Innovators from markets outside the EU often have many questions about what to expect with the European Medicines Agency (EMA). For US sponsors with rare disease products, both significant and subtle differences can be a minefield when seeking EMA approval.
1. Navigating 27 markets and standards of care
First and foremost, while there have been many efforts to harmonise processes in Europe, it must be remembered that the EMA provides centralised regulatory approval for marketing authorisation within the European Union (EU), but healthcare systems, cultural practices and national clinical trial application requirements remain under the jurisdiction of individual Member States. In rare diseases with as-yet no approved treatment options, this can mean very different standards of care between countries, which therefore needs to be considered in the protocol design and in the overall project timelines and strategy.
With these differences in mind, it’s important that innovators engage early with EU patients and regulators about study design and target endpoints, particularly those that will be included in any patient-reported outcomes (PROs).
2. Know the prevalence
Be aware that EU prevalence of rare diseases may differ from the US. The EU has many comparatively “closed” ethnic populations (referred to in scientific terms as consanguinity, where there is very limited external genetic influence) with associated higher prevalences of certain genetic conditions. US-centric literature searches on incidence and prevalence will, therefore, not suffice.
Similarly, the EMA may not accept the same differential diagnoses as the Food and Drug Administration (FDA). If looking at a sub-population, sponsors will need EU-specific expert consensus on diagnostic criteria, including evaluable characteristics that can be plausibly linked to the condition, and which are closely linked to the mechanism of action of the proposed orphan product.
3. Transparency and patient rights
There are important differences in the EU and US with respect to intellectual property protection as well as documentation publication. Notably, the EMA has put in place broad transparency rules meaning that a wider set of documents submitted in clinical trial authorisation applications (CTA), orphan drug designations (ODD), and marketing authorisation applications (MAA) will be made available publicly online. There are also requirements for lay language versions of some documents for the public side of these dossiers.
To mitigate any risk to IP, sponsors need to invest time and effort in creating good lay summaries and redacting publicly facing documents or potentially even some level of dossier redesign regarding the level of detail in different documents. It’s important to understand this sooner rather than later and work with local experts to avoid duplication of effort or onerous re-writes.
4. GMP differences
Due to the mutual recognition agreement between the FDA and EMA, sponsors sometimes believe EMA will not require discussions regarding EMA adapted ISO and ICH guidelines, or how EMA’s good manufacturing practice (GMP) standards affect the US quality system. But one of the most frequent reasons for CTA rejection or withdrawal we see is good laboratory practice (GLP) and GMP standards and manufacturing and import controls not being adequate for the EU requirements. This applies to all products; however, there are additional complexities to consider with rare diseases where distribution logistics can be more challenging, and advanced therapy medicinal products (ATMPs) are more common, as these are often manufactured across several facilities.
Engaging with a local regulatory CMC expert as you prepare your investigational medical product dossier (IMPD) or Module 3 and ensuring any gaps or questions have been discussed with the EMA or a local EU regulator can greatly improve the chances of a ‘right first time’ CTA or MAA.
A big, complex market
It can be extremely challenging to transition from a US system where the sponsor is the ultimate authority on the product to a system where EU authorities need to understand and may even question the product and its results. Navigating this complexity requires being able to speak the European regulatory language — not only in the dossier but in all communications.
Moreover, there are numerous regulatory changes unfolding in the EU as we transition to the Clinical Trial Regulation (CTR), the Medical Device Regulation (MDR) and the In Vitro Diagnostic Regulation (IVDR), never mind the many new digital systems and requirements that are being introduced.
Having a trusted local regulatory partner is crucial when navigating these new guidelines, legislations and regulatory systems. Early and collaborative engagement with regulatory experts, scientific advisors and local competent authorities (CAs) will help mitigate risks and streamline the path to approval.
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It can be extremely challenging to transition from a US system where the sponsor is the ultimate authority on the product to a system where EU authorities need to understand and may even question the product and its results.