Medical Outcome Trials: Trends, Design Approaches and Operational Strategies for Success

Your Presenters Philip Galtry Vice President, Head of Global Operations, Cardiovascular and Metabolic, Quintiles Philip has over 25 years of experience working in Clinical Research including 19 years in project leadership managing large global/multi-national programs and studies across Europe, South Africa, Asia, Australia, North and South America. He has significant experience working in the cardiovascular therapeutic area, including hypertension, acute coronary syndrome, hypercholesterolemia and heart failure. Phil has been responsible for the Project Management and oversight of a number of large and complex Phase 3 and 3b multinational cardiovascular outcomes trials including up to 41 countries across 1,000 sites, and including over 15,000 patients. Patricia Steigerwald Vice President Regional Managing Director, Americas, Real-World & Late Phase Research, Quintiles Patricia has nearly 30 years of clinical research experience. She provides strategic and operational oversight to ensure fit-for-purpose operational delivery of quality data and focus on patient safety. She has almost 15 years of experience in the development and delivery of regulatory-compliant strategies for the conduct of real world and late phase programs across all therapeutic areas. Patricia has extensive experience in providing strategic direction and oversight to large global teams to ensure regulatory adherence and operational appropriateness for the design and execution of real world late phase research. Quintiles Confidential 2

Agenda Trends in mandated requirements and use for medical outcome trials Opportunities and limitations with conducting end-point driven trials Best practice design and implementation considerations for quality data Operational strategies to maximize successful outcomes Case study 3

Today s Webinar Audience 3% 2% Academia Biostatistician Clinical Operations 23% Epidemiology 52% Health Economics/Health Outcomes Medical Affairs 10% 5% 1% Market Access Regulatory Affairs Risk Management 1% 2% 1% Other 4

Polling Questions A small number of polling questions have been added to today s webinar to make the session more interactive? 5

Trends in mandated requirements and use for medical outcome trials 6

Trends in Medical Outcomes Trials Frequency of trials conducted in the last 10 years We have analysed studies registered on ClinicalTrials.gov each year from the year 2003 to 2012 (10 years) > Selecting for possible Medical Outcomes Trials by size, intervention, phase and randomisation > Identified 436 such trials assessing hard clinical endpoints, although: - Size limit is arbitrary (2000 pts) - Not possible to separate endpoint driven studies from studies with hard endpoints as secondary endpoints. 7

Polling Question The chance of developing a blockbuster is declining. What effect will this have on the conduct of Medical Outcomes Trials? Do you believe that there is a trend to conducting more Do you believe that there is a trend to conducting less Do you believe that there is no change? 8

Trends in Medical Outcomes Trials Observed trends NO overall trend in the number of trials started by year over the 10 years* > Cardiovascular indications are the most frequent (~58%), with a modest reduction in frequency over the 10 year period > Medical Outcomes Trials involving diabetes indications increased significantly - Likely due to implementation of FDA Guidance for Industry: Diabetes Mellitus Evaluating Cardiovascular Risk in New Anti-diabetic Therapies to Treat Type 2 Diabetes, December 2008 > Medical Outcomes Trials involving oncology indications decreased significantly - Likely due to move from pivotal studies with mortality endpoints towards progression free survival and tumour response (not hard endpoints) * Quintiles, data on file Johnson et al. J Clin Oncol 21:1404-1411. 9

Trends in Medical Outcomes Trials Implications of requirements for MOTs The FDA is aware of industry concerns about the burden imposed by Medical Outcomes Trials > Financial risk/benefit ratio unfavourable when costs to conduct a Medical Outcomes Trial are so high > Costs may be prohibitive for a small biotech company > Anecdotal evidence exists that the requirement for CV Outcomes Trials in diabetes is inhibiting development of diabetes products 10

Trends in Medical Outcomes Trials CSRC Think Tank In February 2014 a Think Tank took place addressing the requirements for CV outcomes trials > Organised by CSRC, the panel included representatives from the FDA, academia, and industry Purpose: > To understand the variables impacting the threshold for considering the need for Randomized CV Safety Outcome Studies, create a consensus regarding thresholds, and understanding other potential approaches to collect safety data Synopsis published*, meeting conclusions will be issued Opinion piece: http://issuu.com/mark123/docs/jcs_may_2014 *Meeting synopsis: https://www.cardiac-safety.org/think-tanks/february-2014 11

Trends in Medical Outcomes Trials Think Tank output Some consensus reached: > Outcomes trials are not practical for some drugs > Less common indications mean the availability of patients may preclude this approach > However vulnerable patient groups deserve close attention should a safety signal or biomarker be noted > Meta analyses are not a substitute for outcomes data, should be considered as hypothesis generating only > Hazard ratios are used as a standard, but limited in low risk populations where number needed to harm is more useful > Standard definitions should be utilised for CV endpoints, including MI, revascularisation, stroke. > Endpoints should be expanded to cover heart failure (in view of a trend towards worsening HF noted in several endpoint studies on diabetes products) 12

Opportunities and limitations with conducting end-point driven trials 13

Limitations to Conducting MOTs Alogliptin and Saxagliptin > Examine and Savor TIMI 53 CV endpoints studies conducted per FDA guidelines > Presented at the ESC in September 2013 and simultaneously published in NEJM - Positive studies both met specified requirements for non-inferiority of the primary endpoint CV death, MI, stroke - Reception at the conference muted: Cardiologists expressed expectations of reducing endpoint, which was not achieved. Okay, so a drug is noninferior to placebo, why should I use it. Deepak Bhatt 14

Opportunities in Conducting MOTs Consortium studies Combined multi-sponsor, multi-product outcome trial Has been tried, though not in medical outcomes trials > e.g. the I-SPY 2 breast cancer programme Pros: > Common control group > Less competition for patients > Decreased cost > Some flexibility for SOC Cons: > Collaboration and agreement single design > No cross compound comparisons > Restricted range of therapeutic class in one study > Mechanism for blinding 15

Best practice design and implementation considerations for quality data 16

Best Practice Design and Implementation Protocol Considerations Endpoint Selection > Hard endpoints vs. surrogates Treatment Options > Built on standard of care Trial Duration > Longer than phase II/III > Sufficient to accrue endpoints Inclusion/Exclusion Criteria > Potential for more representative patients likely to experience more events* Sample Size > Typically 1000s of patients required for event determination Patient Assessments and Frequency > Minimum sufficient to determine events and monitor patient safety Safety Reporting > May be reduced if safety database already well established (especially in phase IV trials) *Steg PG et al. Arch Intern Med 2007; 167:68-73 17

Best Practice Design and Implementation Right Path, Right Start, Right Patients The Right Path Develop the Right country/site strategy > Future marketing considerations drug launch timing > Regulatory approval timelines > Suitability of the protocol and medical management of subjects within that country > Experienced Team > Historical and Current Data Develop an interactive model that meets study specifications Confirm Right Path with feasibility, if required The Right Start Determine when first SIVs will occur per country Develop a plan for recommended efficiencies Develop templates/processes upon study award Start working with sites as soon as they are selected, leveraging previous experience and relationships The Right Patients Chart review and pre-identification web site Develop final strategy and begin material development 18

Best Practice Design and Implementation Proactive Study Planning Start- Up Initiation Recruitment Phase Retention Close Out Collaboration in identification of the right sites (right patients and patient relationships to drive retention) Minimize site burden use icras, patient management platform, reduced CRF, etc Immediate engagement of patient and clarification of obligations during recruitment and ICF process to drive retention controlled recruitment Data flow effective and timely management of data and reporting Fit-for-Purpose Risk based monitoring strategy that yields high quality data at an acceptable cost point Successful stakeholder collaboration 19

Operational strategies to maximize successful outcomes 20

Operational strategies to maximize successful outcomes Data acquisition strategy Treatment pathways Impact of eligibility criteria Country specific information Reimbursement patterns Country and Medical Experts Internal Proprietary Data Start up timelines Country and site performance Site availability and tiering Co-morbidities Patient interest Patient recruitment strategies Retention feedback Patient Primary Research Data Quintiles Driven Data Approach Driven Approach External Public & Commercial Data Competing trials Country experience Patient populations Incidence/prevalence of indication Patient demographics Standard of care and drug usage Investigator Primary Research Sponsor Data Investigator interest Protocol issues/challenges Enrollment rates Standard of care Competing studies Ability to retain patients Current development plans Protocol synopsis Sponsor-recommended KOLs Reimbursement patterns Site list 21

Operational strategies to maximize successful outcomes Turning Data into Information Data-driven decision making Decision Medic / Clinical (ARO) Review Study Indicator triggers Identify safety signals Detect data flow and quality issues CDM Review of data to highlight trends Information Expert Interpretation Access to integrated, multi-sourced data Data Analytics DATA Integrate data across silos in near real-time EDC Safety IVR Lab CTMS 22

Maintain Contact with Patients Contact/reminder services via opt-in consent along with main ICF Separate Consent at Study Completion Communications Dropout Lost to Follow-Up Alumni Community Consent to receive study communications Reminders Thank you emails Missed visit alerts direct to patient Consent to be contacted to evaluate efficacy endpoints and adverse events if a patient discontinues study medication Consent for themselves or a friend/relative to be contacted if the site loses communication with the patient Consent to receive future communications Study updates Final outcomes report New opportunities Clinical and observational studies Feasibility surveys Market research Over 90% of sites in the US and 80% in ROW use contact/reminder services. Through consent, able to send messages that promote protocol compliance and enable direct patient contact in the event of dropout or lost to follow-up. 23

Operational strategies to maximize successful outcomes Fit-for-Purpose Monitoring Regional CPM: Manage team, issues, trend analysis, operational quality In-house Monitoring: Primary contact for sites Manage data entry timeliness Site training Data cleaning support Recruitment/ Retention On-site Monitoring: SDV Patient safety/endpoint collection Study drug reconciliation Hands on site management LOW RISK HIGH Site 24

Case study 25

Case Study RA with CV outcomes Challenge Very long safety study (over 5 years) All patients required to remain in follow-up until the number of events are reached even if they are no longer receiving study drug Global Study 33 of countries involved Result Excellent enrollment and Discontinuation metrics Randomization rate - Study enrolled one year ahead of schedule Excellent Discontinuation rate 8% vs. anticipated 20 % discontinued study drug.only 0.28% are LTFU or have withdrawn consent Solution Global Reach and Proactive Planning Retention experts - Assign experienced PMs to focus on retention of patients. Quintiles has successfully retained thousands of patients on these long term CVO trials so we have the processes and skills to implement successfully Global Reach Experts that work on CVO trials Local experts to develop optimal country strategy Proactive project management Upfront approvals of contract/budget templates. Ongoing re projections shared with sponsor on impact in startup delays Contracted Metric Actual Total Randomization Rate (Subjects/Per Site/Per Month) Discontinuation from study drug rate 0.2 0.6 20% 8% 26

Conclusions Despite the high cost of conducting Medical Outcomes Trials the incidence appears to have remained fairly constant > Pressure is growing to reduce the requirements > Alternative approaches under review Successful Medical Outcomes Trials remain a most persuasive form of evidence > Demonstrating a positive effect is not easy in mandated trials Plan with the end in mind: > Protocol considerations- lengthy trials; simplify to reduce site and patient trial fatigue > Consider country/site selection > Standard of care/optimal treatment is reflected and achievable Patient recruitment/ retention > Strategies/materials early > Communication and consent to engage and permit follow-up Near real time on-going review of data from multiple sources > Data driven evidence based decisions > Monitoring plan to yield high quality at an acceptable cost point 27

Upcoming Events Real-World and Late Phase Research Webinars Quintiles experts run regular webinars on Real-World & Late Phase services. Topics include: DIABETES VALUE DEMONSTRATION ONCOLOGY VALUE DEMONSTRATION RARE DISEASE REGISTRIES EUROPEAN PHARMACOVIGILANCE LEGISLATION REGISTRIES 201 MARKET ACCESS MAXIMIZING VALUE AND QUALITY IN PHASE IV REAL-WORLD Data To register or view previous webinars please go to www.quintiles.com/real-world-late-phase-webinars 28

Thank you Questions? 29