Regulatory Requirements for Clinical Trials in EU: Endpoints, Comparators, and Study Types

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

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

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 MRP 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 DCP

5. Regulatory requirements in clinical trialsDrugs for IHD

6. AssessmentofCardiovascularDugsfor the treatment ofischemicheartdisease • 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. AssessmentofCardiovascularDugsfor the treatment ofchronicischemicheartdisease • 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 factorsLipids • Approval based on effect on lipid profile • Short term efficacy • Long term safety • Approval based on MACE

10. Cardiovascular Risk factorsBlood 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. Assessmentofinduciblemyocardial 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 antianginalsStudydesigns • Rx vs Placebo • Rx vs Beta blockers • Rx+ beta-blockers vs other antianginals + beta-blockers

15. Assessment of anti-anginal drugs

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

22. Ivabradine and exercise-induced myocardial ischemia All Patients received Ivabradine 10 mg twice / day Dose ranging 80 Increase in time to 1-mm ST-segment depression (s) 60 40 Ivabradine 10 mg (n=31) Ivabradine 5 mg (n=31) 20 Ivabradine 2.5 mg (n=30) Placebo (n=28) 0 0 20 40 60 80 100 120 Time (days) Borer JS, et al. Circulation. 2003;107:817-823.

23. Ivabradine and exercise-induced myocardial ischemia Ivabradine 7.5 mg bid Ivabradine Ivabradine 5 mg bid (n=315) Preselection Ivabradine 10 mg bid Ivabradine Ivabradine 5 mg bid (n=317) Placebo Atenolol 100 mg od 50 mg od Atenolol 50 mg od (n=307) 25 mg od M0 ETT M1 ETT M4 ETT Washout 2-7 days Run-in 7 days 1 month 3 months Run-out14 days Exercise tolerance test ETT: Tardif JC, et al. Eur Heart J. 2003;24:A186(Abstract)

24. Ivabradine and exercise-induced myocardial ischemia Increase in total exercise duration (4 months of treatment) *P<0.0001 P for non-inferiority n=939 78.8 Atenolol 100 mg 86.6* Ivabradine 7.5 mg Time (s) 74 76 78 80 82 84 86 88 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 trialsDrugs for Arterial hypertension

27. Assessment of anti-hypertensive drugs

28. Assessment of anti-hypertensive drugs

29. Assessment of anti-hypertensive drugs

30. Clinical development program • DOSE-SELECTION STUDY1 placebo-controlled study (SPP100A 2204) • CONFIRMATORY EFFICACY STUDIES5 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 STUDY3 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 Association Ali-HCTZ † Aliskiren monotherapy (75, 150 o 300 mg) Washout Placebo HCTZ monotherapy (6,25, 12,5 o 25 mg) Placebo 1 week 2 weeks Randomization 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

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. Regulatoryrequirements in clinical trialsWhatconstitutesmeaningfulchange

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 EndpointEffect evident early and maintained 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 6h 12h * 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.

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

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 • 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) 1.0 0.8 Macitentan 10 mg Placebo 0.6 Probability of freedom from event Survival Probability 0.4 0.2 0 0 6 12 18 24 30 36 Months

49. Pirfenidone in pulmonary fibrosis

50. Pirfenidone in pulmonary fibrosis