Navigating pharmacovigilance complexity in the US and EU: notes for biotechs

Pharmacovigilance obligations present significant challenges for biotechs. Small companies face the same rigor as large pharma – and it does not help that there is divergence between the requirements of the FDA, the EU and its member states. Here, seasoned pharmacovigilance experts and non-executive advisors to Arriello, Eric Caugant in Paris and Judi Sills in New Jersey, chart the main differences between US and EU requirements and suggest a practical path to compliance.

Unrecognisable professional with a series of icons indicating pharmaceutical research/development and compliance with regulations

The reality is dawning for the thriving biotech community that their pharmacovigilance (PV) obligations are equivalent to those of pharma companies several times their size.

For young, ambitious, product-oriented companies, such demands could be a barrier to market success – unless they devise optimum strategies for fulfilling the differing safety demands of respective regulators.

Companies with ambitions for Europe and the US tend to favour filing in the US first. On top of the US market’s vast size, it benefits from being a single country governed by one main agency – the US Food and Drug Administration (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.

Taking the US and EU as key territories, the diverse PV requirements highlighted below give a flavour of just what is involved and where biotechs are likely to need help.

Pre-marketing PV commitments

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 is 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 labelling in relation to side effects are not presented in the same way in Europe.

Macro photo of cogs in a mechanism with COMPLIANCE, REGULATIONS, STANDARDS, POLICIES and RULES words imprinted on metal surface

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 – and plan for multiple markets concurrently (it could take a long time to prepare for EMA’s diverse requirements, and those of each EU country beyond that, plus the UK which now sits outside of the EU/EMA).

It is not just European information and formatting requirements that differ and are more involved than in the US. Standard operating procedures (SOPs) or 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 and cannot be expected going forward.)

Post-marketing PV requirements

The post-marketing regulatory environment is highly regulated and inspection driven. It is here that biotechs are likely to find the greatest challenges in managing their PV obligations and where the differences between US and European requirements are starker.

Europe overhauled its post-marketing PV requirements a couple of decades ago, making these very clear and prescriptive. For post-marketing safety studies, for instance, it has broken down the requirements for interventional versus non-interventional studies and what needs to be reported or left out for each. In the US, equivalent post-marketing safety requirements are much older and leave much to interpretation, so companies tend to tread a more cautious path.

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 has not been collected in the right way for the given market, this could pose problems. So, the different requirements must be well understood and designed into post-marketing and market research studies.

Filling capability gaps

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 establish both the right knowledge and experience, plus skills in writing SOPs and setting up PV systems which, in Europe, must be in place from the time of MA filing.


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. As a result, irrespective of the biotech’s size and scale, it will need to bring in someone experienced who understands PV and can keep a check on vendor quality.

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. There will need to be a designated person inside each region, too: so, a US company with European MA must have a named QPPV based in Europe; and potentially also at a country-level (in France and Spain this is a regulatory requirement).

Determining accountability

Where biotechs have entered into distribution relationships with other MAHs, there will be additional considerations, eg, who will co-ordinate 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 is always ultimately responsible for meeting PV requirements in that country. There is also the decision of who will be the global PV database holder, this is usually the company that developed the product and secured approval.

Relying on a third-party safety services provider to take on this burden without in-house oversight is not recommended”

Meanwhile, the increase in combination treatments involving drugs and devices could trigger new rules clarifying how responsibility for adverse drug reactions is apportioned, another situation that needs to be tracked. Establishing an appropriate PV budget will be essential for any biotech navigating all this international complexity – and taking a strategic approach to filling gaps in capability.

PV capabilities should not stand still either. Biotechs will need to keep pace with both changes to regulatory requirements across all markets globally and evolving channels and technologies when tracking safety signals. They have an obligation to monitor and filter web or social media forums for potentially important real-world safety information, where digital media is company-sponsored.

About the authors

Dr Judith M. Sills and Dr Eric Caugant, both pharma industry and pharmacovigilance veterans, are non-executive directors and advisors to Arriello, a leading provider of risk management and compliance services to the Life Sciences industry.