1. Requirements from regulatory agencies: endpoints, comparators, type of studies

2. 2 Registration in Europe Post Nov 2005 :  Three European Systems Centralised Procedure (via EMA) Mutual Recognition procedure Decentralised Procedure

3. EU Centralised Procedure Legal Basis: Regul. (EC) No 726/2004 (also establishing “EMA” European Medicines Agency) Principle: single application / evaluation  single authorisation  direct access to all EU(27MSs) + Norway, Iceland and Liechtenstein Scope: –Compulsory for:  Biotech (recombinant DNA, gene expressed proteins, hybridoma & monoclonal antibodies)  New Active Substances in Specific Therapy Areas: AIDS, Cancer, Neuro-degenerative disorder, Diabetes, Auto-immune disease, other immune deficiencies, Viral diseases  Orphan Drugs –Optional for:  Any Other New Active Substance  significant innovation (therapeutic, scientific or technical)  in the interests of patients at community level  Generic of Centralised reference prod. (may use CP or MRP/DCP)

4. Two options Mutual Recognition Procedure –Art. 28 para. 2 of Dir. 2001/83/EC –For products with an existing MA Decentralised Procedure –Art. 28 para. 3 of Dir. 2001/83/EC –Only possible, if no authorisation has already been granted –Most significant difference with MRP = consultation between MS‘s before 1st MA issued & :

5. Regulatory requirements in clinical trials Drugs for IHD

6. Assessment of Cardiovascular Dugs for the treatment of ischemic heart disease Acute coronary syndromes: STEMI - NSTEMI Chronic stable angina: 1. risk factors, 2. anti- anginals

7. Assessment of Drug Efficacy in ACS Mortality Cardiovascular Mortality Discharge 30 days 3 months 1 year Reinfarction Sudden death

8. Assessment of Cardiovascular Dugs for the treatment of chronic ischemic heart disease Chronic stable angina: 1. risk factors, 2. anti-anginals Risk factors: events, surrogate end points Anti-anginals: inducible ischemia parameters, GTN consumption

9. Cardiovascular Risk factors Lipids Approval based on effect on lipid profile –Short term efficacy –Long term safety Approval based on MACE

10. Cardiovascular Risk factors Blood pressure Approval based on effect on blood pressure reduction –Short term 12 weeks vs placebo –Short term 12 weeks vs comparator –Long term 52 weeks safety study –Adequate patient groups Approval based on MACE

11. Assessment of efficacy in CSA Drugs: secondary prevention – anti-ischemic Mortality ? Morbidity? Degree of ischemia

12. Assessment of inducible myocardial ischemia Exercise ECG Holter monitoring Myocardial perfusion scintigraphy Stress echo

13. Assessment of efficacy for anti- anginals Exercise time during ETT Time to 1 mm ST segment depression HRQoL Number of episodes of angina No of GTN tablets used RRP to 1 mm ST RPP at peak exercise

14. Assessment of efficacy of antianginals Study designs Rx vs Placebo Rx vs Beta blockers Rx+ beta-blockers vs other antianginals + beta- blockers

15. Assessment of anti-anginal drugs

16. Criteria of efficacy

17. Assessment of anti-anginal drugs Methods of assessment Exercise testing Reproducibility Anginal pain HRQol Morbidity and mortality

18. Assessment of anti-anginal drugs Strategy of assessment Initial therapeutic studies Withdrawal of antianginals Short acting nitrates allowed Dose-ranging studies Studies compared to placebo

19. Assessment of anti-anginal drugs Strategy of assessment Main therapeutic studies Randomized, double-blind, placebo-controlled, parallel groups Active control studies vs an adequate comparator adequately dosed Comparable efficacy and safety to an appropriate standard therapy At least 12 weeks Monotherapy and add-on

20. Example of a development plan of a drug approved for the treatment of chronic stable angina

21. Placebo bid Ivabradine 10 mg bid Open label Placebo bid Ivabradine 10 mg bid Exercise tolerance test 2 weeks 1 week 3 months 1 week ETT 2 to 7 d ETT: Ivabradine 10 mg bid Ivabradine 2.5 mg bid Ivabradine 5 mg bid Placebo bid Ivabradine and exercise-induced myocardial ischemia Borer JS, et al. Circulation. 2003;107:817-823.

22. Increase in time to 1-mm ST-segment depression (s) Ivabradine and exercise-induced myocardial ischemia Time (days) 02020 4040 6060 8080 10 0 12 0 8080 6060 4040 2020 0 Placebo (n=28) Ivabradine 5 mg (n=31) Ivabradine 10 mg (n=31) Ivabradine 2.5 mg (n=30) All Patients received Ivabradine 10 mg twice / day Dose ranging Borer JS, et al. Circulation. 2003;107:817-823.

23. M0 ETT 25 mg od Placebo Atenolol 50 mg od (n=307) Ivabradine 5 mg bid (n=315) Ivabradine 5 mg bid (n=317) Ivabradine 50 mg od Atenolol 100 mg od Ivabradine 7.5 mg bid Ivabradine 10 mg bid M1 ETTM4 ETT Washout 2-7 days Run-in 7 days Run-out 14 days 1 month3 months Preselection Exercise tolerance test ETT: Ivabradine Tardif JC, et al. Eur Heart J. 2003;24:A186(Abstract) Ivabradine and exercise-induced myocardial ischemia

24. 7476788082848688 Ivabradine 7.5 mg Atenolol 100 mg 78.8 86.6* *P<0.0001 P for non-inferiority n=939 P for non-inferiority n=939 Time (s) Increase in total exercise duration (4 months of treatment) Ivabradine and exercise-induced myocardial ischemia Tardif JC, et al. Eur Heart J. 2003;24:A186(Abstract)

25. No benefit in overall mortality/morbidity Increased mortality in patients with angina

26. Regulatory requirements in clinical trials Drugs for Arterial hypertension

27. Assessment of anti-hypertensive drugs

30. Clinical development program DOSE-SELECTION STUDY 1 placebo-controlled study (SPP100A 2204) CONFIRMATORY EFFICACY STUDIES 5 active-controlled studies 4 in mild to moderate hypertension – not adequately responding to aliskiren or HCTZ monotherapy (SPP100A 2331, 2332, 2333, 2309) 1 in uncomplicated severe hypertension (SPP100A 2303) LONG TERM EFFICACY STUDY 3 studies 2 double-blind, active controlled 6-month studies (2306, 2323) 1 open-label 12-month study, including a one-month, randomized, double- blind withdrawal period to confirm long-term efficacy (2302) and a 4-month extension to this study (2302E1)

31. Study 2204 PlaceboAliskiren 75 mgAliskiren 150 mgAliskiren 300 mg Placebon=195n=184n=185n=183 HCTZ 6,25 mgn=194n=188n=176– HCTZ 12,5 mgn=188n=193n=186n=181 HCTZ 25 mgn=176n=186n=188n=173 Placebo 1 weekRandomization Placebo HCTZ monotherapy (6,25, 12,5 o 25 mg) 2 weeks Aliskiren monotherapy (75, 150 o 300 mg) Washout 8 weeks (double blinded) † Ipatients randomized to HCTZ 25 mg in association with aliskiren 150 or 300 mg received aliskiren/HCTZ 150/12,5 mg for one week before up titration Association Ali-HCTZ †

32. Studies for approval of therapeutic agents for the treatment of heart failure

33. Selection of patients AHF Patients hospitalised because of HF should be randomised within a reasonable time in order to be able to adequately assess efficacy CHF -LVD alone will not suffice. -Patients should exhibit a wide range of severity of CHF. Alternatively the information can be gathered by separate studies in different patient subsets -Patients should be in stable conditions, however a shorter period from the acute event and randomisation may be considered in patients with more severe forms of HF -It is advisable to exclude patients within 3 months from a MI and with a short (<3 months) duration of the disease

34. Selection of patients AHF Patients hospitalised because of HF should be randomised within a reasonable time in order to be able to adequately assess efficacy Patients needing optimisation of background Rx Patients already maximal Rx HHF Patients included at discharge after an unplanned hospitalisation for HF CHF -LVD alone will not suffice. -Patients should exhibit a wide range of severity of CHF. Alternatively the information can be gathered by separate studies in different patient subsets -It is advisable to exclude patients within 3 months from a MI and with a short (<3 months) duration of the disease

35. Criteria to assess efficacy AHF -In Hospital and 4 wks mortality -Depending on the indications claimed, long term mortality and duration of hospitalisation -Improvement in haemodynamic state and symptoms (categorical composite) -Relief of other manifestations of AHF including need of inotropic support and vasodilators CHF -Mortality, morbidity -Primary composite

36. Cardiovascular mortality Since no correlation exists between short term improvement in clinical symptoms and/or exercise capacity and mortality, many drugs are likely to require a trial which includes survival amongst its primary objectives before requesting an approval regardless of the claim being sought If the investigational drug belongs to a new pharmacological class or when agents of the same class have been associated with detrimental effects, a prospective, RCT aimed at assessing survival is requested Distinction should be made between a) sudden death b) death due to acute deterioration of clinical status c) death due to chronic progression of CHF

37. Composite end points May be appropriate but should include selected aspect of cardiovascular morbidity along with overall mortality. They all should be clinically relevant  Hospitalisations for HF  Causes of hospitalisation (co-morbidities, non adherence etc)  Worsening Heart Failure without Hospitalization  No. of hospitalisations/year  Patient journeys  Recurrent morbid events

38. Secondary end points Exercise tolerance: 6MWT seems to correlate better than Maximal exercise test (with or without gas exchange analysis) with the clinical effect of the drug Haemodynamic data: are insufficient to demonstrate benefit but may be useful to elucidate the mechanism of action Neuroendocrine status: data may be included but they can be only be accepted as supportive Physical signs and renal function: can be accepted as supportive only Symptoms: the effect on symptoms should always be coupled with data on mortality and morbidity QOL: supportive only

39. Safety aspects Hypotension End organ consequences (Heart, CNS, kidney) Effect on cardiac rhythm Pro-ischaemic events

40. Regulatory requirements in clinical trials What constitutes meaningful change

41. Meaningful change Any change in a primary end point that correlates with an improvement in mortality/morbidity A change in a primary end points that significantly improves QOL in end stage disease patients

42. Dyspnoea in AHF

43. Significant Improvement of VAS AUC Endpoint Effect evident early and maintained * P-value is based on a two-sided two sample t-test for serelaxin versus placebo comparing area under the curve (AUC, mm- hours) of change from baseline of dyspnea visual analog scale (VAS) from baseline to Day 5. 19.4% increase in AUC with serelaxin from baseline through day 5 (Mean difference of 447.7 mm-hr) AUC with placebo, 2308 ± 3082 AUC with serelaxin, 2756 ± 2588 *P=0.0075 6h12h

44. cm mm 4 mm Absolute value of changes in VAS scale

45. Exercise capacity

46. Riociguat in pulmonary arterial hypertension Ghofrani et al N Engl J Med 2013; 369: 4

47. Macitentan on exercise capacity and on Mortality- Morbidity end points 6-MWT + 7.4 m macitentan - 9.4 m in Placebo -(treatment effect 16.8 m; 97.5% CI, −2.7 to 36.4; P=0.01)

48. Macitentan on exercise capacity and on Mortality- Morbidity end points Survival Probability 0 0 0.2 0.4 0.8 1.0 0.6 12182430366 Macitentan 10 mg Placebo Placebo (n=250) Macitentan (n=242) Number of M/M Events11676 Hazard ratio (HR)0.55 97.5% CI of HR0.392, 0.762 p-value< 0.0001 48 Probability of freedom from event Months 6-MWT + 7.4 m macitentan - 9.4 m in Placebo -(treatment effect 16.8 m; 97.5% CI, −2.7 to 36.4; P=0.01)

49. Pirfenidone in pulmonary fibrosis

51. How to define a meaningful change Change in a parameter that correlates with mortality and/or morbidity or that has a clinical relevance No fixed value Has to be related to baseline function Attenuation of the decline in function Must be significantly related to the disease Must have a biological plausibility