FDA vs EMA: biotechs & the challenges of international pharmacovigilance

Biotechs involved in drug discovery have to navigate increasingly complex regulatory environments across borders. Experienced experts and non-executive advisors to Arriello, Eric Caugant in Paris and Judi Sills in New Jersey highlight the main differences between US and EU requirements, and advise on best preparations.

Small biotech companies are commanding an increasingly prominent role in the drug discovery market but they are finding there is a cost to participating in the global market – because they share the same pharmacovigilance (PV) obligations as large pharma companies, which means they are likely to face a steep learning curve in understanding what they need to do and how this may differ from market to market, or indeed across their product portfolio.

Relying on an individual contract research organisation (CRO) partner to manage PV requirements on their behalf may be appealing for biotechs, but this is a risky strategy – unless there is experienced CRO oversight to ensure that the regulatory requirements are met in all countries where a compound is studied and/or marketed. A far safer approach is for biotech companies to develop at least some capabilities of their own.

Before launch: safety

In the pre-marketing stage of development, most PV requirements are harmonised across the European and US markets, in line with agreements and guidance on standardisation via the ICH. But there are some small, noteworthy variations.

Companies tend to favour filing in the US first, because on top of the market’s vast size the US benefits from being one country, governed by one main agency – the United States 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.

Even at a central level, EMA submissions have a different look and format to US dossiers so require different handling. 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.

Plan registrations in tandem

All of this means that biotechs need 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 inadvisable, 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, following Brexit which means it is no longer under the jurisdiction of 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.

Remain vigilant

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 – so that companies now know exactly where they stand and what they must do to comply. In the US, equivalent post-marketing safety requirements are considerably older and quite vague in their language, leaving much to interpretation. There isn’t much guidance available to help with this, either.

For post-marketing safety studies, for instance, Europe has done quite a nice job of breaking down the requirements for interventional versus non-interventional studies and what needs to be reported – or not – for each. In the US, companies tend to tread a much more cautious path, interpreting the requirements more conservatively because precise guidance is lacking. 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).

It’s important to look beyond primary markets too, when considering PV strategies and measures; that is, to develop a global perspective. This is because any issues in one market will have a knock-on effect on all other regions. And, although there have been numerous pledges towards global harmonisation of PV and other regulatory requirements over the last two-three decades, in recent years there has been more rather than less divergence.

Particular to products

With so many considerations to get to grips with, biotechs clearly need to increase their regulatory capabilities, especially with regard to pharmacovigilance – and given that biotech operates at the cutting edge of life sciences, where monitoring of outcomes is especially crucial.

A further variable in all of this is that categorisation and treatment of different products types by the authorities can differ between regions. A ‘device’ or ‘combination product’ (device plus medicine) may carry different definitions and requirements from one region to another, for instance. Being aware of this, and building this into PV processes and planning, is another international regulatory imperative then.

Ask an expert

The challenge for biotechs is that, while these companies have extensive product expertise, this is not typically matched in understanding and expertise in PV requirements and process rigour. To mitigate safety compliance related risk, they need to fill that gap – both with the right knowledge and experience, and with skills in writing SOPs and setting up PV systems which, in Europe, must be in place from the time of filing for marketing authorisation (checks for which could be made during filing/pre-authorisation if the regulator feels in any doubt about a company’s PV provisions).

Relying on a third-party safety services provider to take on this burden without in-house oversight is not a practical or advisable solution. This is not least because the marketing authorisation holder retains ultimate responsibility for PV compliance: it is they rather than the CRO (contracted partner) that will be liable if anything goes awry.

So, irrespective of the biotech’s size and scale, the company 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.

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).

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.

Volume 22, Issue 3 – Summer 2021

About the authors

A non-executive director and advisor to Arriello, Dr Judith Sills, Pharm.D. is president of JM Sills Consulting, specialising in pharmacovigilance and benefit-risk management. She has over 30 years’ experience in pharmacovigilance in the pharmaceutical industry, FDA, and consulting. Prior to establishing a consulting practice in 2018, she was VP and head of global pharmacovigilance at The Medicines Company. Sills has also held senior positions at Novartis, Warner-Lambert and The Degge Group.

Also a non-executive director and advisor to Arriello, Dr Eric Caugant has over 25 years’ experience in pharmacovigilance, drug safety, risk management, and more broadly pharmaceutical medicine. In 2017, he founded Pharmacovigilance Systems Consulting (PhVSC). Prior to this, Caugant held senior positions in various pharmaceutical and biotech companies including Alexion, Bayer Lilly and Wyeth as well as the French Ministry of Health.

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