In the global landscape of clinical trials, regulatory frameworks vary significantly from one region to another. One of the most critical aspects of these frameworks is the role of the Qualified Person (QP), a function that is mandatory in the European Union but differs considerably in other regions, such as Israel. Understanding these differences is essential for bio-startups and pharmaceutical companies that operate across borders, as it impacts the management and release of investigational medicinal products (IMPs). This article explores the distinctions between the QP roles in Israel and the EU, providing insights into the regulatory expectations and practical implications for companies navigating these complex environments. 

Who is a QP?  

The QP is an EU origin regulatory term referring to an experienced professional with the requisite qualifications and expertise in the pharmaceutical industry. The QP is responsible for certifying that each batch of IMP complies with the relevant regulatory requirements of the clinical trial authorization (CTA) and with Good Manufacturing Practice (GMP) before it can be released for use in clinical trials. 

The Qualified Person (QP) term, originally established by the European Union, has been adopted by Israel and integrated into local regulations. This alignment was a result of the finalization of the Agreements on Conformity Assessment and Acceptance of Industrial Products (ACAA) between the European Communities, their member states, and the state of Israel. The ACAA agreement ensures that Israeli standards conform to EU norms, allowing for mutual recognition of quality assurance measures, including the QP role in clinical trials. 

Responsibilities of a QP  

1. Batch Certification: The QP certifies that each batch of an IMP has been manufactured, tested, and transported in accordance with GMP and GDP standards, reviews the Product Specifications File (PSF) and the approved clinical trial protocol to ensure all trial specific needs are met.  

2. Regulatory Compliance: The QP ensures that all necessary documentation is complete and that the IMPs meet all regulatory requirements.  

3. Risk Management: The QP assesses and manages risks associated with the IMPs, ensuring that any potential issues are identified and addressed before release.  

Differences Between Israel and EU Regarding QP Function 

The role of the Qualified Person (QP) is well-defined and mandatory within the EU, whereas Israel has a different regulatory approach to this function. In the EU, the QP must certify that each batch of an investigational medicinal product (IMP) complies with the regulatory requirements before it can be released for use in clinical trials. This certification is a critical component of the clinical supply chain, ensuring that the IMPs meet the stringent standards set by the EU. In the EU, a depot must be used, acting as the Importer of Record (IoR). After QP release, the depot is responsible for managing the supply chain within Europe. Once a QP certification is performed in any EU country, it covers all member states. 

In Israel, the QP function exists but differs from the European system. While Israel has rigorous regulations for the manufacturing and distribution of medicinal products, the QP release process is not identical to the EU’s. In Israel, QP recertification relies on the European QP, or the authorized person in other recognized countries, release and is mandatory only for Phase 3 and 4 studies although the release of IMPs to use in Phase 1 and Phase 2 studies required to be performed according to the same guidelines. This approach means that production facilities intended to manufacture IMPs to use only in Phase 1 and 2 will not be inspected by the Israeli MoH and cannot obtain a GMP certificate. Moreover, unlike in the EU where QP release is a regulatory requirement for all phases of clinical trials, Israel requires this process primarily in the later stages of drug development. This distinction can create challenges for companies’ conduction trials in both regions, as they must navigate and comply with differing regulatory expectations.  

Example: Handling IMPs Between Israel and the EU 

Consider a scenario where an investigational drug is manufactured in Israel and then imported into the EU for use in a clinical trial. In Israel, the IMP would be produceds under strict GMP conditions but not necessarily in GMP certified facility. Upon arrival in the EU, the IMP must undergo QP release, also for early stages clinical studies before it can be distributed to the clinical sites. 

This QP release involves a thorough review of the batch documentation, testing results, and adherence to EU-specific regulations. The QP must confirm that the IMP meets all EU requirements, regardless of the standards applied in Israel. Additionally, the EU QP holds the authority to audit and qualify a manufacturing site in Israel, irrespective of the site’s existing GMP certification, to ensure full compliance with EU standards. Only after the QP certifies the batch, the IMP can be released for use in the clinical trial. This dual compliance ensures that the IMPs adheres to both Israeli and European standards, but it also highlights the complexities involved in managing cross-border clinical supplies which affects the study timelines and costs. 

Conclusion  

Accessing the European market requires a thorough understanding of the clinical supply chain, and the role of QP release in clinical trials. By focusing on regulatory compliance, efficient logistics, and robust risk management, bio-startups can overcome challenges and seize the opportunities presented by the EU market. At IMP Clinical Supply Services Ltd., we are committed to supporting our clients through every step of this journey, ensuring their success in the dynamic and challenging European landscape. 

Written by:  
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. 

Portugal is mostly seen abroad as a country of good food, beautiful beaches and wonderful to spend some sunny days, but for Biotech and pharmaceutical companies, especially those that are dedicate to rare diseases, there are good opportunities. 

Why must Biotech invest in Portugal? 

The rare disease market in Portugal is quite “young,” starting almost 20 years ago with two companies, Genzyme followed by Shire, focused on lysosomal storage diseases; both companies’ success opened the way for other companies. 

However, currently, not all companies, especially startups, look to Portugal as an opportunity to invest or to start operating. 

Why?  

Portugal has been seen as having a very low pharmaceutical market price, a complicated and long process for Pricing and Reimbursement (P&R), and small and unprepared investigational centres. This is no longer true, and the National Health Authority (Infarmed I.P.) is more than ever acknowledging that Clinical trials (in all their phases), a more expedited new drug evaluation, and the sharing of knowledge are vital for Portuguese patients. 

Startups that are looking for affordable investigational centres for their new drugs candidates must consider Portugal as an opportunity. 

In 2022, the chairman of P-Bio, the Portuguese Association for Biotechnologies, said, “Small in dimension, but rich in competence and specialisation.” How can we use this knowledge in rare diseases? 

Portugal had one of the first EU National plans for rare diseases and very clear and defined hospital reference centres. This was a breakthrough for patients, hospitals, and physicians, significantly increasing knowledge in this area. 

In December 2022, the National Plan 2023-2027 for rare diseases was approved with six pillars: 

1-Improving early diagnosis  

2-Strengthening the care network  

3-Supporting Research and development  

4-Promotion Training and Capacity  

5-Strengthening patients’ rights  

6-Raise awareness and information  

The MoH stated, this plan reflects the commitment to provide a coordinated and effective response to the needs of rare diseases patients, ensuring equitable access to quality healthcare across the country. 

This opens the doors to innovation, new drugs, and treating patients that are waiting to be saved. 

Fortunately, like in the past, there are some bold start-up CEOs who have figured out the potential of the Portuguese market; however, more are needed. 

Portugal deserves to have more Startups considering it as a potential place to invest in I&D since we have centres and people rich in competence, quality, and specialisation  

Hugo Canhão has over twenty years of experience in the pharmaceutical and biotechnology industry, during the last years focusing in bringing Biotech companies (focusing on rare diseases) to invest in Portugal and Brasil. 

With his business partner, both are responsible to help some of the most important rare disease companies to be established in Portugal. 

Unlock Europe’s biotech revolution! In this exclusive piece, David Brühlmann, Managing Director of Brühlmann Consulting and Host of the Smart Biotech Scientist Podcast, reveals five key drivers transforming the European bio-startup landscape. From ancient academic powerhouses to cutting-edge funding models, discover how Europe’s unique ecosystem is reshaping biotech’s future. Whether you’re a scientist, startup entrepreneur, or industry leader, learn how to harness these game-changing attributes for your success in Europe’s thriving biotech scene. 

From Lab to Limelight: Immunos Therapeutics and the European Biotech Revolution 

In 2014, a team of passionate scientists from the Universities of Zurich and Basel embarked on a journey that could reshape cancer treatment. This marked the birth of Immunos Therapeutics, a company that would soon exemplify the unique power of Europe’s biotech ecosystem. 

Fast forward to today, and Immunos has evolved from a promising startup into a clinical-stage powerhouse. They’re pioneering a new frontier in immunomodulatory proteins. Their innovative HLA-based platform remodels the entire tumor microenvironment, potentially amplifying the efficacy of existing immunotherapies. 

As a biotech leader, you’re no stranger to the delicate balance between groundbreaking innovation and the daunting complexities of biologics development. Looking at Immunos’ success, you might wonder, “How can I navigate this European landscape while keeping our development on track?” 

Rest assured, you’re not alone in feeling the weight of these challenges. Many in your position have stood at this crossroads, contemplating the potential risks and rewards of venturing into European biotech waters. 

The critical aspect to note is that Europe’s biotech ecosystem isn’t just different — it’s a treasure trove of untapped opportunities. Immunos has leveraged this, attracting an international consortium of top-tier investors like Samsara Biocapital and Pfizer Ventures. Imagine tapping into such cross-border collaborations and accessing funding streams you never knew existed. 

Sounds intriguing, doesn’t it? 

In this article, we’ll dissect five unique attributes that are revolutionizing Europe’s bio-startup scene — the same attributes that have propelled companies like Immunos from university spin-offs to potential game-changers in global healthcare. 

We’ll examine the evidence, explore the possibilities, and provide you with insights that could potentially accelerate your biotech venture’s progress. 

Let’s dive in and unravel the DNA of Europe’s biotech revolution. 

1. Academic Powerhouses: Centuries of Knowledge Driving Commercial Success 

Europe’s biotech scene isn’t built merely on modern innovations — it stands on the shoulders of giants. Centuries of scientific breakthroughs have laid a foundation as solid as the stone walls of its oldest universities. 

But what does this mean for you, a biotech leader aiming to make your mark? 

Let’s start with the legacy. From Pasteur’s germ theory to the discovery of DNA’s structure, European scientists have been shaping biotechnology’s building blocks for generations. It’s a living, breathing ecosystem of knowledge that continues to evolve. Imagine tapping into a network where groundbreaking ideas are as common as coffee breaks. That’s the reality in Europe’s top biotech hubs. 

Now, let’s talk talent. You’re familiar with the challenge of finding the right minds to drive innovation forward. In Europe, you’re looking at a talent pool fed by some of the world’s top universities. Cambridge, ETH Zurich, Imperial College London — these aren’t mere names on a rankings list. They’re incubators of the next generation of biotech pioneers. According to the 2024 QS World University Rankings, these institutions consistently top the charts for life sciences and biotechnology. 

What does this mean for you? 

Access to a pipeline of fresh, brilliant minds ready to tackle your toughest challenges. 

The true power, however, lies not just in individual brilliance, but in the collective output of this academic powerhouse. The European Commission’s “Science, Research and Innovation Performance of the EU 2022 Report” underscores this: the EU produces 21% of the world’s top 10% scientific publications. The game-changing nature of this statistic cannot be overstated — it exemplifies Europe’s impressive contribution to the global biotech landscape. 

2. Synergistic Public-Private Partnerships: Accelerating from Lab to Market 

You’ve got the ideas, you’ve got the talent — but how do you bridge that crucial gap between lab success and market viability? This is where Europe’s public-private partnerships shine, turning academic theories into commercial realities. 

Take Oxford University’s ecosystem as a prime example. They aren’t content with academic publications alone. Instead, they’ve cultivated a thriving ecosystem where innovation flourishes, transforming scientific discoveries into real-world applications. 

Such an ecosystem is a place where your next big idea can rub shoulders with centuries of academic excellence and cutting-edge industry know-how. Feeling overwhelmed by the prospect of commercialization? Oxford’s model shows how academia and industry can work in harmony, each amplifying the other’s strengths. 

But let’s not forget Cambridge. Their technology transfer department is a launchpad for biotech success. And here’s something that might raise your eyebrows: the Cambridge Enterprise Accelerator, which serves as a direct line to private investment for university-linked companies. Imagine having a team of professionals dedicated to turning your research into revenue, backed by serious private capital. Sounds too good to be true? In Cambridge, it’s just another Tuesday. 

Let’s talk about one of the unsung heroes of the European biotech scene: research facilities. Many European universities open their state-of-the-art labs to startups, and EPFL (École Polytechnique Fédérale de Lausanne) stands out as a prime example. 

This Swiss powerhouse fosters industry collaborations, launches entrepreneurship programs, and spearheads thematic initiatives to bolster business partnerships. Their shared research facilities aim to expedite connections with interested researchers. 

Why is this a big deal? Picture this: you’ve got a groundbreaking idea, but the equipment needed to test it costs millions. Through partnerships with institutions like EPFL, you might find that equipment just a collaboration away. It’s like having a fully stocked kitchen before you’ve even written your recipe — the possibilities are endless, and the initial hurdles are significantly lower. 

3. Strategic Clustering: Amplifying Resources and Opportunities 

Ever felt like you’re working in a vacuum, cut off from the pulse of the industry? Europe’s biotech clusters are the antidote to isolation. 

Carefully cultivated ecosystems designed to amplify innovation, these clusters are far from mere geographical coincidences. 

Let’s start with the crown jewel: Cambridge/London, the so-called “Golden Triangle” along with Oxford is a biotech powerhouse. With AstraZeneca’s global R&D center calling it home, along with giants like GlaxoSmithKline and innovators like Abcam, it’s less of a location and more of a biotechnology nerve center. Imagine your startup nestled among these titans, with opportunities for collaboration, learning, and growth at every turn. 

Hop across the channel, and you’ll find yourself in Basel, Switzerland — the heart of the trinational BioValley, spanning Switzerland, Germany, and France. Home to pharma behemoths Novartis and Roche, Basel isn’t playing around when it comes to pharmaceuticals and medical technology. The air here buzzes with potential breakthroughs. 

But maybe you’re drawn to German engineering precision? Munich’s got you covered. The Bavarian biotech cluster prides itself on being home to over 450 life science companies. From Morphosys to Medigene, it’s a place where German efficiency meets biotech innovation. Can you imagine the collaborations waiting to happen in a place like this? 

And let’s not forget the Nordic powerhouse: Copenhagen-Malmö, or as it’s known in the biotech world, Medicon Valley. Spanning the Øresund region, this cross-border cluster is breaking down barriers in more ways than one. Strong in neuroscience, cancer research, and diabetes, with heavyweights like Novo Nordisk and Lundbeck leading the charge, it’s proof that the best innovations happen when you bridge divides — both geographical and scientific. 

4. Borderless Innovation: Harnessing the Power of European Collaboration 

In the world of biotech, breakthroughs don’t care about borders — and neither does Europe. The EU, along with non-EU members like Switzerland and Norway, has created a playground for international partnerships that would make any biotech leader’s head spin with possibilities. Think about it: how often have you hit a wall in your research, wishing you could just reach out to that one expert in another country? Europe facilitates these cross-border collaborations, turning the entire continent into your extended team. 

Let’s zoom in on a prime example: BioValley Basel. This trinational powerhouse stretches across Switzerland, Germany, and France. We’re talking 40 scientific institutions, 900 companies (including 40% of the world’s biggest pharma players), 100,000 students, and more than 11 Life Science Parks. It’s like someone took all the ingredients for biotech success and created a supercharged smoothie of innovation. 

Here’s the real game-changer: it’s not just a numbers game. The true power lies in the collaborative spirit that infuses every interaction in this borderless ecosystem. Imagine attending a conference where the person sitting next to you could be your next research partner, investor, or even the key to solving that problem that’s been keeping you up at night. That’s the reality of Europe’s borderless biotech scene. 

And let’s not forget the practical benefits. Need a specific type of equipment? There’s probably a lab in a neighboring country that has it. Looking for a particular skill set? You’ve got a continent-wide talent pool at your fingertips. It’s like having a backstage pass to the world’s most exclusive biotech concert, where every interaction could lead to your next big hit. 

5. Diverse Funding Landscape: Fueling Growth at Every Stage 

Money makes the world go round, and in biotech, it can make or break your next big breakthrough. But here’s where Europe throws you a curveball: the funding landscape here is a whole different ballgame compared to what you might be used to in the US. 

First up, let’s talk about the elephant in the room: venture capital. Yes, it’s generally less abundant in Europe than in the US. According to PitchBook data, in 2022, US-based companies raised $238.3 billion in venture capital (source), while European companies raised €91.6 billion (approximately $100 billion, source). 

But before you start packing your bags, consider this: what Europe lacks in VC, it makes up for in grants and public funding. It’s like trading in your high-stakes poker game for a more stable, long-term investment strategy. 

Enter Horizon Europe, the EU’s flagship funding program. This initiative boasts a whopping €93.5 billion budget for 2021-2027. It’s a launchpad for innovation across various sectors, with a special sweet spot for health and biotech. Imagine having access to non-dilutive capital that not only fuels your research but also gives you the European seal of approval. That’s the kind of credibility money can’t buy. 

But what if you’re eyeing Switzerland, the land of precision and innovation? Well, they’ve got their own ace up their sleeve: Innosuisse. The Swiss Innovation Agency is dedicated to transforming scientific breakthroughs into tangible economic and societal benefits. It’s like having a government-backed catalyst that turns innovative ideas into impactful realities, benefiting both the economy and society at large. 

Here’s where it gets fascinating: The European approach to biotech funding isn’t just about throwing money at projects. It’s about nurturing a sustainable ecosystem for innovation. When you secure funding here, you’re getting more than a check — you’re gaining a support network, mentorship opportunities, and access to a vast web of connections. It’s this holistic approach that can transform your biotech aspirations into tangible realities. 

And let’s not forget the hidden gem in all of this: the blended funding approach. By combining grants, public funding, and yes, even some venture capital, European biotech startups can create a funding cocktail that’s both potent and stable. It’s like having a diversified investment portfolio for your company’s growth. 

So, while the absence of Silicon Valley-style VC floods might seem like a drawback at first glance, it has pushed Europe to innovate in how it funds innovation. The result? A funding landscape that’s more sustainable, more supportive, and potentially more aligned with the long-term nature of biotech development. 

In this diverse funding ecosystem, your next breakthrough isn’t just possible — it’s bankable. And isn’t that worth its weight in euros? 

Seizing Your Place in Europe’s Biotech Revolution 

As you process this whirlwind tour of Europe’s biotech landscape, you might be feeling both exhilarated and overwhelmed. That’s normal. 

You might be thinking, “This is incredible, but where do I even start?” It’s a valid concern, but remember — every biotech giant started exactly where you are now. 

You’ve just unlocked a treasure trove of insights into a biotech ecosystem centuries in the making. From Oxford’s hallowed halls to Munich’s cutting-edge labs, you now have a roadmap to navigate this rich terrain. 

It might seem daunting, but isn’t that what drew you to biotech in the first place? The thrill of pushing boundaries and changing lives? 

Let’s recap your newfound arsenal: 

1. Centuries of academic excellence, now at your fingertips 

2. A network of partnerships primed to catapult your ideas to market 

3. Strategic clusters that amplify your impact exponentially 

4. A borderless innovation landscape, turning an entire continent into your playground 

5. A funding ecosystem designed to nurture your venture from concept to commercialization 

It’s more than just another market entry strategy. It’s your ticket to pioneering the future of medicine. Europe’s biotech scene isn’t waiting for the next big breakthrough — Europe is cultivating it. And you’re now equipped to be at the forefront. 

So, what’s your next move? Will you let the complexities hold you back, or will you harness these unique European attributes to propel your startup forward? The choice is yours, but remember: in biotech, the biggest risks often yield the most revolutionary rewards. 

You’ve got the knowledge. You’ve got the drive. Now, it’s time to make your mark on Europe’s biotech revolution. The future of medicine is in your hands. Are you ready to take that leap and make history? Europe’s biotech scene is waiting for you! 

Navigating the regulatory landscape for medical devices and pharmaceuticals is a complex endeavor for startups aiming to enter both the EU and US markets. While securing approval from the European Medicines Agency (EMA) or, for medical devices, compliance with the Medical Device Regulation (MDR), is often seen as an initial step, it is crucial to concurrently consider the requirements set by the US Food and Drug Administration (FDA). Aligning FDA evidence requirements with those of payer medical policies can significantly streamline market access and ensure the commercial success of innovative medical technologies. 

The European Union (EU) regulatory framework for medical devices is governed by the MDR, which emphasizes rigorous post-market surveillance (PMS) and vigilance activities. For pharmaceuticals, the EMA provides centralized approval across the EU. The decentralized nature of the EU system for medical devices allows manufacturers to work with various Notified Bodies within the European Economic Area (EEA), providing some flexibility. However, this flexibility should not deter companies from preparing for the more centralized and stringent requirements of the FDA. 

The FDA’s regulatory pathway includes the 510(k) submission process and Premarket Approval (PMA) for medical devices, as well as the New Drug Application (NDA) and Biologics License Application (BLA) for pharmaceuticals. These processes demand comprehensive evidence demonstrating a product’s safety and effectiveness. These steps are essential for ensuring that medical devices and drugs meet the high standards required for market entry in the US. The FDA also mandates post-market surveillance to continuously monitor the performance of medical devices and drugs. 

A significant challenge for manufacturers is the misalignment between FDA regulatory evidence requirements and payer coverage policies in both the US and Europe. Payers, including insurance companies and Health Technology Assessment (HTA) bodies, often have different evidence requirements compared to regulatory bodies. This misalignment can lead to delays in patient access and additional financial burdens for manufacturers who need to generate further evidence post-market to satisfy payer requirements. 

In the European context, reimbursement and payer landscapes are highly varied and fragmented across countries. Each country in the EU has its own healthcare system, and reimbursement decisions are made at the national level. HTA bodies play a critical role in evaluating the cost-effectiveness of new medical devices and drugs before they are reimbursed by public health systems. This means that even after gaining regulatory approval from the EMA or achieving CE marking under the MDR, companies must navigate a complex web of national reimbursement processes to ensure market access across Europe. 

One strategy to address these challenges is to develop regulatory and reimbursement strategies in tandem. This involves engaging with both the FDA, EMA, or Notified Bodies, and payers (in both the US and Europe) early in the development process to ensure that clinical studies meet the requirements of all parties. In Europe, this might mean engaging with HTA bodies and national payers to understand their specific evidence requirements, which can differ significantly from one country to another. 

Aligning FDA evidence requirements with payer medical policies is crucial for successful market access. For instance, the FDA’s Accelerated Approval pathway, which expedites the availability of therapies for serious conditions based on surrogate endpoints, often requires additional evidence generation post-launch to meet payer standards. Similarly, in Europe, even if a medical device or drug has been approved by the EMA, additional data might be required to satisfy HTA bodies for reimbursement purposes. Therefore, it is essential to integrate market access considerations into the clinical development process from the outset. 

Case studies highlight the importance of real-world evidence (RWE) in meeting both regulatory and payer requirements. For example, the approval and reimbursement of treatments for spinal muscular atrophy and certain types of cancer have shown that incorporating RWE can address the gaps left by randomized controlled trials (RCTs) and ensure comprehensive evidence for both FDA and payer decisions. In Europe, RWE is increasingly being used to support HTA submissions and to negotiate favorable reimbursement terms. 

In conclusion, startups in the medical device and pharmaceutical sectors should prioritize aligning FDA and EMA (or MDR) regulatory evidence requirements with payer medical policies to facilitate smoother market access. By developing parallel strategies and engaging in early dialogues with all stakeholders, companies can mitigate delays, reduce financial burdens, and ensure that their innovative products reach patients efficiently and effectively. This approach not only enhances the chances of regulatory approval but also ensures favorable reimbursement decisions, ultimately driving the commercial success of new medical technologies. 

www.dreambighealth.org

The Clinical Data Interchange Standards Consortium (CDISC) is a non-profit organisation devoted to the development data standards for use in broader medical and especially in clinical research. Both the US FDA and the Japanese PMDA require the use of specific CDISC standards in submissions, but notably the EMA in Europe does not have equivalent requirements. 

As with any well-thought-out standard, implementation of CDISC standards offers significant advantages and increases in efficiency, especially when multiple organisations are involved – which in drug development is invariably the case with sponsor companies typically working with various service providers before finally submitting to regulatory authorities. 

In the 2000s (CDISC was started in 1997 and became international in 2001), it was thus my naive belief that CDISC implementation would rapidly become an industry-wide fact in pharma and biotech and across all stages of development without exceptions, especially after the FDA started to “recommend” its use in 2006 (it took another ten years, until 2016, for the US regulator to finally require CDISC in submissions). 

In the intervening 20 years, not only have I witnessed that this rapid and complete adoption did indeed not happen, I also learned to look past my own enthusiasm for CDISC standards and their ongoing development and understand circumstances in which adoption might actually offer little or even no tangible benefit to a company – circumstances that are more likely to apply to start-ups than to established companies. 

The first question to consider is a question of place. As already pointed out, the US FDA requires the use of CDISC in submissions, as does the Japanese PMDA. The EMA in Europe does not. Accordingly, depending on where one wishes to submit, CDISC may or may not be required. If you want to go to the US (or Japan) you must have CDISC. If you want to go to Europe, it is up to you whether to use CDISC or not. 

The second question to consider is a question of time. Again, the requirement for CDISC pertains to submission. Before submission, CDISC is not required. Especially in the early stages of clinical development (First in Human and other Phase I studies and moving into Phase II), any potential later need for CDISC is thus going to be well in the future. Depending on whether you even plan to do pivotal studies and/ or handle any submissions yourself, this need for CDISC may even come up only after an in-development asset has been acquired by another company. 

The final question then is to assess the pros and cons of going with or without CDISC in those circumstances where or when you do not need it, and this boils down to a question of costs (direct and indirect). The equation is simple: Deciding to go with CDISC brings the already mentioned increases in efficiency (and interoperability with other users), but the implementation of the standards requires you to draw from a limited expert pool for recruiting (for your internal processes including building those processes in the first place – alternatively, you can of course instead invest resources in training your existing staff) as well as from a limited pool of vendors (for outsourced aspects) already fluent in CDISC; deciding to go without CDISC will broaden the pools you can draw on (both internally and externally) and will allow you to focus your selection criteria on other areas than CDISC knowledge/ compliance – this may very well be cost-efficient in the short-term, but you should remain aware that once you are (re-)orienting towards a US submission, conversion to CDISC standards will become necessary. The efforts you will need to expend at that point will depend on the amount, structure and quality of the data to be converted – and while conversion will always be possible, sometimes more work will be required (e.g., when data structure differs significantly between individual studies). 

CDISC homepage: 
https://www.cdisc.org

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