Navigating the differing requirements in the EU and US

One of the transformations currently being seen in the pharmaceutical industry is the rise of the biotech – with some companies carving their own path (rather than succumbing to acquisition), as in the case of Moderna.

This has a bearing on their pharmacovigilance (PV) obligations, which match those of pharma companies several times their size. Particularly given the scale of variation in the requirements from one geographical region to the next, not least between the US and Europe.

Pre-marketing safety reporting

Companies with ambitions for Europe as well as the US tend to favor filing in the US first. That’s because, on top of the market’s vast size, the US benefits from being one country governed by one main agency – the FDA. In Europe, marketing authorisation can take much longer because beyond the central European Medicines Agency (EMA) each EU member state has its own unique requirements to navigate.

Although in the pre-marketing stage of development, most PV requirements are harmonised across the European and US markets, there are some small, noteworthy variations – for instance the FDA’s particular requirements around causality assessment, affecting what’s submitted in the two regions.

Even at a central level, EMA submissions have a different look and format to US dossiers so require different handling. For instance the Summary of Product Characteristics (SmPC), and labeling in relation to side effects, are not presented in the same way in Europe.

Differences exist too between the risk management approaches – the FDA’s Risk Evaluation and Mitigation Strategies (REMS) versus EMA’s Risk Management Plan (RMP) – and one cannot be substituted for the other. Failure to factor in these differences could present an issue at the time of filing. In addition, national EU-specific requirements may be requested in certain countries, on top of the RMP EU requirements, even for centralised procedures.

To successfully and efficiently navigate the differences between regions, biotechs must set out a clear strategy and timeline for how they will file to their target markets. Leaving Europe to one side until sales in the US are up and running is not advisable, given the additional time that is likely to be required to prepare for EMA’s differing requirements – and those of each EU country beyond that. And of course the UK must now be treated as its own market, outside of the EU and EMA.

It isn’t just European information and formatting requirements that differ and are more involved than in the US. Standard operating procedures (SOPs)/process requirements can be more complex in Europe too.

Although, during the pandemic, ‘crisis mode’ enabled emergency acceleration of these processes to expedite the marketing authorisation of vital products such as the US-originating Moderna vaccine for use in European markets, this approval was ‘conditional’ and such measures are temporary. At any other time getting such a product approved in Europe would be a much more protracted affair – and will continue to be so in the future.

Post-marketing vigilance

The post-marketing regulatory environment is highly regulated and inspection driven, and it is here that biotechs are likely to find the greatest challenges in managing their PV obligations. Here, the differences between US and European requirements differ more significantly.

In the early 2000s, Europe revised its post-marketing PV requirements, making these very clear and prescriptive. For post-marketing safety studies, for instance, Europe has broken down the requirements for interventional versus non-interventional studies and what needs to be reported – or not – for each.

In the US, equivalent post-marketing safety requirements are considerably older and quite vague in their language, leaving much to interpretation. Here, then, companies tend to tread a much more cautious path, interpreting the requirements more conservatively.

Where Europe is content with a final study report, in the US companies still file expedited single case reports (in the EU, expedited reporting is required for Individual Case Safety Report (ICSRs) for post- marketing safety studies).

If studies are used to support a product claim, and the right data hasn’t been collected in the right way for the given market, this could pose problems. So the different requirements do need to be well understood – and designed into post-marketing and market research studies – to avoid potential problems later.

Buying in PV expertise

Although biotechs may lead the way with product expertise, this is not typically matched in understanding and expertise in PV requirements and process rigor. To mitigate safety compliance related risk, they need to fill that gap. They need to establish both the right knowledge and experience, and skills in writing SOPs and setting up PV systems which, in Europe, must be in place from the time of filing for marketing authorisation.

Relying on a third-party safety services provider to take on this burden without in-house oversight is not recommended – not least because the marketing authorisation holder (MAH) retains ultimate responsibility for PV compliance. Irrespective of the biotech’s size and scale, then, it will need to bring in someone experienced who understands PV and can keep a check on vendor quality – rather than simply send someone on a course.

In Europe, a nominated Qualified Person responsible for PV (QPPV) is personally responsible for the safety of the human pharmaceutical products marketed by that company in the EU – a position with considerable (and justified) gravitas. There will need to be a designated person inside each region, too. That is, a US company with European marketing authorisation must have a named QPPV based in Europe – and potentially also at a country-level (in France and Spain this is a regulatory requirement).

Partnerships, future-proofing & budgeting for PV

Where biotechs have entered into distribution partnerships/ relationships with other MAHs, there will be additional considerations – such as who will coordinate and be responsible for the PV requirements in a given market and how this will be written in any contracts. The MAH in the local country always is ultimately responsible for meeting PV requirements in that country. For PV, there is also the decision of who will be the global database holder (usually the company that developed the product and got it approved).

PV capabilities need to evolve, too – not just to keep pace with changes to regulatory requirements across all markets globally, but also to stay on top of evolving channels and technologies when tracking safety signals. Where web sites and social media platforms create scope for market feedback, companies have an obligation to monitor and filter that content for potentially important real-world safety information, where digital media is considered to be company-sponsored.

Meanwhile, the increase in combination treatments involving drugs and devices may drive new rules which clarify how responsibility for adverse drug reactions is calculated and apportioned between those relative components. So this situation needs to be tracked, too.

Ultimately, setting aside a PV budget to develop the right internal knowledge and connect with appropriate external guidance will be essential for any biotech navigating all of this international complexity. It may seem a lot for a small emerging biotech to take on board, but lay the right foundations early on and there will be a world to play for.

Judith M. Sills, Pharm.D. and Dr Eric Caugant are non-executive directors and advisors to Arriello