What You Need To Know About The EMA Before Setting Up A Clinical Trial In The EU

Conducting research – including clinical trials – has increasingly become more and more globalized, with US-based sponsors showing interest in holding clinical trials abroad. In addition, with the current trend towards patient-centricity and the drive to establish trial sites where the patients are, pharmaceutical companies and contract research organizations (CRO) are realizing the challenges in understanding international clinical trial regulations, and ensuring compliance.

The European Union (EU) in particular, offers a number of advantages for clinical trial coordinators, including newly-released International Conference on Harmonisation Good Clinical Practices (ICH GCP E6) guidelines designed to allow sponsors to submit one application which encompasses all EU countries involved in a proposed trial. Unfortunately, dealing with European regulators – such as the European Medicines Agency (EMA) – can be very different compared to what clinical trial professionals are used to with the US Food and Drug Administration (FDA).

Without the establishment of GCPs, site coordinators could be underprepared for imminent EMA audits. In an effort to better understand the regulations set forth by the EMA, I spoke with Dianne Dalton, MPA, and President of Clinical Research Consulting. Dianne has 20 years’ experience in international clinical development and clinical trial management.

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What is the number one piece of advice you’d give to research sponsors interested in conducting clinical trials in the European Union?

Prepare all of your process documents. Make sure standard operating procedures (SOPs) are complete, accurate and define clear processes. The EMA will look at each SOP and ask specific questions on how you ensure that the staff is following each procedure. They will ask about training: how often you train on SOPs, how people are notified that a new SOP is to be reviewed, and what type of tracking you are using to ensure all employee training records are up to date. It is important that all sponsors show that vendor oversight was a priority during the course of the trial.

How do audits conducted by the EMA differ from those conducted by the FDA in the US?

The EMA focuses on processes while the FDA looks more closely at data. While the EMA is focused on training, trial master file (TMF) and how you go about ensuring compliance with your SOPs, the FDA will take a close look at your data, laboratory harmonization, and electronic data capture (EDC). It is important to both agencies that your systems – EDC, clinical trial management (CTM), and interactive web-based response system (IWRS) – are validated, and that a clear audit trail is available for inspection.

What are some of the most common hurdles research sponsors face when setting up clinical trials abroad?

Informed consent procedures. All informed consents need to be translated by a certified translation service with proper documentation maintained in the TMF. If you have multiple versions of an Informed Consent Form (ICF), all of these versions need to be tracked and translations need to be transcribed and approved by the regulatory authorities in that country. This can take a lot of time, so ensuring that the ICF is complete and accurate to the study procedures is extremely important. When the study changes, amendments and updated ICFs need to be reviewed by each country’s regulatory authority and in certain instances – in New Zealand and Australia, for example – by the government authorities as well.

In your experience, do you find that clinical trial professionals underestimate how difficult it might be to enter into the European clinical trials market?

Yes, language barriers are often an issue. The study personnel in that country need to understand the protocol, ICF, and laboratory manual in their native language. If they participate in the kick-off meeting and do not understand the study, it is the responsibility of the sponsor to get all study reference materials translated in their native language. Also, timeframes to get approvals from regulatory agencies are a factor and can cause expensive delays.

What are some of the first steps pharmaceutical sponsors should take to start an international clinical trial?

Choose a CRO that has a presence in the countries you are targeting. They will have the resources to provide the documents in the native language and be familiar with the regulatory environment. Research the demographics of the patient population to ensure the country/site can meet the study enrolment goals. Ask the sites how long and to whom they have to submit for regulatory approval. Some sites need to submit the study to the institutional review board (IRB), hospital and/or government authorities, therefore drastically delaying the process of site approval.

What are some of the violations you’ve identified when conducting international audits?

• SOPs are not in place or inadequate to cover all GCP/ICH guidelines. Vendor oversight is a big issue with the EMA. You can use your vendors to conduct certain functions of a clinical trial but you need SOPs to ensure that the sponsor is overseeing all functions of the trial, including monitoring, safety reporting, ICF development, IP shipment, and blinding. It is not acceptable to say “XYZ company” handles monitoring – the ownership belongs to the sponsor.
• Informed consent: The processes for tracking and maintaining the correct version of the informed consents is often lacking. Translations are not always available by certified translators, the wrong versions are being used at sites and ICF are not always approved by the IRBs before being used.
• TMF: EMA wants to know that the sponsor has all of the necessary documentation to prove vendor oversight. The TMF, if electronic, needs to be a validated system; if paper, they want to ensure that it is fully being maintained and all essential documents are there. They will ask for you to pull specific documents from the TMF to prove that it is maintained and organized well.

Are there mistakes that are more commonly made at international clinical research sites, compared to those in the US?

Yes. Often international sites are not aware of GCP regulations and trained as often as domestic sites. GCP practices need to be emphasized, reviewed and documented by the monitors at every site visit. GCP training records will be reviewed by an EMA inspector at each site. The sites need to keep their training records for all protocol reviews, investigator brochures, and pharmacy manuals to be prepared to show an EMA inspector.

Safety reporting needs to be done in a timely, accurate manner and these processes need to be understood and adhered to at each clinical site. The 24 hour clock of reporting safety events applies to international sites as well as domestic ones. It is important that each trial participant understands the ICF and the risks involved in the study. The international sites need to be monitored as frequently as domestic ones to ensure study compliance and sponsor oversight is the key in maintaining compliance.

How do you ensure that your overseas clinical trial is compliant with EMA regulations? Share your views in the comments section below!