The proposals of the EU Commission for the revision of the IP legislation

May 12, 2023

Bolar exception, central examination, central SPC database, Chips Act, compulsory licensing, crisis, EFPIA, emergency, EUCOPE, EUIPO, European Commission, fragmentation, FRAND, generics, HERA regulations, intellectual property, IPR holders, Medicines for Europe, member states, plant protection products, regulation, remuneration, revision IP legislation, revision pharmaceutical legislation, SEP, single application, Single Market Emergency Instrument, SMEs, SPC, standard developing organisation, Standard Essential Patents, Supplementary Protection Certificates, technical standards, unitary patent, Unitary Patent Court, unitary SPC, UPC, voluntary licensing

By Giuliana Miglierini

In parallel to the new pharmaceutical legislation, on 27 April 2023 the EU Commission issued the proposal for the new framework protecting intellectual property (IP). The reform package impacts on the pharmaceutical industry, as it contains proposals on Supplementary Protection Certificates(SPCs) and compulsory licensing (CL) in crisis situations. It also includes a new Regulation on Standard Essential Patents(SEPs).

The proposed reform, which is part of the EU Industrial Strategy, will now undergo the scrutiny of the European Parliament and Council. It aims to improve European competitiveness, innovation and technological sovereignity, with a special attention to the role played by SMEs. The proposal is based on comments received during the consultation on the Action Plan on Intellectual Property issued in November 2020. The IP legislative framework will complement the Unitary Patent system, that will fully entry into force on 1 June 2023.

Supplementary Protection Certificates

Central to the reform of the SPC system is the creation of a unitary SPC to complement the Unitary Patent. The aim is to reduce the current fragmentation in the issuing of SPCs at the national level, which often leads to complex interpretation of patents’ expiry dates, and consequent legal uncertainty. The new system would not replace the existing national SPC schemes.

Procedures should be simplified, with a single application to be submitted to the EU Intellectual Property Office (EUIPO), which would be responsible for its central examination in close cooperation with EU national IP offices. The process would lead to national SPCs granted for each of the designated member states (MS), plus a unitary SPC if required by the applicant (here the Q&As).

According to the Commission, approx. 25% of current SPC procedures have contradictory outcomes. The mean number of annual SPC applications is 81 per MS, with a total cost of €192,000 over the 5 years of duration (compared to roughly €3,000 in the US and €4,200 in Japan). Savings from the new procedures may amount to up €137,000 for the EU27 wide, five years long SPC protection. A central SPC database is also planned in order to increase transparency.

The proposed reform is comprehensive of a Regulation specific to medicinal products and a second one focusing on plant protection products, plus parallel recasting regulations to review the current legislative provisions (i.e. Regulation (EC) No 469/2009). Innovators would be incentivised to use unitary SPCs, since otherwise a unitary patent could be extended at higher costs only by means of national SPCs. Infringements of unitary SPCs would fall under the judgement of the UPC Court.

The Commission expects the development and access to generic medicines will be facilitated. In particular, SMEs will be able to submit observations during the examination of a centralised SPC application, and to file an opposition in order to centrally challenge the validity of the SPC protection, if justified. The new framework complements the proposed pharmaceutical legislation, for example on the Bolar exception. This should allow the generic industry to perform research and testing for preparing regulatory approval also while a patent/SPC is still in force.

Compulsory licensing

Compulsory licensing may be used during crisis in order to provide access to relevant products and technologies, should result in impossible (or not adequate) to close voluntary licensing agreements with owners of IP rights. The current fragmentation of procedures at the national level results in a wide legal uncertainty (see also the published Q&As). The new framework would complement other EU crisis tools, such as the Single Market Emergency Instrument, HERA regulations and the Chips Act.

According to the proposal, a Union compulsory licence can only be granted after activation of an emergency or crisis mode at EU level. Instruments to trigger this fundamental passage are listed in an Annex, so to improve legal certainty. A remuneration scheme for IPR holders is also included, on the basis of successive steps in the activation and termination of compulsory licensing.

The existing national frameworks on compulsory licensing will continue to operate, and they may be used to manage local crisis. Compulsory licensing of exported products would not be allowed.

Standard Essential Patents

SEPs refer to technologies essential for the implementation of a technical standard adopted by a standard developing organisation. They are typical of the ITC industrial sector, and central to building the Internet of Things.

To improve the transparency and legal certainty of SEPs, the proposal aims to ensure innovation would be run in the EU by both EU SEP owners and implementers. End users would benefit from products based on the latest standardised technologies at fair and reasonable prices. SEPs licensing is based on the FRAND scheme (fair, reasonable and non-discriminatory) for the remuneration of patent holders.

Comments from the stakeholders

EFPIA granted positive feedback on the simplification and harmonisation of the SPC system and to the opportunities offered by the unitary SPC. On the other hand, the proposals on compulsory licensing didn’t find the agreement of the research-based pharmaceutical industry.

According to a note, voluntary licensing would be the preferred instrument for innovators, as it allows for the choice of the best-positioned and trusted partners to speed up production and distribution of medicinal products during health crisis. On the contrary, compulsory licensing is seen as a threat to investment stability of the EU’s IP system and to the overall innovation pipeline.

“Protecting the EU’s intellectual property framework could not be more important if we are to close the investment gap between Europe, the US and increasingly China and continue to offer patients the best possible treatments. Yet we are seeing multiple proposals emerging from the European Commission in the pharmaceutical legislation and patent package which tend towards the opposite”, said EFPIA Director General Nathalie Moll.

Medicines for Europe (MfE), on behalf of the generic and biosimilar industry, said that while “voluntary licensing agreements are relevant for health crises, we will contribute constructively to the EU-wide compulsory licensing system”. The request to the Commission is to make it a remedy also for anti-competitive abuses of the patent system, according to art. 31(k) of the TRIPS Agreement.

As for new SPCs, MfE highlights the new regime would extend their geographical scope from the current 20 out of 27 MS covered on average. “The proposal for a reform in the SPC system has the potential to reduce fragmentation in Europe but the legislation must ensure improved quality and transparency of granting procedures to prevent misuse by right holders to delay competition”, said MfE Director General Adrian van den Hoven.

Critics of the proposed scheme for compulsory licensing also came from EUCOPE, representing pharmaceutical entrepreneurs. According to the Confederation, the Commission’s proposal would further weakening the value of intellectual property rights within the EU. “Together with the proposal on the revision of the general pharmaceutical legislation, it is another indicator that the development of an innovation-friendly environment is not a priority, contrary to statements in the Intellectual Property Action Plan”, it states in a note.

For EUCOPE, the proposed SPC regime would not amend the substantive elements of the current system. Furthermore, a centralised SPC application would only be possible on the basis of a European patent, including a unitary patent, and for products with a centralised marketing authorisation. EUCOPE position goes for an optional EU-wide SPC, so to allow flexibility for IP owners in deciding their strategy for the protection of IP rights.

Webinar: ICH Q12 Product Lifecycle Management – open road or dead end?

March 24, 2023

American Sociaty for Testing Materials, ASTM, British Pharmacopoeia, College Cork, Compliance Information, E55, EFPIA, eipg, Graham Cook, guideline, ICH, ICH Q12, MQEG, PIER, Product development, Product Lifecycle Management, Q12, Quality Intelligence, Technical Comittee, webinar

Next EIPG webinar is to be held on Tuesday 18th April 2023 at 17.00 CEST (16.00 BST) in conjunction with PIER and University College Cork. Graham Cook, former Pfizer’s Quality Intelligence and Compliance Information team leader and chair of EFPIA’s Manufacturing and Quality Expert Group (MQEG) will explain the context for the development of the ICH Q12 guideline on Product Lifecycle Management.

The ICH Q12 Product Lifecycle Management guideline reached step 4 in the ICH process in November 2019 – where are we with the adoption of this guideline? This webinar will provide an overview of the content, and discuss the opportunities and implications for implementation of Q12 by industry and regulators.

Graham Cook is a pharmacist with a Ph.D. in pharmaceutics. He was appointed to the British Pharmacopoeia Commission between 2010 and 2021 and chairs the Medicinal Chemicals (MC2) Expert Advisory Group and the Analytical Quality by Design Working Party. Between 2012-2018 he was Chairman of the American Society for Testing Materials (ASTM) International E55 Technical Committee developing pharmaceutical manufacturing standards and continues to serve as a member of the E55 Executive Committee. He was a past chair of Pfizer’s Quality by Design Council and previous roles include Technical Director supporting Wyeth Europa Manufacturing and External Supply, and Director Formulation Development for Wyeth Consumer Healthcare (Richmond, Virginia, USA).

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

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

February 10, 2023

Alliance for Regenerative Medicine, API sources, ATMPs, ATMPs withdrawn, Canada, centralised ePI repository, complex clinical trials, cost of inflation, decentralised clinical trials, declining competitiveness, developers headquarters, digitalisation of regulatory processes, drug-device combinations, dynamic regulatory assessment, economic model for generic medicines, EFPIA, electronic product information, EMA’s committee structure, EMVS, ePI, epidemiological data, EU Commission, European reporting system, European strategic reserve, expedited regulatory pathways, Falsified medicines directive, flexibility, global open supply chains, harmonisation of packs, harmonised EU prevention and mitigation system., ICH Q12, in-vitro diagnostics, innovation model, innovative approaches to clinical trials, interoperable IT European monitoring/ notification system, iterative data generation, joint procurement, Medicine Security Act, Medicines for Europe, national stockpiling requirements, New Industrial Strategy for Europe, notified bodies, ongoing industry clinical trials, parallel advice, pharmaceutical product lifecycle management, Pharmaceutical Strategy for Europe, pharmaceutical supply chains, price caps requirements, Public Procurement Directive, real-world data, real-world evidence, reduction of variations, regulatory flexibility for packaging, regulatory framework, regulatory mitigation measures, review of the pharmaceutical legislation, rolling reserves, root cause of shortages, shortage prevention plans, shortages of medicines, Staff Working Document, standard definition of shortage, structured dialogue, targeted incentives, thresholds for nitrosamines, transformative treatments, Transparency Directive, unmet medical need, Variation Regulation

By Giuliana Miglierini

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

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

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

EFPIA proposals for action

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

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

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

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

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

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

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

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

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

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

Medicines for Europe, focus on access and prevention of shortages

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

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

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

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

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

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

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

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

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

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

The vision of the ATMP sector

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

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

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

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

November 25, 2022

addendum method validation strategy, analytical knowledge, Analytical Procedure Development, Analytical Quality by Design, Analytical Target Profile, API intermediates, APIC, APIs, biosimilars, calibration model, characterisational assays, EANM, ECA Foundation, EFPIA, eipg, ema, European Association of Nuclear Medicine, European QP Association, EWG, Expert Working Group, generics, Gliossay, guidelines, harmonisation, ICH, ICH Q12, ICH Q14, ICH Q2(R2), International Society for Pharmaceutical Engineering, ISPE, lifecycle management, Medicines for Europe, multivariate analytical procedures, multivariate calibration, MVA models, OMICS methods, overview documents, PACMP, performance characteristics, performance criteria, pharmaceutical active ingredients, Phil Borman, Plasma Protein Therapeutics Association, plasma-derived and recombinant analog therapies, Post Approval Change Management Protocol, post-approval changes to analytical procedures, PPTA, precision, public consultation, radoopharmaceuticals, range, regulatory change management, risk assessment, TAE, Total analytical error, traditional analytical methods, training case studies, validation, validation elements, Validation of Analytical Procedures, webinar

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.

EFPIA’s Annual Report on the Pharmaceutical industry 2022

September 9, 2022

Annual Report 2022, Brazil, China, direct employment, EFPIA, export, fast-growing markets, fragmentation, France, Germany, high-growth pharmaceutical markets, highly skilled jobs. brain draining, import, India, indirect employment, Italy, market value at ex-factory prices, new chemical entities, new launches, parallel trade, pharmaceutical expenditure, Pharmaceutical industry 2022, prescription medicines, R&D expenditure, retail price of medicines, Spain, statutory health insurance systems, Switzerland, time to approval, top 5 European pharmaceutical markets, total costs of R&D, trade balance, UK, US, value of production, VAT rates for medicines

by Giuliana Miglierini

“In the 21 years from 2000 to 2021 – in which time we’ve come through the Global Financial Crisis and a pandemic – EFPIA companies have more than doubled production, increased exports by a factor of six, and recorded a trade balance that puts it far ahead of other high-tech sectors in Europe”, writes EFPIA’s Director General Nathalie Moll commenting the Annual Report2022.

Despite this marked growth, many challenges are still to be faced to allow the European pharmaceutical industry to maintain and even strengthen its role as primary hub of innovation, thus contributing to the overall success of the EU’s economy. It can be expected, for example, that the energy crisis will be highly impacting pharmaceutical productions, also in the form of increased difficulties to guarantee a constant supply of raw materials. This would represent just the last drop adding to existing regulatory barriers slowing down R&D and to the impact of fiscal austerity policies that may discourage investors.

“At the same time, we have seen the growth of Brazilian, Chinese and Indian markets outstrip growth in the top 5 European markets. Our global competitors have prioritised life sciences and we must respond with similar ambition”, adds Nathalie Moll.

The 2021 of the pharmaceutical industry

According to EFPIA’s Annual Report 2022, the value of production for the research-based European pharmaceutical industry has grown from 127.5 billion euro in year 2000 to 300 billion in2021. Even more relevant is the growth of export, increased from €90.9 bln to €565 bln over the same period. In 2021 imports counted for €390 bln, with a positive trade balance of €175 bln.

The research-based pharma industry employed last year 840,000 units (125,000 of which in R&D) and invested €41.5 bln in research and development activities.

The total European pharmaceutical market value at ex-factory prices increased from €89.4 bln in 2000 to €255 bln in 2021. The pharmaceutical expenditure supported by statutory health insurance systems (and referred to ambulatory care only) grown from €76.9 bln to €157.5 bln over the same time.

Despite these positive figures, EFPIA warns about the danger of migration of many R&D activities from Europe towards fast-growing markets such as Brazil, India and China, thanks to the more favourable conditions. The pharmaceutical market in these countries grown, respectively,11.7%, 6.7% and 11.8% in the period 2016-2021, compared to 5.8% of top EU countries (France, Germany, Italy, Spain and United Kingdom) and 5.6% of the US.

North America still represents the wider market area for pharmaceuticals (49.1%, vs 23.4% for Europe), and accounts for the higher proportion of new launches (64.4%, vs 16.8% of top five EU countries). In 2020 China marked the higher pharmaceutical R&D expenditure (78,5 billion Yuan, from 1.9 bln Yuan in 2000), overcoming for the first time the US ($72.4 bln), while Europe is positioned far behind (€39,7 bln). Not less interesting is the 3.2% market share assigned to emerging, high-growth pharmaceutical markets including many African, South American and Asiatic countries (Algeria, Argentina, Bangladesh, Brazil, Colombia, Chile, China, Egypt, India, Indonesia, Kazakhstan, Mexico, Nigeria, Pakistan, Philippines, Poland, Russia, Saudi Arabia, South Africa, Turkey and Vietnam).

Parallel trade is a characteristic of the European pharmaceutical market, due to the persistent fragmentation of many policies in different countries. Denmark saw in 2020 the higher share of parallel imports in pharmacy market sales (26.9%), well above other countries (e.g. 10.9% Sweden,9.1% UK, 8.3% Germany).

Issues slowing down R&D

According to EFPIA, the length of time needed to bring a new medicine to the market (up to 12-13 years) is still a major issue impacting the attractiveness of European R&D. An average of one-two new synthetic substances out of every 10 thousand exiting the labs passes all the scrutiny steps needed to reach approval. The total costs of R&D was estimated in 2014 to reach €1.97 billion, indicates the report.

Germany, Switzerland and the UK are the European countries more active in research and development (€7.8 bln, €7.4 bln and € 5.6 bln expenditure in 2020, respectively). Clinical research accounts for the higher percentage of investment (44.1%, mainly in phase III studies), far above pre-human and pre-clinical research (14.9%) and phase IV studies aimed to post-marketing surveillance (11.5%). Approval studies account for 4.3% of the total R&D expenditure.

The US generated 159 new chemical entities (both chemical and biological) in years 2017-2021, almost doubling Europe (72) and a group of other countries (71), excluding Japan (41). Even more worrying, in 2021 China lagged just behind Europe as originator of new active substances launched for the first time on the world market (18 vs 19, respectively), while the US confirmed its leading position (35). According to EFPIA, this trend is associated with a marked lower annual growth rate of pharmaceutical R&D expenditure in Europe (4.0% for years 2017-2021), compared to that in the US (8.5%) and China (12.9%). Despite this, health industries still position at the first place of the ranking of industrial sectors by overall R&D intensity (12.4%, vs 8.7% of ITC services and 7.4% of ITC products).

The pharmaceutical production

Switzerland, Germany and Italy are the leading European hubs for pharmaceutical production (€53.2 bln, €32.3 bln and €34.3 bln of value, respectively). This corresponds in Germany to a significant higher number of people employed in the sector (115,519, vs 66,400 in Italy and 47,000 in Switzerland). EFPIA also mentions that the research-based pharmaceutical industry generates about three times more indirect employment along its value chain (both upstream and downstream) than it does directly, thus significantly contributing to the overall European job market. This is even more true for highly skilled jobs, thus preventing the phenomenon of brain-draining towards more attractive countries for scientific talents.

The US remains the favoured trading partner for the EU pharmaceutical industry, accounting for 32.2% EU exports and 30.2% imports. Switzerland is at the first place for EU imports (36.4%, and 11.8% EU exports); more distanced are the UK, China and Japan.

Fragmentation still impacts the European market

Fragmentation of policies on price and reimbursement and different VAT rates for medicinal product sis a very typical phenomenon still limiting the potentiality of the European pharmaceutical market.

According to EFPIA, in 2020 the retail price of a medicine corresponded on average to 66.8% rewarding for the manufacturer, 17.4% for the pharmacist, 10.6% for the State and 5.2% for the wholesaler. The top 5 countries for market value at ex-factory prices were Germany (€42.9 bln), Italy (€23.4 bln), France (€29, 5 bln), the UK (€24.6 bln) and Spain (€17.6 bln); Russia also represented a relevant market (€18,4 bln). Italy sees the higher market share for generics (67.6%), well above Poland (58%) and Austria (49%). EFPIA also monitored the VAT rates applied to prescription and OTC medicines in different European countries, compared to the standard VAT rates. Malta (0%), Sweden (0%), France (2.1%), Switzerland (2.5%), Luxembourg (3%), Spain (4%), Lithuania, Croatia, Cyprus, Hungary (5%) marked the lower VAT rates on prescription medicines. In some case, these same rates applies also to OTC products (Croatia, Cyprus, Hungary, Luxembourg, Malta, Spain, Switzerland), while in other countries the rates for this category of medicines is higher (France 10%, Lithuania 21%, Sweden 25%).

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

July 8, 2022

accepted reference regulatory authorities, Access Consortium, Annual Regulatory GMP/GDP Inspection Survey 2021, BIA, collaboration, Communication, Compliance Monitor Process, Compliance Protocol, consultants, decision making, document review, domestic inspections, EC Decision Reliance Procedure, ECDRP, EFPIA, experience, foreign inspections, GDP, GMP, GMP compliance history, good regulatory practices, IAG, inspection planning, inspections, listed third countries, MHRA, MRA, Mutual Recognition Agreements, national competent authorities, NCA, on-site presence, physical inspections, Project Orbis, qualitative tool, Reflection paper, regulatory flexibility, reliance, Reliance Assessment Report, risk-based evaluation, risk-ranking quality metric, virtual tools

by Giuliana Miglierini

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

Main trends in inspections

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

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

A new mix of inspection tools

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

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

There is still space for improvement

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

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

How to further improve inspections

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

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

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

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

UK’s pilot of a Compliance Monitor Process

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

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

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

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

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

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

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

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

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

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

The main contributions to the consultation on the revision of the pharmaceutical legislation

March 4, 2022

academics, active pharmaceutical ingredients, advanced therapy medicinal products, Affordable Medicines Europe, Alliance of Regenerative Medicines, API manufacturing, ARM, ATMP, bedside manufacturing models, biosimilar medicines, Bolar exemption, centralised EU monitoring system, citizens, civil society organisations, combination products, community pharmacists, cross-border healthcare, Decentralised procedure, EFPIA, electronic Product Information (ePI), EU SPC framework, European Commission, GDP, generic manufacturers, genetically modified organisms, GIRP, GMOs, GMP, healthcare professionals, hospital exemption, hospital pharmacists, incentives, innovator industry, MAH, manufacturing, medicine repurposing, Medicines for Europe, medicines shortages, microbiome science, off-patent industry, parallel distributors, patent linkage, PGEU, pharmaceutical compounding, Pharmaceutical Group of the European Union, pharmaceutical industry, pharmaceutical legislation, post-authorisation activities, pricing and reimbursement, public consultation, public service obligations, radiopharmaceutical legislation, rare diseases, RDP, real-world data, redistribution mechanism, Regulatory Data Protection, regulatory framework, Repeat Use Procedure, repurposing, research institutions, revision, Summary Report, supply chain, Variations Regulation, wholesale distribution

by Giuliana Miglierini

The European Commission has published the summary of the outcomes of the public consultation on the Evaluation and revision of the general pharmaceutical legislation, which closed on 21 December 2021. A total of 478 contributions were received, mostly by companies and business organisations (25.10%), non-governmental organisations (19.67%) and business associations (14.02%). At the geographical level, Germany contributed the 18.2% of feedbacks, followed by Belgium (16.7%), and France (9.2%); 12.8% of contributions came from non-EU countries.

Almost half of the respondents (48.1%) are registered in the EU Transparency Register; one third (33.1%) provided also separate position documents. The Summary Report and single contributions to the consultation are available at the Commission’s dedicated webpage.

Large companies represented the main industrial contributors (39%). Feedback from the pharmaceutical sector accounts for 28.4%, those from patient or consumer organisations 13.8%. A great part of the comments from public authorities (26 respondents in total) came from public authorities at national level (82.6%).

The main themes emerged from the answers

The Summary Report provides an outlook of the received comments from the perspective of the different categories of stakeholders.

Key topics of interest for the Industry included the decline of R&D investment and clinical trials in Europe, paralleled by the need of a more attractive regulatory framework for global investment and a facilitated access to value-added products and over-the-counter switching. Slow response rates of regulatory agencies, high administrative costs, convergence of data requirements of EMA and HTA, digitalisation of regulatory processes and optimisation of regulatory pathways for vaccines are other issues looking for solutions.

The impact of parallel trade on the security of supply, a predictable system of incentives for innovative products and unmet medical needs, a strong framework for intellectual property (IP) protection, and attention to the EU manufacturing of active pharmaceutical ingredients (APIs) were also reported.

Some of these topics were also addressed under the perspective of public authorities and healthcare payers. Comparative safety assessments, coherence with the blood, tissues and cells (BTC) legislation, affordability issues due to high prices/monopoly positions, transparency of medicinal product R&D and market launch costs, and abuse of existing incentives are other issues on the table, together with incentives for APIs manufacturing in the EU and a clear framework for medicine repurposing. On the clinical perspective, regulators ask for the inclusion of up-to-date clinical information in the Summaries of product characteristics, and for patient involvement in the definition of unmet medical needs.

The Summary Report also provides feedback on comments received by academics and research institutions, civil society organisations, citizens, healthcare professionals and other respondents. A total of six different campaigns were identified through the statistical analysis of the received answers, addressing respectively the need to update the radiopharmaceutical legislation, medicines shortages and the role of wholesale distribution, incentives for the innovative pharmaceutical industry and for generic manufacturers, access to treatments for rare diseases from the patient perspective, and the integration of microbiome science in the legislation.

EFPIA’s contribution

EFPIA, representing the innovator industry, highlighted the “significant interdependencies between the R&D policy environment and the manufacturing ecosystem downstream”. At the regulatory level, suggestions include the reinforcement of expertise-driven assessment and a more agile centralised authorisation framework, the improvement of expedited pathways framework supporting innovation, an expanded role of EMA in the assessment of drug-device/diagnostic combination products, and the replacement of the paper patient information leaflets with electronic versions.

The impact of further modifications of the EU SPC framework would need a careful assessment, while a Regulatory Data Protection (RDP) would support a better evaluation of products with lower development times, insufficiency/inadequacy of patent protection and new indications.

EFPIA also provides its vision on the sustainability of the off-patent market, including procurement practices and interchangeability of medicinal products. Actions to prevent and mitigate medicines shortages should be differentiated and coordinated at the European level, on the basis of a harmonised definition of shortage. Harmonisation should also represent a target for quality requirements at the global level, as well as for supply chain and GDPs. Other identified barriers at the manufacturing level include manufacturing site authorisations referring only to the local premises specified, full import testing, Official Medicines Control Laboratory testing for vaccines and biologics, and the revision of the Variations Regulation.

Comments from Medicines for Europe

Medicines for Europe, representing the off-patent industry, asks for a fit-for-purpose, efficient and fully digitalised regulatory framework. Among the priorities at the regulatory level are the optimisation of the Decentralised and Repeat Use Procedures. The regulatory framework should also avoid the unnecessary and unethical repetition of clinical studies, so to encourage generic and biosimilar medicines development. Global access and competition in the field of off-patent medicines should benefit of a single global development framework for multiple jurisdictions.

According to Medicines for Europe, the revision of the pharmaceutical legislation should also address the absence of rewards for manufacturers, in order to find a balance with their obligations of supply. As for IP protection, the association asks for the clarification of the Bolar exemption and the legal ban of patent linkage in all EU member states. The availability of multiple API suppliers should be encouraged through a single and efficient assessment of ASMP (Assembling Surfactants-Mucoadhesive Polymers) and API authorisations, and the separation between the regulatory dossier (regulatory assessment-subject of variations) and GMP (subject of inspection) should be introduced; a broader use of virtual inspections should also be promoted.

Other comments from industrial associations

AESGP, representing the self-care industry, considers the incentive of one added year of data protections not sufficient to reward investment in innovative switches. The burden posed by the Sunset Clause is also critical with regard to un-marketed licences, as well as extending the data exclusivity for a new indication or a switch. Stringent pharmacovigilance and post-approval change requirements are considered by AESGP unjustified or disproportionate, due to the limited gains in patient protection. The suggestion is for a risk-based approach for the submission of Risk Management Plans as a part of Market Access Authorisation, based on existing API safety info and provided there are no great differences in conditions of use. At the regulatory level, the applicant should be free to choose the procedure to authorise the product, and all procedures should perform equally and according to defined timelines. A broader definition of unmet needs would allow for more non-prescription medicines to be accessed; differences in the legal status of this type of medicines in different EU’s countries may also affect their availability to patients.

The European Healthcare Distribution Association (GIRP) addressed mainly issues related to medicines shortages. Among these are the need to strengthen the existing obligations for supply chain actors, and a better framework for the implementation of Article 81, paragraph 2 and 3 of Directive 2001/83 in member states legislation, so to place obligations on both marketing authorisation holders (MAHs) and pharmaceutical full-line wholesalers. The latter should be appropriately and continuously supplied by MAHs with the full range of products. Unjustified supply quotas based on legal and ethical grounds should be abolished.

A legal basis should be established for a EU-wide early warning system for anticipated/potential and verified/confirmed shortages for critical medicines. EU-wide harmonised categories for root causes of shortages should be implemented in the shortages databases managed by member states. GIRP also addressed access to market, suggesting pricing and reimbursement for centrally registered products should be separated from the availability of centrally registered products on national markets.

Market access has been addressed also by Affordable Medicines Europe, representing parallel distributors. The suggestion is for the Commission to develop a guidance on the launch of centrally approved products by parallel distributors in markets where the MAHs have not launched. An obligation for MAHs to supply entities launching in markets not covered by MAHs is also envisaged. To better manage withdrawals, Art 123 (2) of Directive 2001/83 should be amended, and a notification by MAHs should be made no less than 12 months before the withdrawal for commercial reasons. MAHs should also compulsory supply entities continuing marketing in markets undergoing commercial withdrawal; in this instance, guidance to member states should be provided on how to delegate pharmacovigilance tasks to another member state where pharmacovigilance data are available, so to limit technical measures aiming to reduce availability and ensure that products can still enter the market.

The Alliance of Regenerative Medicines (ARM), representing producers of advanced therapy medicinal products (ATMP), highlights the risk for Europe of loose positions in the competitive scenarios due to policy and regulatory barriers. According to ARM, all medicines falling under the ATMP definition should undergo the same regulatory requirements. A mandatory centralized procedure of authorisation should be maintained, in order to provide the level of expertise needed for the assessment of these complex products. GMP and pharmacovigilance aspects should be also coordinated at EU level. Bedside manufacturing models or other schemes should be avoided in order to prevent a two-tiered regulatory framework for ATMPs, leading to different quality and safety standards. Hospital Exemption (HE) should also be strictly regulated and harmonised across member states, with application only to individual patients on a case-by-case basis. Accelerated market approval procedures are expected to maintain rigorous regulatory requirements and high-quality standards for ATMPs. A pan-EU infrastructure and standards for collecting, storing and using ATMP-related real-world data, also for regulatory decision-making, is supported. The association asks for changes to the regulatory requirements for medicines containing genetically modified organisms (GMOs). Implementation of the EU cross-border healthcare legislation would support the administration of ATMPs to patients; HTA should be also coordinated at the EU-level.

Obligations accompanying any novel incentives should carefully take into considerations differences compared to traditional pharmaceuticals, as well as withdrawals due to market failures. A new business model is also recommended by ARM to address the shift in cost from chronic to one-time treatment. No modification of the current definition of ATMP to differentiate with respect to BTC products would be needed.

The position of community pharmacists

The Pharmaceutical Group of the European Union (PGEU) also contributed to the consultation with a position paper, providing the perspective of community pharmacists. The document suggests that issues of medicine shortages and patients’ access would require a “bold, ambitious, and coordinated actions at all policy levels”. According to PGEU, the revision of the pharmaceutical legislation should take the form of a new Directive, so to better respect the existing social, cultural and economic differences between European countries, which are reflected in the organisation of their healthcare systems.

An expanded role for EMA in the prevention and management of shortages, in coordination with the HMA, and the availability of a centralised EU monitoring system for (anticipated) shortages of all medicines in the EU would support the improved availability and access for patients. PGEU also asks for a better transparency and timely communication on shortages to affected stakeholders, as community pharmacists are deeply impacted; clarification of European and national laws related to the public service obligations of supply chain actors would also help to improve compliance.

A more effective redistribution mechanism for medicines available on the European market, irrespective of the country of residence of the patient, would help to face health crises and other special circumstances (i.e. the Brexit and its impact on medicines supply in Malta, Ireland and Cyprus). PGEU also suggests that pharmaceutical companies asking for a centralised marketing authorisation for their products should then commercialise them in all member states. Unmet needs of small patient populations may find an answer in pharmaceutical compounding by community and hospital pharmacists; this practice may also help to face shortages in cases where no suitable alternatives are available.

On their regulatory perspective, PGEU suggests that electronic Product Information (ePI) should complement, and not completely replace, printed leaflets. Digitalisation is deemed important also with respect to the exploitation of real-world data for regulatory decision making and Health Technology Assessment. To this instance, the association suggests to consider a rewarding for evidence generation in community pharmacies at the national level, so to better intercept data useful to evaluate the effectiveness, safety, off-label use and therapeutic added value of medicines in practice. According to PGEU, pharmacy organisations should also be better involved in integrated medicines development and post-authorisation activities, in coordination with other actors.

Repurposing of off-patent medicines should be targeted to areas where important public health benefits are likely to be achieved, but attention should be paid not to limit patients access to these medicines for the currently authorised indications. The association of community pharmacists also supports the reshoring of pharmaceutical manufacturing in the EU (e.g. active ingredients, excipients and basic chemical compounds particularly critical in terms of supply), a goal to improve European competitiveness and reduce the direct dependence from extra-EU countries. An improved diversification of the medicines supply chain is also envisaged.

Environmental issues should be tackled by the availability of innovative incentive and business models for the development of new antimicrobials and antibiotics, and a full compliance with environmental quality standards for pharmaceuticals. A coordinated approach among member states to the evaluation of cost-effectiveness and added therapeutic value of new therapies, including HTA, would support the affordability and fiscal sustainability of medicines. According to PGEU, pricing decisions in one country should not negatively impact on patient access in other countries. Cost-effective pharmaceutical care services at national level should be promoted as a mean to support the rational use of medicines through the adequate remuneration.

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

February 4, 2022

academics, ACT EU, Artificial Intelligence, clinical research, clinical trials, Clinical Trials Information System, Clinical Trials Regulation, coordinated scientific advice, CTIS, decentralised trials, decisional evidence, EFPIA, ema, EMRN, EU CTR Coordination Group, European Commission, European medicines agencies network strategy, European Pharmaceutical Strategy, GCPs, HMA, IVDR, KPIs, multi-stakeholder platform, patient-oriented medicines development, safety monitoring, working parties

by Giuliana Miglierini

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

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

Six objectives and ten priorities of action for 2022-2023

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

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

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

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

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

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

Four principles to guide all actions

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

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

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

Comments from EFPIA

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

Steps towards the final approval of the IP action plan

December 10, 2021

Artificial Intelligence, biosimilar medicines, blockchain, Bolar exemption, clinical trials, divisional patent applications, EFPIA, EPO’s mandate, European Commission, European IP Information Centre, European Parliament, fragmentation, Free Trade Agreements, FTA, generic medicines, guidelines, innovator industry, intellectual property, intellectual property rights, IP Action Plan, IP coordinator, IP index, IP protection, IP Scan, IP vouchers, IPR, IPR-intensive industry, knowledge-intensive industry, licensing, market entry, marketing authorisation, open technology standards, patent linkage, patent validation, pharmaceutical patents, pharmaceutical spending, R&D intensive industry, recovery and resilience capacity, shortages, SPC, SPC manufacturing waiver, Supplementary Protection Certificates, supply chain, traceability, transparency, Unified Patent Court, Unitary Patent Protection, UPP

By Giuliana Miglierini

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

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

The main points of the resolution

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

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

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

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

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

Unitary patents and improved market competition

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

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

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

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

Comments from the industry

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

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

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

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

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

November 12, 2021

clinical trials, crisis preparedness, data protection, draft agreement, drug development, EFPIA, ema, EU clinical trial register, EU Commission, European Health Union, European Medicines Agency, European Parliament, European Shortages Monitoring Platform, funding, high-risk medical devices, major event, medical devices, Medicines for Europe, Medicines Shortages Steering Group, not-for-profit organisations, off-patent medicines, pharmaceutical industry, positive opinion, product information, public health emergencies, Q&A document, reformulation, regulatory pathway, regulatory submission, regulatory-ready evidence, repurposing, research, scientific advice, shortages of medicines, shortages steering groups, sponsors, study protocol, transparency, Union budget

by Giuliana Miglierini

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

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

Three new key targets for EMA

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

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

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

How to tackle shortages of medicines

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

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

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

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

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

EMA’s pilot project for the repurposing of medicines

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

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

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

Comments from the industry

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

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

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