In 1995, I attended a conference in Paris where a significant announcement was made—the establishment of the European Medicines Agency (EMA). At the time, the vision was ambitious: within three years, all medicinal products would be approved through a centralized procedure, streamlining the process across Europe. Nearly three decades later, while this vision remains only partially realized, the EMA has undoubtedly transformed the regulatory landscape in the European Union. 

My journey with the EMA began with the submission and approval of the first product under the centralized procedure—a recombinant human growth hormone. Since then, as the president and founder of a pharmaceutical regulatory affairs consultancy, I have been deeply involved in numerous consultation meetings with the EMA and have worked on the submission and approval of Orphan Medicinal Product Designations (OMPDs) and applications from Small and Medium-sized Enterprises (SMEs). Throughout these experiences, I have found the EMA’s procedures to be exceptionally well-organized, with clearly defined timelines that greatly facilitate strategic planning. 

Understanding the EMA’s Role in the European Union 

The EMA, established in 1995, was created to unify the approval process for medicines across the European Union (EU). Before its inception, each EU member state had its own regulatory authority, leading to inconsistencies and delays in the availability of medicines. The EMA was designed to address these issues by enforcing rigorous scientific standards and providing a centralized system for the approval of medicines. 

The centralized authorization procedure, managed by the EMA, is mandatory for certain categories of medicines, including those targeting rare diseases, HIV, cancer, neurodegenerative disorders, and other serious conditions. This procedure also applies to biotech products, gene therapies, and monoclonal antibodies. For these medicines, a single application to the EMA results in a marketing authorization valid across all EU member states, as well as Iceland, Liechtenstein, and Norway. 

For medicines outside the mandatory scope of the centralized procedure, the EMA offers alternative pathways such as the national procedure, decentralized procedure, and mutual-recognition procedure. These options provide flexibility for companies developing products that may not fit the centralized criteria but still require regulatory approval within the EU. 

Leveraging EMA’s Scientific Advice and Protocol Assistance 

One of the EMA’s most beneficial offerings for startups is access to scientific advice and protocol assistance. These services are particularly useful when existing EU guidelines or Pharmacopoeia monographs lack the specificity needed for a company’s unique product. If a company opts to deviate from established guidelines, it can seek tailored scientific advice from the EMA to ensure its development plan remains viable. 

Startups can also request advice on the relevance of specific guidelines to their products, which is crucial when harmonizing global development strategies that align with both FDA and EMA requirements. This approach not only streamlines the approval process across multiple regions but also reduces potential regulatory hurdles. 

One of the most valuable resources offered by the EMA is the Innovation Task Force (ITF), which provides scientific advice during the early stages of product development. Unlike traditional regulatory guidance, the ITF’s advice is focused on scientific challenges, offering startups a unique opportunity to refine their development strategies at no cost. This early-stage support can be a game-changer for startups navigating the complex and competitive landscape of the European market. 

Navigating the Procedures for Scientific Advice 

The EMA’s procedures for scientific advice and protocol assistance are designed to be both flexible and responsive to the specific needs of each company. The type of procedure is determined on a case-by-case basis, with a standard timetable of 70 days, although this can be shortened to 40 days, depending on the nature of the request. 

For protocol assistance, the EMA often invites sponsors to participate in discussion meetings, fostering a collaborative environment that ensures the development plan aligns with regulatory expectations. For scientific advice, companies may express a preference for a discussion meeting when submitting their initial request, though the final decision rests with the Scientific Advice Working Party (SAWP). 

Conclusion: The EMA as a Strategic Partner for Startups 

For biomedical startups aiming to enter the European market, the EMA is more than just a regulatory body—it is a strategic partner. Understanding and leveraging the EMA’s resources can significantly enhance a startup’s chances of success. The EMA’s centralized procedures, scientific advice, and early-stage support through the Innovation Task Force offer invaluable guidance that can help startups navigate the complex regulatory landscape of the EU. By engaging with the EMA, startups can bring their innovative products to market more efficiently, ultimately benefiting patients across Europe and beyond. 

An “orphan designation” is granted by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for a drug/biologic to create financial incentives for developing therapies for rare diseases.  

This article focuses on incentives offered, the prevalence that defines an orphan disease, as well as the procedural process of obtaining the designations. 

Introduction 

A rare disease is, as implied, a disease that affects a relatively low number of patients in the population. Many (over 6,000) rare diseases have been identified to date, and it is estimated that 3.5% – 5.9% of the worldwide population is affected by these diseases. 72% of rare diseases are genetic, while others result from infections, allergies, and environmental causes. Due to the low prevalence of each disease, medical expertise is rare, and knowledge and effective care are extensively lacking. In the past, drug manufacturers would not invest in therapies for rare diseases as they could not cover the vast costs of drug development and profit from marketing drugs to such small groups of patients. Despite the urgent need for rare disease¹ medicines, they came to be known as orphans of health systems, as companies would not develop these medicines, and the patient was often denied proper diagnosis and treatment² of therapies for orphan diseases.   

In order to encourage the development, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) launched programs to create financial incentives for developing these therapies. An “orphan designation” is granted for a drug/biologic developed to treat an orphan disease. However, the agencies have some differences in the incentives offered, the prevalence that defines an orphan disease, as well as the procedural process of obtaining the designations.  

Since their inception, orphan designation programs have successfully created incentives for developing orphan drugs. For example, in 1983, the US Congress passed the Orphan Drug Act (ODA) laid down in 21 Code of Federal Regulations (CFR) §316³ to create financial incentives for orphan drug developers. Since 1983, the Act has resulted in the development of more than 250 orphan drugs, which are available to treat a potential patient population of more than 13 million Americans². 

The current article provides information on the EMA orphan designation program.  

Orphan Medicinal Product Designation in EMA (EU) 

Orphan Medicinal Product Designation (OMPD) is based on the criteria laid down in Regulation (EC) No 141/2000⁶. To be eligible for orphan designation in Europe, a medicine must meet the following criteria: 

• It must be intended for treating, preventing, or diagnosing a life-threatening or chronically debilitating disease 

• No satisfactory method of diagnosis, prevention, or treatment of the condition concerned can be authorized, or if such a method exists, the medicine must be of significant benefit to those affected by the condition 

• The condition’s prevalence in the EU must be at most 5 in 10,000, or it must be unlikely that marketing the medicine would generate sufficient returns to justify the investment needed for its development 

How to Submit a Request for an OMPD 

Sponsors need to use EMA’s secure online IRIS platform⁷ to submit applications for orphan designation and to manage pre- and post-designation activities. To submit via IRIS, the company should be incorporated in the EU or be submitted under a representative incorporated in the EU. The application can be submitted directly to EMA or have a pre-submission meeting (teleconference) with the EMA, should the sponsor feel they could benefit from a preliminary discussion before the submission. For example, suppose this is the first time the sponsor approaches the COMP (Committee for Orphan Medicinal Products). In that case, the pre-submission call explains in detail the process, what is expected to be included in the application, and in which order.  

The scientific document of the application (~30 pages) includes the following: 

• Description of the condition: details of the condition, proposed orphan indication, medical plausibility, justification of the life-threatening or debilitating nature of the condition  

• Prevalence of the condition: prevalence of the orphan disease or condition in the European Union (based on established literature references and current EU population estimates) 

• Potential for return on investment: (only if prevalence is more than 5 in 10,000) 

• Other methods for diagnosis, prevention, or treatment of the condition: details of any existing diagnosis, prevention or treatment methods, justification as to why methods are not satisfactory / justification of the significant benefit 

• Description of the stage of development: summary of the development of the product (proof of concept studies, in vitro and in vivo data [including toxicology if available], clinical studies [if available]), details of current regulatory affairs status and marketing history in the EU and non -EU countries  

In addition, sponsor and regulatory details are provided, as well as translations of the active substance and the indication (26 EU languages) should be submitted. Companies that have a “micro, small and medium-sized enterprises” (SME) status⁸ are not required to submit translations. 

The application can be submitted only on specific dates according to predetermined timelines⁹. An initial draft application is submitted for validation, after which the final documents are submitted.  

Applications for orphan designation are examined by the EMA’s Committee for Orphan Medicinal Products (COMP). The evaluation process takes a maximum of 90 days from validation confirmation. The agency sends the COMP opinion to the European Commission (EC), which is responsible for granting the orphan designation. 

The benefits of an EMA orphan designation  

• Ten years of market exclusivity 

• Access to the centralized authorization procedure. This allows companies to make a single application to the EMA, resulting in a single opinion and a single decision from the EC, valid in all EU Member States. Sponsors may also have access via orphan designation to conditional approval (which is conducted under the centralized procedure) 

• Additional incentives for SMEs – administrative and procedural assistance from the Agency’s SME office and fee reductions. For example, the translation mentioned above is not required 

• Fee reductions- companies applying for designated orphan medicines pay reduced fees for regulatory affairs activities. This includes reduced fees for protocol assistance (and free for academia sponsors), marketing authorization applications, inspections before authorization, applications for changes to marketing authorizations made after approval (variations), and reduced annual fees 

Annual report  

An annual summary of information on the status of orphan drug development should be submitted. These are short documents (~10 pages) submitted between 12 and 14 months from the date of initial designation acceptance annually. The summaries include a review of preclinical and clinical studies performed and planned, a short description of the investigation plan for the coming year, and any anticipated or current problems/difficulties in testing/potential changes that may impact orphan designation.  

Acronyms and abbreviations 

COMP, Committee for Orphan Medicinal Products; EMA, European Medicines Agency; OMPD, Orphan Medicinal Product Designation; SME, Small and Medium-Sized Enterprises. 

References 

At IMP Clinical Supply Services Ltd., we are privileged to oversee a crucial aspect of the clinical trial process: the clinical supply chain. The European market presents a unique set of challenges and opportunities for bio-startups, particularly in the realm of clinical trials. Understanding and navigating these complexities is essential for any company looking to successfully bring their products to market.  

The Importance of a Robust Clinical Supply Chain  

The clinical supply chain encompasses the entire process of managing investigational medicinal products (IMPs) from manufacturing through to delivery at clinical trial sites and study closure. In Europe, this process is particularly complicated due to the diverse regulatory environments across different countries. Ensuring a seamless supply chain is critical for the timely and efficient execution of clinical trials. Any disruption can lead to significant delays, increased costs, and potentially, the failure of the trial.  

Key components of a robust clinical supply chain include:  

• Regulatory Compliance: Each country within the EU has its own regulatory requirements as well as the overriding EU regulation which obligate all member states. A deep understanding of these regulations is essential to avoid compliance issues. This includes adherence to Good Manufacturing Practice (GMP), Good Distribution Practice (GDP), and ensuring all necessary documentation is in place.  

• Logistics and Distribution: Efficient logistics are vital for maintaining the integrity of IMPs. This involves temperature-controlled transportation, real-time tracking, and ensuring timely delivery to trial sites.  

• Inventory Management: Accurate inventory management is crucial to avoid shortages or overages, both of which can be costly and detrimental to the trial’s progress. The complete balance of a clinical study is also included in the ICH E6 Good Clinical Practice (GCP).  

• Communication and Coordination: Effective communication and coordination with all stakeholders, including sponsors, CRO’s, manufacturers, regulatory bodies, and clinical trial sites, are essential for a smooth supply chain operation.  

Temperature Monitored Distribution Throughout the EU  

A critical aspect of clinical supply logistics and distribution is temperature-monitored transportation. As this is such a critical part of the clinical supply chain, this is required as part of the GDP requirements. Many IMPs, particularly biologics, require challenging temperature conditions throughout the supply chain, including refrigeration, freezing and deep freeze conditions, are sensitive to temperature variations, and must be stored and transported under strict conditions to maintain their efficacy and safety.  

Strategies for Temperature-Controlled Distribution  

1. Cold Chain Logistics: Cold chain logistics involves a series of actions and equipment that maintain a product within a specified low-temperature range from manufacture to end use. This includes refrigerated storage facilities, temperature-controlled vehicles, and insulated containers.  

1. Real-Time Temperature Monitoring: Advanced tracking systems allow for real-time monitoring of temperature conditions during transit. These systems alert stakeholders to any deviations, enabling immediate corrective actions to prevent product spoilage.  

2. Qualification and Validation: All equipment and processes used in temperature-controlled logistics must be qualified and validated to ensure they meet required standards. This includes regular maintenance and calibration of temperature monitoring devices.  

Challenges and Solutions  

• Geographical Variability: The EU comprises a diverse range of climates, from the cold northern regions to the warm southern areas. This variability necessitates robust and adaptable temperature control solutions.  

• Logistical Coordination: Coordinating temperature-controlled logistics across multiple countries with different regulations can be challenging. Partnering with experienced logistics providers and leveraging technology for real-time monitoring can help mitigate these challenges. 

Written by:  

Limor Teomim, CEO at IMP Clinical Supply Services Ltd.  
Sofi Glam, VP of Business Development & Customer Success at IMP Clinical Supply Services Ltd.  
Aviva Feifer, Business Development Manager at IMP Clinical Supply Services Ltd. 

In the dynamic and highly regulated landscape of biopharmaceuticals, compliance with international regulations is crucial for maintaining operational integrity and securing future business opportunities. One critical regulation that biopharma companies worldwide must prioritize is the General Data Protection Regulation (GDPR) when conducting clinical trials in the European Economic Area (EEA) or the United Kingdom (UK).  

Understanding GDPR and Its Implications  

The GDPR is a comprehensive data protection law enacted by the European Union (EU) that came into effect on May 25, 2018. It sets stringent requirements for the collection, storage, and processing of personal data of individuals within the EEA and, by extension, has been adopted in the UK post-Brexit. Its primary aim is to give individuals greater control over their personal data and to ensure that organizations handling this data do so responsibly and transparently. 

For biopharma companies, GDPR compliance entails recognizing that key-coded data processed in clinical trials is considered personal data under the Regulation, unlike its treatment under US and other international laws. This requires implementing robust data protection measures, ensuring a lawful basis for processing participants’ data, and maintaining transparency and respect for their privacy rights. Additionally, biopharma must understand that it has a direct responsibility to ensure compliance with the GDPR and cannot delegate this to the CRO. First, because the CRO cannot be legally responsible for the sponsor’s compliance, and second, because ensuring compliance requires close oversight of the service providers’ activities. 

The Importance of GDPR Compliance in Clinical Trials  

GDPR is crucial in clinical trials for several reasons. Firstly, it ensures that sensitive personal data, such as health records and genetic information, are handled securely and ethically. This builds trust with trial participants, which is essential for successful enrollment and retention. Secondly, non-compliance with GDPR can lead to significant fines and sanctions, up to 20 million euros or 4% of the company’s annual global turnover. Such penalties can disrupt business operations, especially for small and medium-sized biopharma companies. Finally, GDPR compliance is a key factor in mergers and acquisitions. Large pharmaceutical companies conducting due diligence will prioritize acquiring firms that adhere to GDPR, as non-compliance poses legal and financial risks. Overall, GDPR compliance is vital for protecting participant data, maintaining smooth operations, and enabling strategic growth in the biopharma industry. 

GDPR Compliance as a Strategic Asset in M&A  

Big pharma companies are highly risk-averse, especially concerning regulatory compliance. During the due diligence process, acquiring companies will thoroughly evaluate the target’s adherence to relevant regulations, including GDPR. Any lapses or violations in data protection practices can be significant red flags, potentially derailing a deal. For large pharmaceutical companies, acquiring a non-compliant entity poses substantial risks, including hefty fines and damage to reputation. By ensuring GDPR compliance, biopharma companies can position themselves as low-risk, attractive acquisition targets, thereby increasing their chances of securing lucrative deals. Demonstrating a robust commitment to GDPR compliance can significantly enhance a company’s market value. It not only showcases the company’s dedication to ethical practices and regulatory adherence but also strengthens its negotiating power during M&A discussions. Compliance becomes a strategic asset that underscores the company’s reliability and forward-thinking approach.  

Regulatory Mandates for Data Protection in Clinical Trials 

GDPR compliance is not merely a strategic choice but a regulatory necessity for the approval and conduct of clinical trials. Regulatory authorities and clinical trial regulations impose stringent data protection controls to safeguard participant information, making it impossible for studies to gain the necessary approvals to proceed without these measures. Sponsors often assume hiring a CRO ensures GDPR compliance, but CRO regulatory and clinical operation teams are not GDPR experts, and they are not legally allowed to provide GDPR advice to sponsors. Additionally, informed consent forms and privacy notices typically require the contact details of the sponsor’s Data Protection Officer (DPO) or EU Data Protection Representative to be included, which is crucial for the approval process. 

Economic Advantages of GDPR Compliance in the Biopharma Sector  

Implementing a GDPR-compliant program for clinical trials involves significant initial costs, such as hiring a Data Protection Officer (DPO), establishing data protection controls, conducting audits, and maintaining compliance records. However, without such a program, companies face financial impacts from study approval delays and risk substantial fines. Investing in GDPR compliance also significantly enhances a company’s market value and attractiveness for investments and acquisitions. Moreover, a strong commitment to data privacy underscores a company’s reliability and strategic foresight, making privacy compliance not just about avoiding fines but a strategic move towards long-term success and growth in the competitive biopharmaceutical industry. By proactively investing in GDPR compliance, companies can safeguard their operations, build trust with trial participants, and secure their future in the market.  

Conclusion  

GDPR compliance is essential for sustainable success and fostering innovation in the biopharma sector. Companies should proactively include compliance costs in their fundraising efforts, anticipating the increasing regulatory demands from the EU. These developments will necessitate enhanced controls over the processing of personal data, making early investment in compliance a crucial step toward long-term viability and competitiveness. To navigate these complexities effectively, consider consulting with data protection experts if you are planning to conduct clinical trials in the EU or UK, to minimize risks and maximize efficiency in your clinical trial operations. 

In the competitive and innovation-driven pharmaceutical industry, accessing the European market can be both a challenge and an opportunity for bio-startups. European Union (EU) non-dilutive funding offers vital support to startups aiming to navigate this complex environment, providing the financial and strategic resources needed to bring innovative solutions tothe market. 

The Power of EU Funding for Israeli Startups 

Israeli startups have consistently demonstrated their innovative prowess, and their success in securing EU funding is a testament to this. For instance, in 2024, nine Israeli startups secured €130 million (approximately $142 million) through the European Innovation Council (EIC) Accelerator program, part of Horizon Europe. This substantial funding underscores Israel’s position as a leading player in the global innovation ecosystem. 

One standout example is MediWound Ltd., which received $17.75 million in blended funding from the EIC Accelerator. MediWound, known for its innovative burn treatment using pineapple-based gel, leveraged this funding to expedite the clinical development of EscharEx, a wound therapy for diabetic foot ulcers. The EU grant enabled MediWound to advance its product’s market introduction by four years, significantly boosting its market potential in both the U.S. and Europe​ (The Judea). 

Another notable recipient is JaxBio Technologies, a medical diagnostics startup from Netanya, Israel. JaxBio was awarded a $2.73 million grant, with the potential for additional mixed financing of up to €18.2 million. This funding is crucial for developing a revolutionary diagnostics platform for early lung cancer detection. In an industry where early diagnosis can save lives, EU funding is helping JaxBio accelerate its journey toward commercialisation and market entry​. 

Navigating the Funding Landscape: Strategies for Success 

For bio-startups, especially those from Israel, entering the European market requires more than just innovation—it requires strategic use of funding to overcome regulatory and market entry barriers. The Horizon Europe program, with its €95.5 billion budget, offers a range of funding opportunities tailored to different stages of product development and market readiness. 

Key funding mechanisms include Research and Innovation Actions (RIAs) and Innovation Actions (IAs). RIAs support early-stage research projects (TRLs 3-5), helping startups and research institutions develop proof of concepts. IAs, on the other hand, are designed for projects closer to market application (TRLs 6-8), providing the resources needed to scale and commercialise products​(Aurora Israel). 

The EIC Transition program is another critical tool for startups looking to bridge the gap between innovation and market readiness. This program provides grants of up to €2.5 million to support the development of technologies that have already demonstrated their feasibility. By focusing on advancing these technologies towards market entry, the EIC Transition helps startups mitigate risks and overcome the “valley of death”—the challenging phase where many innovations fail due to a lack of funding​. 

Paving the Way for Market Success 

For bio-startups, the European market represents not just a target but a strategic milestone that can propel them onto the global stage. The financial backing and strategic guidance provided by EU non-dilutive funding programs are invaluable tools in this journey. By leveraging these resources, startups can overcome the barriers of regulatory complexity and market entry, transforming innovative research into viable, market-ready products. 

Israeli startups, with their demonstrated agility and innovation, are particularly well-suited to harness these opportunities. Their successes, like those of MediWound, JaxBio Technologies, and Nurami Medical, exemplify how strategic use of EU funding can accelerate growth and facilitate entry into one of the world’s most competitive markets​. 

At Twinnovation, we recognize the potential of these funding opportunities and are dedicated to helping startups navigate this complex landscape. By connecting innovation with funding and market strategy, we aim to empower the next generation of bio-entrepreneurs to not just access the European market, but to lead it. 

Investigational product (IP) labeling for clinical trials is a critical aspect of regulatory compliance and patient safety in both the United States (US) and the European Union (EU). While there are similarities in their respective requirements, several key differences exist that sponsors and clinical trial managers must understand and navigate effectively. 

Regulatory Framework 

In the US, investigational product labeling is governed primarily by the Food and Drug Administration (FDA) under Title 21 of the Code of Federal Regulations (CFR). Specifically, Part 312 (Investigational New Drug Application) outlines the requirements for labeling. The EU, on the other hand, is regulated by the European Medicines Agency (EMA) through Directive 2001/20/EC and Regulation (EU) No 536/2014, which provide comprehensive guidelines for clinical trial conduct, including labeling. 

Key Differences in Labeling Requirements 

1. Language Requirements: 

• US: The FDA mandates that all labeling must be in English. While additional languages can be included, English remains the primary required language. 

• EU: Labeling must be translated into the local language(s) of the member states where the clinical trial is conducted. This multilingual requirement ensures that participants in different countries can understand the information provided. 

2. Content and Information: 

• US: The FDA requires labels to include critical information such as the statement “Caution: New Drug—Limited by Federal (or United States) law to investigational use,” the investigational drug name or code, dosage form, route of administration, and storage conditions. Additionally, there must be an identifier to ensure traceability. 

• EU: EMA regulations stipulate that labels must include the phrase “For clinical trial use only” (or equivalent), the trial reference code, the name and address of the sponsor, the batch number, expiration date, and the unique patient identification code. Furthermore, it must include the protocol number and the instructions for use. 

3. Expiration Date: 

• US: The FDA does not require the expiration date to be on the label if the information is provided elsewhere (e.g., investigator brochure or protocol). 

• EU: The EMA mandates that the expiration date be clearly stated on the label, reflecting the importance of ensuring that IPs are not used beyond their stability period. 

4. Additional Safety Information: 

• US: Labels must include specific cautionary statements but are less prescriptive about additional safety information beyond what is stated in 21 CFR Part 312. 

• EU: The EMA requires comprehensive safety information, including special storage and handling conditions, to be explicitly mentioned to enhance patient safety and compliance with Good Manufacturing Practice (GMP) standards. 

Harmonization Efforts 

Efforts are ongoing to harmonize clinical trial regulations globally, including labeling requirements. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) plays a pivotal role in these endeavors. However, as of now, sponsors must comply with both FDA and EMA requirements when conducting multinational trials. 

Conclusion 

Understanding and adhering to the differing IP labeling requirements between the US and the EU is crucial for regulatory compliance and patient safety. By recognizing these differences and implementing appropriate measures, sponsors can ensure successful clinical trial execution and contribute to the development of safe and effective medical products.

Good Manufacturing Practices (GMP) are outlined in several guidelines. For commercial Active Pharmaceutical Ingredients (APIs), the primary reference is ICH Q7 (Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients). However, when manufacturing biological products during clinical studies in the EU, the quality requirements detailed in ICH Q7 may be overly stringent. It is advisable to refer to the EMA’s guideline on ‘quality documentation for biological investigational medicinal products’. 

The EMA guideline addresses the development and clinical trial phases of biological products such as vaccines, monoclonal antibodies, and recombinant proteins. It emphasizes the unique characteristics of biological products, including their complex structures, source materials, and biological activities. 

ICH Q7 covers both chemical synthesis and biological processes but does not delve into the specific complexities of biological manufacturing. In contrast, the EMA guideline provides detailed descriptions of the biological manufacturing process, including upstream processes (e.g., cell culture, fermentation) and downstream processes (e.g., purification, formulation). It also specifies controls and validation for biological processes, considering the variability and complexity inherent in biological production systems. 

Regarding starting materials, ICH Q7 offers general provisions for controlling and documenting raw materials, intermediates, and starting materials for API manufacturing. The EMA guideline, however, provides more specific and detailed requirements for documenting biological starting materials such as cell banks and tissues, including their characterization, qualification, and traceability. 

The EMA guideline also emphasizes extensive characterization and quality control testing specific to biological products, including assays for biological activity, immunogenicity, and structural integrity. This is due to the complex nature of biological molecules. In contrast, ICH Q7 focuses on general GMP principles for quality control and testing. 

An important addition in the EMA’s biological guideline pertains to stability and shelf life determination. The guideline allows for extending the shelf life beyond the period covered by real-time stability data, provided it is supported by relevant data, including accelerated stability studies or stability data generated with representative material. The maximum extension should not exceed double the initial period or more than twelve months longer than the period covered by real-time stability data obtained with representative batches. This provision is crucial during the clinical phases of product development when limited stability data is available. 

In summary, the EMA guideline on quality documentation for biological investigational medicinal products and ICH Q7 serve different but complementary purposes in the regulation of medicinal products. The EMA guideline provides detailed requirements tailored to the complexities of biological products, while ICH Q7 offers broad GMP principles applicable to both chemical and biological APIs. 

Uniquely in Europe, Germany offers a pathway for certified digital health applications of risk class I or IIa according to MDR to be prescribed by medical doctors and the manufacturers are reimbursed by the statutory health insurance companies. Only digital health applications that are listed in the so called DiGA directory of the BfArM (Federal Institute for Drugs and Medical Devices) are eligible for reimbursement. 

Listing in the DiGA directory requires the prior completion of an assessment process at the BfArM, which is designed as a fast-track procedure. 

In addition to the fulfilment of technical and data protection requirements, this procedure checks whether a positive care effect is achieved by the DiGA. 

Positive care effects are either a medical benefit in terms of improving quality of life, prolonging of survival, or shortening of the duration of illness or patient-relevant structural and procedural improvements in care. In the case of structural and procedural improvements, the DiGA aims to support the actions of patients or to integrate the processes between patients and service providers. DiGA can be used, for example, to support patients in coping with illness-related difficulties in everyday life or in the coordination of treatment processes. Treatment adherence, patient safety, patient sovereignty, and health literacy are other areas that can be achieved or supported with the help of digital health applications. 

The positive care effect must be proven by clinical studies. If a clinical study has already been carried out and completed that sufficiently demonstrates the positive care effect, a permanent listing in the DiGA directory can be applied for directly. If no clinical data is yet available, it is only possible to apply for provisional listing, which grants a 12-month trial period that can be extended one time on application. 

When planning the clinical trial, the conduct in Germany and the preparation of the evaluation concept to be submitted by a manufacturer-independent scientific institute must be considered. Based on the CIP, the SAP, a systematic data analysis of data generated from the DiGA and a systematic literature search, this concept describes how the positive care effect of the DiGA is to be demonstrated. 

The BfArM offers the opportunity to discuss open questions and clarify ambiguities as part of a consultation procedure prior to submission of the application.  

The time of submission for evaluation of the planned study by the ethics committee(s) must also be considered, as the trial period begins directly after the fast-track procedure has been completed. 

The Fast-Track-Procedure – brief overview 

1. electronic application, including the evaluation concept 

2. evaluation of the submitted documents by BfArM within three months 

3. provisional or permanent listing in the DiGA directory 

• Start of trial period, if applicable 

• Start of prescription/reimbursement 

More information can be found at: https://www.bfarm.de/EN/Medical-devices/Tasks/DiGA-and-DiPA/Digital-Health-Applications/Interesting-facts/_node.html

Regulatory references Germany: 
German Social Code Book V (Fünftes Buch Sozialgesetzbuch, SGB V) Section 33a, 139e 
Digital Healthcare Act (DVG) 
Digital Act (DigiG) 
Digital Health Applications Ordinance – DiGAV 

The European Patent Office issued a decision which could allow a broader range of claimed innovations to benefit from the so-called “second medical use” exception of Article 54(5) of the European Patent Convention (EPC). 

Such an exception is limited to a “substance or composition” only and is thus not available for medical devices. Historically, compounds that provide a therapeutic effect by way of a 3D macrostructure have been considered medical devices due to their mechanical, rather than chemical, cause of action, thereby not benefiting from the exception. 

The application at issue describes the use of amphiphilic peptides, which are introduced into blood vessels via a catheter in aqueous solution form. Upon contact with body fluid, these peptides aggregate to form a hydrogel, effectively blocking the blood vessel and inducing tissue necrosis. This process, known as embolization, can be employed to treat various pathological conditions, including cancer, patent ductus arteriosus (PDA), and major aortopulmonary collateral artery (MAPCA). 

The Examining Division previously refused the application, citing a lack of novelty over the prior art. They argued that the peptide solutions did not qualify as a “substance or composition” under Article 54(5) EPC, their mode of action being purely mechanical. 

The Board of Appeal rejected this view, emphasizing that the claimed material is a liquid solution of peptides and does not possess device-like mechanical features at the time of administration. The transformation of the solution into a 3D hydrogel structure inside the body, which then acts mechanically to block blood vessels, does not alter its qualification as a substance, irrespective of the fact that the active principle is not a chemical mode of interaction.  

The Board noted that neither the EPC nor prior legal interpretations mandate that a material’s qualification be based on its mode of action and instead maintained that the definition should focus on the nature of the material itself. The Board further noted that the mechanism of action may not be understood in detail, or original assumptions about the mechanism of action may later turn out to be wrong and that not even for the purpose of sufficient disclosure under Article 83 EPC is it required that the mechanism underlying a therapeutic use be disclosed or understood. 

As such, if this decision is followed in future cases, there may be a benefit to fully describing the state of compounds (such as self-assembling bio polymers) at the time of introduction to the body prior to any changes leading to a mechanical therapeutic effect. 

Please do not hesitate to reach out with any questions in this matter and other Biotechnology related matters to:

Caleb Gilliam-Scott, European Patent Attorney, UK Patent Practice Group, Pearl Cohen: CGilliam-Scott@pearlcohen.com

Hili Rashkovan, Partner, Chair of IL Technology Transactions Practice Group, Pearl Cohen: HiliR@PearlCohen.com

Hadar Solomon, Partner, Head of China Desk, Pearl Cohen: HSolomon@PearlCohen.com

The European Medicines Agency (EMA) is a cornerstone in the regulation of medicines across the European Union (EU). Recognizing the unique challenges faced by small and medium-sized enterprises (SMEs) in the biopharma and MedTech sectors, the EMA has established a dedicated SME initiative. This program is designed to support innovation by simplifying regulatory processes and providing critical resources to startups aiming to bring innovative treatments and medical devices to market. 

Understanding the SME Initiative 

The EMA’s SME initiative offers a range of incentives and support services aimed at easing the regulatory burden on smaller companies. The primary goal of the initiative is to foster innovation by helping these companies navigate the complex regulatory landscape that often poses significant challenges for startups with limited resources. 

Importantly, the SME status is not limited to pharmaceutical companies; it is relevant to all types of biomed and biotech companies, including those involved in medical devices, digital health technologies, and other life sciences fields. This broad applicability ensures that a wide range of innovative companies can benefit from the EMA’s support, regardless of their specific focus within the biomedical ecosystem. 

To qualify for SME status, companies must meet the European Commission’s definition of an SME, which includes having fewer than 250 employees and meeting specific financial criteria related to annual turnover and balance sheet totals. Both European and non-European companies can apply for SME status. However, non-European companies must appoint a pharmaceutical regulatory affairs consultancy to serve as a European Economic Area (EEA) representative to handle their application. The process involves registering with the EMA, submitting relevant financial and legal documentation, and, for non-European companies, coordinating through an appointed representative within the EEA. 

It’s also worth noting that the EMA’s SME Office does not charge any fees for registering SME status. This makes the initiative even more accessible to small companies, allowing them to take advantage of the available resources without incurring additional costs. 

When to Seek SME Status 

For startups, the ideal time to seek SME status is during the early stages of development, particularly when the company is preparing to engage with regulatory bodies or seeking investment. Early-stage companies often face significant challenges in navigating regulatory requirements and securing funding. Obtaining SME status can provide crucial support and resources that help mitigate these challenges. 

The Strategic Value of SME Status for Startups 

For startups, particularly those in the early stages of development, obtaining SME status with the EMA can significantly enhance their attractiveness to investors. Investors often view SME status as a positive indicator, signaling that a company is positioned to benefit from specific regulatory and financial incentives. These benefits can reduce development costs and expedite the time-to-market for new therapies and devices, which are critical factors for investors assessing the risk and potential return on their investments. 

Moreover, SME status provides companies with access to scientific advice and support services that are crucial during the early stages of product development at a fee which is 10% of the full fee.  An SME status will save you a lot of money, not only when you wish to get EMA advice but also when you approach European National Authorities. 

This access can help companies refine their development strategies, ensuring alignment with regulatory requirements and ultimately improving the chances of successful product approval. 

SME Status and Its Impact on Regulatory Affairs Milestones 

SME status is particularly relevant when considering key regulatory milestones such as the Paediatric Investigation Plan (PIP) and PRIME (PRIority MEdicines) designation. 

The PIP is a mandatory component for the approval of new medicines, even for those which are not intended for the pediatric population. For SMEs, the EMA offers fee reductions on PIP submissions, making it more feasible for smaller companies to meet this regulatory requirement without compromising their financial stability. 

Similarly, the PRIME designation is designed to support the development of medicines that offer significant advantages over existing treatments.   When submitting for PRIME designation, having an SME status reduces the burden of submitting clinical evidence at early stages of development. 

The SME office has many initiatives aimed to assist companies with an SME status, that include training sessions, publications focused on hot topics, availability to answer questions related to the procedures within EMA, etc. 

Conclusion 

The EMA’s SME initiative is an invaluable resource for startups in the biopharma, MedTech, and broader biotech sectors. By offering regulatory assistance, financial incentives, and educational resources, the initiative helps SMEs overcome the barriers to bringing innovative products to market. Whether you are a European startup or an international company looking to enter the EU market, leveraging the EMA’s SME initiative could be the key to unlocking success in these highly competitive industries.