Trials and Tribulations of Investigator Initiated RCTs: A Study Chair s Perspective

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1 Trials and Tribulations of Investigator Initiated RCTs: A Study Chair s Perspective Douglas Bradley, MD Director, Division of Respirology, University of Toronto Clifford Nordal Chair in Sleep Apnea and Rehabilitation Research University Health Network Toronto Rehabilitation Institute and Toronto General Hospital

2 The Clinical Problem Sleep apnea is common (approximately 50% prevalence), in patients with heart failure, and is associated with increased morbidity and mortality Will treating sleep apnea in patients with heart failure reduce morbidity and mortality?

3 Challenges: Primary Endpoint Mortality rates for HF are declining: recent RCTs required 4-8,000 patients to detect mortality benefit Limited funding precludes mortality alone as a primary endpoint Therefore, composite endpoint is more feasible, but more problematic

4 Hypothesis In patients with systolic HF on optimal medical therapy, treatment of patients with central sleep apnea (CSA) and non-sleepy patients with obstructive sleep apnea (OSA) with adaptive servo-ventilation (ASV) will reduce the composite endpoint of death from any cause, CV hospitalizations, appropriate ICD shock and atrial fibrillation requiring anti-coagulation

5 Challenges: Multinational Trial For adequate sample size, a multicenter, multinational RCT was necessary Needed to forge partnership between sleep medicine and cardiology Needed standardized methods and centralized data management

6 Challenges: Funding CIHR funding insufficient, therefore needed to negotiate an industry partner via CIHR University-Industry peerreviewed grant in partnership with an unrestricted grant from Philips- Respironics Inc. who also provided ASV devices

7 ADVENT-HF ADAPTIVE-SERVO VENTILATION FOR TREATMENT OF OSA AND CSA IN HEART FAILURE Jointly funded by CIHR and an unrestricted grant from PHILIPS/RESPIRONICS HF patients 18 yrs of age with LVEF 45% on optimal HF therapy, undergo a sleep study AHI 15 ( 50% obstructive = OSA, >50% central = CSA) Baseline QOL, NT-pro-BNP, 6MWT, LVEF, LVEDV and LV mass Randomization Control no ASV, n = 430 ASV titrated on sleep study to eliminate OSA and/or CSA, n = month clinic visit, sleep study and QOL 3 month clinic visit 6 month clinic visit, QOL, NT-pro-BNP, 6MWT, LVEF, LVEDV and LV mass 6 monthly clinic visits and QOL until end of trial at 60 months Primary outcome: composite of death, CV hospitalizations, appropriate ICD shock and AF requiring anti-coagulation over the follow-up period Endpoint is 540 primary events which we estimate will require a 3-year accrual time with minimum and maximum follow up times of 2 and 5 years 2 interim analyses after 50% (n=270) and 75% (n=405) of the predicted number of primary events have occurred

8 GLOBAL IMPACT: ADVENT-HF TRIAL TO SEE WHETHER TREATING SLEEP APNEA REDUCES MORBIDITY AND MORTALITY IN PATIENTS WITH HEART FAILURE IN 42 CENTRES IN 9 COUNTRIES

9 Challenges: Infrastructure Started from scratch due to lack of multi-centre RCT infrastructure capability at our institution Had to set up: centralized data management system core sleep and echocardiography laboratories Insufficient funds to hire CRO to run the trial and perform monitoring Insufficient funds for regular investigator meetings Translation of trial documents into 6 languages

10 Challenges: Bureaucracy

11 Challenges: Bureaucracy Massive increase in red tape for RCTs recently largely due to overestimation of risk for subjects has made conduct of investigator initiated RCTs daunting: major barrier to progress While academic institutions solicit donations from the public to make a clinical impact through research, and put pressure on investigators to make a clinical impact, they simultaneously erect barriers that actively discourage investigator-initiated RCTs

12 Challenges: Bureaucracy Assumption by REBs and regulatory agencies that all RCTs are run by industry, are motivated by profit and have unlimited money to deal with country-specific regulatory issues, legal representation in some countries, unnecessary trial insurance, complex and time consuming contract negotiations, need for trial monitoring when, in reality, CIHR does not provide a budget for any of these items Failure to take into account different set of circumstances for investigator compared to industry initiated RCTs

13 Challenges: Bureaucracy Excessively long consent forms (11 pages!) and patient information sheets that emphasize risks and downplay benefits: this discourages participation Lack of uniformity of REB requirements across sites and countries Lack of uniformity of trial contract principles across sites and countries Double taxation of trial funds: research institutes at the core centre, plus taxation of transferred moneys when they reach trial sites As a result of these barriers, it took 1 ½ years to randomize the 1 st patient and more than 2 years to get the initial 25 trial centres initiated

14 Challenges: Motivating sites Unless there is true academic interest, it is difficult to motivate investigators to recruit and retain study subjects because there is no financial incentive due to limited funds

15 Adaptations Freed up some of my time from other duties to focus more on the trial Engaged many sites where investigators were either trained by me, or I knew them well and had confidence in them Created in-house core sleep and echo labs as well as data management system Negotiated with sites to waive REB review fees, and reduce institutional taxation

16 Adaptations Hired very experienced trial manager capable of creating CRFs, negotiating contracts and overseeing monitoring Used risk-based monitoring, with monitoring done by trial personnel where possible to reduce costs Used CROs only for complex regulatory regimes that we could not negotiate ourselves Closed some sites for non-recruitment

17 Progress 32 active sites in 7 countries, with 16 more sites soon to start in 2 more countries 301 patients randomized as of March 3, 2015

18 Solutions? Some academic institutions specializing in RCTs with appropriate infrastructure and personnel who can be hired for particular trials and have some continuity of employment when a trial ends REBs and contract depts that take into account differences between industry sponsored and investigator initiated trials: insurance only when necessary shorter REB submissions and consent forms

19 Solutions? Centralized REB for multiple sites within a multicentre RCT to reduce redundancy, costs and turn-around times Recognition by institutions that investigatorinitiated trials are not cash cows and should not be taxed at the same level as industrysponsored trials Some form of low-cost, multicentre mutual insurance (where necessary) Creation of RCT consortia to reduce start up times and need to start from scratch each time