International Inspections

Fergus Sweeney & Gunnar Danielsson

Session chaired by: David Montgomery MICR CSci

Reporter: Judit Varkonyi-Sepp MICR CSci

Keywords

European Medicines Agency (EMEA), Good Clinical Practice (GCP), Third country, Regulatory Authority, Inspection, Marketing Authorisation Application (MAA)

---

 

I went to this session with an expectation to learn about the ever-changing (and ever-stricter) requirements of inspections, especially within Europe. I heard about quite a different aspect of inspections, though, and I do not mind it at all. It was extremely interesting to see the inspectors ‘back-stage’. I never gave any thought to how hard it is to be an inspector and I appreciate them now even more than before. I also value the vision that one day, regardless of geography, the major differences in the clinical research world will be ironed out, at least as far as the quality of work, validity of data and protection of subjects is concerned. This is what our whole life is about and it is good to know that we are working on this together.

The talk dealt with two aspects of inspections: one about how regulators work together, the other about the life of an inspector.
International co-ordination of inspections

Dr Fergus Sweeney explained the EMEA’s role in co-ordinating international inspections. He is the chairman of the GCP Inspectors Working Group and ad-hoc Pharmacovigilance Inspectors Working Group and is responsible for the co-ordination of the GCP and pharmacovigilance inspections for the European Medicines Agency (EMEA). The EMEA focuses on evaluation of marketing applications and during this process, GCP inspections might be requested. The EMEA does not have a GCP inspectorate, but liaises with the GCP inspectorates of the European Member States’ Competent Authorities (CAs). The EMEA hosts the GCP Inspectors Working Group, the members of which are inspectors from EU Member States and European Economic Area (EEA) countries, joined by observers from Turkey, Croatia, Former Yugoslavian Republic of Macedonia and Switzerland.

Through, and in addition to, joint inspections, these states also share experience, aim to develop common policies, harmonise practices and establish and maintain a network.

What leads to a GCP inspection?

The EU Member States have their own inspection programmes, which usually focus on ongoing clinical trials and where inspections take place at the sponsor, CRO or investigator site, be they commercial or academic trials. The EMEA-initiated inspections are largely retrospective and are requested in the process of medicinal product evaluation. The Marketing Authorisation Application (MAA) can drive inspections both via the member states’ CAs and the EMEA activities. Inspections are either triggered or routine.

Routine inspections

Routine inspections survey the quality of studies submitted for approval. Not all applications give rise to a routine GCP inspection. They are conducted on a sample of applications and the following aspects are considered when deciding which applications are to be inspected:

• Size of sponsor company: large/medium/small
• Type of product: gene therapy, cell therapy, orphan product etc.
• Geographic origin of data/clinical trial
• Therapeutic area
• Patient population: paediatric, adult, geriatric etc.
• Scope of clinical package: single/small trial, standard package, retrospective data collection/bibliography

Triggered inspections

Triggered inspections are requested by the EMEA when:

• Problems identified by Rapporteur/Co-Rapporteur assessors
• Targeted, (potential) cause for concern emerge through:
• Issues identified by assessors
• Major impact factor, eg, a vaccine to which an entire infant population might be exposed
• Critical dependence on a single study or small group of studies
• Implausible results
• Biologically unlikely
• Conflicting results between studies
• Analytical or data management problems
• Other information about the sites or study, eg, previous negative inspection outcome

Inspections outside Europe

Although the EMEA’s focus is Europe, it can request inspections in third countries where the data from a clinical trial in the country are included in a MAA submitted in EU/EEA. When a trial is conducted in a third country, there is no specific requirement for an EU regulator to review the clinical trial dossier before the study starts there. To ensure that the MAA process deals with this gap, there are various clauses in the EU Directives which request verification:

• “… that these trials were conducted in accordance with the principles of good clinical practice and the ethical requirements equivalent to the provisions of that Directive.” (Directive 2001/83/EC as amended by Directive 2004/27);
• “… a statement to the effect that clinical trials carried out outside the European Union meet the ethical requirements of Directive 2001/20/EC.” (Article 6(1) of Regulation No (EC) 726/2004 and Article 8 (ib) of Directive 2001/83/EC); and
• “… clinical trials, conducted outside the European Community, which relate to medicinal products intended to be used in the European Community, shall be designed, implemented and reported on what good clinical practice and ethical principles are concerned, on the basis of equivalent principles to those set out in the provisions of Directive 2001/20/EC. They shall be carried out in accordance with the ethical principles that are reflected, for example, in the Declaration of Helsinki.” (Section 8 of Introduction to Annex I, Directive 2003/63/EC).

These changes in the clinical trial environment led the EMEA to develop a work programme for third countries, including increased numbers of GCP inspections. This Work Programme was finalised in 2008. The EMEA also published a strategy paper, which can be found on the EMEA website.¹

The EMEA’s strategy is to provide the same kind of advice and consultation on third country trials as they do for European ones (eg, regarding protocol design, scientific advice, conduct of clinical trials and medicinal product development, MAAs, orphan drug designation, Paediatric Investigation Plan and inspections). It aims to understand third-country specifics, such as the drive behind patient recruitment and actions as responses to non-compliance issues. Additional objectives are to train these countries on the ethical standards within the EU area, the role of the EMEA and to establish links to European states (including EEA) to ensure a closer relationship.

The life of an inspector

How does all this translate into the everyday-life of an inspector? Gunnar Danielsson, an Inspector with the Swedish Medical Products Agency let us look behind the scenes…

From the MAA point of view, the pre-approval inspections focus on data quality, ethical standards and MAA dossier specific issues. In these instances, more than one European inspectorate may participate. The inspectors increasingly harmonise their working practices and inspecting together is good learning for all. They inspect laboratories, investigator sites, sponsors, CROs and phase I units, focusing on both the sponsor’s and the investigator’s/institution’s responsibilities. The scope is the same as that for GCP inspections in ongoing clinical trials: ensure subject safety and integrity, data validity and adherence to all applicable laws and regulations. They also look at the Clinical Study Report and the MAA dossier.

The number of this type of inspections in 2008 is given by site type in figure 2 and by geographical area in figure 3.

Difficulties of international inspections

Inspections take a lot of time: not only the time spent at the actual site being inspected, but also the time for preparation, time for travel and then putting together the information and report.

Travel can be long, tiring and often outside business hours. Jet lag might kick-in, climate might be torturous, yet the inspector has to be at his best in time for the inspection and his vigilance cannot fade.

Co-operation of the inspected party is essential for the success of the inspection. Therefore, the inspector has to be well prepared about the culture of the country or region, the dress-code and behaviour. In addition, they have to be informed about the safety of the region and have to be prepared for the challenges of different dietary habits and microflora.

Language might be another difficulty, especially in regions where many dialects are spoken. It is expected that most investigators speak English, but study staff might not and medical records and patient information will be in the local language. The inspectors might have to resort to using translators, which could make the inspection much lengthier and communication with site staff much more challenging.

Inspectors from European agencies always have to inform the local agencies in other countries about the forthcoming inspection, and local agency inspectors have the opportunity to accompany as observers (although, according to Mr Danielsson, this rarely happens).

For an effective inspection, the inspector also has to understand the specific clinical research environment of the third country, which is important because many inspectors are relatively new on the clinical research scene. Therefore, the clinical trial authorities might not have the required standards or procedures, or there might be no legislation on certain aspects of clinical research. The standard of patient care might vary, as might the allocation of responsibilities within the research team (eg, how much the PI is involved and what members of staff do). The patients might not speak the same dialect as the investigator; the patient might not be able to read or write (in some countries, law demands an independent witness, but who can this be?). They might live very far from the investigational site and might not have the means to contact the investigator to provide follow-up information or they might get lost to follow-up.

Monitors might also be inexperienced. IMP handling (eg, in controlled conditions) might also be a problem, particularly if there is no continuous electricity supply.

These and many other details must be understood by the inspector and, besides ensuring that subject safety, integrity and data validity are met, inspectors provide continuous training to the sites/CROs and sponsors.

Findings from 3rd countries

Looking through the list of findings from third country inspections, we find that many are the same as European observations, with a few differences that are listed in Figure 4.

Third countries increasingly contribute to the data in European MAAs, therefore it is imperative that these data are valid and of good quality. Inspecting third countries (and most of all emerging countries) is quite a new activity for European regulators, physically and intellectually challenging and often the setting where these studies are conducted is uncharted water for the inspector (and the clinical researchers). Should we feel sorry for the poor inspectors?

Mr Danielsson says no. Inspecting clinical trials in third countries, who by the way are learning very quickly and might one day become the favourites to get most of the clinical trials, gives inspectors a broader view. They can work with other EMEA colleagues and other authorities and best of all it is good fun. New ideas, new geographical areas and new collaborations enrich the lives of the inspectors, the regulatory bodies and ultimately the clinical research scene. With these new additions, clinical research becomes more complex but, after the initial challenges of training to the highest standards, becoming truly global will benefit sponsors, CROs, researchers and, most importantly of all, patients.

Reference

1. European Medicines Evaluation Agency (2008): “Acceptance of clinical trials conducted in third countries, for evaluation in Marketing Authorisation Applications”, available via www.emea.europa.eu/Inspections/docs/22806708en.pdf [Accessed May 8th 2009].

---

 

Dr Fergus Sweeney is the Head of the EMEA’s Inspections Sector and Chairman of the GCP Inspectors and Pharmacovigilance Inspectors Working Groups.
Gunnar Danielsson is Pharmaceutical Inspector with emphasis of GCP inspection at the Swedish Medical Products Agency.
Judit Varkonyi-Sepp MICR CSci is a Clinical Trials Manager.