology, they explained the opportunities and challenges that are likely to arrive. All this information is intended for those at any stage of their Pharmacy career who want to understand their potential within the Pharmaceutical Industry.

The target of the project is to evaluate and determine the roles where the Industrial Pharmacist will work in the future and what knowledge, competencies and skills are needed to fulfill the requirements in these future roles. It is a shared understanding that there are gaps in the current curricula, but academia cannot cover all the needs of the Pharmaceutical Industry. For this reason, the Advisory Group have made some recommendations and proposals to recognize and fill those gaps. Hence, Pharmacists will have a clear view of the various roles in the pharmaceutical life cycle, and will be able to identify areas to develop on order to secure selected roles in the industry. This document may also be helpful in differentiating Pharmacists from other professions when applying for these roles.

You may find the full paper here.


The New Pharmaceutical Legislation

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by Jane Nicholson

To celebrate the 70th Anniversary of the foundation of the Belgian Association of Industrial Pharmacists (UPIP-VAPI) a Seminar on “The New Pharmaceutical Legislation” was held on 8th September in the European Parliament. The meeting was arranged in conjunction with the General Assembly of the European Industrial Pharmacists Group (EIPG) with attendance from participants of at least 15 European countries.

Frank Peeters, President of UPIP-VAPI opened the meeting and Alexia Rensonnet, a Board Member, described the new legislation as the largest reform in the past 20 years. The existing directive and regulations are to be replaced by new legislation with the objective of creating a single market to ensure all patients have timely and equitable access to safe, effective and affordable medicines whilst continuing to offer an attractive and innovation friendly market for suppliers.

Lilia Luchianov, Policy Officer at DG Sante – European Commission, said that the new legislation envisaged a leaner regulatory environment through simplification, regulatory modernisation and digitalisation. There will be access to both innovative and established medicines and incentives for innovation so that European companies remain globally competitive. Regulatory responsibilities will be shared between the EU and Member States. As well as changes to the General Pharmaceutical Legislation there will be changes to the Orphan and Paediatric legislation. Pre-authorisation support and a faster approval process including “targeted approach” rather than the current “one size fits all” are proposed.

The proposed reduction of protection for innovative products and the market launch conditions were questioned by several participants. Some of the current challenges for the Commission were said to be that pricing, reimbursement and procurement are a national competence.

In response to the current growing concerns on shortages, the Commission’s suggestions include the publication of an EU list of critical medicines, improved coordination of monitoring, earlier industry notification of shortages and withdrawals, improved industry shortage prevention plans, stronger coordination by the EMA and more legislative powers for the Member States and the Commission. During the discussion period Maggie Saykali, Director of the European Fine Chemical Group challenged the Commission to provide economic conditions for the manufacture in Europe of raw materials used by the pharmaceutical industry. Rather than dependence on China or India, European supply of raw materials would enormously improve security of supply of pharmaceuticals as well as improve worldwide environmental sustainability.

Par Tellner, Director of Regulatory, Drug Development and Manufacturing for the European Federation of Pharmaceutical Industries and Associations presented EFPIA’s views on the proposed revision to the pharmaceutical legislation. Whilst he welcomed the opportunities for regulatory modernisation such as simplification of the EMA structure by reducing the Scientific Committees from 5 to 2 and abolishing product licence renewals there are a number of challenges ahead. These include the notable reduction of research and development incentives, the added burden for industry to implement environmental risk assessments and the actual root causes of non-availability of medicinal products in the markets of Europe.

Jean-Paul Pirnay, head of LabMCT, Queen Astrid Military Hospital presented the past present and future of bacteriophage therapy. Wherever you find bacteria, you find phages which have been used since 1923 with the establishment of the Phage Institute in Tblisi (GEO). Although abandoned in the West many years ago, the Russian USSR has kept using phage therapy. Some isolated laboratories have been further developing and using phages and it has been shown that you need a handful of phages to target one bacterial spp.

Jean-Paul’s laboratory has helped establish a phage bank in a controlled environment. A single phage API can be produced according to a monograph. Individual phages can then be mixed together to target a particular bacterium. 100 seriously ill patients with resistant bacteria have been treated in 35 hospital of 29 cities and 26 phages were found to be needed. Eradication of the target bacterial infection was found in 61% of cases. In addition, phages were found to be synergistic when used with antibiotics. Jean-Paul considers commercially viable broad spectrum phage cocktails may be produced in the future.”

Geert Verniers (Lector SCM and Researcher BM-expertise center VIVES University) and his colleague described the use of Drones in the transportation of medicinal products,biological samples and tissues. With traffic congestion on roads causing gridlock around many hospital centres and personalised medicines needing urgent delivery from one area to another, the use of drones for professional transportation is compelling. Various significant points for consideration were discussed. These included the type of drone, drone pilots and Cargo Ports, the design of routes and the complexity of regulation, environmental impact, vibration problems and temperature control.

Following a lengthy discussion period, Frank Peeters thanked the speakers for their interesting contributions and all those responsible for this meeting being held in the European Parliament.


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

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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.


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.


How to prepare to the entry into force of CEP 2.0

By Giuliana Miglierini

The implementation process of the revised Certificates of suitability to the EU Pharmacopeia (CEP 2.0) is marking a new step, as announced by the European Directorate for the Quality of Medicines & HealthCare (EDQM).

Starting on 1 June 2023, it will be mandatory to provide, in the application forms for new dossiers, sister files and revisions and renewals, the EMA SPOR/OMS ORG_ID and LOC_ID for all companies involved in CEP dossiers. According to the Directorate, revised application forms for CEP submissions will also soon be available.

The process to redesign CEPs started in late 2020 with a public consultation, followed by a second, more targeted one in 2022. Received comments have supported the shaping of new CEPs by the Certification Steering Committee; CEPs 2.0 are expected to entry into force in 2023.

All changes made in the nine areas related to CEP’s submission and processing are detailed in a document available at the EDQM website. These include among others the assessment of CEP applications, on-line public certification and authorities’ databases, information sharing between CEP holders and marketing authorisation holders, the reduction of revisions, the assessment of the impact of changes and their implementation, training for both CEP holders and users, and the revision of documents available on the EDQM website.

The new mandatory data

ORG_ID and LOC_ID are unique identifiers for, respectively, an organisation and its locations. CEPs 2.0 will mention these details together with the company name and address in order to support a better identification of the specific facility involved in the manufacturing process.

The EDQM’s suggestion is to obtain as soon as possible an ORG_ID and LOC_ID, as these data will be requested for ongoing submissions during the evaluation of the dossier. The responsibility to assign the two identifiers falls under the European Medicines Agency (EMA), and it is managed through the SPOR/OMS database. All information needed to request the identifiers is available at the dedicated page on EMA’s website.

The EDQM has also launched a public consultation on the draft template of the letter of access deemed to replace the declaration of access box on the CEP document. The consultation will remain open until 16 April 2023, and it can be accessed from the consultation space of the EDQM’s website.

Insights of the new CEP 2.0

CEP 2.0 will be a digitally signed electronic document, that applicants for a marketing authorisation need to include in the authorisation dossier. CEP holders can choose to print it or share it with their customers in the pdf format.

The undergoing revision of the CEP’s renewal procedure will lead to a change in the numbering of the certificates. As mentioned above, the previous declaration of access box will be replaced by a letter of access, and ORG_ID and LOC_ID validated organisation data will become mandatory for all CEPs’ applications.

CEP’s contents will also be revised, with respect to the information provided for chemical purity, Herbal Drug/Herbal Drug preparations and related to the quality of the substance.

A new appendix detailing the specification applied by the CEP holder and the additional methods to control the quality of the substance approved during the assessment of the CEP dossier will replace the section on “Technical” information (e.g. additional controls for impurities or solvents). CEP 2.0 will also contain information on the quality of water used in the last steps of the synthesis of the substance.

Under the new framework, the CEP dossier, the assessment performed, and the approved specifications will be fully aligned. This means that unapproved information shall be excluded from the dossier. For example, process description and specifications should refer only to information corresponding to the claimed quality. Inclusion of stability data in CEP applications will be encouraged, also with reference to additional climatic zones.

CEPs 2.0 will be available through the public CEP database on the EDQM website. The information provided will include ORG-ID and LOC_ID identifiers and the history of the finalised procedures for each CEP application, so to make available a more transparent source of information but avoiding any reference to the exact changes introduced in the CEP dossier.

The revision of CEP 2.0 is expected to run more smoothly, as only changes impacting on CEP contents will lead to the issuing of a revised certificate. This means also that the numbering of CEPs will change, as it will be removed the part related to renewal.

Sharing of information with authorities and customers

Confidential information on the lifecycle of CEP applications, together with copies of the current CEPs and CEP assessment reports, will be available within a the separate Authorities database. Access to this database shall be granted to licensing authorities of the member states of the Ph. Eur. convention, in order to support the review of marketing applications for medicinal products where a CEP is included. This second database will also be enriched with the new information, including the two mandatory identifiers, CEP number and CEP document corresponding to each procedure of a dossier. Access may also be granted to regulatory authorities upon signature of confidentiality agreements or a Memorandum of Understanding.

Under the new CEP 2.0 framework, CEP applicants shall also commit to share information with their customers as part of the application form for a CEP. Not only a specific sentence will be added to the CEP document, but compliance will also be verified during inspections.

Steps in the implementation of CEP 2.0

The “new look” electronic CEPs will include all the above-mentioned innovation in contents, i.e. move of specifications and additional methods to an appendix, new numbering, SPOR/OMS LOC/ORG ID, letter of access, e-signature, etc. This type of document will be issued for any new CEP granted and after the renewal procedures (request of dossier integration is possible).

As for already existing CEPs, “hybrid look” certificates will be granted after approval of revision applications and notifications should the content be impacted, but without appending the company’s specifications. “Old look” CEPs refer to certificates granted before the implementation of CEP 2.0. These will maintain their validity until revision occurs.

The EDQM announced the publication of some training materials to facilitate users to navigate across the different types of CEPs. Webinars should also be organised in May 2023 to support the implementation of CEP 2.0.

The new framework will also impact on a series of other EDQM documents available under the “Certification policy documents and guidelines” section of the website. These will also undergo a progressive revision, and include among others applications forms, content of the dossier for chemical purity and microbiological quality, EDQM guideline on requirements for Revisions/Renewal of Certificates of Suitability to the EU Pharmacopoeia Monographs, etc.


The Windsor Framework

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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.

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EDQM introduces a consultation phase in the management of CEP documents

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by Giuliana Miglierini

The new process implemented by the European Directorate for the Quality of Medicines and HealthCare (EDQM) for the elaboration of documents related to the Certification of Suitability  (CEP) procedure includes a newly inserted consultation phase. This new step, which may be public  or targeted to specific groups of stakeholders, aims to increase the transparency of the  elaboration process and offers stakeholders the possibility to forward comments to the draft documents  in order to optimise them.

Transparency and efficiency are also the main goals inspiring the overall new elaboration process, which covers the entire pathway of CEP documents, from development, through consultation,  up to final adoption, publication and implementation.

A dedicated page on the EDQMs’s website will host the documents open to consultation, together with the respective instructions for the stakeholders wishing to submit comments. Announcements  on new documents available for consultation will be made on EDQM Certification webpages.  The CEP Steering Committee will be responsible for the elaboration process for CEP documents, in compliance with the EDQM document CEP Terms of Reference and Rules of Procedure (PA/PH/CEP (01) 1).

The elaboration process will cover both public documents (the main part), as well as those the CEP Steering Committee would indicate as restricted for use by the bodies involved in the CEP  procedure. The new process does not cover the Resolution on the Certification procedure, which falls under another specific process established by the Council of Europe.

A guidance to understand the new process

The management of CEP guidelines and operational documents for the CEP procedure has been described in a specific guidance issued in November 2022 by the EDQM’s Certification of Substances Department.

The guidance covers a broad range of documents participating from different perspectives to the CEP procedure. The elaboration of the different types of documents may slightly differ from one another, with possible exemptions from some steps, for example in the case of minor revisions (which in any case always have to be full justified and documented). All CEP documents will be drafted in English; the guidance provides indication of the format to be used to establish the unique reference code for governance documents and technical guidelines (PA/PH/CEP (XX)  YY), as well as for the revision number (ZR) where needed.

 The EDQM specifies that the implementation date of the newly approved CEP documents will be such to allow interested parties to have enough time to comply with the new or revised requirements.

Governance documents define procedural aspects for the practical implementation of the CEP procedure. The initial draft will be prepared by the EDQM and reviewed and agreed upon by the CEP Steering Committee before entering the consultation phase. Comments collected will serve as the basis to consolidate the final version of the document. A second round of consultation may be needed in case of critical comments preventing finalisation. The adoption of the final document falls under the responsibility of the CEP Steering Committee, which may also indicate the need to improve and re-submit the draft before adoption. Once the final version of the document is available, its publication on the EDQM’s website and implementation will close the process.

Technical guidelines inform about the requirements applicants should fulfil for the submission or evaluation of CEP applications. Their drafting may be initiated also by members of the relevant Technical Advisory Board (TAB), in addition to the EDQM. The TAB is also called to review and agree upon the draft document before the assessment and approval by the CEP Steering Committee and the following consultation phase can take place. The same applies to the consolidation of comments and finalisation of the document, that has to be approved by the relevant TAB. In this case too, a second round of consultation is possible should criticalities arise during the first one, followed by adoption by the CEP Steering Committee (and a possible second round of updating and approval by the TAB, if needed), and publication and implementation.

The management of specific aspects of the procedure can be supported by the issuing of administrative or operational documents. These documents fall under the responsibility of the EDQM, that may consult the CEP Steering Committee of other parties where necessary.

The consultation phase

A specific chapter of the EDQM’s guidance describes the newly inserted consultation phase, those details (type of process and duration) will be decided on a case-by-case basis by the CEP Steering Committee.

In the case of a public consultation, the draft document will be made available at the dedicated page of the EDQM website. The draft may also be sent to identified relevant stakeholder organisations, to ensure a better awareness of the ongoing process.

Targeted consultations aim to obtain feedback from selected stakeholders on specific areas of intervention. In such instances, the forwarding of the draft document will be restricted only to identified interested parties, including regulators and relevant industrial associations or other organisations.

According to the type of document and/or the topic under consultation, the consultation phase may vary in duration. To this instance, the guidance indicates a possible range between 3 weeks and 3 months, with the effective duration to be communicated as a part of the call for consultation.  A template will also be available to submit comments, which should be always justified and contain concrete proposals for action to tackle the issue under consideration. All comments and justifications received will be transmitted to the groups in charge of approving and adopting the documents.

At the end of the elaboration process, the final approved versions of CEP documents will be published on the EDQM’s website.   


ICMRA report on best practices against antimicrobial resistance

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by Giuliana Miglierini

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

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

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

Regulatory flexibility

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

Antimicrobials for veterinary use

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

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

Regulatory agilities during the Covid-19 pandemic

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

Non-prescription availability of antibiotics

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

Reimbursement models for novel antimicrobials

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

Selective antibiograms to inform antimicrobial choice

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

Feedback on prescriber data

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

Common infections in outpatient care

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

Methods for monitoring AMR in the environment

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

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