The European Medicines Agency (“EMA”) has released their report giving detailed information regarding numbers of patients, sites and inspections with respect to pivotal clinical trials submitted in marketing authorization applications (“MAA”) between January 2005 and December 2011.
As we noted in a previous blog there has been an increase in concern amongst regulators and the public about how well clinical trials are conducted from an ethical and scientific/organizational standpoint, and especially with regard to good clinical practice (“GCP”) compliance. An applicant has to provide information in every MAA regarding the location, conduct and ethical standards applied in respect of the clinical trials conducted in third countries.
The report relates mainly to new applications (485), line extensions (95), and variations where new clinical trial information was provided (97). Generic applications are included as part of the new applications, but they generally do not add much to the number of patients, because these applications are mainly based on small bioequivalence trials, but they do provide information on the locations where these trials were conducted.
Supportive trials were not included, i.e., Phase I, most Phase II, and some Phase III trials. Post authorization Phase IV trials were only included where they had been used in line extensions or some variations. Clinical trials on those products that never came to market were not included.
Most of the patients recruited in the pivotal trials included in the MAAs came from European Union (“EU”)/European Economic Area (“EEA”)/European Fair Trade Association (“EFTA”) (38.1%) and North America (34.1%). The regions Central/South America and Middle East/Asia/Pacific follow, both with 9.4%. Smaller numbers were recruited in the Commonwealth of Independent States (“CIS”) region (4.4%), Africa (2.6%), Australia-New Zealand (1.5%), and Eastern Europe-non-EU (0.5%). Interestingly, over the period, the number of patients involved has steadily increased from around 86,000 in 2005 to around 145,000 in 2011, but recently there appears to be a trend towards an increase in the use of patients from the Rest of the World (“ROW”) at the expense of patient numbers in EU/EEA/EFTA and North America.
With regard to investigator sites, the highest numbers of sites were located in North America (42.4 %) and EU/EEA/EFTA (36.2 %), followed by Middle East/Asia/Pacific (6.6%) and Central/South America (6.0%) with smaller numbers in the rest of the ROW region. The trend in ROW for 2010 and in 2011 is a general increase of both the number of sites and number of patients with the exception of Africa (with an increase in the number of sites but decrease of patients), CIS (with a decrease of the sites but increase of patients) and Eastern Europe-non EU (with small increase of sites, but decrease of the patients).
Over the whole period the countries with highest number of pivotal trials were USA (681), Canada (427), Germany (421), France (342), UK (313), Spain (305), Italy (289), Poland (259), Belgium (239), Russia (222), Australia (217), and other countries with more than 100 clinical trials were Czech Republic, Denmark, Finland, Hungary, Netherlands, Romania, Sweden, Switzerland, Argentina, Brazil, Mexico, Israel, India, South Africa, South Korea, and Ukraine. The number of patients per investigator site was around 17 patients per site in the ROW, 13 patients per site in the EU/EEA/EFTA, and 10 patients per site in North America regions.
Overall the report shows that there were more than 1,340 trials from around 677 MAAs submitted since 2005. GCP inspections were requested for 357 sites (out of 70,291 investigator sites counted as part of the pivotal trials in these MAAs) from 1997 up to 2011. Note only a very small sample of sites were inspected, the number of sites being far larger than the number of inspections requested. The EMA comments that “[T]he key to the process is to test, by sampling, the processes and systems for different regions/regulatory frameworks, companies, therapeutic areas, population types (pediatric, adult, elderly, in-patient/out-patient), orphan product, commercial or academic sponsor, etc., rather than validating sites per se.” As discussed in our previous blog, the current collaboration with the FDA through the EMA/FDA GCP initiative is very important as an inspection in the ROW region is mainly dependent on FDA and EU activities. This report again highlights the importance of improving, strengthening, and supporting local supervision by increasing capacity, better networking, and information exchange and by taking advantage of opportunities for joint or observed inspections.
According to the report, the countries with highest number of sites GCP inspected were USA (21.57%) followed by Canada (4.48%), India (4.48%), Russia (3.08%), and Argentina (2.24%).
In the EU/EEA/EFTA states, Bioequivalence (“BE”) trials made up only a small number of trial inspections (4.6 %), while in Asia, Africa, North America, and CIS-Eastern Europe this was about half of the trial inspections (66, 30, 30, and 12 %, respectively). There were no BE trial inspections reported in South America. In particular, India had 63 inspections (82% of all inspections), Italy 60 (37% of all inspections), and Canada 28 (63% of all inspections).