Clinical Trials in Third Countries

ENVI meeting, 29 January 2015

Presented by Fergus Sweeney

European Medicines Agency

An agency of the European Union

Overview

Distribution of clinical trials submitted in support of marketing applications to EMA

Inspection of these clinical trials

Generic medicines, bioequivalence studies and CROs

Inspection of GVK and subsequent referral to EMA/CHMP

Future steps

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Clinical trials submitted in Marketing Authorisation

Applications (MAAs) to the Centralised Procedure at EMA

Typically involve 10-100 clinical trials and several thousand patients in each dossier.

EMA receives only a small proportion of generic applications (each involves 1-3 clinical trials
of ~24 subjects).

Most generic applications are submitted to Member States via national, mutual recognition or
decentralised procedures

Inspections conducted by inspectors of the Member States competent authorities.

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Patient recruitment in Clinical Trials included in Marketing

Authorisation Applications submitted to EMA 2005 -2013.
4.4%

36.9%

4.7%

3.13%
9.5%

30.6%

0.9%

2.5%
2.12%

9%
2.17%
2.13%

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2.5%

Total number of patients in Clinical Trials included in

Marketing Authorisation Applications submitted to EMA.

(ROW = Rest of World)

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Clinical trials: the dilemma

Between 2005 and 2013 (Centrally Authorised Products):
1,196,104 patients in pivotal trials
(36.9% in Europe, 35.1% in North America, 2.5% Africa, 9.5% Middle East/Asia
Pacific, 4.7% CIS, 9 % Latin America, 2.3% other)
100,789 clinical trial sites in 107countries
635 new Marketing Authorisation Applications plus line extensions
419 Good Clinical Practice (GCP) inspections

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Good Clinical Practice (GCP) inspections conducted for the

EMA centralised procedure by year and region

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GCP inspection related activities in international arena

GCP inspections in countries outside of EU and North America increasing

Increasing contacts with third country regulatory authorities (information sharing and
capacity building)

Ad hoc collaboration in the event of negative inspection outcomes.

EMA FDA GCP Initiative commenced 2009

New extension to EMA FDA GCP Initiative to include generic medicines

Initiative launched in January 2014
Sharing inspection plans, and sites of major interest
Sharing inspection outcomes
Using inspection outcomes

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EMA GCP inspection training

Annual GCP Inspection training courses (participation of EU and non-EU authorities).

Launch in 2014 of an online GCP training for new GCP inspectors.

Bioequivalence training courses in collaboration with French Agency in 2014 (participation of

EU authorities and WHO).

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Generic medicines and bioequivalence (BE) studies

Generic medicine - a copy of the originator medicine. Marketed once the data protection and
marketing exclusivity period of the originator medicine has expired.

The Marketing Authorisation Application (MAA) of a generic therefore relies entirely on 1-3
bioequivalence studies*, usually in healthy volunteers.

A bioequivalence (BE) study is performed to demonstrate that the pharmacokinetics (blood

levels) of the generic are equivalent to those of the originator ( and cross references the
originators safety and efficacy clinical trials).

A BE study typically involves 24 healthy volunteers each of whom takes the originator
medicine in one phase of the study and the generic in the other phase.

Blood levels of the medicine are measured at different time points.

The profile of blood levels of the generic must be equivalent to those of the originator, so that
the same clinical effect will be obtained.

* (Not all MAAs for generic medicines require a BE study)

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Bioequivalence (BE) studies and CROs

BE studies are carried out by CROs (Contract Research Organisations) with a clinic and a
laboratory.

Multiple Marketing Authorisations, held by different companies, may use the same generic
product (bulk tablets) and therefore the same BE study, but packaged with different local
names

Unlike manufacturing sites, CROs are not authorised/licensed by the regulatory authorities

Assessment of a MAA relies on evaluation of each application and the bioequivalence study it
contains. A risk based approach is used to determine the need for an inspection taking into
account previous inspection history of the CRO and the assessment of the submitted
bioequivalence study data.

The responsibility for conduct of the BE trials lies with the sponsor of the trial and
responsibility for the quality of the data submitted in the Marketing Authorisation Application
dossier lies with the applicant requesting the Marketing Authorisation

EMA and Members States co-operate in the preparation of an annual CRO inspection program
of the CROs most often used to conduct BE studies in marketing applications and the sharing

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Top five countries by number of Bioequivalence (BE)

inspections

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GCP inspection by the French Medicines Agency in 2014 at

GVK Biosciences:

GVK is a CRO based in India with both clinic and laboratory facilities

Nine bioequivalence trials used to support national marketing authorisation applications for
generic medicines were inspected.

The inspection revealed GCP violations associated with end of study ECG (electrocardiogram)
recordings.

ECGs from the same subject were labelled with different subjects names.

These violations took place over many years and involved multiple staff at the GVK clinic.

The ECGs themselves are not part of the bioequivalence assessment but are part of the
medical check performed on the study subjects before discharge from the trial.

The inspection concluded that the findings raised concerns on the reliability of the study data
for studies conducted at the site between 2008 and 2014.

A parallel UK inspection of the GVK laboratory revealed no systematic problems of

significance.

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GVK Referral Procedure

The European Commission referred the matter to EMA under Article 31 of Directive
2001/83/EC asking the CHMP :

to assess the potential impact of the inspection findings on the benefit/risk of the medicinal
products which have been authorised by MS on the basis of trials performed at the GVK site;

to consider if studies conducted at GVK prior to 2008 should also be included in the review.

The CHMP concluded that the inspection findings undermined the credibility of the
trials conducted at the GVK clinical site.
CHMP concluded that all bioequivalence studies with clinical activities carried
out at the GVK site, since these activities started in 2004, are considered
unreliable to support the benefit risk of the concerned medicinal products.

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GVK Bioscience issues Referral Procedure

The CHMP review involved over 1,000 pharmaceutical forms, strengths of medicines and active
ingredients.
For over 300 of them, sufficient supporting data from other sources were available; these will
therefore remain on the market in the EU.
For medicines that lack data from other studies, the CHMP recommended suspension unless
they are of critical importance for patients because alternatives will not be able to meet
patients needs.
The decision on whether a medicine is critical for patients lies with the national authorities of EU
Member States depending on the situation in their country. For medicines that are
considered critical, companies are given 12 months to submit additional data.

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Ongoing and Future steps

Consolidate information available to regulators on the CROs conducting bioequivalence

studies and the link of each study/CRO to the marketing authorisations based on them.

Increase international information sharing on the CROs, the planning, conduct and follow-up
of inspections (with FDA, WHO and regulators in those countries where significant numbers of
bioequivalence studies are carried out).

Improve risk based planning and coordination of CRO inspections at EU and international
level.

Workshop with generic industry associations to stress need for supervision of the clinical trials
on which their MAAs are based, and devise better, proactive processes for industry to
implement to prevent problems arising.

Implementation of the enhanced information sharing and coordination of GCP inspections

foreseen by the new Clinical Trial Regulation, including in the context of generic medicines
and CROs.

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Thank you
Questions?

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