Agenda

1. Investigating recent developments in clinical trials in Belgium: analysis of the data available at the Federal Agency for Medicines and Health Products (FAGG/AFMPS)

2. Agenda

3. Belgium has a long and important tradition in clinical trials • The pharmaceutical industry in Belgium takes 40% of the private investments in R&D on their account • Belgium has the highest number of medicines under development per capita • High availability of skilled research staff, excellent infrastructure, the proximity of knowledge centers and suppliers,… • Outstanding expertise in clinical research, both in academic research programs as in industry-sponsored research programs • In 2007, Belgium was ranked as best country in the world for academic research, according to scientific journal The Scientist The Belgian pharmaceutical sector has a leading role in the achievement of the R&D investment targets which the EU member states set themselves as part of the Lisbon Strategy.

4. Challenges in the near future (1/2) Less expensive E.g. a trial for a standard drug in the US can cost up to $150 million. A similar drug could be tested in India for less than half of that amount. • Currently the majority of clinical trials is still conducted in Western countries • However, the number of trials performed in emerging countries is increasing quickly. • E.g. the number of clinical trials initiated in Central and Eastern Europe more than tripled from 2002 to 2007 • Clinical trials with innovative drugs should remain in Western countries Availability of large patient populations EMERGING COUNTRIES E.g. India: genetically diverse, drug-naive population of over a billion people Reformation of rules & legislations E.g. India: reformation of regulatory approval in 2006 India will automatically accept certain protocols if approved in the recognized countries

5. Challenges in the near future (2/2) Future conditions for clinical research in Europe • Regulation vs. Directive • Academic vs. commercial research  risk-based approach • 5 Key areas for improvement : • Single CTA • Co-sponsorship • Risk-based approach • Ethical review • Safety reporting • Inclusion of Clinical Trial Facilitation Group (CTFG) in the EMA-infrastructure

6. The goal of this project is to assess the developments in clinical trials in Belgium Objective of project • Objective: assess the recent developments in clinical trials in Belgium • Methodology: analysis of the database of clinical trial applications (CTA’s)of the Federal Agency for Medicines and Health Products (FAGG/AFMPS) • Study period:all clinical trials submitted to the FAGG/AFMPS between 2006and mid 2009 Organization of project • Tripartite project: • Deloitte: project lead and execution • FAGG/AFMPS: access of database to investigators of Deloitte and support for all issues related to the database content and clinical trials • pharma.be:external expert providing input on clinical trial related issues

7. Agenda

8. The number of submitted and accepted trials at the FAGG/AFMPS has increased Figure1: Number of submitted and accepted trials at the FAGG/AFMPS *No data availablefor Sem. 2 2009 at moment of analysis • An increase has been observed in clinical trial applications over the first 3 years • In the first semester of 2009 the number of trials is particularly low compared to previous periods. Additional data post-analysis reveal a total number of 527 submission in FY 2009 • The share of clinical trials accepted after resolution of major objections has increased • Overall the acceptance rate without major objections of the FAGG/AFMPS varies between 80.8% and 92.7% with an average of 85.8%

9. The number of amendments steeply increased over the total observation period Figure 2: Total number of amendments and distribution to ethics committees (EC) or FAGG/AFMPS • A clear shift is observed from the proportion of amendments to be treated by the EC towards theFAGG/AFMPS • The acceptance rate of amendments by the competent authority is high and varies between 88.5% and 97.7%

10. Most of clinical research in Belgium is performed in Phase III Figure 4: Percentage of trials per research phase *Others= trials coded erroneously in the database • Most of the clinical research in Belgium is performed in Phase III (=37.0%). Phase IV (=10.4%) research is the least performed • More than 50% of all clinical trial activity happens in early phase research (Phases I and II). • In general the share of trials per phase stays stable over the studied research period

11. Industry sponsored trials constitute the majority of Belgian trials Figure 5: Percentage of industry sponsored and academic trials per semester • The share of industry sponsored trials has been increasing and varies between 81.7% and 89.0% • Number of non-commercial trials is rather low compared to other EU memberstates, while the Belgian legislation is rather positive for academic trials.

12. This is also valid for Phase I research Figure 6: Percentage of industry sponsored and academic trials per phase (2006 to Sem. 1 2009) • Industry sponsored research in Belgium is mainly focused on pre-launch studies • Only for Phase IV research, the percentage of industry sponsored and academic trials is relatively similar • Phase I research is the least sponsored by academia

13. The top 5 pharmaceutical companies account for 40.9% of initiated industry trials Figure 7: Total percentage of trials per phase for top 5 companies (2006 to Sem.1 2009) 3.7% 14.6% 4.3% 5.2% 2.2% 3.4% 7.1% 9.7% 4.7% 15.1% 6.8% 7.1% 2.4% 1.4% 9.7% 8.7% 9.2% 8.8% 6.3% 19.7% 4.7% 16.1% 11.7% 7.9% 7.4% • For all Phase I trials initiated by pharmaceutical companies, the top 5 companies have an important shareequaling 56.5% • The top 5 companies account for 41.9% of all industry sponsored Phase IV research and 30.0% and 29.1%of Phase III and Phase II research respectively

14. The top 5 academic institutions account for 69.7% of initiated academic trials Figure 8: Total percentage of trials per phase for top 5 academic institutions (2006 to Sem.1 2009) EORTC* 7.2% 16.5% • EORTC 11.5% Erasme 10.1% 10.7% 5.4% 7.7% 16.9% 4.1% UCL12.7% 17.5% 15.4% 6.2% 12.2% UZ Gent18.3% 15.4% 11.5% 24.3% KULeuven24.1% 12.3% 19.2% 35.0% 9.5% 7.7% *EORTC= European Organization for Research and Treatment of Cancer • Of all newly initiated academic clinical trials per phase, the top 5 institutions represent 79.6% of all PhaseIV research, followed by Phase I (65.4%), Phase III (58.5%) and Phase II (55.4%) • Very high contribution of the top 5 academic institutions compared to the share of the top 5 industrycompanies

15. Almost 1 out of 5 clinical trials target cancer research Figure 9: Percentage of newly started clinical trials per indication (2006 to Sem. 1 2009) Genito and urinary system Other Other Respiratory system Musculo-skeletal system *Phase I research (all therapeutic domains) is reported separately due to the specificity and importance • Cancer research is followed in order of importance by trials in the Alimentary tract and metabolism system (7.9%), Nervous system (7.8%) and Cardiovascular system (7.3%)

16. Most clinical research is performed in adults Figure 10: Percentage of initiated clinical trials per age group • The results show clearly that most research is performed in adults followed by the elderly • The percentage of trials per age group remainsstable in 2008 • During the first semester of 2009 a trend towards more research in children (=15.8%) is observed

17. On average, 39 patients are to be recruited for a clinical trial Figure 11: Average number (N) of patients to be recruited per trial type and share (%) of global to be recruited patients • The least patients are needed for phase I and phase II research (approximately 28 patients) whereas for phase IV research most patients are needed (=63.7). On average 39.2 patients are needed per trial • The average number of patients to be recruited for academic trials (=60.1) is much higher compared to industry sponsored trials (=32.2) • The share of Belgian patients to be recruited for all trials initiated in Belgium equals 5.9%

18. The average number of sites to be recruited for a clinical trial is 2.8 Figure 12: Average number (N) of sites to be recruited per trial type and share (%) of single site trials • The least sites are needed for Phase I and Phase II research whereas for Phase III research most sites are needed (=3.9). On average 2.8 sites are needed per trial • The average number of sites to be recruited for academic trials (=2.3) is somewhat lower compared to industry sponsored trials (=2.9) • 41.2% of all initiated trials are single site trials

19. The top 5 ethicscommittees are responsiblefor 70% of all ethicsadvices Figure 13: Top 5 ethics committees based on the percentage of submitted applications. 70.1% • KULeuven is by far the most important ethics committee in Belgium with 26.9% of all unique advicesgiven evaluated over the entire observation period.. • The top 5 ethics committees are all university centers. reason for this is two-fold: • a large proportion of clinical trials will be performed in university centers (e.g. Phase I trials and trials for selection of therapeutic areas) • the leading ethics committee for multicenter trials has to be a university centre

20. Agenda

21. Conclusions • An average of 539 clinical trials per year were submitted at FAGG/AFMPS • Between 2006 and 2008, an increase in the number of clinical trial applications (+17.0%) was observed. In the first semester of 2009 a substantial decrease in applications is observed. Possible explanations can be related to the economic crisis which started mid-2008 • The acceptance rate of clinical trial applications by FAGG/AFMPS is high • A strong trend is observed towards a growing number of submitted amendments. Comparing the first (N=471) to the last studied semester (N=839), the number of amendments has almost doubled • The acceptance rate of amendments is in line with the acceptance rate of full applications and varies between 88.5% and 97.7% • There has been a clear shift from the number of amendments to be treated by the ethics committees towards the FAGG/AFMPS • Most of trials are performed in Phase III (=37.0%). Phase IV (=10.4%) research is the least performed in Belgium • More than 50% of all clinical trial activity happens in early Phase research (Phases I and II) • The share of industry sponsored trials has been increasing and varies between 81.7% and 89.0% • The top 5industry players account for 40.9% of all newly initiated trials. The most important contribution of these top 5 companies is observed during Phase I research with 56.6%

22. Conclusions • The top 5 academic institutions represent a very important share in all phases of academic trials. Their contribution in the total of all academic trials per phase represent 79.6% in Phase IV followed by Phase I (65.4%), Phase III (58.5%) and Phase II (55.4%) • Most clinical trials target cancer research (23.7%) followed by trials in the alimentary tract and metabolism system (7.9%), nervous system (7.8%) and cardiovascular system (7.3%) • Most of research is performed in adults followed by elderly. • Most of patients to be recruited are for Phase IV research (on average 63.7 patients per trial) • The average number of patients to be recruited for academic trials (=60.1) is much higher compared to industry sponsored trials (=32.2) • Industry sponsored trials have on average more investigational sites to recruit (N= 2.9) compared to academic sponsored trials (N=1.8). The highest number of sites are recruited for Phase III (N=3.8) research whereas the least sites are recruited for Phase I (N=1.1) research • In total the top 5 ethics committees are responsible for 70.0% of all ethic advices regardingclinical trials