Evidence Of Clinical Superiority:

1. Evidence Of Clinical Superiority: From hMG to HP-hMG

2. Gonadotrophins differences:why should we still talk about? • To update our knowledge and understanding • To provide evidence for decision-makers • To provide new clinical evidence for the best care of our patients

3. But Evidenceis not all the same

4. EVIDENCE The Evidence Pyramid

5. Why SR are on the Top • Rigorous methodology • Peer reviewed • Relatively large sample size • Ensure the highest quality evidence (based on RCTs)

6. RCT Design Pts enrolled Treated Group Treated Group Follow-up Randomly Assigned Outcome Compared Control Group Control Group Follow-up

7. IVF/ICSI cycles • Multifollicular development is an integral component for ovarian stimulation in IVF / ICSI cycles (Keck et al, 2005)

8. hMG rFSH In the market vs

9. LH supplementation: is it needed? • Lisi et al, 2001 • Filicori et al, 2001 • Westergaard et al, 2001 • Tesarik and Mendoza, 2002 • Commenges-Ducos et al, 2002 • Schats et al, 2000 • Balasch et al, 2001 • Daya, 2002 • Balasch et al, 2003

10. Theory should be tested “large randomised trial is needed to estimate the difference between hMG and rFSH” (van Wely et al., 2003)

11. Sample size calculation for such RCT • To reach 80% of power to detect a difference of 5% in ongoing pregnancies (or live births), more than 2400 women should be randomised (Andersen et al, 2006) • This condition is quite unlikely to happen (huge fund and long duration)

12. So We conducted a systematic review and meta-analysis of randomised trials comparing the effectiveness of hMG versus rFSH following a long down-regulation protocol in IVF-ICSI cycles

13. Most important outcome Live Birth Rate per Woman

14. How to interpret the figures! • A benefit from recombinant FSH would be displayed graphically to the left of the centre-line. • A benefit from hMG would be displayed graphically to the right of the centre-line

15. Live Birth Rate Al-Inany et al., RBM Online, (2008) hMG (363/ 1453) vs. rFSH (324/ 1484) (P < 0.04; O.R = 1.20, 95% CI = 1.01 - 1.42)

16. Odds ratio 95% CI NhMG rFSH Odds ratio (95% CI) 1.17 [0.82, 1.66] 72723% 21% EISG 2002 68 31% 23% Gordon 2001 1.50 [0.51, 4.41] 1.00 [0.22, 4.62] Ng 2001 40 20% 20% Westergaard 2001 379 35% 28% 1.42 [0.92, 2.18] MERIT 2006 731 27% 22% 1.20 [0.93, 1.55] 1.09 [0.53, 2.24] Kilani 2003 100 24% 22% 0.75 [0.30, 1.90] Balasch 2003 50 20% 27% Pooled results for truly randomised trials 1.18 [1.02, 1.38] 27% 23% 0.1 0.2 0.5 1 2 5 10 Increased with rFSH Increased with hMG A significantly better Live Birth Ratewith hMG versus rFSH Arri Coomarasamy et al.Hum Reprod 2008; 23: 310-315

17. Primary outcome hMG was associated with a 4% increase in Live Birth Rate when compared to rFSH in IVF-ICSI treatment following a long down-regulation protocol.

18. OHSS The rate of OHSS (O.R = 1.21, 95%, CI = 0.78 to 1.86) was not significantly different between hMG and rFSH.

19. Secondary outcome Miscarriage rate and multiple pregnancy rate were not significantly different between groups

20. Previous Evidence (10 years ago) • In the 1990s, a meta-analysis showed that rFSH was better than hFSH • And that hFSH was better than hMG in achieving clinical pregnancy rate(Daya 1995, 1999) BUT • In the 1990s, rFSH was not directly compared to hMG

21. Gonadotrophins The technological developments of Gn over the last years have shown improvements in specific activity, purity, degradation and impurities(Bassett & Driebergen, 2005)

22. Observation More than 2/3 of participants in hMG arm used HP-HMG which could be the influencing factor to change the evidence

23. HP-hMG Current purification processes allowed the production of highly purified human menopausal gonadotrophin (HP-hMG) with human chorionic gonadotrophin (hCG) constituting most of its LH like activity (Wolfenson et al., 2005 )

24. HP-hMG Highly purified hMG has been demonstrated to have a different mechanism of ovarian stimulation through inducing a different follicular development profile(Platteauet al, 2006).

25. In addition hCG has a longer plasma half-life than LH and provides a more prolonged and stable occupancy of LH receptors.

26. Based on these findings It would be logic to move from hMG to HP-hMG, that can be given subcutaneously, however, a direct comparison between the products is needed

27. Aim of the study “To compare the effectivenessof highly purified hMG (Merional)to the widely used traditional hMG (Menogon)”

28. As multifollicular growth is direct action of gonadotrophin administration in assisted reproduction, the number of oocytes was chosen as the primary outcome in this study.

29. Materials & Methods • Long luteal protocol for down-regulation was only used as it is the gold standard in ovarian stimulation in ICSI program. • We did not use depot GnRH agonist for down-regulation as it is known to result in profound pituitary suppression, which might artificially contribute to the advantages of excess LH-like activity

30. Study Design • 174 women undergoing ICSI were enrolled: • Group “A”: 56 women received Merional (IBSA) • Group “B”: 118 women received Menogon (Ferring) • Standard ICSI procedure • Monitoring (US & E2) • hCG (Choriomon, 10.000 IU) • OPU (34-36 hrs later) • ICSI • E.T. (under US guidance) • Luteal phase support (Cyclogest 400 mg) • -hCG (2 weeks later)

31. Why ICSI to document unequivocally oocyte maturity on the day of oocyte retrieval to eliminate the occurrence of fertilization failures dependent on factors unrelated to the quality of the ovarian stimulation.

32. p <0,01 p <0,01 Results • Higher number of oocytes and metaphase II oocytes retrieved

33. p <0,001 Results • Lower number of ampoules with HP-hMG • Similar days of stimulation

34. Results

35. Results Merional Menogon Mean + SD Mean + SD p -value NS Pregnancy Rate % 51.79 38.39

36. Results • There was no statistically significant difference in the incidence of ovarian hyperstimulation syndrome in both groups • No recorded serious local reaction from either the HP-hMG or the hMG treated groups

37. Distinguished study This is the first study in the world comparing between HP-hMG and hMG

38. hMG HP-hMG HP-FSH rFSH It fills in a gap in evidence as rFSH was compared to hMG and to HP-hMG but no one compared hMG to HP-hMG Study

39. Italian Merional Study group, 2007 • “Merional® is characterized by a high degree of purification leading to the following final specific activity of the individual hormone components: LH > 1,000 IU/mg, FSH > 3,000 IU/mg, hCG > 6,000 IU/mg” • This purity level allows S.C. self-administration (Alviggi C, Revelli A et al, Reprod Biol Endocrinol. 2007 Dec 4;5:45)

40. Conclusion Our findings suggest that IBSA HP-hMG produces more mature oocytes with fewer ampoules with similar pregnancy rate compared to hMG