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 1. Introduction and objective 2. Results 3. Conclusions

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) EMERGING COUNTRIES Less expensive Availability of large patient populations Reformation of rules & legislations 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. E.g. India: genetically diverse, drug-naive population of over a billion people E.g. India: reformation of regulatory approval in 2006 India will automatically accept certain protocols if approved in the recognized countries 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

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

6. The goal of this project is to assess the developments in clinical trials in Belgium Objective 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 Organization 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 2006 and mid 2009

7. Agenda 1. Introduction and objective 2. Results 3. Conclusions

8. The number of submitted and accepted trials at the FAGG/AFMPS has increased Figure 1: Number of submitted and accepted trials at the FAGG/AFMPS 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% *No data available for Sem. 2 2009 at moment of analysis

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

10. Most of clinical research in Belgium is performed in Phase III *Others= trials coded erroneously in the database Figure 4: Percentage of trials per research phase 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 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. Figure 5: Percentage of industry sponsored and academic trials per semester

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) For all Phase I trials initiated by pharmaceutical companies, the top 5 companies have an important share equaling 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 11.7% 9.2% 7.1% 5.2% 19.7% 7.4% 16.1% 15.1% 4.7% 6.3% 9.7% 8.8% 3.4% 9.7% 8.7% 14.6% 2.2% 2.4% 1.4% 4.3% 4.7% 6.8% 3.7% 7.9%

14. The top 5 academic institutions account for 69.7% of initiated academic trials *EORTC= European Organization for Research and Treatment of Cancer Figure 8: Total percentage of trials per phase for top 5 academic institutions (2006 to Sem.1 2009) Of all newly initiated academic clinical trials per phase, the top 5 institutions represent 79.6% of all Phase IV 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 industry companies KULeuven 24.1% UZ Gent 18.3% UCL12.7% Erasme 10.1% EORTC* 7.2% EORTC 35.0% 7.7% 9.5% 19.2% 12.3% 24.3% 17.5% 11.5% 10.7% 15.4% 12.2% 16.5% 6.2% 4.1% 16.9% 5.4% 11.5% 7.7% 15.4%

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) * 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%) Other Genito and urinary system Respiratory system Musculo-skeletal system

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 remains stable 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 ethics committees are responsible for 70% of all ethics advices Figure 13: Top 5 ethics committees based on the percentage of submitted applications. KULeuven is by far the most important ethics committee in Belgium with 26.9% of all unique advices given 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 70.1%

20. Agenda 1. Introduction and objective 2. Results 3. Conclusions

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 5 industry 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 regarding clinical trials