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Summary of the Online Pharma FORUM webcast on “Approval Strategies in Europe”

On 25 June 2024, one webcast of the Online Pharma FORUM webcast series focused on 'Approval Strategies in Europe,' featuring Dr Ulrich Granzer from Granzer Regulatory Consulting & Services. The webcast addressed submission options within the EU in comparisons to the US, and highlighted recent updates to the regulatory framework in Europe. The upcoming EU Pharmaceutical Legislation will bring changes to protection periods, consolidate regulatory committees (with a greater emphasis on the CHMP and the dissolution of the PDCO, CAT and COMP), and introduce further innovations.

With the EU-HTA deadline fast approaching on 12 January 2025, an important question arises on how to coordinate future scientific advice meetings with national authorities or the EMA alongside consultations with HTA bodies. Dr Ulrich Granzer recommended a sequential approach instead of joint meetings with regulatory and HTA bodies.
In the second part of the webcast, Dr Granzer examined specific programmes in both the EU and the US (EU: PRIME, Conditional Approval, Accelerated Approval; US: Breakthrough, Accelerated Approval) and the emerging opportunities in conjunction with Big Data and AI. While Big Data and AI analyses currently do not yet lead directly to new innovations, they can nonetheless support a better understanding of medication safety profiles.

To close, Dr Granzer briefly discussed the US Inflation Reduction Act, which will also initiate discussions on 'Reimbursement & Price Reduction Negotiations' in the US.
 
Author
Dr Henriette Wolf-Klein
Department Manager Pharma & Healthcare
h.wolf-klein@forum-institut.de

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Online Seminar: 'Hot Topics in Regulatory Affairs'

The online seminar 'Hot Topics in Regulatory Affairs', held in German language on 18 and 19 September 2024, provided participants with a comprehensive overview of current developments in the field of drug approval. Key topics included the EU pharmaceutical legislation, regulatory procedures in the UK, USA, and EU, as well as the latest innovations in eSubmission processes.

The first session featured presentations by Dr Peter Bachmann and Markus Ambrosius, who highlighted the most significant aspects of the EU pharmaceutical legislation reform and its expected timeline. On 26 April 2024, the European Commission introduced proposals for a new regulation and a new directive concerning the authorisation of medicinal products. These are subject to the ordinary legislative procedure, in which the European Parliament and the Council of the European Union jointly adopt laws based on proposals from the Commission. On 3 October 2023, the rapporteurs Pernille Weiss and Tiemo Wölken from the Committee on the Environment, Public Health and Food Safety (ENVI) presented their reports. The European Parliament adopted its position at first reading on 10 April 2024, prior to the European elections in June 2024. The proposals are now awaiting approval by the European Council, but the timeframe for a final decision remains uncertain.

The reform includes significant changes, such as the reorganisation of data protection periods, shifting from the current 8+2+1 years system to a new 6+2+0.5+0.5+2+1 model. The authorisation procedure at the European Medicines Agency (EMA) will be streamlined, and scientific committees restructured. Centralised authorisation will be also possible for products targeting antimicrobial resistance or public health emergencies. Additionally, stricter requirements for environmental risk assessments will be enforced, and member states will have the authority to decide on the format of package leaflets - whether electronic, paper-based, or both.

Dr Stefan Blesse then focused on the UK regulatory landscape post-Brexit. Despite the challenges posed by Brexit, collaboration with the UK regulatory authority, the MHRA, is improving. One major advancement is the introduction of the International Recognition Procedure (IRP), which replaced the Reliance Procedure in January 2024, allowing for simplified and accelerated approval of products already approved by recognised reference regulators.

Dr Blesse also discussed the Access Consortium, which includes the UK, Canada, Singapore, Switzerland, and Australia. This initiative fosters cooperation in the evaluation and authorisation of medicinal products, following a procedure similar to the Decentralised Procedure (DCP) in the EU, with labelling managed by national authorities. So far, three drugs have been authorised through this procedure.

Dr Blesse concluded with an overview of regulatory procedures in the USA, providing guidance on effectively organising meetings with both the EMA and the FDA to facilitate parallel development and approval processes in both regions.

Markus Ambrosius closed the first day with an analysis of recent legal cases affecting regulatory affairs, including issues surrounding market exclusivity for orphan drugs and the sourcing of medicinal products from third countries, particularly Switzerland.

Day two began with Dr Ulrich Granzer’s presentation on the centralised authorisation procedure and special authorisation routes. Conditional approval, for instance, is granted for one year and is renewable for serious or life-threatening diseases, public health emergencies, or orphan drugs. This authorisation can later be converted into a regular marketing authorisation.

Dr Granzer also addressed the accelerated approval process under Article 14 of regulation 726/2004, which is reserved for therapeutic innovations of significant public interest. Although this procedure shortens the approval period, it requires robust justification, such as potential benefits for a large patient group or a breakthrough therapy.

The PRIME (PRIority MEdicines) programme, which is modelled after the US breakthrough therapy designation (BTD) and RMAT programmes, was also discussed. PRIME offers a clear development pathway and fosters early engagement with regulatory authorities. Approval requires a well-defined medical need and substantial supporting data demonstrating proof of concept.

Beate Kienzler shared updates on the mutual recognition procedure (MRP) and the decentralised procedure (DCP), noting new regulations for the DCP introduced in March 2024, specifically when Germany acts as the reference member state (RMS). The BfArM now employs a strict slot allocation system for marketing authorisation applications. The zero day MR procedure, an administrative variant of the MRP, was also highlighted as a swift solution for addressing drug shortages.

Frank Dickert concluded the seminar with a presentation on innovations in eSubmission. The regulatory authorities are currently transitioning from eCTD 3.2 to eCTD 4.0, with varying implementation timelines across regions. The EMA is in a voluntary pilot phase. eCTD 4.0 offers several advantages, such as document reuse, the adoption of controlled vocabularies, a new XML schema, and integration with standardisation organisations. The HL7 regulated product submission (RPS) will also be part of this process, with the final version becoming an ISO standard.

The EMA is gradually implementing the ISO standards for the identification of medicinal products in compliance with EU Regulation No. 520/2012. The data is organised into four domains: Substance, product, organisation and reference data (SPOR). The product management service (PMS) went live on 31 May 2024, and its user interface (PUI) enables various reports and data exports. Non-centrally authorised medicinal products were integrated into the PMS on 11 September 2024. However, work on the SPOR processes is currently paused as the target operating model (TOM) is still under development.

Another notable development is the introduction of the European shortages monitoring platform (ESMP), set to go live on 2 February 2025. The platform aims to monitor and manage shortages of medicines, particularly in times of crisis or public health emergencies, to ensure a stable supply of medicines across the EU.

Author
Dr Rebekka Bitsch
Conference Manager Pharma & Healthcare
r.bitsch@forum-institut.de
 
 

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Summary of the online seminar “Environmental Risk Assessment (ERA) in Drug Approval”

The online seminar 'Environmental Risk Assessment (ERA) in Drug Approval,' held in German language on 10 September 2024, provided a comprehensive overview of the current requirements, legal frameworks, and practical challenges associated with the environmental risk assessment of pharmaceuticals in the EU. The seminar covered the fundamental aspects of ERA, the role of German regulatory authorities, the current guidelines, as well as specific case studies and applications in detail.

Dr Susanne Brendler-Schwaab and Dr Axel Korth introduced the ERA in European approval procedures. Dr Brendler-Schwaab highlighted the role of the Federal Institute for Drugs and Medical Devices (BfArM) and the German Environment Agency (UBA) in ERA evaluation, while Dr Korth discussed the legal framework, including European regulations and the potential tightening of ERA obligations through the EU pharmaceutical legislation.

According to article 8(3) of Directive 2001/83/EC, an ERA is required for all new marketing authorisation applications, regardless of whether they are submitted through the centralised, decentralised, national, or mutual recognition procedures. Type II variations and extension applications must include an updated ERA dossier if increased environmental exposure is expected. An ERA is not required for renewals and certain Type IA/IB variations, unless new ERA data is submitted. Importantly, an ERA is currently not intended to be a criterion for the refusal of a marketing authorisation.

ERA documents are assessed exclusively by UBA assessors, while the validation of the application is carried out by BfArM or the EMA. Since 2006, BfArM has been responsible for forwarding application documents to UBA and integrating the returned evaluations into the assessment reports.

The revised European ERA guideline, which came into force on 1 September 2024, includes significant adjustments, such as the introduction of decision trees for risk assessment and PBT (persistent, bioaccumulative, and toxic)/vPvB (very persistent and very bioaccumulative) screening in Phase I. New guidelines for Phase II risk assessment were also introduced, including the assessment of secondary poisoning, antibacterial substances, and endocrine-active substances.

Since the new ERA guideline (September 2024) is based on the current EU legislation, a further revision will be necessary once the new EU pharmaceutical legislation ('EU pharma package') comes into effect. The new regulations will impose stricter requirements for ERA in the marketing authorisation of pharmaceuticals, expanding the scope to cover the entire lifecycle of a medicine, including manufacturing. New protection goals, such as the risks of antimicrobial resistance, will be introduced, and ERA assessments will be made publicly available.

For products approved under current legislation, ERA assessments must be updated, and corresponding risk mitigation measures must be implemented. Products approved before October 2005 will only require minor adjustments. The new regulations make it more difficult to refuse or revoke a marketing authorisation, which can only be done if a justified, complete ERA is lacking, and the risks cannot be mitigated. Such decisions must also consider the benefit of the product, the needs of patients, and available alternatives. Marketing authorisations for products approved before 2005 can be revoked if the ERA is incomplete and the product is identified as potentially harmful to the environment.
 
With the establishment of the ERA-ESEC (Environmental Risk Assessment European Specialised Expert Community) in July 2024, a platform has been created to promote information exchange among experts from regulatory authorities and academia. ERA-ESEC supports the work of the CVMP (Committee for Medicinal Products for Veterinary Use) ERA Working Party and the CHMP (Committee for Medicinal Products for Human Use) Non-clinical Working Party, without the involvement of industry representatives.

Dr Angela Vogt-Eisele then delved deeply into the content, structure, underlying studies, and calculations of the ERA. The ERA independently evaluates two aspects: risk assessment, which examines the likelihood of an effect occurring, and hazard assessment, which considers the intrinsic properties of the substance. These separate assessments are only combined at the end to provide an overall risk assessment. The decision tree for the various phases of risk assessment was discussed in detail. Ultimately, the implementation of risk mitigation measures is crucial, achieved exclusively through specific texts in the product information (SmPC and PIL).

In the afternoon, Dr Vogt-Eisele led through detailed calculation examples for determining the predicted environmental concentration (PEC) for various indications and substances, including refining PEC calculations using prevalence data and specific cases such as chemotherapeutics.

Dr Vogt-Eisele highlighted that scientific advice is particularly useful when studies cannot be conducted in compliance with guidelines and an acceptable compromise must be reached. It is also helpful in clarifying uncertainties in study design, such as tailored assessments for endocrine-active substances, and in coordinating timelines for larger study sets. Generally, scientific advice provides the advantage of having a specific point of contact within the authority, which can facilitate the process.

Since the revision of the guideline, generic manufacturers are required to submit a complete ERA. The repetition of studies should be avoided, and where access to existing ERA data is available with a 'letter of consent,' the original reports, along with an adapted ERA, can be submitted. If the ERA was created according to the old guideline, additional studies may be required.

In summary, the seminar provided a detailed insight into the current and future ERA requirements in the EU. The innovations and growing importance of ERA throughout the lifecycle of medicines indicate that regulations are moving towards stricter environmental standards that will encompass both manufacturing and the long-term effects of pharmaceuticals.


Author
Dr Rebekka Bitsch
Conference Manager Pharma & Healthcare
r.bitsch@forum-institut.de
 

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Summary: PharmaFORUM Webcast Biologics 'ICH Q 9 'Quality Risk Management' – What to watch out for?', July 26th 2024

On July 26th 2024 Dr Cornelia Hunke contributed to the live webcast series with her talk on 'ICH Q 9 'Quality Risk Management' - What to watch out for?'.
She covered the following content:

• Risk management as general topic
• Update on the new revision
• Tips for the implementation (it’s never to late)
• Useful tools for handling risks
• Hands-on tips and suitable tools

 
First, Dr Hunke provided an overview of the complexity/”non-conformity of the “wording” = risk terminology, citing different sources (ZLG, ICH Q9, chapter 7, ChatGPT). She invited/advised to “translate” to the company’s specific “language”/environment/requirements.
 
“Risk management – what for?”: Dr Hunke gave examples for the risk topic in the pharmaceutical environment, emphasising the patient safety/the view on the life of others.
One example: A warning letter of the FDA, which describes the inadequacy of the company’s quality system and which states the requirements regarding the completion of the corrective actions.
 
“Risk documentation - which one –what for –who must?”: Dr Hunke summarised the requirements/”expectations” of the different organisations involved (EMA, ICH, ISPE, WHO).
She gave an overview of the relation between the ICH guidelines 8-10, with a particular view on the ICH Q9(R1) (and related documents).
 
“Risk standards”: Dr Hunke gave additional information on the ICH Q9(R1), information on what is new and more detailed information on the scope and the actual requirements.
 
“Risk based approach”: Dr: Hunke demonstrated the options to implement and improve the risked based approach. The benefit from the “interpretation” of the relation and interplay of other ICH guidelines ICH Q7 to 13 and even others is highly underestimated.
Dr Hunke invited professionals to make profit of the use of Q&A documents and other related documents to the ICH guidelines (training material, endorsed documents).
One practical example: The application of AI for risk based approaches in the pharmaceutical sector – some helpful and some controverse input.
 
Dr Hunke closed with some more details on audits/inspections.

Last but not least an excerpt from the final take home message:

• 'Ask yourself always: What is your goal? What is the purpose?”
• “Pick the right focal point and avoid distractions: Focus on critical aspects (-> prioritisation)”
• “Avoid unnecessary effort (-> Process efficiency, similar quality expectations, wording)”
• “Avoid lacking responsibilities (-> e.g. Process/risk ownership)”
• “Avoid unnecessary bureaucracy (-> Processes that are willingly completed)”
• “Question inadequate team size or team composition at all times”
• “Know your standards: regulatory requirements & legal compliance”

Author
Dr Birgit Wessels
Conference Manager Pharma & Healthcare
b.wessels@forum-institut.de

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Summary of the PharmaFORUM Webcast International on the topic “China's Regulatory Landscape: Key Updates and Procedures” on 9 July 2024

 
In the latest episode of the PharmaFORUM Webcast International on 9 July 2024, key updates and procedures regarding China's regulatory landscape were presented by Jenny Zhang (CSL Vifor, China). Enclosed is a summary of essential points regarding clinical trial applications (CTA), pre-submission activities, and marketing authorization applications (MAA) to consider.

China's CTA procedures have become more streamlined and now resemble those in the EU and US, albeit with unique and evolving requirements. Understanding Chinese regulations and authorities is essential and maintaining effective communication with the Centre for Drug Evaluation (CDE) is crucial for navigating the approval process successfully.

Pre-submission activities include essential consultation meetings, such as Pre-IND, End of Phase II/Pre-Phase III, and Pre-MAA meetings. Adequate sample preparation for testing and conducting a gap analysis between different pharmacopoeias should be factored into registration testing. Additionally, being prepared for potential site inspections covering R&D, manufacturing, and clinical sites is crucial. Consideration should also be given to bundled reviews for APIs, excipients, and primary packaging materials (PPM).

Factors impacting MAA approval include the frequently prolonged practical timeline for clinical trial data inspection, which can exceed the specified timeline and cause delays. Strong communication before and during the inspection helps set expectations and address issues proactively, reducing the need for extensive post-inspection follow-ups and minimizing delays. Planning and conducting testing prior to MAA filing can streamline the approval process, as a second testing request after submission can significantly delay approval. Additionally, a deficiency letter necessitates an 80-working day preparation period. Upon receipt of the supplemental dossier, the CDE resumes the review process, extending the standard timeline by one-third and the priority review timeline by one-quarter, potentially causing further delays.
 
Author
Verena Planitz
Conference Manager Pharma&Healthcare
v.planitz@forum-institut.de

You can watch the entire webcast here upon subscription:
https://forum-institut.vidivent.de/event/pharmaforumwebcastinternational/willkommen
 

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Summary OPF March and May

On 21 March and 29 May 2024, Online Pharma FORUM hosted two significant sessions addressing the comprehensive revision of EU pharmaceutical legislation and select legal issues in drug regulation. These sessions provided valuable insights into the implications for pharmacovigilance and the anticipated changes in commercial protection periods.

‘Complete Revision of Pharmaceutical Legislation – Implications for Pharmacovigilance’ was the topic addressed on 21 March. Dr Thomas Grüger reviewed the reform of EU pharmaceutical legislation presented by the European Commission on 26 April 2023 from the perspective of drug safety. Professor Burkhard Sträter, founder of Sträter Rechtsanwälte in Bonn, chaired the event, clarifying questions and providing insights into the consequences for the pharmaceutical industry.

The primary goal of the Pharma Package is to create a single market for medicines where all patients in the EU have equal access to safe, affordable and effective medicines. It aims to maintain an innovation-friendly legal framework for the research, development and manufacturing of medicines in Europe, reduce administrative burdens, combat antimicrobial resistance and make medicines more environmentally sustainable.

A new directive, a new regulation, a new implementing regulation for pharmacovigilance and an amended variation regulation and classification guideline will be introduced. These regulations will come into effect at different times: the implementing regulation for PV activities in 2024, the variation regulation in 2025 and the new directive and regulation between 2027 and 2028.

Mandatory renewal procedures will generally no longer be required in pharmacovigilance, with a few exceptions. The validity of changes to the EURD list will be reduced to four months, with corresponding adjustments to GVP modules. Additionally, the inclusion of sales volume and patient exposure in PSURs both within and outside the EU will be mandatory to better evaluate the effectiveness of risk minimisation measures (RMM). Relevant GVP modules will also be adapted accordingly. Ad hoc data requests for RMM implementation will become possible in the future.

The black symbol will be abolished, and work-sharing for EudraVigilance monitoring for specific substances by marketing authorisation holders will be eliminated, to be conducted solely by national authorities and the EMA. Waiver options will be introduced for risk management plans in specific approval procedures. The planned electronic package leaflet (ePI) will be facilitated with specific requirements.

Antimicrobial resistance vouchers will be introduced to promote the development of new antibiotics. These vouchers could enable a company to obtain an additional year of data protection for another drug, such as a blockbuster, or sell this right to another company, thus cross financing the development of antibiotics.

On 29 May, Markus Ambrosius, partner at Sträter Rechtsanwälte, addressed the expected changes in commercial protection periods under EU pharmaceutical legislation. Currently, new drugs can receive eight years of data protection and two years of market protection. A reduction of data protection to six years is anticipated, with new options for extending protection rights. Additional market protection for a new indication can be obtained, and new options include a two-year extension for product launches in all member states with valid approval, a 12-month extension for addressing an unmet medical need and a six-month extension for a new active substance in a clinical trial with a relevant and evidence-based comparator.
 
The current draft regulation lacks specifics on reference data once the data protection period has ended. Currently, preclinical and clinical data can be referenced, but not quality data. This clarification is still missing in the draft.

With regard to the next step, the European Parliament has voted on the regulation and sent it to the European Council. It is expected to return to the Parliament for further readings, making an effective date before 2026 unlikely.

In the second part of the session, Jan-David Hoppe, a specialist lawyer for criminal law at Sträter Rechtsanwälte, discussed current criminal proceedings for regulatory violations. He presented four case studies illustrating how criminal proceedings can arise and how conflicts can be resolved. The focus was on proceedings initiated by supervisory authorities following inspections. Hoppe emphasised that inspection deficiencies suspected of a crime must be reported by the authorities to the public prosecutor’s office. The key message was that early intervention by a company can successfully prevent criminal proceedings. This requires immediate legal file inspection and a written statement following a criminal complaint by the authority. Most conflicts, including administrative offences, can be resolved in this manner. The latter should also be prevented as they can hinder subsequent cooperation with the authorities (keyword ‘suitability’ or ‘reliability’ of a company).
 
Authors: Dr C. Michaela Gottwald and Dr Henriette Wolf-Klein
FORUM institute
Pharma & Healthcare department
m.gottwald@forum-institut.de, h.wolf-klein@forum-institut.de
 
 

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Harnessing AI in Drug Regulatory Affairs: A Comprehensive Seminar

In our recent German language seminar titled 'Artificial Intelligence in Drug Regulatory Affairs' experts Dr Matthias Rüdiger (Head of AI, INCONSULT GmbH) and Sebastian Bergmann (Head Regulatory Operations, STADA Arzneimittel AG) offered an in-depth exploration of the integration of artificial intelligence (AI) in the pharmaceutical regulatory affairs sector.

The seminar started with Dr Matthias Rüdiger introducing AI and ML, covering definitions, real-world applications, and the evolution of AI technologies including neural networks and generative AI models like ChatGPT. He explained the differences between supervised, unsupervised and reinforcement machine learning as well as deep learning. Then he introduced natural language processing and large language models, concluding with some useful advice for prompt engineering.

Sebastian Bergmann then delved into structured content management (SCM), discussing its crucial role in regulatory affairs and its necessity for leveraging AI/ML technologies effectively. He elaborated on the prerequisites for SCM implementation in the pharmaceutical industry, underscoring the advantages and potential to transform unstructured documents into structured, actionable data. SCM offers the opportunity of dynamic and variable content creation, meticulous content organization and structuring, effective metadata management, robust version control, strategic content reuse and repurposing, efficient workflow and approval management, seamless content publishing and delivery, and comprehensive translation management.

The afternoon sessions further detailed the practical applications of AI/ML in regulatory affairs. Sebastian Bergmann presented a number of use cases for AI/ML in regulatory affairs. In interactive breakout sessions participants engaged in ideation and discussions about future AI/ML applications in regulatory affairs and developed further concrete ideas for implementing AI/ML in combination with SCM together with both speakers. The examples presented and discussed were from the areas of 'regulatory texts/labelling', 'regulatory data management' and 'regulatory intelligence'.

The seminar not only outlined the technical capabilities of AI but also addressed the current challenges and limitations of these technologies in the regulatory framework.  


Author
Dr Rebekka Bitsch
Conference Manager Pharma & Healthcare
r.bitsch@forum-institut.de
 

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Online seminar “Regulatory Lifecycle Management” on February 22, 2024

Our comprehensive online seminar on maintenance and sustainment of human medicinal product approvals offered a deep dive into all aspects of maintenance activities throughout the product lifecycle. This one-day event was designed to provide participants with thorough training on important regulatory responsibilities encompassing dossier updates, variations, pharmacovigilance (PV) activities, and labelling maintenance duties.

Dr. William Shang from Kenvue, Part of the Johnson & Johnson Family of Companies, commenced the seminar with a detailed overview of lifecycle management, focusing on crucial elements such as time and deadline management, internal company interactions, and coordination, alongside change control and planning strategies. The morning session continued with Ingrid Prieschl (hier fehlt ihre Firma) discussing the variations system and procedures, enlightening attendees on Type IA/B and Type II variations and notifications under Article 61(3). She explained the variation classification with practical examples and showed how grouping and work-sharing can safe time and efforts.

Next, Siniša Belina from MAIN5 GmbH & Co. KGaA led an engaging session on electronic lifecycle management, covering essential topics like eCTD, eAF, European portals (CESP, PLM), as well as updates on SPOR and IDMP.

Dr. Shang returned to delve into safety-related obligations, highlighting the management of labelling and product information changes, as well as the implementation of PRAC decisions. He also covered regulatory product activities in the lifecycle, including the roll-out of approvals in other markets and product reclassification issues (RX, OTC).
The day concluded with Ingrid Prieschl exploring other post-approval activities such as renewals, referrals, and various procedures post-approval, including Articles 45 and 46 of the Paediatric Regulation, transfer of marketing authorisation, and post-authorisation measures. The seminar ended with a session for final questions and a lively discussion.
 
Author
Dr Rebekka Bitsch
Conference Manager Pharma & Healthcare
r.bitsch@forum-institut.de
 

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Das Lieferkettensorgfaltspflichtengesetz – nur was für „die Großen“?

Drei Gründe, warum sich auch Mittelständler mit dem LkSG beschäftigen sollten.
Von Dr. Andreas Müller^*)
 
Kaum ein nationales Gesetz hat bereits vor Inkrafttreten soviel Diskussionen ausgelöst wie das Lieferkettensorgfaltspflichtengesetz (LkSG). Auch die juristischen Ansichten gehen weit auseinander, wie einige 1.000 Seiten an Kommentaren eindrucksvoll belegen. Hierbei werden von verschiedenen Gruppen sich teilweise ausschließende Positionen vertreten, was sowohl bei den LkSG-betroffenen Unternehmen als auch bei Zulieferern der aktivierten Lieferketten erhebliche Verunsicherung erzeugt. Formal gilt das Gesetz – vereinfacht formuliert - seit dem 01.01.2024 für Unternehmen mit mindestens 1.000 Mitarbeitern in Deutschland. Diese sind der Aufsicht und Kontrolle durch das Bundesamt für Wirtschaft und Ausfuhrkontrolle (BAFA) direkt unterworfen. Das BAFA hat in einer sehr konzentrierten Informationskampagne und mit mehreren Handreichungen detailliert und verständlich nicht nur erläutert, was an Aufbau- und Ablauforganisation in den betroffenen Unternehmen erwartet wird. Das BAFA ist auch sehr deutlich im Hinblick auf Umfang und Angemessenheit notwendiger Implementierungen und welche Pflichten an Zulieferer weitergereicht werden können. Beim Studium der Handreichungen wird schnell klar, dass eine passive Haltung nicht LkSG-betroffener Zulieferer schnell zu Wettbewerbsnachteilen und später notwendigem Aktionismus führen kann. Ungeachtet der Diskussion um strittige Details im Gesetz sind der Grundgedanke und die notwendigen Umsetzungsschritte intuitiv klar. Die Richtung, die mit der Verabschiedung des LkSG eingeschlagen wurde, ist nicht umkehrbar, und eine Außerkraftsetzung des LkSG dürfte illusorisch sein.  Im vorliegenden Artikel werden daher drei Gründe diskutiert, warum sich auch mittelständische Unternehmen mit den Inhalten des Gesetzes und einer pragmatischen Umsetzung beschäftigen sollten, obwohl keine direkte Betroffenheit vorliegt.   
 
Kontext des Gesetzes – betroffene Unternehmen und unmittelbare Zulieferer
Der erste Paragraph des LkSG regelt den Anwendungsbereich des Gesetzes mit den bekannten Schwellen für die Mitarbeiterzahl: 3.000 Mitarbeiter ab Januar 2023 und 1.000 Mitarbeiter ab Januar 2024.  Regelungen für Leih- und Zeitarbeitskräfte sowie die Berechnungsregeln für Konzernstrukturen mit verbundenen Unternehmen in Deutschland sind komplex. Es kann aber festgestellt werden, dass mit der üblichen Definition von „KMU“ (z.B. Mitarbeiterzahl kleiner als 250, Jahresumsatz kleiner als 50 Millionen Euro) der weitaus überwiegende Teil der Unternehmen in Deutschland derzeit nicht unmittelbar vom LkSG betroffen ist. Der diskutierte EU-Richtlinienentwurf zum selben Thema sieht erheblich niedrigere Grenzen der Mitarbeiterzahl als das LkSG vor. Bei Inkrafttreten werden eine Anpassung und Erweiterung des LkSG in vielen Punkten notwendig werden.
 
Gleichwohl behandelt das LkSG bereits jetzt Lieferketten, und damit sind KMU indirekt betroffen, falls sie nicht ausschließlich „kleine“ Unternehmen im Sinne des LkSG im Kundenstamm haben. Eine Abbildung wird über eine anlassbezogene oder vertraglich auferlegte Pflicht seitens der unmittelbar betroffenen Großkunden erfolgen. Damit ergeben sich in der Regel vertragliche Verpflichtungen und ggf. auch erweiterte Haftungsregelungen für KMU aus den bilateralen Verhältnissen mit Großkunden. Eine bußgeldrechtliche Verantwortlichkeit insbesondere dem BAFA gegenüber ergibt sich heute für KMU nicht. Im Grunde unterscheiden sich damit also betroffene Unternehmen von den unmittelbaren Zulieferern nur durch ihre Berichtspflicht dem BAFA gegenüber und der Art der Sanktionierung, die bei betroffenen Unternehmen vom BFA auferlegt werden kann. Diese ist beim betroffenen Unternehmen gesetzlich abgestützt, im Kunden-Zulieferverhältnis werden Sanktionsmöglichkeiten üblicherweise durch bilaterale individuelle Vereinbarungen im Innenverhältnis abgebildet (aus Sicht des BAFA).  
 
Aus diesem Kontext heraus lassen sich daher (mindestens) drei Gründe ableiten, warum sich auch KMU inhaltlich, organisatorisch und durch geeignete Abläufe mit dem LkSG auseinandersetzen sollten, auch wenn die unmittelbare Betroffenheit (noch) nicht gegeben ist.
 
Erster Grund: Kaskadierung angemessener Handlungen durch LkSG-betroffene Unternehmen
Im Kundenkreis von KMU befinden sich wahrscheinlich Unternehmen, die vom LkSG direkt betroffen sind und damit der direkten Berichtspflicht an das BAFA unterliegen. Ohne aktive Mithilfe der KMU kann das LkSG-betroffene Unternehmen wesentliche Bewertungen zu Risiken in der nahen Lieferkette nicht hypothesenfrei erstellen, was sich für die Position des Zulieferers ungünstig auswirken kann, wenn die Zusammenarbeit ausbleibt. Betroffene Unternehmen fordern KMU (die unmittelbaren Zulieferer) zur Mitarbeit auf und kaskadieren Anforderungen aus dem Gesetz weiter. Dies ist in einem gewissen Umfang auch vom BAFA empfohlen bzw. gebilligt. Einhergehend mit der Installation von Beschwerdekanälen entlang von Lieferketten ist darüber hinaus zu erwarten, dass es zukünftig häufiger zu anlassbezogenen Überprüfungen, Aktionen und auch zu notwendigen Abhilfemaßnahmen bei mittelbaren Lieferanten auf der Grundlage substantiierter Kenntnis von Pflichtverletzungen im Sinne des LkSG kommen wird. Hierzu gehören insbesondere:

• Risiken bei Vorlieferanten identifizieren, im Sinne des LkSG gewichten und priorisieren
• bei Kenntnis von Pflichtverletzungen im Sinne des LkSG Pläne zur Beseitigung von Pflichtverletzungen erstellen und deren Umsetzung bis zum Abschluss kontrollieren und die Wirksamkeit implementierter Maßnahmen in angemessenem Umfang sicherstellen
• (mindestens) anlassbezogenen Zugang zur Lieferkette erhalten und diese dem LkSG-betroffenen Unternehmen auch gewähren
• LkSG bezogene Risiken bei der Auswahl von Lieferanten und Ursprungsländern berücksichtigen
• von Seiten LkSG-betroffener Unternehmen auferlegte vertragliche Verpflichtungen inhaltlich an Vorlieferanten weiterreichen
• Vorort-Kontrollen und LkSG-bezogene Audits bei unmittelbaren und – anlassbezogen – auch bei mittelbaren Lieferanten durchführen und Fremdaudits ggf. unterstützen

Gut vorbereitete KMU werden diese unvermeidlichen anlassbezogenen Überprüfungen und Aktionen aufwandsarm und mit gut dokumentierten standardisierten Abläufen wirkungsvoll unterstützen und sich so unter Umständen auch Wettbewerbsvorteile verschaffen können. Spätestens wenn in der Lieferkette von KMU eine schwerwiegende Pflichtverletzung bekannt und eine anlassbezogene Überprüfung der Managementsysteme und Vorlieferanten im Sinne des LkSG vorgenommen werden muss, werden Verfahren offenlegt werden müssen. Größere Lücken sind dann unter Umständen im Innenverhältnis mit Großkunden belastend und je nach Grad der Abhängigkeit sogar existenzbedrohend.
 
Zweiter Grund: Mitgestaltung
KMU sind dem LkSG nicht direkt unterworfen und haben keinerlei Berichtspflicht dem BAFA gegenüber. Eine Zusammenarbeit mit LkSG-betroffenen Kunden, die Anforderungen des Gesetzes weiterreichen, ist zumindest aus gesetzlicher Sicht weitestgehend freiwillig. Damit können KMU streng genommen eine Unterstützung der LkSG betroffenen Kunden auf ein Minimum reduzieren insbesondere dann, wenn das KMU eine starke Marktposition in der Lieferantenwelt besitzt. Dieser minimalistische Umgang ist jedoch mittel- und langfristig kontraproduktiv. Das LkSG-betroffene Unternehmen muss dem BAFA die Konformität mit den Anforderungen nachweisen ohne wesentlichen Spielraum. Der notwendige Bericht ist standardisiert, die Berichtsfragen sind frei verfügbar und können von jedem eingesehen werden. Die regelmäßige Risikoanalyse der unmittelbaren Zulieferer ist hierbei das zentrale Element der Durchsetzung des Gesetzes.
Gern und auch hitzig geführte Diskussionen um Themen wie

• Zulieferer aus Deutschland sind „grundsätzlich“ sicher (falsch)
• Zulieferer für Büromaterial u. ä. brauchen nicht berücksichtigt zu werden (sehr schwierig)
• C-Lieferanten brauchen nicht betrachtet zu werden (falsch)
• Seit dem 01.01.2024 ist der Zulieferer selbst LkSG-betroffen und muss nicht mehr berücksichtigt werden (sehr schwierig)
• Das BAFA „schießt über das Ziel hinaus“ (Aber das BAFA setzt JETZT um und wird Bescheide erstellen, gegen die zwar ein Einspruch zulässig sein wird, der aber keine aufschiebende Wirkung hat).  

lenken von eigentlichen Kernfragen ab. Ohne inhaltliche Zuarbeit der KMU in der Lieferantenbasis muss das LkSG-betroffene Unternehmen die Risikoanalyse auf Annahmen zu den Risiken in den Lieferketten und auf Medienberichte und publizierte Risikoindizes abstellen. Unter Umständen werden aus Gründen des Selbstschutzes maximale Annahmen zu Risiken zu Waren, Lieferketten, Herkunftsländern usw. getroffen, um bei einer Revision des BAFA keine Angriffsfläche zu bieten und einen möglichen Vorwurf „bewussten Wegsehens“ unmittelbar entkräften zu können.  Dies kann sich innerhalb kurzer Zeit nachteilig für zuliefernde KMU auswirken, da ausbleibende Mitarbeit und Passivität die Suche nach mehr kooperativen Alternativlieferanten auslösen und vorantreiben werden. Eine kurze Phase der Ressourcenschonung im KMU wird erkauft mit einem möglichen mittel- und langfristigen Wettbewerbsnachteil.
 
Dritter Grund: die herannahende EU Richtlinie
Die im Entwurf schon länger vorliegende EU-Richtlinie über die Sorgfaltspflichten von Unternehmen übernimmt viele Ansätze des LkSG, erfindet aber auch neue, teilweise deutlich verschärfende Elemente (z.B. extraterritoriale Anwendung, Ausweitung der Gültigkeit „downstream“ d. h. Einbeziehung von Kunden). Insbesondere werden die Schwellen für betroffene Unternehmen erheblich abgesenkt. Es ist zu erwarten, dass in der nationalen Industrie ein Großteil der KMU direkt betroffen sein wird bei in weiten Teilen LkSG-deckungsgleichen Taktiken der Herstellung der Konformität. Mit einer Übergangsfrist ist zu rechnen, aber ein frühzeitiger Beginn der Maßnahmenimplementierung sichert die Wettbewerbsfähigkeit, erzeugt einen Erfahrungsvorsprung und erlaubt proaktive Zusammenarbeit mit Großkunden, was ein entscheidendes Differenzierungsmerkmal zu Marktbegleitern im In- und Ausland sein kann. Eine Umsetzung ohne Zeitdruck erlaubt darüber hinaus ein viel sehr geordnetes und überlegtes Vorgehen ohne verschleißenden Aktionismus nach Inkrafttreten.
 
Aufwandsoptimierte Umsetzung
Das Vorgehen bei der Umsetzung der zentralen Risikoanalyse ähnelt den Risikobetrachtungen aus Prozessstandards und bekannten Managementsystemen. Natürlich sind die Attribute zur Risikoumschreibung von Waren, Herkunftsländern und Lieferanten verschieden. Viele KMU sind auch aus anderen Gesetzen heraus Berichtspflichten unterworfen, die teilweise zur Herstellung einer (informellen) Konformität mit dem LkSG genutzt werden können. Hierzu gehören z. B. obligatorische Berichte zur Corporate Social Responsibility für mindestens mittelgroße Kapitalgesellschaften in Deutschland. Für eine sehr effiziente und pragmatische Implementierung verweist der Autor auf einschlägige Veranstaltungen, die sich auch an KMU richten. Eine optimale Unterstützung LkSG-betroffener Unternehmen seitens proaktiv agierender unmittelbarer Zulieferer wird sicher das Kunden-Lieferanten-Verhältnis verbessern und langfristig weiter festigen können.   
 
^*) Andreas Müller ist Physiker und Ingenieur und dafür bekannt, in seinen Seminaren „vom Praktiker für Praktiker“ komplexe Themen zu veranschaulichen und anwendbare Umsetzungshilfen zu geben. Zum LkSG kam er, weil er sich zum einen in seiner Haupttätigkeit kontinuierlich mit Risiken in stark verzweigten Lieferketten beschäftigt. Zum anderen hat er aus früheren Tätigkeiten im internationalen High-Tech-Industriesegment intensive Praxiserfahrungen mit dem Bundesamt für Wirtschaft und Ausfuhrkontrolle (BAFA), welches die durchsetzende Bundesbehörde (auch) für das LkSG ist. Andreas Müller ist Autor mehrerer Fachartikel zum LkSG und Co-Autor zweier Bücher zum Thema. Für das Forum-Institut referiert er zum LkSG und seiner pragmatischen Umsetzung am 13. März 2024.
 

Nähere Informationen erhalten Sie in der Online-Veranstaltung 'Lieferkettensorgfaltspflichtengesetz (LkSG)'.


 

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Insightful Seminar on Navigating Upcoming EU Pharmaceutical Legislation Changes

The online seminar 'EU Pharmaceutical Legislation - Consequences for your Regulatory Strategy' took place in German language on December 8, 2023 and offered a detailed insight into the upcoming changes to EU pharmaceutical legislation and their effects on the regulatory strategy of pharmaceutical companies.

The seminar was opened by Dr Axel Korth explaining the overarching goals of the EU pharmaceutical legislation revision: “Access, Affordability, Availability, Competiveness, Compliance and Combating antimicrobial resistance”. The need for a comprehensive revision of directive 2001/83/EC and Regulation (EC) No. 726/2004, which exist for over 20 years, was emphasized by Dr Korth. The EU Commission's ambitious schedule calls for a vote as early as April 2024. However, given the parliamentary elections in September 2024, this schedule should be seen with caution. Dr Korth presented various scenarios for the entry into force of the new directive and regulation between Q1/2028 and Q4/2029. He saw an entry into force in mid/late 2028 as the most resilient scenario.

Dr Korth then discussed the planned changes according to the revision. This includes accelerating the Centralized Procedure (CP) from 210 to 180 days and proposing an opt-in mechanism for member states for Mutual Recognition Procedures (MRP, Articles 35, 36 of the directive). The latter issue is highly debated because it conflicts with the right to freedom of economic activity. The importance of a planned early agreement with the EMA on submission dates for marketing authorisation applications was discussed. An important challenge in this respect will be that pharmaceutical development often does not proceed linearly. Dr Ulrich Granzer emphasised how important open communication between the authority (rapporteur and co-rapporteur) and the pharmaceutical company is already under the current legislation to achieve mutual planning.

The shortened approval procedures are planned to be presented more clearly in the new legislation. According to Dr Korth, the new texts reflect the existing law, but there is more clarity regarding the already existing shortened application types. In addition, the planned shortening of document protection to 6 plus 2 years (or to 8 plus 2 years if special requirements are met) was explained.
Afterwards, Dr Granzer addressed the concept of “(high) unmet medical need”. The vagueness of the planned EU legal texts and the scope for interpretation were highlighted, in contrast to the detailed guidelines that already exist in the USA. The criteria existing in the USA were presented and the prospect that the directive from the USA could be used as the basis for a directive at EU level was explained. Dr Korth added that the concept of “(high) unmet medical need” is one of the most discussed topics at EU level, alongside with changing the protection periods.

In the further course of the seminar, Dr Granzer spoke about the approval of “orphans” in various countries. It was highlighted that a tailored strategy is required for successful approval in different jurisdictions. For example, in some cases clinical trials must be carried out in the exact country in which approval is sought - a prominent example of this is Japan. Drd Granzer also highlighted the so-called “access countries” – the United Kingdom, Switzerland, Canada, Australia and Singapore – that have formed a work-sharing union. These countries accept both EU and US dossiers, supplemented by specific forms. This simplifies the approval process and enables approval in all these countries on a more efficient basis. In addition, the importance of regular meetings with regulatory authorities and obtaining scientific advice was emphasised. These interactions contribute significantly to the planning and strategic alignment of the approval processes.

Finally, Dr Granzer summarised that innovations are of central importance in the pharmaceutical industry. They allow companies to determine the price of their products and take a pioneering role in the market, even when it comes to developing generic versions. It was also emphasised that it is essential to define a clear strategy before the development phase begins to ensure success in this complex and regulated market.

Another focus of the seminar was on lifecycle management, whereby the current requirements for a renewal after five years are to be replaced by a permanent approval. However, continuous safety assessments, such as Periodic Safety Update Reports (PSURs), will not lose any importance even without the previous ritual of regularly renewing approval after five years. Regarding further adjustments and changes in lifecycle management, the topic of 'Variations' was dealt with intensively. Dr Korth presented the planned revision of the Variation Regulation. A two-stage process was pointed out: First, an independent revision of the Variation Regulation is planned for the beginning of 2024, followed by changes to the legislation as part of the pharmaceutical package. The aim of these revisions is to reduce administrative burdens and make the processes more efficient.

Furthermore, the topic of Environmental Risk Assessment (ERA) was discussed in detail. An ERA is currently mandatory for specific medicinal products, but the environmental impact alone is not a criterion for refusing approval. However, the proposed amendment is intended to handle this much more strictly, in line with the European environmental strategy, the European Green Deal. A revised ERA guideline, still in current law, is scheduled to be published in the first quarter of 2024. Particular attention was drawn to the expected challenges for companies, especially small and medium-sized enterprises (SMEs). Products approved before October 30, 2005 could potentially even be subject to retrospective restrictions, based on a risk-based approach by the EMA.
 

Author

Dr Rebekka Bitsch

Conference Manager Pharma & Healthcare

r.bitsch@forum-institut.de

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Summary ExpertFORUM Labelling

The Expert FORUM Labelling, an online conference focussing on digital, patient-friendly and safety labelling, took place on October 16^th and 17^th 2023. Nine European authority and industry experts provided the latest on the impact of the EU pharmaceutical legislation on labelling, the future of the digital package leaflet and important aspects about fulfilling the requirements of product information, patient empowerment and safety labelling.

Dr Peter Bachmann opened the conference with a summary of the impact of the EU pharmaceutical legislation on labelling. First, he highlighted the main objectives of the new legislation by the European Commission: access to and availability of affordable medicines across the entire EU, a competitive and innovation-friendly regulatory environment, environmental sustainability and addressing antimicrobial resistance. The new regulations on product information can be found combined all together in chapter VI of the new Directive. Importantly, the new Directive leaves the definition of the package leaflet as “paper only”, “paper and electronically” or “electronically only” in the responsibility of the member states. In addition, there is no definition of “electronically” included but the right for the patients to always receive a paper version on request. However, it is stated that “the Commission shall adopt implementing acts (…) to establish common standards for the electronic version of the package leaflet”. The specific required items of labelling are not longer listed in the Directive itself but in the Annex which also contains a correlation table of current and planned requirements. 

Dr Kim Sherwood from the Swedish Medical Products Agency (MPA) thereafter started her talk with an important clarification of the definitions around electronic product information. Remarkably, ePI refers to a dynamic digital (semi-)structured format for product information, whereas ePL is the same content and structure of the paper version of the package leaflet displayed electronically. The EMA is currently running an ePI pilot providing a portal and editor tool for semi-structured PI documents. The approved PIs are published in ePI format as well as other usual formats. Dr Sherwood highlighted the advantages that a dynamic structured format has for the searchability and the transferability between different portals/sources. Furthermore, she presented three applications of AI (artificial intelligence) that are in testing at the Swedish MPA: identification of sentences of similar content for further harmonisation and standardisation of PI, sorting of package layout (mockups) into categories to avoid similar packages which could lead to mix up medication errors and categorisation of adverse events from a plain text.

Nina Malvik from the Norwegian Medicines Agency highlighted that the European Commission confirmed that Directive 2001/83/EC requires a printed package leaflet to be included in the medicinal package. However, there are exemptions possible to market medicinal products without a printed package leaflet in national language for orphan medicinal products, medicinal products to be administered by health care professionals or in case of severe availability issues. Currently, the Directive opens the possibility to have a link to additional digital information. For the access to additional information or the digital PL in the national language for example QR codes or the 2D matrix code (FMD code) can be used. Among the advantages is that information can be faster updated compared to print versions. However, the digital process behind the scenes is highly complex. In general, the aspects to be considered before having digital PL only are legislation, accessibility, awareness and delivery. For the delivery the legislation would most likely require a “push” situation. It won’t be acceptable that patients need to search on different websites for the information they need, but there has to be a QR code or similar on the pharmaceutical package for a barrier-free access.

Diving deeper into the topic of patient-friendly labelling, Dr Rüdiger Faust from UCB Biosciencs GmbH addressed the challenge of achieving a label for childbearing and breastfeeding individuals. Dr Faust highlighted that there is a clear unmet need in this respect and that a big problem is the systemic lack of data for individuals of childbearing and lactating age. At the moment, data generation happens mostly post-authorisation with safety data and registries. Thereafter the labelling language to be used should be adopted to the data in respect to discouraging use or not. It will be very important in the future to follow a structured approach to encourage earlier conduct of reproductive toxicology studies, as well as clinical studies for pregnancy and lactation as it will be also included in ICH E21 guideline.

Dr Jörg Fuchs from PAINT-Consult® talked about different methods for readability tests to ensure legible, clear and easy-to-use package leaflets. He opposed the verbal interview (Australian method) and the written readability test by PAINT- Consult®. The focus of the readability testing should be the systematic optimisation of the entire package leaflet instead of only achieving success criteria.  Dr Fuchs stipulated that the QRD checklist focuses on a test report evaluation of how verbal interview tests have been performed, instead of the package leaflet’s quality. He would suggest to reduce the current QRD template from over 850 to 200 words to achieve better patient compliance (Fuchs et al., PharmInd, 2007, 69(2):165-172).

Dr Olga Kolcak from Bayer Consumer Care AG talked about the importance of labelling compliance. She highlighted that any inaccuracy or errors can lead to significant risks to the user and serious legal troubles for the provider. Dr Kolcak explained the company core data sheet (CCDS) as the company position on the medicinal product and its labelling. According to her, a CCDS can also be very important for OTC products not only for Rx products. In organising the labelling process a pharmaceutical company should also keep in mind that an isolated labelling system can loose the contact to the regulatory information management system but often you need the full picture of all product related changes and not only the labelling changes.

Dr Thomas Grüger talked about educational material as tool for additional risk minimisation. Importantly, educational material should add or augment and not duplicate the SmPC and PL. For educational material user testing is encouraged (according to GVP XVI, draft Rev 3). Dr Grüger presented different ways of communicating the access to educational material, like the blue hand symbol (Germany). Since April 2023 France has established a red-box warning on the outer package with a QR code to scan for further information e. g. on severe side effects and their reporting. In regards to the impact of the EU pharmaceutical legislation on labelling Dr Grüger stressed the discontinuation of renewals, the discontinuation of the black symbol for adverse drug reactions (ADR) reporting and the mandatory Rx status as well as the “awareness cards” for antimicrobials. There has then been a short discussion about the necessity of readability testing according to the new EU pharmaceutical legislation. In the Directive it is clear that readability testing will be further required. It seems like the readability testing results have been forgotten in the list of documents that need to be submitted which can be found in the Annex to the Directive.

Robert Begnett from Kyowa Kirin International plc linked to the presentation of Olga Kolcak and talked on global labelling compliance throughout the product lifecycle. He highlighted the cross-functional nature of labelling and the importance that all involved departments are aware of labelling. A key take away of his presentation was that the labelling personnel needs to be involved early in the lifecycle, at the clinical development stage, to be aware of risks and to evolve a developmental reference safety information (dRSI). Concerning the global labelling aspect reference labelling (CCDS, RSI) is core guidance, but Mr Begnett recommended to be flexible for local adaptation on an approved basis.

The conference was concluded by Tris Nockles who is the Regulatory Networks Leader at Navitas Life Sciences giving insights on ePI from industry pioneers. She showed that there are numerous initiatives for the testing of ePI, especially on the national level. Patient safety, supply chain resilience, streamlined regulatory processes and sustainability are reasons to progress with ePI. However, the benefits inevitably come with challenges like complexity, technology requirements, compliance and fitness for purpose. Mrs Nockles recommendation to industry was to get involved and give it a try.
 
Author

Dr Rebekka Bitsch

Conference Manager Pharma & Healthcare

r.bitsch@forum-institut.de




 

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Online Pharma FORUM – Drug co-distribution: PV challenges

On September 15, 2023, the Online Pharma FORUM took place on the topic of 'Drug co-distribution: PV challenges'. First, lawyer Dr Christian Moers from the law firm Sträter Rechtsanwälte in Bonn differentiated the terms co-marketing, co-promotion and co-distribution. In the case of co-promotion, the marketing authorization holder allows other companies to make use of the marketing authorization and to market a drug under their own name by means of agreements. Dr Moers explained that the co-distributor is also considered a pharmaceutical entrepreneur (although EU law does not recognize this term) and thus the corresponding regulatory obligations apply under the AMG. Marketing authorization holders and co-distributors must assign tasks at the interfaces via appropriate agreements. The pharmaceutical entrepreneurs are also obligated to mutual oversight, depending on the assumption of responsibility.

Dr Axel Thiele, Consultant and Auditor Pharmacovigilance, Berlin, then explained in detail the requirements with regard to pharmacovigilance. He explained that the marketing authorization holder must have a QPPV, and the co-distributor must have at least one step-by-step plan officer. The latter must collect and document suspected cases of adverse drug reactions and forward them to the marketing authorization holder. Detailed delineation of duties agreements must be established for this and other PV obligations. The co-distributor is part of the MAH's PV system and must be named in its PSMF.
 
Author

Dr C. Michaela Gottwald
Conference Manager Pharma & Healthcare
m.gottwald@forum-institut.de
 

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The new “Lieferengpassgesetz” (ALBVVG) – dealing with drug shortages in Germany

 
 
On 12 September 2023, the conference on the new German law ALBVVG – dealing with drug shortages and its consequences took place online. Dr Lars-Christoph Nickel (Federal Ministry of Health) created a good basis for discussion by explaining the law and the new resulting requirements for all stakeholders. In this context, he particularly addressed the regulations for medicinal products for children. The pilot project on drug tenders to diversify the supply chains for antibiotics was also in focus. Here, new tenders will focus more on the location of the production site of active ingredients. An extension to other medicines/indications is provided for in the law if necessary. Moreover, a re-evaluation of the measures is planned for 31.12.2025.
 
Dr Michael Horn then went into the shortage management of German BfArM. Due to the ALBVVG, the pharmaceutical entrepreneur has extended information obligations in case of impending supply shortages. In addition, an AI-based early warning system is currently being developed.
 
In the further course of the conference, representatives from industry, wholesalers and health insurance companies addressed the challenges and implementation possibilities - especially in the field of new tenders. It became clear that shortages and possibly supply bottlenecks can only be combated by all stakeholders working together.

Author
Dr Henriette Wolf-Klein
Department Manager Pharma & Healthcare
h.wolf-klein@forum-institut.de



 

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Summary: PharmaFORUM Webcast Biologics 'Non-clinical aspects of RNA-based drug development', July 19^th 2023

On July 19^th 2023 Dr Anika Schröter contributed to the live webcast series with her talk on 'RNA-based drugs – classification and impact on non-clinical development'.
She covered the following content:
- Variety of RNA-based product class
- Regulatory classification
- Why does definition and classification matter?
- Non-clinical programs dependent on classification
- „Real life“ examples: some common hurdles and pitfalls
 
First, Dr Schröter provided an overview of the variety of RNA-based products, which are „generally“ divided into a) Coding (mRNA) and b) Non-coding drugs (ASO, RNAi, saRNA  etc.). She illustrated exemplarily the mode of action of products of the two main categories.
 
She summarised the definition of product classes by regulatory authorities: 1. Small Molecule, 2. Biological Medicinal Product (a) Advanced Therapy/Cell and Gene Therapy, b) Biotechnology-derived Product), 3. Vaccine.
In addition, Dr Schröter gave an overview of the relevant key guidelines, e.g. ICH M3(R2), ICH S6(R1), WHO guidelines, FDA Guidance for Industry etc.
 
She than explained the factors, which influence regulatory classification of mRNA-based drugs: a) mode of action, b) manufacturing process/origin, c) indication (and d) regulatory agency)).
With the help of a list of different products, Dr Schröter explained the classification very clearly.
An example: Two mRNA products having the same mode of action, differing in the indication are classified as two different products.
Dr Schröter gave some additional information on the regulatory classification of “gene therapy“ and underlined with “real life examples/cases”.
„Borderline Case Oligonucleotides“: As all non-coding RNAs are currently chemically derived, they are not considered as „biological medicinal products“, consequently they cannot be defined as advanced therapy / gene therapy.
BUT principles of ICH S6 might be applied for the non-clinical development of oligonucleotides.
The EMA plans on a separate non-clinical guideline on oligonucleotides (until 2024).
 
Dr Schröter demonstrated the different regulatory views of classification of RNA-based products between the EMA and the FDA too. Again ,she provided real life examples and emphasised the challenges during the non-clinical development stage.
The definition “gene therapy“ (and therefore the harmonisation between different regulatory areas) is still under discussion, and an aligned definition is not yet available, except for a description as provided in the newly released ICH S12 guideline.
 
As a first take-home message, Dr. Schröter emphasized that It is important to define what product you develop, as based on the definition/classification different guidelines apply and thus, a different non-clinical program might be needed.
The three keystones of a NC program for RNA-based products are: a) pharmacology, b) pharmacokinetics, c) toxicology.
Dr Schröter compared the non-clinical program for different products dependent on the classification. And again, she underlined with a couple of real-life examples/cases and also outlined the implication on timeline and costs of the non-clinical program dependent on the classification of the product.
 
Dr Schröter closed with some more real life examples on class-related risks and challenges.
 
An excerpt from the final take home message:

• 'RNA-based drugs are a highly variable class of products“
• 'Dependent on indication, mode of action, source (manufacturing) and regulatory region RNA-cased products can be classified as small molecule, vaccine, ATMP/GTMP, (biotech drug)'
• 'Classification matters as it significantly influences the required non-clinical program'
• „The overall aim of the non-clinical program (i.e. risk/benefit evaluation), is independent from the classification of a product,  but the program to get there differs between different product classes“

Author
Dr Birgit Wessels
Conference Manager Pharma & Healthcare
b.wessels@forum-institut.de
 
 
The next dates in the PharmaFORUM Webcast Biologics 2023 program:

• 'Advantages and disadvantages of different approval procedures (MRP/DCP/CP)', 12 October 2023
• 'Hospital exemption in the initial application and regulatory context', 9 November 2023
• 'CMC requirements for Gene Therapy Medicinal Products (GTMPs): US and EU jurisdiction”, 14 December 2023
• and more

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The online conference 'Biosimilars 2023 – the Aut idem rules' took place on 5 July 2023.

The starting point of the event was the Federal Joint Committee (G-BA) decision of 15 June 2023, which regulated the interchangeability of medically prescribed preparations of finished medicinal products with biotechnologically produced active ingredients in pharmacies and thus gave the starting signal for biosimilar aut idem.
In the current regulations, both the area of application and the type of application must be the same for the exchange; an extrapolation of indications for the exchange is not possible, unlike in drug approval procedures.

In the next step, it is planned to allow aut idem in all active substance classes, again only for the same area of application and the same route of administration. However, Professor Hecken, impartial chairman of the G-BA, announced a re-evaluation in 2-3 years.

Dr. Sabine Vogler from Gesundheit Österreich compared the biosimilars regulations across Europe. It was interesting to see that Germany, along with Denmark, the Netherlands, Sweden and Iceland, is one of the few countries without a price link for biosimilars. In addition, in first countries of the EU there is already an automatic biosimilars substitution obligation, e.g. in Estonia.

Detlef Böhler, BARMER, then addressed the next planned open house tender in Bavaria together with the KV Bavaria (Association of Statutory Health Insurance Physicians in Bavaria), the AOK Bavaria and other partners in the field of chemically defined oncological products, which can, however, be seen as a blueprint for subsequent possible biosimilars tenders.

Finally, Walter Röhrer from the AG Pro Biosimilars expressed the hope that the Federal Ministry of Health will still object to the G-BA decision and that the regulations will not come into force as they are.

Author
Dr Henriette Wolf-Klein
Department Manager Pharma & Healthcare
h.wolf-klein@forum-institut.de
 

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EU Legislation 2023: Update on Orphans, Paediatrics, EU-HTA & Pharma Legislation

 

On 28 April 2023, the online conference on the upcoming EU legislation took place. The focus was on the Pharmaceutical Legislation with the Draft-Regulation 2023/0131 and the Draft-Directive 2023/0132 as well as the upcoming EU-HTA procedure.

Regulation 2023/0131 will in future also include the orphan drug and the paediatric legislation. An important change will be the transformation of the COMP and the PDCO into EMA Working Parties. Many novelties are to be expected, especially in the orphan legislation, starting with different periods of market exclusivity (depending, among other things, on the availability of medicinal products throughout Europe) up to the orphan designation, which will expire in future with the granted marketing authorisation. Possible property rights in the area of repurposed medicinal products will come in addition.

In general, the pharmaceutical legislation aims to simplify and accelerate marketing authorisations in Europe. For this reason the assessment periods will be shortened, both at the EMA and at the EU Commission prior to the granting of the marketing authorisation. The renewal and sunset clause are to be abolished, and pre-authorisation consultation is to be linked more closely with HTA aspects. Environmental Risk Assessment will also gain in importance in the area of medicinal products for human use, as a lack of an ERA may also result in a refusal of marketing authorisation in the future.

The timetable for the implementation of this legislation as a whole is currently still open. The situation is different in the EU-HTA area. The Co-ordination Group as an important body has taken up its work, the corresponding subgroups have been founded and the first Implementing Acts are expected in September 2023.

AuthorDr Henriette Wolf-Klein
Department Manager Pharma & Healthcare
h.wolf-klein@forum-institut.de

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Summary: PharmaFORUM Webcast series „CMC requirements in Asia, Japan and Eastern Europe“, webcast session on March 7^th 2023 – Fokus on Japan and South Korea

 
On March 7th 2023 Dr Christina Juli contributed to the live webcast series with her lecture on „CMC requirements in Japan and South Korea“. Further webcasts of the series focus on China, India and Russia/EAEU. The series covers the requirements for the product classes small and large molecules.
 
First, Dr Juli summarised the regulatory landscape in Japan and South Korea. She pointed out the most important authorities and the relevant pharmaceutical laws and regulations in each country.
She furthermore compared the clinical trial process, the new drug application process and the handling of post approval changes in Japan and South Korea (key facts: specific pharmacopoeia in both countries, extensive work on GMP dossier to be considered for approval in South Korea, PACMP approach (analogous to EU and US approach) available in Japan, not available in South Korea).
 
During the second part of her presentation, Dr Juli highlighted the country-specific requirements and differences with regards to ICH requirements.
 
For Japan she considered

• CMC related sections of J-CTD (key facts: Module 3 is the most important document/the basis, Module 2 is the basis for the approval decision)
• J-AAF (key facts: legally binding document, basis for all post-approval changes, during the lifecycle only this form needs to be updated, streamlining of the descriptions in the specifications and test methods sections)
• Foreign Manufacturer Accreditation
• GMP Inspection (key facts: in advanced countries only paper-based inspections, delays in requesting inspection can lead to delays in approval)
• J-DMF Registration (key facts: voluntary process for items as drug substance and new excipients, needs to be in place for the sale of corresponding items)

 
For South Korea she considered

• ICH implementation (key facts: ICH member since 2016, harmonisation process still ongoing – still country-specific requirements)
• Specific requirements for CTD sections (key facts: CMC/quality part - „long“ list of market-specific requirements (different from EU requirements), use of analytical methods according to pharmacopoeia)
• GMP Evaluation and Inspections (key facts: pre submission of GMP dossier (a lot of documentation – long table of content) in parallel to MAA dossier, GMP certification is for the manufacture of one product at one site, import licenses are linked to a product SKU and not to a family of product)
• Biological testing during NDA (comparable to requirements in China)

 
Last but not least, Dr Juli presented a series of case studies to raise awareness of the challenges of complying with and maintaining regulations and consistency during the marketing authorisation process and lifecycle management.
 
An excerpt from the take home message:
„The alignment of local requirements to global standards and regulations are an effective and demonstrated way to promote simplification, harmonization, acceleration to approval and a quicker patient access. Thus, driving global harmonization on regulatory requirements is still very important.“
 
 
If you would like to see an excerpt of the slide deck, then take a look at our whitepaper MA and lifecycle Management in Japan. 

Author
Dr Birgit Wessels
Conference Manager Pharma & Healthcare
b.wessels@forum-institut.de
 

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Oncology: Evidence, HTA and Reimbursement

 
The 'Oncology: Evidence, HTA and Reimbursement' conference 2023 took place on 27 and 28 February 2023 - online.
 
Dr Markus Follmann, German Cancer Society, addressed current possibilities of evidence assessment, especially through the GRADE methodology and the HTA tool of the OL Office (OL = Guidelines Programme Oncology).
 
Dr Uwe Vosgerau, G-BA, focused among other things on the transition period: start of EU-HTA and  AMNOG procedures in parallel. In his opinion, these procedures should run analogously and lead to congruent decisions. An important topic - that of the submission of new data slicer - has not yet been conclusively clarified on the EU-HTA level; in national procedures, slicer are still possible after marketing authorisation until the benefit assessment procedure. In contrast, Dr Vosgerau saw the issue of label changes in the context of marketing authorisation as a minor challenge. In the course of the lecture, the differences between the current and the future Joint Scientific Consultation (JSC) according to EU HTA rules became clear. Especially the non-offering of pre-submission meetings at EU level will be a challenge, as these meetings represent a substantial part of the current G-BA meetings. Also, in the future, the JSC will only offer early consultations on very selective products (unmet medical need, first active substance in a completely new class of drugs...) and not on the topic of PICO schemes either.
 
In the afternoon, Hans-Holger Bleß, fbeta, addressed the register landscape. It is currently open how far the national consolidation of cancer registry data from the regional cancer registries has progressed. The law for merging the registries to one national registry was already adopted in 2021.
 
Tim Steimle, Techniker Krankenkasse, announced the model agreement for the combination discount (AMNOG products) as of 2 May 2023; presumably, health insurance working groups will be formed for this purpose so that each individual health insurance fund does not have to act individually.
 
Dr Alexander Csaki, Bird & Bird LLP, concluded by discussing the upcoming biosimilar aut idem, but had great doubts as to whether we will see discount agreements in the area of parenteral preparations in general and with biosimilar exchange in the near future.
 

Author
Dr Henriette Wolf-Klein
Department Manager Pharma & Healthcare
h.wolf-klein@forum-institut.de

 

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Summary: AMNOG 2023 & EU-HTA

 
On 26 January 2023, the online meeting 'AMNOG 2023 & EU-HTA' took place. Marcus Guardian, Chief Operating Officer of the EUnetHTA Secretariat went into the details of the roadmap to the launch of EU-HTA in 2025. A large part of the EUnetHTA21 deliverables have already been published, accepted by the EU Commission and now forwarded to the HTA Coordination Group. The coordination group can now adopt the guidelines, but also modify them.

From April 2023, the subgroups of the coordination group will work on the following topics
- Joint clinical assessment
- Joint scientific consultation
- Identification of emerging health technologies
- Methodologies (procedural and methodical framework)

Professor Josef Hecken, impartial chairman of the G-BA, made it clear that the G-BA has a high interest in chairing the subgroup 'Joint scientific consultation'. He expected about 5 more years of parallel procedures (AMNOG/EU-HTA).

Subsequently, Professor Hecken addressed national topics and went into the challenges of the German ”anwendungsbegleitende Datenerhebung (AbD). An AbD is only indicated in the area of orphan drugs, special approvals, etc., but not if a regular RCT would have been possible. The G-BA would also like to speed up the internal G-BA processes here, as the AbD start is very late at the moment. Dr. Beate Wieseler, Head of the Department of Drug Evaluation at IQWiG, referred in this context to German registries that require comprehensive expansion in quality aspects for AbD use. For evidence generation, she suggested register-based pragmatic RCTs or adaptive/platform studies, especially for orphan drugs/ATMPs.

Prof. Dr. Stefan Huster, Chairman of the Arbitration Board according to § 130b SGB V and Dr. Antje Haas, Head of the Department of Pharmaceuticals and Therapeutic Products, GKV-Spitzenverband, concluded by discussing the new requirements for reimbursement amount negotiations and adjudication practice under the GKV-FinStG. Prof. Dr. Stefan Huster saw the subsequent reimbursement by the PU as the rule in future and no longer - as is currently the case - as the exception. A first decision on the price-quantity regulation (PMR) has already been made.

Author
Dr Henriette Wolf-Klein
Department Manager Pharma & Healthcare
h.wolf-klein@forum-institut.de
 

   Here you can download the entire newsletter.
 

Online Pharma FORUM “Update Clinical Trials Regulation”

On 8 December 2022, the Online Pharma FORUM webcast took place with regard to the Clinical Trials Regulation. PD Dr Thomas Sudhop was the expert lecturer.
At the beginning of the webcast, Dr Sudhop addressed the principles of submitting a clinical trial application under the new Clinical Trials Regulation (CTR), which has been active since 31 January 2022. Part 1 of the application consists of, among other things, the protocol, IMPD, IP, label, GMP documents and is the same for all Member States concerned (= MSC). Part 2 covers national concerns of individual Member States such as informed consent, insurance, data protection, compensation, etc.

For Part 1, there is a joint assessment coordinated by a Reporting Member State (RMS), the decision is then binding for all MSCs. In most Member States, the assessment is carried out jointly by Ethics Committees and National Competent Authorities.

Part 2 is evaluated purely nationally, usually under the lead of the ethics committees; in Germany, only the ethics committees evaluate. Currently, 50 ethics committees are still evaluating in the old system; for the application procedure according to CTR, the ethics committees had to re-register. Currently, slightly more than 30 committees are actively registered.

Applications under the CTR are submitted via CTIS, consisting of an EU portal and an EU database. The prerequisite for this is a first registration in OMS (Organisation Management Service) of the EMA. CTIS is not 100% stable at the moment, but EMA is in the process of fixing the bugs by the end of January 2023. An increase in the file size that can be uploaded is also planned.

Regarding the timelines: From 31.1.2023, all new clinical trial applications must be made in the CTIS system. For ongoing clinical trials, there is a transition period until 30 January 2025, by which time they must be transferred to the new system, otherwise the clinical trial will be considered terminated at that time.

Author
Dr Henriette Wolf-Klein
Department Manager Pharma & Healthcare
h.wolf-klein@forum-institut.de