In recent years we have seen an increase in the number of trials conducted for EU marketing authority applications (MAA) in areas other than what was considered to be in the two main European [European Union (EU) / European Economic Area (EEA) / European Free Trade Area (EFTA)] and North America [USA / Canada] territories. In this first of two pieces on the European Medicines Agency (EMA) and its regard for ‘foreign data’ we shall look at the statistics on trial activity in the various territories and in the second piece, how the EMA regards foreign data and aims to maintains the quality.
Revisions to pharmaceutical legislation [Regulation (EC) No 726/2004 and Directive 2004/27/EC], which came into being back in 2005, reinforced the emphasis on the ethical standards required of clinical trials conducted in third countries to be included in MAAs submitted in the EU. This raised some concern among regulators as well as in public debate about the level of ethical, scientific and organisational standards such as compliance with good clinical practice (GCP) and also about the available framework for the supervision and audit of these trials. The EMA issued guidance in 2006 providing an overview of key-procedural elements affected by the new legislation that could have an impact on applications or existing marketing authorisations .
The EMA groups all non-EU or North America regions into a third ‘Rest of the World’ (ROW) accounting category, itself comprising six zones: Africa; Middle East/Asia/Pacific; Australia/New Zealand; Commonwealth of Independent States (CIS i.e. 12 countries including Russia, Ukraine, Georgia etc. – incidentally, in which Clinical Accelerator principally operate along with some other non-EU countries); E Europe (Non-EU) and Central & South America. It has been monitoring statistics on MAAs with trial activity for the various countries and has published reports on the data, which inform us of the changes in emphasis over the years since 2005. The most current report available, published in December 2013 covers yearly data up to and including 2011; whilst not completely up to date it does reveal interesting information and trends . Table 1 shows some information from 2005 and 2011 abstracted from this report to highlight changes in involvement of patients and number of sites over this period.
Between the years 2005 – 2011 almost 62% of the patients in trials submitted in marketing-MAAs to the EMA were recruited outside of the European Economic Area (EEA) and Switzerland, 34% being enrolled in Nth America and the remaining 28% in the other ‘ROW’ territories. Notably, 9.4% of patients were recruited in the Middle East, Asia or the Pacific and another 9.4% in Central or South America.
Information on the geographical location of clinical trials allows the European medicines network to allocate resources for inspections where they are most needed, and to promote cooperation with local regulators to ensure efficient supervision of trials to expected standards.
Particular trends in the number of patients submitted in MAAs to the European Medicines Agency during the accounting period included:
– Middle East / Asia / Pacific: an increase from 2.0% in 2005 to 12.8% in 2011;
– CIS (Ukraine, Russia, Georgia etc.): an increase from 0.8% in 2005 to 7.5% in 2011.
In the EU (+ EEA / EFTA) itself, there was a decrease from 37.0% in 2005 to 31.2% in 2011. Within this region, the contribution of the 15 countries that were members of the EU before May 2004 plus Norway, Iceland and Liechtenstein fell from 32.1% to 19.4% over the observation period. The contribution of the countries that became Member States of the EU in 2004 and 2007 subsequently increased from 4.7% in 2005 to 11.7% in 2011, perhaps demonstrating one of the benefits of becoming EU members.
Meanwhile, from North America, there was a decrease in proportion of patients contributing to MAAs from 42.8% in 2005 to 31.5% in 2011.
Where there was an increase in number of patients involved in clinical trials, as one might expect, we also see a marked increase in number of sites becoming involved e.g. CIS countries from 72 to 807 sites (proportion of patients in all submissions rising from 1.3% to 6.2%). Increases in trial activity can also be seen in the other ROW territories in terms of patient involvement but, as mentioned previously, the proportion (percentages) of the total are down as the ROW increases involvement.
|Table 1 Statistics on enrolment and numbers of sites in 2005 and 2011*|
|– E Europe (Non-EU)||69||0.1||8||0.1||⇒||742||0.5||107||0.8|
|– C / S America||13,075||15.1||213||3.8||⇒||19,459||36||902||7.0|
|(*figures abstracted from EMA publication 2013 )|
What seems to have driven this emergence of trial activity particularly in areas such as Asia/Middle East and Central & Eastern Europe are somewhat simpler and pragmatic regulatory and approval systems coupled with an abundance of patients very willing to participate in trials with investigators also eager to be involved. This has been considered, by some, to offer a more favourable and less costly trial environment than in the EU and associated states (and N America).
Understandably, this increased trial activity demonstrated in these figures – likely to be maintained or increased further since 2011 in new figures when published – does lead one to ask about data quality and adherence to Good Clinical Practice in areas not directly regulated by the EMA or, indeed, the FDA. In the second piece on this topic we shall look at the EMA’s regard to such ‘ROW’ trial data and how it ensures quality and acceptability for successful marketing authorisations.
- Practical considerations on the impact of the new pharmaceutical legislation on Marketing Authorisation Applications via the Centralised Procedure and Centrally Authorised Medicinal Products for Human Use. EMEA/243280/2005
- Clinical trials submitted in marketing-authorisation applications to the European Medicines Agency: Overview of patient recruitment and the geographical location of investigator sites. Published 11 December 2013 (EMA/INS/GCP/676319/2012)
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