Two-Arm Double Randomised Clinical Trial Using Drugs and Devices Dr Sunita Ahir Regulatory Affairs Manager D-Target SA Insert your logo in this area then delete this text box. Disclaimer • The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. • These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, Drug Information Association Inc., DIA and DIA logo are registered trademarks. All other trademarks are the property of their respective owners. 2 Contents 1. What is STEMI? 2. Regulatory Requirements for Global Clinical Investigations 3. Conclusions of this Clinical Investigation 4. Importance of Clinical Investigations to establish evidence based medicine 3 ST Elevation Myocardial Infarction STEMI 4 ST Elevation Myocardial Infarction STEMI 5 ST Elevation Myocardial Infarction STEMI 6 ST Elevation Myocardial Infarction STEMI 20 mins t = 30 7 ST Elevation Myocardial Infarction STEMI 12 7 6 1 hour 4 3 10 hours 5 2 8 t = 11 9 hours hours 8 ST Elevation Myocardial Infarction STEMI 9 ST Elevation Myocardial Infarction STEMI R P Q 10 ST Elevation Myocardial Infarction STEMI 11 ST Elevation Myocardial Infarction STEMI 12 ST Elevation Myocardial Infarction STEMI 13 STEMI The treatment options for vessel occlusion are:  Anticoagulants  Percutaneous Coronary Intervention  Or both 14 Study Design  Drug and device commercialized but investigational for their intended use  3604 randomized (3602 enrolled) patients with ST segment Elevated MI (within 12 hours of symptoms onset) in whom a primary PCI strategy was intended 15 Clinical Study A dual arm double randomized trial in patients with STEMI comparing: ARM A: RANDOMIZATION 1: Anticoagulant B Anticoagulant A 16 Clinical Study ARM B: RANDOMIZATION 2: Bare Metal Stent Drug Eluting Stent 17 Randomization Schedule RANDOMIZATION 1 - pt. 1:1 Anticoagulant A Anticoagulant B BMS BMS DES RANDOMIZATION 2 - pt. 1:3 (if indicated for PCI) 18 DES Study Design Arm A: Pharmacology – 30 days  Primary Endpoint: • The composite of major adverse ischemic events and major bleeding (net clinical benefit endpoint)  Major Secondary Endpoints: • Major adverse ischemic events (death, reinfarction, stroke or ischemic target vessel revascularization) • Major bleeding 19 Study Design Arm B : Stent – 1 year  Primary Efficacy Endpoint: • Ischemic target lesion revascularization  Primary Safety Endpoint: • The composite rate of death, reinfarction, stent thrombosis or stroke  Major Secondary Endpoint (13 months): • Binary restenosis (angiographic subset) 20 Regulatory Requirements for a global clinical investigation 21 FDA Status Update Prospective, single blind, multi-center trial with FDA approval Initial IDE submission 14 Oct 2004 Enrollment Begins… 25 March 2005 IDE resubmit IDE resubmit IDE resubmit 25 May 06 20 Sept 06 13 Apr 06 DSMB Findings Safety – 500 Pts Safety – 250 Pts. FDA Approval 12 Nov 04 250 patients 25 sites FDA Approval 07 Jan 05 1000 pts 200 sites FDA Approval 18 Apr 06 FDA Approval 02 Aug 06 1400 pts 200 sites 2600 pts 200 sites 22 Regulatory Requirements The study was conducted in compliance with:  the CIP (protocol),  the sponsor`s standard operating procedures,  the United States Food and Drug Adminisation requirements  the International Conference on Harmonisation (ICH) GCP guidelines  the Declaration of Helsinki  local regulations where applicable 23 Participating Countries North & South America Europe 24 Israel European Union and Israel: Clinical Trial Requirements Clinical Trials must be approved by Ethics Committees/Competent Authorities before the start of the trial Medical Devices Directive: Article 15, Annex VIII; ISO 14155 25 Device Clinical Trial Submissions: Competent Authority requirements Medical Device Directive Annex VIII section 2.2 Proof of payment Notification forms ISO 14155 Investigator Brochure Clinical Investigation Plan Clinical investigation of medical devices for human subjects Part 1 General Requirements Confirmation of Insurance CA submissions Place, starting date List of sites Informed Consent Documents Case Report Forms Ethics Committee Approval Agreements between Sponsor, Investigator and site CVs of investigators 26 Device Clinical Trial Submissions: Competent Authority requirements Medical Device Directive Annex VIII section 2.2 Proof of payment Notification forms ISO 14155 Investigator Brochure Clinical Investigation Plan Clinical investigation of medical devices for human subjects — Part 1 General Requirements Section 7.3; Annex B Confirmation of Insurance CA submissions Place, starting date List of sites Informed Consent Documents Case Report Forms Ethics Committee Approval Agreements between Sponsor, Investigator and site CVs of investigators 27 Device Clinical Trial Submissions: Competent Authority requirements Medical Device Directive Annex VIII section 2.2 Proof of payment Notification forms ISO 14155 Investigator Brochure Clinical Investigation Plan Clinical investigation of medical devices for human subjects Part 1 General Requirements Section 7.3; and 9.1 Confirmation of Insurance CA submissions Place, starting date List of sites Informed Consent Documents Case Report Forms Ethics Committee Approval Agreements between Sponsor, Investigator and site CVs of investigators 28 Device Clinical Trial Submissions: Competent Authority requirements Medical Device Directive Annex VIII section 2.2 Proof of payment Notification forms ISO 14155 Investigator Brochure Clinical Investigation Plan Clinical investigation of medical devices for human subjects Parts 1 and 2 Confirmation of Insurance CA submissions Place, starting date List of sites Informed Consent Documents Case Report Forms Ethics Committee Approval Agreements between Sponsor, Investigator and site CVs of investigators 29 Device Clinical Trial Submissions: Competent Authority requirements Medical Device Directive Annex VIII section 2.2 Proof of payment Notification forms ISO 14155 Investigator Brochure Clinical Investigation Plan Clinical investigation of medical devices for human subjects Part 1 General Requirements Confirmation of Insurance CA submissions Place, starting date List of sites Informed Consent Documents Case Report Forms Ethics Committee Approval Agreements between Sponsor, Investigator and site CVs of investigators 30 Device Clinical Trial Submissions: Competent Authority requirements Medical Device Directive Annex VIII section 2.2 Proof of payment Notification forms ISO 14155 Investigator Brochure Clinical Investigation Plan Clinical investigation of medical devices for human subjects Part 2 Clinical Investigation Plan Confirmation of Insurance CA submissions Place, starting date List of sites Informed Consent Documents Case Report Forms Ethics Committee Approval Agreements between Sponsor, Investigator and site CVs of investigators 31 Drug Clinical Trial Submissions: Competent Authority requirements Pharmaceutical Directive Proof of payment Covering Letter Clinical Trial Application EMA Decision 2001/20/EC Protocol CA submissions Scientific Advice IMPD Dossier if needed Investigator Brochure IMPD Ethics Committee Approval QP Declaration on GMP and site Manufacturer`s authorisation 32 European Union: similar but different! Data Protection: Required in France Netherlands Belgium Denmark Legal Representative: Required by France Radiation Protection: Germany 33 Drug and Device Clinical Trial Submissions: Ethics Committees Submission Form Confirmation of Insurance Clinical Investigation Plan Summary Informed Consent/ Clinical Investigation Plan Patient Information Sheet Ethics Committee Approval Patient Diaries Investigator Brochure Advertising Material Agreements between Sponsors, Sites and Investigators 34 Case Report Forms Regulations in Israel Israel Regulated by the Ministry of Health (MoH); Legislated by national laws  MoH has two departments: • Device – ISO 14155 for the conduct of clinical trials • Drug trials – ICH GCP for conduct of clinical Combination products are usually reviewed by the drug department of the MoH 35 Study progression 36 Site Selection  Site selection is normally an activity of the sponsor although it is discussed with the CRO.  In this case study, based on their experience, the sponsor identifies good centers and investigators who can provide reasonable patient numbers. 37 International Clinical Sites Norway Netherlands UK Sweden Poland Germany Austria France Spain Denmark Italy Israel 38 Patient Enrollment 4000 3500 3000 2500 Total 2000 EU 1500 US 1000 500 0 2005 2006 39 2007 Patient Enrollment  Poor patient enrollment in the US  Europe and Israel enrolled 72% of patients  Conclusion: site selection, patient enrollment can be difficult – proper site assessment, qualification, ability to generate good quality data and experience is necessary. 40 Monitoring Visits Follow-Up Visits Required:  1, 6, 12 months, and then yearly up to 5 years total, for all patients undergoing at least primary randomization  Angiography at 13 months for 1,500 stent randomized patients only 41 Study Close Out  The study was terminated early (truncating the study from 5 years to 3 years). The FDA, IRB, competent authorities, and ethics committees were informed.  The study outcome was achieved within 3 years. 42 Final Report  The database was locked on 4 November 2010.  The final report was submitted to the FDA on 11 November 2010. 43 Study Conclusions 44 Study Conclusions: Safety reports: Drug and Devices Bare Metal Stent (BMS) Anticoagulant A Anticoagulant B Drug Eluting Stent (DES) Net Adverse Clinical Events 27.60% 25.50% Net Adverse Clinical Events 28.0% 24.50% MACE 1 21.80% 21.90% MACE 1 24.0% 20.0% MACE 2 16.00% 13.40% MACE 2 12.9% 13.6% 7.70% 5.90% 6.6% 5.6% - cardiac 5.10% 2.90% - cardiac 3.8% 3.2% - non cardiac 2.80% 3.10% - non cardiac 2.90% 2.4% 2.00% 1.70% Ischemic TVR 17.6% 12.4% 10.50% 6.90% Ischemic TLR 15.1% 9.4% 5.10% 4.50% Death Stroke Major bleeding Any stent thrombosis Death 45 Study Conclusions  A significant 34% reduction in major bleeding and a significant 24% reduction in reinfarction, with comparable rates of stent thrombosis, target vessel revascularization and stroke is maintained to three years. 46 Study Conclusions  The improvement in survival in patients treated with anticoagulant B is maintained to three years with a significant 44% reduction in cardiac mortality and a 25% reduction in all-cause mortality. 47 Study Conclusions  The DES group continues to show superiority for the primary efficacy endpoint of ischemic target lesion revascularization (TLR) with a 40% reduction and no evidence of late catch-up at three years. 48 Study Conclusions  The DES showed superiority over the BMS when used in combination with anticoagulant B. 49 Importance of Clinical Investigations to establish evidence based medicine 50 Clinical Regime This has resulted in a change in clinical regime for patients with ST Elevated MI and incorporated into: “ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction.” 51 The Lancet  December 2011 Volume 378, Issue 9807,  Bivalirudin for patients with ST-elevation myocardial infarction  Gregg Stone and colleagues assessed the sustained benefit of bivalirudin monotherapy at 3 years for patients with ST-elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention. Stone and colleagues report that the long-term benefit in the bivalirudin group was consistent with delayed effects from reduction in major bleeding. 52 Combining mechanical reperfusion and pharmacologic therapy to improve myocardial perfusion  Establishes Primary Percutaneous Coronary Intervention (PCI) to restore coronary blood flow as the current standard of care for STelevation myocardial infarction Now additional resources are utilized by hospitals and clinicians to achieve this goal.  Door-to-balloon time of less than 90 minutes as one of the core performance measure to motivate clinicians and hospitals to adhere to this important class IA recommendation of American College of Cardiology (ACC)/ American Heart Association (AHA) guidelines. 53 The future …… 54 The future …….. % fractionated heparin Prasugrel eptifibatide abciximab unfractionated heparin tirofiban 55 Collaborate to Innovate 56 Thank you for your attention Dr. Sunita Prem Ahir Regulatory Affairs Manager DTarget SA 11 Avenue Des Sciences Yverdon-les-bains Switzerland phone: + 41 24 424 2688 [email protected] 57