In the field of rare disease innovation, there has been a tendency to put off planning for the EU, perhaps due to concerns over the requirements or uncertainty as to how to navigate its complex, multi-national landscape.
This has, unfortunately, led many sponsors to see “Europe as a problem for later” (or “a problem for our EU licencing partner when we get one”). This mindset has meant missing out on opportunities to take advantage of avenues for advice on how best to streamline their clinical, non-clinical and quality CMC development strategies, and risks putting off EU and globally minded partners.
The problem with delayed EU engagement
The “Europe as a problem for later” attitude also often means not allowing enough time for EMA pre-submission engagements, which are even more critical in rare diseases where data gathered will be limited and patient populations are so much smaller. Getting FDA approval to start a study and then engaging EMA later looks good on a regulatory plan, but if the results from the US study are only going to be of continuing use following the results of the EU study, then any delay in the EU might as well have been a delay in the US.
Furthermore, seeking advice or a designation too late and rushing submission dossiers can lead to poor outcomes, including application rejections, increased regulatory scrutiny, and costly study redesigns, which may cause significant delays in trial initiation and market entry.
The importance of capturing QALY metrics
We also often see a lack of understanding about the importance of quality adjusted life year (QALY) metrics, which frequently means sponsors fail to capture this data early enough in the study process.
Safety and efficacy data are the obvious focal point for the EMA when evaluating potential orphan products; however, when approved, many EU reimbursement systems are based on some level of QALY metrics – especially in the rare disease arena. Thus, if the product is ever to get onto the market, the patient outcome-related metrics will be needed, and the sooner these are gathered, the less delay there will be when seeking reimbursement approvals.
GLP and GMP mismatch
Another challenge we see with non-EU sponsors – not just those focused on rare disease – is all too often their good laboratory practice and good manufacturing practice standards and import controls are not adequate for EU requirements. Unfortunately, this often results in CTA rejections and withdrawals.
Engaging with a local regulatory CMC expert as you prepare your dossier 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 submission, and EMA designations such as SME, PRIME and ODD are designed to facilitate this process (and make it more affordable).
The problem with investor milestones
Often, we see pressure on sponsors to meet investor milestones such as “achieve CTA/MAA submission/approval by X date”, which can be at odds with an effective and efficient regulatory strategy.
These milestones may have worked for standard pharmaceuticals and blockbuster products for adults, but in the modern era and for rare diseases where the patient population is so much smaller and frequently includes children, and the medicines are often far more complex, careful planning and regulator engagement to ensure the data gathered is optimal needs to be a priority. It is this approach that the EMA want to see, and it is this approach that will get medicines that really work on to the market and to the patients who need them fastest.
It would be so much more effective – both in terms of clinical outcomes and ultimately investor returns – if more investors were asking sponsors about their globalisation plans. This includes discussing CMC critical quality attributes (CQA’s) and clinical endpoints with both the FDA and the EMA, as well as patient groups, KOLs and payors. This might include using milestones like agreeing a paediatric investigation plan (PIP) or protocol designs with the EMA and FDA prior to beginning pivotal clinical trials, or production of a clinical development plan and/or GMP development milestones and regulatory strategy that is supported by both FDA and EMA feedback.
Late paediatric investigation plans (PIP)
A large proportion of rare diseases affect the paediatric population. The EMA’s Paediatric Committee (PDCO) offer highly valuable insights into regulatory strategy, study design and CMC elements for age-specific formulations during the PIP procedure. A well-planned and timely submission of a PIP to the EMA adds significant value to the overall development strategy for a product.
A PIP, and a successful PIP Compliance Check, both approved by the EMA, are mandatory pre-requisites for an EU MAA. However, sponsors may overlook or delay the PIP process, seeing it more as a bureaucratic hurdle rather than an opportunity to optimise their protocols. This is a costly mistake. For a rare disease that affects patients under 18, completing the PIP procedure is vital before commencing Phase 2 clinical trials to avoid unnecessary delays.
EU representative requirements
Sponsors without an office or registered address in the EU who want to perform clinical trials in the EU or apply for an ODD or SME status need an EU representative. Smaller sponsors often fail to recognise this requirement, leading to missed opportunities for EMA incentive programs such as SME, ODD and PRIME designations, as well as unnecessary delays in regulatory approvals. Additionally, non-EU based sponsors may not realise that an EU legal representative is mandatory for clinical trials. Leaving this appointment too late causes unnecessary delays in CTA submission and study start up in the EU.
Whether seeking a legal representative, looking to maximise the value of EMA incentive schemes, or trying to navigate requirements for CTA in the EU, sponsors should make use of local expertise to help understand the different regulations and standards and to help adapt the language used in the FDA IND (eCTD) to align with European regulatory requirements and language.
Conclusion
Taking a proactive approach to EU regulatory planning is essential for rare disease drug development. Avoiding the common mistakes outlined here – delaying EU engagement, neglecting QALY metrics, misaligning GLP/GMP standards, rushing submissions due to investor pressure, overlooking PIP requirements, and failing to appoint an EU legal representative in time – will help streamline approval processes and ultimately get life-saving treatments to patients faster.
“It would be so much more effective … if investors asked sponsors about their globalisation plans and if they have discussed their CMC critical quality attributes or clinical endpoints with the FDA and EMA.”