The EU Commission proposal of the new pharmaceutical legislation

May 5, 2023

AESGP, antimicrobial medicines, approval time, CHMP, comparative clinical trials, Council Recommendation, daptive clinical trials, data protection, Directive, earlier warnings, early scientific advice, EFPIA; Medicines for Europe, electronic product information, EMA Committees, environmental risk assessment, EUCOPE, EuropaBio, European Commission, European Council, European Parliament, exclusivity protection, generic and biosimilar medicines, health data, innovative medicines, list of critical medicines, market protection, marketing authorisation renewal, medical needs, medicines shortages, new indications, paediatric medicines, patient representatives, patient-centricity, PRAC, prevention plans, price negotiations, rare diseases, real world evidence, regulation, regulatory flexibility, regulatory procedures, regulatory protection, regulatory sandboxes, repurposing, revision of the European pharmaceutical legislation, rolling review, single European market for medicines, temporary emergency marketing authorisations, Transferable data exclusivity voucher, transparency on public funding for R&D, unmet medical needs

By Giuliana Miglierini

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

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

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

A single market for medicines

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

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

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

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

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

Actions supporting innovation

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

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

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

A more flexible regulatory framework

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

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

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

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

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

The first comments from interested parties

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

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

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

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

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

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

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

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

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

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

How to prepare to the entry into force of CEP 2.0

April 7, 2023

By Giuliana Miglierini

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

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

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

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

The new mandatory data

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

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

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

Insights of the new CEP 2.0

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

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

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

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

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

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

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

Sharing of information with authorities and customers

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

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

Steps in the implementation of CEP 2.0

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

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

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

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

The Windsor Framework

March 3, 2023

Brexit, ema, European Commission President Ursula von der Leyen, European Medicines Agency, MHRA, Northern Ireland, Northern Ireland Protocol Bill, political declaration, Prime Minister Rishi Sunak, Protocol on Ireland/Northern Ireland, The Windsor Framework, UK

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

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

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

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

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

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

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

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

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

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

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

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

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

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EDQM introduces a consultation phase in the management of CEP documents

January 27, 2023

administrative documents, CEP documents, CEP Steering Committee, Certification of Suitability, comments, consultation phase, duration of consultation, EDQM, efficiency, elaboration process, governance documents, Guidance, interested parties, operational documents, PA/PH/CEP (22) 44, public consultation, public documents, publication, restricted documents, revision number, TAB, targeted consultation, Technical Advisory Board, technical guidelines, template, transparency, type of consultation, unique reference code

by Giuliana Miglierini

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

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

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

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

A guidance to understand the new process

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

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

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

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

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

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

The consultation phase

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

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

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

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

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

ICMRA report on best practices against antimicrobial resistance

December 9, 2022

advanced purchasing agreements, AMR, antibiograms, antibiotic-resistant secondary bacterial infections, antimicrobial market failure, antimicrobial resistance, antimicrobials for veterinary use, BARDA, bioterrorism infections, Canada’s Food and Drugs Regulation, case studies, clinical trials, Covid-19 pandemic, DEL, Drug Establishment Licensing, ema, GMPs, Health Canada, ICMRA, Interim Order, International Coalition of Medicines Regulatory Authorities, MCMs, medical countermeasures, Memorandum of Understanding, MHRA, minimum annual guaranteed revenue, non-traditional therapies, partially delinked reimbursement model, PHAC, procurement strategy, Public Health Agency of Canada, Public Health Agency of Sweden, public-private partnerships, reformulation, regulatory agilities, regulatory and non-regulatory best practices, regulatory master plan, regulatory review, report, restriction of prescribing, security stock, selection pressure, selective reporting, supporting data packages for regulatory review, temporary regulatory pathway, The Lancet, therapeutic options, transition measures, treatment of acute sore throats, tyrothricincontaining lozenges, VASR, Veterinary Antimicrobial Sales Reporting system

by Giuliana Miglierini

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

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

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

Regulatory flexibility

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

Antimicrobials for veterinary use

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

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

Regulatory agilities during the Covid-19 pandemic

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

Non-prescription availability of antibiotics

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

Reimbursement models for novel antimicrobials

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

Selective antibiograms to inform antimicrobial choice

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

Feedback on prescriber data

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

Common infections in outpatient care

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

Methods for monitoring AMR in the environment

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

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

The FDA warns about the manufacture medicinal and non-pharmaceutical products on the same equipment

November 4, 2022

acceptance criteria, active ingredients, Annex 15 of EU GMP, batch records, BMZ, CAPA plan, change management, Chapter 3 GMP, clean areas, cleaning procedures. EMA, cleaning validation, Comparison of EU GMP Guidelines with WHO Guidelines, containment, cross-contamination, data integrity, decontamination, equipment, FDA, GMP, guideline on shared facilities, ICH Q2, identity testing, ISO 14644, laboratory controls, manufacturing of pharmaceutical products, PDE, Permitted Daily Exposure, premises, process validation, qualification programme, quality risk management, risk assessment, risk of errors, sanitisation, shared equipment, specifications, Threshold of Toxicological Concern, TTC, Warning Letter, WHO Annex 4, WHO Annex 6

by Giuliana Miglierini

A Warning Letter, sent in September 2022 by the US FDA to a German company after an inspection, addresses the possibility to use the same equipment for the manufacturing of pharmaceutical and non-pharmaceutical products. The FDA reject this possibility, that is considered a significant violation of cGMP.

The letter addresses the lack of process validation for the manufacturing of over-the counter (OTC) drugs and of qualification documentation proving acceptance criteria were met and the process was under control. Deficiencies were reflected in the batch records missing important pieces of information. Aspects pertaining cleaning validation were also found critical.

The requests of the FDA

The Warning Letter asks the company to provide the FDA with a full qualification programme of the equipment and facility. This should include a detailed risk assessment for all medicinal products manufactured using shared equipment. Plans are also needed on how to separate the manufacturing areas for pharmaceutical and non-pharmaceutical productions.

Furthermore, the program for cleaning validation should be reviewed to include at least (but not limited to) drugs with higher toxicities or potencies, drugs of lower solubility in their cleaning solvents and that may result difficult to clean. Maximum holding times before cleaning and swabbing locations for areas that are most difficult to clean should be also provided. A retrospective assessment of the cleaning process has to be included in the required CAPA plan; change management for the introduction of new manufacturing equipment or a new product should be also discussed.

The FDA also addressed many other violations, such as the lack of robust laboratory controls, identity testing of incoming raw materials including active ingredients (APIs), and the inability to demonstrate the respect of minimum USP monograph specifications and appropriate microbial limits for drug manufacturing. Management and controls on data integrity were also found deficient.

The European perspective

In the EU, the possibility to use the same equipment and premises for the manufacturing of both pharmaceutical and non-pharmaceutical products can be referred to the provisions set forth by Chapter 3 (Premises and Equipment) of the EU GMPs.

The document clearly states that the “premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination”.

The application of Quality Risk Management principles is used to assess the specific risk of cross-contamination and the consequent measures to be put in place. Dedicated premises and equipment may be needed in some cases, especially if the risk cannot be adequately controlled by operational and/or technical measures, the product has an unfavourable toxicological profile, or relevant residue limits cannot be satisfactorily determined by a validated analytical method. Attention should also be paid to the positioning of equipment and materials, so to avoid confusion between different medicinal products and their components, and to guarantee the correct execution of process controls. Particular provisions are needed in the case dusty materials are used, also with respect to cleaning validation.

All cleaning procedures should be available in written form, designed to allow for an easy and thorough cleaning (including drains, pipework, light fittings, ventilation points and other services). In the case of exposed materials, the interior surfaces of the premises should be smooth and easy to clean and disinfect.

All documentation needed to support the above mention requirements should be prepared according to Chapter 4 (Documentation) of the European GMPs.

EMA’s Guideline on shared facilities

The European Medicines Agency (EMA) published in 2014 a guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities.

Threshold values expressed in terms of Permitted Daily Exposure (PDE) or Threshold of Toxicological Concern (TTC) are the key parameters to be used to run the risk assessment. The so determined threshold levels for APIs can also be used to justify carry over limits used in cleaning validation. EMA’s guideline discusses how to address the determination of the PDE, also with respect to specific types of active substances (e.g. genotoxic, of highly sensitising potential, etc.)

The WHO guidelines

The World Health Organisation released in 2011 its GMP guideline Annex 6 (TRS 961) on the manufacturing of sterile pharmaceutical products. Clean areas are the location of choice for such productions. High-risk operative areas for aseptic manufacturing are classified in Grade A, with Grade B representing their background zones. Grade C and D areas are reserved to less critical steps of the production process.

A frequent and thorough sanitation is important, coupled with disinfection with more than one biocide and/or a sporicidal agent, as appropriate. The effectiveness of the cleaning procedure should be closely monitored to exclude the presence of contaminants, both in the form of vital and not vital particulate.

The guideline specifically mentions the case of preparations containing live microorganisms (such as vaccines), that can be prepared in multiuser facilities only if the manufacturer can demonstrate and validate effective containment and decontamination of the live microorganisms. To transport materials, the conveyor belt should be continuously sterilised as a requirement to pass through a partition between a Grade A/B and a processing area of lower air cleanliness.

A “Comparison of EU GMP Guidelines with WHO Guidelines” was published by the German Federal Ministry for Economic Cooperation and Development (BMZ) to support the understanding of differences between the two approaches, and with a special emphasis to the alleged higher costs of implementation and compliance to EU GMPs.

Analysing the requirements relative to premises and equipment, they aim to guarantee the suitability of rooms to the intended tasks, minimise the risk of failure and cross-contamination and ensure easy cleaning and maintenance. According to the BMZ, EU’s and WHO’s requirements are the same, even if the WHO guideline is more detailed in some aspects (to this instance, the BMZ document was published prior to the release of the new Annex 1 to the GMPs). The theme of equipment is also discussed in other WHO guidelines, i.e. the “WHO good manufacturing practices: starting materials” and the WHO guidelines on transfer of technology in pharmaceutical manufacturing.

Cleaning and sanitation should be addressed according to the provisions set forth by the ISO 14644 family of technical standards. Cleaning validation is also treated in Appendix 3 of the WHO TRS 937 Annex 4. Cleaning validation should be used as the main tool to ensure the removal to pre-established levels of all residues of an API of a product manufactured in any equipment with direct contact to the surface, so that the next product manufactured using the same apparatus would be not cross-contaminated.

According to the BMZ, indications on qualification, process validation and cleaning validation contained in Annex 15 of EU GMPs (paragraph 6) should be integrated with the contents of the ICH Q2 guideline. The only two points of the EU GMPs not covered by the WHO’s guide refer to the allowance that toxic or hazardous substances can be substituted under special conditions for the validation process and the indication that “Test until clean” is not considered an appropriate alternative to cleaning validation.

Patient involvement in the development, regulation and safe use of medicines

September 30, 2022

by Giuliana Miglierini

The Council for International Organizations of Medical Sciences (CIOMS) has published the CIOMS report on “Patient involvement in the development, regulation and safe use of medicines”.

The report marks an important step forward towards a harmonised approach to patient involvement through the entire medicines’ lifecycle and under all the different perspectives which are part of it. The document is the result of four years of work by the CIOMS Working Group XI on Patient involvement in the development, regulation and safe use of medicines, in collaboration with other relevant stakeholders. Comments were collected during two meetings in Switzerland and Uganda and a public consultation phase.

The report offers recommendations on how to systematically involve patients along the pathway leading from early development and regulatory processing to marketing and monitoring of the safety and efficacy in the real-world contest of use of a medicine. Remaining challenges and practice gaps are also discussed. CIOMS’s secretary Dr. Lembit Rägo gave a presentation at EMA’s Joint PCWP-HCPWP Meeting held in Amsterdam on 4 March 2020.

CIOMS is an international umbrella organisation jointly established by WHO and UNESCO in1949. Members include representatives of the biomedical scientific community, national academies of sciences and medical research councils, jointly committed to develop guidance on health research and policy including ethics, medical product development and pharmacovigilance. CIOMS is an ICH Observer since 2016, and many of its guidelines served as the basis to develop ICH’s ones.

Structure and ethical guiding principles

The CIOMS report consists of eleven chapters and five appendices. After the discussion of the landscape and the guiding principles that should inspire patient involvement, CIOMS has addressed the possible contribution arising from patients aimed to advancing treatments, for each of the steps of development of a new product. Chapter 5 addresses specifically the use of real-world data and evidence generated by patients, a central theme in many new policies in the healthcare sector. The document includes also chapters discussing product labelling and rapid safety communications, as well as additional risk minimisation. Clinical practice guidelines are discussed in Chapter 9. Attention is also paid to low- and medium-income countries and to pandemic considerations.

The rich section discussing case studies includes how to address a medication formulation created to meet patients’ and doctors’ needs and, under the regulatory perspective, the case of EMA’s public hearing on valproate as an example of patient involvement. Partnerships between industry and patient groups for therapy development are also discussed, as well as patients’ engagement in early development plans for a novel treatment. Other case studies address patient involvement in the developing of additional risk minimisation measures and patient activism to counter AIDS denialism and improve access to HIV medicines in South Africa.

The CIOMS report should be read as a pragmatic handbook, recommending ‘best practice’ to serve as a guide, but not necessarily to be entirely adopted. Its contents have been developed on the basis of ethical considerations and fundamental principles of bioethics, highlighting the importance of the opinion of patients as expert partners in the use of medicines. Only patients “can meaningfully contribute their preferences, concerns, understandings, and lived experiences of a medical condition to improve medicine development and use”, states the document.

Another key principle is the respect for persons, which should be always treated as autonomous and making independent decisions, while protection should be provided to persons with diminished autonomy. The result of this vision is a shared decision-making between clinicians and patients, also known as the patient-as-partner approach to medicine. The approach should also include the adequate protection of patients’ personal data and the understanding of their tolerance or acceptance of the risk connected to the use of a certain medicine.

The promotion of wellbeing (beneficence) and the avoidance of harm (nonmaleficence) are other ethic principles inspiring the report. The exercise should take into consideration not only the pharmacological profile of the medicine, but also its possible impact at the logistic, psychological, financial, and social level, as well as opportunity costs. Access to medicines remains a central issue in many instances; to this regard, the report states that “Thus, despite understanding the ethical obligation to provide medicines, individuals or institutions may not necessarily act to fulfil this obligation”.

The concept of “justice” includes modalities for the recruitment of patients for clinical studies, and the fair access and distribution, and knowledge of medicines. Informed consent remains a fundamental principle to be always and freely exercised, while informed assent can apply especially in the case of young children and adults who do not have the legal capability to give consent.

Not only medicines; the patient perspective is fundamental

Contents of the CIOMS report on patient involvement does not apply strictly only to medicinal products, but also to the broader range of products consisting of vaccines, medical devices, drug-device combinations, and diagnostics. All these products are subject to regulatory scrutiny and approval and are aimed to treat or prevent a illness, to make a diagnosis, or to maintain or alter the way the body works.

Patients are identified as the individuals using these products, often flanked and supported by their families, caregivers, patient organisations, and patient representatives. The contribution of patients is deemed essential to correctly identify medical needs on the basis of their daily experience of the health condition. The patient’s perspective can inform early development of new medicines, as well as provide data on safety and efficacy during the post-marketing phase of the lifecycle. All views should be gathered, including the ones arising from often marginalized communities of patients, or those of family carers and other caregivers.

This sort of information may be collected by involvement of patient organisations in the different phases of development and commercialisation, even though there are still some barriers to be overcome. The main one is represented by the cultural shift needed to end seeing patients are passive subjects: they should be regarded as true “research partners” in the development, regulation and safe use of medicines. Other existing barriers include legislative and regulatory burdens as well as language and communication obstacles.

Patient participation to development should be incentivised through reimbursement of time and expenses, suggests the report, while maintaining the independence of patient organisations in order to build a long-lasting and respectful relationship. Digital technologies are suggested as a tool to improve the transparency of communication and to enable telemedicine.

Training should be also provided (for example by patient organisations) in order to optimise patient involvement in the different activities. According to the report, it should include information on medicines-related sciences, ethics of health-related research, clinical trial methodology and interpretation, and medicines legislation and regulation.

Patient involvement in research and development

Patients should be involved in research activity from the very early phases, so to provide their input on candidate medicines. To this instance, key activities may include the definition of research goals and expected treatment benefits, the planning and design of clinical trials and the clear and timely circulation of emerging research information. Preferences of users on formulation and packaging may be also obtained.

The report suggests using well-designed “patient preference studies” as a mean to better understand important elements under the patients’ perspective relevant to their medical conditions and treatment (or prevention).

The regulatory approval process should increasingly take into consideration patients’ opinions on the benefits and risks of a certain medicine, as well as on information arising from the continuous monitoring of side effects. The recommendation is to strengthen the inclusion of patients as members of formal scientific and decision-making committees or working groups on specific scientific aspects of medicine regulation.

Data management and protection and product information

“Patient-centred initiatives” are the tool suggested by the CIOMS report in order to better involve patients in the planning and management of real-world data arising from their daily use of medicines. Patients should be enabled to control the actual protection of their data and privacy, and how data are collected, stored, managed and released. Digital technologies represent the preferred tool to reach this objective, and they can also support patients in playing a more active role in the management of their real-world data.

Product information (i.e. the information leaflet contained in each package) is an essential element of a medicine, as it supports its correct use by the patient. The format and clarity of product information has been long debated; the CIOMS report supports the involvement of patients in drafting this information, as a way to improve its relevance and contents. A better compliance to treatment remains a main target, and it may benefit from the information patient scan provide on local customs and traditions, health literacy, and healthcare structures.

Additional risk minimisation measures and safety information

Many innovative therapeutic approaches are characterised by a risk profile significantly higher compared to more traditional treatments. In such instances, the report indicates that the standard information provided to patients may prove insufficient, and additional risk minimization measures may be needed. These measures may create an extra burden on patients, which maybe subject for example to regular testing or need to take extra care. It would be thus important to gather patients’ opinion right from the design and development of the additional measures.

Patients may also contribute to plan how the measures are communicated and put in practice (also using digital technologies where appropriate).

A key pharmacovigilance activity is the rapid dissemination of safety information in case issues arise with the safety of a medicine. To this instance, the report suggests patients to be involved in the decision about issues needing urgent communication, the groups of patients to be informed, and how the information can be designed for patients. Patient organisations can play a central role in the dissemination of such type of information.

Clinical practice guidelines and pandemic preparedness

Patients should be also involved in the development of clinical practice guidelines, aimed to describe how medicines should be used in day-to-day healthcare. This is deemed important in order to overcome the possible bias between patients’ expectations about benefits of the treatment and the consequent acceptance of risks, and the view of these items proper of clinicians and other healthcare professionals.

The importance of patient involvement in the above discussed points has become clear through the experience gathered during the Covid-19 pandemic. The report highlights the importance to consider the lack of knowledge on how new medicines and vaccines are developed and the consequent need to address public concerns about vaccination, the need to deal with misinformation and to provide comprehensive information for patients to make an informed decision.

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

July 8, 2022

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by Giuliana Miglierini

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

Main trends in inspections

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

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

A new mix of inspection tools

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

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

There is still space for improvement

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

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

How to further improve inspections

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

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

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

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

UK’s pilot of a Compliance Monitor Process

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

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

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

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

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

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

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

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

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

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

Approval of the Data Governance Act, and EMA’s consultation on the protection of personal data in the CTIS

June 24, 2022

anonymization, CCI, Clinical Trial module, Clinical Trials Information System, Clinical Trials Regulation, commercially confidential information, common good, control over personal data, CTIS, CTR, data altruism, Data Governance Act, data intermediation services, data wallets, DGA, digital platforms, EDIB, ema, EU Portal and Database, EudraVigilance safety module, EUPD, European Commission, European Council, European Data Innovation Board, European data strategy, European Parliament, GCP inspections, GDPR, general interest, inspection reports, international transfer of data, logo, model contractual clauses, national register of recognised data altruism organisations, non-personal data, Open Data Directive, personal data, personal data spaces, pseudonymization, public information, public-sector data, reuse of data, searchable electronic register of public-sector data

by Giuliana Miglierini

The Data Governance Act (DGA) was approved and adopted in May 2022 by the European Council, following the positive position of the EU Parliament; the new legislation will entry into force after being signed by the presidents of the Parliament and of the Council and twenty days after the publication in the Official Journal of the European Union. The new rules governing data collection and sharing will start to apply 15 months after the entry into force of the new regulation.

The protection of personal data is also central to the new transparency requirements established by the Clinical Trials Regulation (CTR). To support pharmaceutical companies dealing with personal data within the Clinical Trials Information System (CTIS), the drafting of a dedicated guideline is ongoing. The European Medicines Agency has published a document to support the public consultation which will remain open until 8 September 2022.

The Data Governance Act

The new DGA regulation is part of the European data strategy and aims to promote the availability of data within a trustworthy environment, with the final goal to improve their use for research and the creation of innovative services and products.

Central to the DGA are some categories of public-sector data that are subject to property rights (i.e. trade secrets, personal data and data protected by intellectual property rights), which were not covered by the previous Open Data Directive (2019). Under the new rules, the reuse of such data shall be permitted provided that the public-sector bodies allowing it are technically equipped to ensure the preservation of privacy and confidentiality.

The DGA will also parallel the General Data Protection Regulation (GDPR) in providing appropriate safeguards against the unlawful international transfer of or governmental access to non-personal data (as the GDPR does for the personal ones). Secondary legislation may be issued by the Commission, for example, to ensure specific non-EU countries provide appropriate safeguards for the use of non-personal data transferred from the EU, on the basis of the existence of local equivalent measures of a similar protection level to that existing in the EU.

The reuse of public-sector data shall be justified with respect to the provision of a service of general interest; exclusive arrangements are needed, with a duration of 12 months for new contracts and 30 months for the existing ones. The access to data will operate through a searchable electronic register of public-sector data to be established by the European Commission and available via national single information points. Model contractual clauses may be adopted by the Commission in order to support public-sector bodies and re-users with the transfer of nonpersonal data covered by the DGA to third countries.

Data intermediation services

Data intermediation services are the core of the new business model resulting from the Data Governance Act; they will be listed in a register to improve transparency and trust. The final target is to enable a secure environment for the sharing of data.

Digital platforms shall represent the reference point for voluntary data-sharing between companies; they should fulfil all data-sharing obligations at the European and national level. Individuals shall maintain full control over their personal data; service providers should support them in exercising their rights according to the GDPR. New tools may be introduced to facilitate sharing on the basis of data holder’s consent, i.e. personal data spaces or data wallets. Service providers won’t be able to share data for purposes other than the allowed ones, and cannot benefit from selling data, even though they can charge for the transactions the carry out.

Data altruism is another key concept of the DGA regulation, making possible to voluntary share its own data for the common good, for example in the field of medical research. Data altruism will apply to both individuals and companies; the access to data should be possible upon registration of the interested entities in a national register of recognised data altruism organisations. A specific logo will support the easy identification of both compliant providers of data intermediation services and data altruism organisations.

The new European Data Innovation Board (EDIB) will be in charge of assisting the EU Commission on issues relative to the interoperability of data intermediation services and the development of guidelines on the creation of data spaces.

Data protection in the regulatory field

EMA’s draft guideline provides a description of the Clinical Trials Information System, its components and functionalities, as well as the rules for the publication of clinical trials information submitted to the CTIS (chapter 2). The protection of both personal data and commercially confidential information (CCI) submitted to the CTIS is then discussed (chapters 3 and 4), together with the protection of personal data and CCI in inspection reports (chapter 5).

The CTR established the CTIS as the single entry point for the submission of data and documents relating to clinical trials; the corresponding EU Database contains such data and documents, and the two are jointly referred to as the EU Portal and Database (EUPD).

The EUPD is the first component of the CTIS, representing the Clinical Trial module providing secure domains accessible to regulatory authorities and sponsors along the entire life cycle of the medicinal product and a public website where to find public information. The second component of the CTIS is represented by the EudraVigilance (EV) safety module, consisting of the Repository of Annual Safety Reports (ASRs) and the Clinical Trial Module (EVCTM) for Individual Case Safety Reports (ICSRs) of suspected unexpected serious adverse reactions (SUSARs) related to Investigational Medicinal Products. The optimisation of regulatory data flow also involve the use of data contained in the Extended EudraVigilance Medicinal Product Dictionary (XEVMPD), in the Organisation Management Service (OMS), and in the Identity Access Management (IAM).

The CTR regulation establishes the rules preventing the access to data stored in the EU Database on the basis of confidentiality information. Is this the case, for example, of personal data falling under Regulation (EU) 2018/17255 governing the protection of natural persons and their personal data. Commercially confidential information may also fall under this provision, upon consideration of the status of the marketing authorisation and unless there is an overriding public interest in disclosure. This means no data from the clinical trial application dossier can be made public before the decision on the clinical trial has been taken.

All personal data (such as the ones of trial participants) in documents submitted to the CTIS should follow the general principles on anonymisation and pseudonymisation of personal data. The draft guideline provides examples of the public information that should be made available with respect to a certain clinical trial. This should include as a minimum the main characteristics of the trial, the conclusion on Part I of the assessment report for the authorisation, the decision on the authorisation of a clinical trial, the substantial modification of a clinical trial, and the clinical trial results including reasons for temporary halt and early termination.

A dedicated module of the CTIS is meant for inspectors to manage all information relative to GCP inspections conducted under the CTR, including the uploading of the final report. To this instance, the guideline indicates no personal data should be included in the version of the inspection report due for publication.

PIC/S Annual Report 2021

May 20, 2022

AEC, Aide Memoire, Analytical Expertise Center, Annex 1, Annex 11, Annex 13, Annex 16, Annex 21, Annex 2A, Annex 2B, Annex 5, Annexes 4, Annual Report, ANVISA, Bangladesh’s Directorate General of Drug Administration, Blood establishments, Bulgarian Drug Agency, Chapter 1, Chapter 4, Chinese National Medical Products Administration, Cross-Contamination in Shared Facilities, data integrity, data management, distant assessment, Drug Regulatory Authority of Pakistan, EMA Joint Audit Programme, FGBU IMCEUAOSMP, FSBI SCEMD, FSI SID & GP, GMP inspections, ICH Q12, Inspection Report Format, JAP, Joint Reassessment Programme, Jordan Food and Drug Administration, JRP, Medsafe, Ministry of Health of Azerbaijan, Minpromtorg Russia, NADFC, NMPA, Paul Gustafson, PE 005, PE 009-15, Pharmaceutical Inspection Co-operation Scheme, PI 008, PI 013-3, PI 041-1, PI 043-1, PI 049, PIC/S, PIC/S GMP Guide, PIC/S Inspectorates’ Academy, plasma warehouses, pre-accession procedure, Regulated GMP/GDP Environments, Roszdravnadzor, SAHPRA, Saudi Food & Drug Authority, SCDMTE, virtual training, written procedure

by Giuliana Miglierini

The Annual Report of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) resumes the many activities and results achieved in 2021, despite the ongoing pandemic that required remote coordination and on-line virtual meetings. To this regard, a written procedure has been used to manage important decisions. PIC/S also supported the harmonisation of the distant assessment procedures used by the various regulatory authorities to run GMP inspections during the pandemic period.

The non-binding co-operative arrangement between international regulatory authorities aims to implement harmonised GMP standards and quality systems in support to harmonised inspection procedures. PIC/S’ new strategic plan for 2023-2027 will be presented at the PIC/S 50th anniversary in 2022. The PIC/S Committee has elected Paul Gustafson (Canada/ROEB) as the new Chairperson for the period 2022-2023; he takes the place of Anne Hayes (Ireland/HPRA).

New memberships and re-assessments

Last year saw the entry into the PIC/S scheme of the Brasilian Agência Nacional de Vigilância Sanitária (ANVISA), one of the main regulators of South America, representing the largest market for medicinal products for this geographic area. ANVISA is the 54th member of PIC/S.

Five other membership applications continued the process of assessment. These include the application of Armenia’s Scientific Center of Drug and Medical Technologies Expertise (SCDMTE), that was requested to update its documentation; the preliminary report should be issued soon.

The Bulgarian Drug Agency (BDA) will benefit of a partial assessment of its application, due to the fact the agency already went through an audit under the EMA Joint Audit Programme (JAP) whose report was shared with PIC/S. Health Canada will also collaborate to this assessment under a MRA procedure.

The Jordan Food and Drug Administration (JFDA) also filed a membership application, as well as another regulator from Africa, the Saudi Food & Drug Authority (SFDA), whose preliminary report is soon expected.

Particularly complex is the case of the application by several Competent Authorities of the Russian Federation that jointly submitted a complete membership application in December2020. A larger team, consisting of a Rapporteur and several Co-Rapporteurs, shall be nominated to better manage the procedure. The involved Russian authorities are the Ministry of Industry and Trade of the Russian Federation (Minpromtorg Russia), the Federal Service for Surveillance in Healthcare (Roszdravnadzor), including the “Information and Methodological Center for Expertise, Accounting and Analysis of Circulation of Medical Products” (FGBU “IMCEUAOSMP” of Roszdravnadzor),the Federal “State Institute of Drugs and Good Practices” (FSI “SID & GP”), and the Federal “Scientific Center for Examination of Medical Devices” of the Ministry of Health of the Russian Federation (FSBI ”SCEMD”).

Among authorities undergoing the pre-accession procedure is the Chinese regulatory agency National Medical Products Administration (NMPA), whose application will be assessed by Jacques Morenas (France/ANSM) as Rapporteur and Raphael Yeung (Hong Kong SAR, China/PPBHK) as Co-Rapporteur.

Reviewing of the pre-accession application is also ongoing for the Analytical Expertise Center (AEC) of the Ministry of Health of Azerbaijan, the Bangladesh’s Directorate General of Drug Administration (DGDA, this 2-year timeframe for the pre-accession expired in February 2021, and a new application was required) and the Drug Regulatory Authority of Pakistan (DRAP), that was invited to apply for membership subject to the implementation of the PIC/S GMP Guide.

PIC/S also run a Joint Reassessment Programme (JRP) in parallel with the EU’s JAP to re-evaluate its members for equivalence on a regular basis. In 2021 the JRP included the reassessment of regulatory authorities from Indonesia (NADFC), New Zealand (Medsafe), and South Africa (SAHPRA).

PIC/S also established new contacts in 2021 with other non-member authorities, including Cameroon’s Laboratoire National de Contrôle de Qualité des Médicaments et d’ Expertise, China’s Institute of Veterinary Drug Control, Cuba’s Centro para el Control Estatal de Medicamentos, Equipos y Dispositivos Médicos (CECMED), and Montenegro’s Institute for Medicines and Medical Devices.

New guidances and revisions of existing ones

Among the new guidances adopted in 2021 are the Annex 2A for the Manufacture of ATMP for Human Use and Annex 2B for the Manufacture of Biological Medicinal Substances and Products for Human Use, that entered into force on 1 May 2021 (PE 009-15). The documents were finalised by the PIC/S Working Group on the revision of Annex 2 of the PIC/S GMP Guide.

The Working Group on Data Integrity issued two other guidance documents that entered into force on 1 July 2021, the Guidance on Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (PI 041-1) and a restricted Aide Memoire on inspection of data management and integrity (PI 049).

PIC/S also issued the Good Practice Guidelines for Blood Establishments and Hospital Blood Banks (PE 005) and the related Aide Memoire to Inspections of Blood Establishments and Plasma Warehouses (PI 008), that entered into force on 1 June 2021. The dedicated Working Group will now address the revision of PI 019 (PIC/S Site Master File for Source Plasma Establishments) and PI 020 (PIC/S Site Master File for Plasma Warehouses).

PIC/S and EMA’s joint Working Group on Annex 1 reviewed the comments received to the second public consultation and drafted the final version of the Annex.

The Working Group on Harmonisation of the Classification of Deficiencies is finalising the revision of the PIC/S SOP on Inspection Report Format (PI 013-3) in order to align it with the abovementioned PI 040-1. The Working Group on Controlling Cross-Contamination in Shared Facilities is as well finalising the revision of its Guidance on Cross-Contamination in Shared Facilities (PI 043-1).

PIC/S is also working to harmonise its GMP Guide and Annexes to the rules established by the European Union, in collaboration with EMA through the PIC/S-EMA Joint Consultation Procedure. Many chapters and annexes of the PIC/S-EU GMP Guide were considered during 2021, including Chapter 1 (Pharmaceutical Quality System), Chapter 4 (Documentation) and Annex 11 (Computerised Systems), Annexes 4 and 5 (Veterinary Medicinal Products), Annex 13 (Investigational Medicinal Products), Annex 16 (Certification by an Authorised Person & Batch Release), and Annex21 (GMP Obligations for Importation to the EU).

Virtual training in the pandemic period

Four virtual training events were organised in 2021, among which a PIC/S webinar for inspectors on ICH Q12 (Pharmaceutical Product Lifecycle Management) that was attended by around350 participants from 50 agencies and 44 different jurisdictions.

The webinar on Distant assessment/Remote Virtual Inspection co-organised with the EU Commission Expert Sub-Group on Inspections in the Blood, Tissues and Cells Sectors (IES) was attended by around 325 participants.

The 2021 PIC/S annual seminar was hosted by the Ministry Food and Drug Safety (MFDS) of the Republic of Korea, and saw the participation of 315 inspectors from 54 authorities.

The 2nd meeting of the PIC/S Expert Circle on Controlling Cross-Contamination in Shared Facilities (CCCISF) was virtually hosted and was attended by 375 participants.

Last year saw also the provision of new harmonised and standardised GMP training activities for inspectors under the PIC/S Inspectorates’ Academy (PIA) initiative, a web-based educational centre also involved in setting up a standardised qualification process of inspectors.

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