Alternatives to Randomized Premarket Studies Laura Mauri, M.D., M.Sc. Brigham and Women’s Hospital Harvard Medical School Boston, MA

Disclosures - Laura Mauri, M.D., M.Sc.   Research grants from Abbott, Boston Scientific, Cordis, Medtronic, Eli Lilly, Daiichi Sankyo, Bristol-Myers Squibb, Biotronik, and Sanofi-Aventis Consulting Medtronic, Eli Lilly, Biotronik, ReCor, St. Jude

Medical Technology Innovation Scorecard The medical technology innovation ecosystem, long centered in the United States, is moving offshore. Innovators are going outside the United States to seek clinical data, new-product registration, and first revenue. US consumers aren’t always the first to benefit from medical technology and could eventually be last. Innovators already are going first to market in Europe and, by 2020, likely will move into emerging countries next. The nature of innovation is changing as developing nations become the leading markets for smaller, faster, more affordable devices that enable delivery of care anywhere at lower cost. http://www.pwc.com/us/en/health-industries/health-research-institute/innovation-scorecard/index.jhtml

“Opening the FDA Black Box” Goodman and Redberg. JAMA Premarket approval (PMA) commonly includes single arm studies 510K pathway and PMA supplements for medical devices often approved without clinical testing Dhruva  SS, Bero  LA, Redberg  RF.  Strength of study evidence examined by the FDA in premarket approval of cardiovascular devices. JAMA. 2009;302(24):2679-2685. Institute of Medicine. Medical Devices and the Public’s Health: The FDA 510(K) Clearance Process at 35 Years. Washington, DC: National Academies Press; 2001. Rome  BN, Kramer  DB, Kesselheim  AS.  FDA approval of cardiac implantable electronic devices via original and supplement premarket approval pathways, 1979-2012.  JAMA. 2014;311(4):385-391

Criticism of Medical Device Trials Performed for Approval or Clearance Trials not always required for new product approval Frequently not randomized, small, sometimes unblinded, use surrogate endpoints

Devices are Different from Drugs Small changes in drug design may lead to off target effects Device iterations lead to changes in local effects How stents might differ from heart valves

What is unique about devices? Iterative improvement based on mechanical design Failure mode may be predicted by modelling, bench testing, or detected in single arm safety studies Short product life cycle

Range of Appropriate Trial Designs Objective performance criteria for single arm study comparison (surgical heart valves) Blinded randomized trial with valid surrogate endpoints (renal denervation) Open label randomized trial compared with medical therapy with mortality endpoint (percutaneous heart valves)

Heart Valve Evaluation: the OPC Standard Heart valve approval on basis of OPC since 1994 Trial must demonstrate observed rates less than 2x OPC, with OPC of 1.2%/year or more for Thromboembolism 3%/year Paravalvular Leak 1.2%/year Endocarditis 1.2%/year Stable reference population Well understood, easily ascertainable endpoints, arguably free of bias or involvement of placebo effect. Grunkemeier, Jin and Starr. Ann Thorac Surg 2006;82:776-80

Prosthetic Heart Valves: Objective Performance Recently, the Artificial Valve Endocarditis Reduction Trial (AVERT) was designed to compare a new Silzone sewing ring, designed to reduce infection, with the Standard sewing ring on a St. Jude Medical heart valve. This was the largest heart valve RCT ever proposed (4,400 valve patients, followed for as long as 4 years), but it was stopped prematurely because of a high leak rate associated with the Silzone valve. Examining the results showed that a much smaller, OPC-based study with 800 patient-years would have been sufficient to disclose this complication of the Silzone valve. (Ann Thorac Surg 2006;82:776–80). Insert Figure 1 from this paper. Prosthetic Heart Valves: Objective Performance Criteria Versus Randomized Clinical Trial Gary L. Grunkemeier, PhD, Ruyun Jin, MD, and Albert Starr, MD (Ann Thorac Surg 2006;82:776–80)

Objective Performance Goal to Facilitate Single Arm Studies >5000 BMS treated patients with 1 year follow up in RCT Mulitvariate OPC with modelling of impact of known risk factors for restenosis as empirically observed

Post-market Requirements Applications for a Performance Standard from Historical Data in Drug-Eluting Stents (>140,000 patients with 5y follow up) New Product To provide comparator data to determine the ST or TLF incidence or components with certainty relative to approved products Applicable where clinical impact of design is likely to be isolated to 1 year safety or efficacy elements Label Expansion Generalizability Age>75, Female Sex, Underpresented Race and Ethnicity, Low EF, CKD Post-market Requirements To provide comparator data for broadly inclusive population representing actual practice APPROVED by FDA DM Long lesions, Small vessels, ISR NOT YET APPROVED by FDA NSTEMI, STEMI Bifurcation, LM, 3 Vessel Stenting, SVG ACC/AHA PCI Guideline on Left Main: 2.2 Revascularization to Improve Survival: Recommendations Left Main CAD Revascularization CLASS I 1CABG to improve survival is recommended for patients with significant (≥50% diameter stenosis) left main coronary artery stenosis (24,25,26,27,28,29,30). (Level of Evidence: B) CLASS IIa 1PCI to improve survival is reasonable as an alternative to CABG in selected stable patients with significant (≥50% diameter stenosis) unprotected left main CAD with: 1) anatomic conditions associated with a low risk of PCI procedural complications and a high likelihood of good long-term outcome (e.g., a low SYNTAX score [≤22], ostial or trunk left main CAD); and 2) clinical characteristics that predict a significantly increased risk of adverse surgical outcomes (e.g., STS-predicted risk of operative mortality ≥5%) (13,17,19,23,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48). (Level of Evidence: B) 2PCI to improve survival is reasonable in patients with UA/NSTEMI when an unprotected left main coronary artery is the culprit lesion and the patient is not a candidate for CABG (13,36,37,38,39,45,47,48,,). (Level of Evidence: B) 3PCI to improve survival is reasonable in patients with acute STEMI when an unprotected left main coronary artery is the culprit lesion, distal coronary flow is less than TIMI (Thrombolysis In Myocardial Infarction) grade 3, and PCI can be performed more rapidly and safely than CABG (33,50,51). (Level of Evidence: C) CLASS IIb 1PCI to improve survival may be reasonable as an alternative to CABG in selected stable patients with significant (≥50% diameter stenosis) unprotected left main CAD with: 1) anatomic conditions associated with a low to intermediate risk of PCI procedural complications and an intermediate to high likelihood of good long-term outcome (e.g., low-intermediate SYNTAX score of <33, bifurcation left main CAD); and 2) clinical characteristics that predict an increased risk of adverse surgical outcomes (e.g., moderate-severe chronic obstructive pulmonary disease, disability from previous stroke, or previous cardiac surgery; STS-predicted risk of operative mortality >2%) (13,17,19,23,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,). (Level of Evidence: B) CLASS III: HARM 1PCI to improve survival should not be performed in stable patients with significant (≥50% diameter stenosis) unprotected left main CAD who have unfavorable anatomy for PCI and who are good candidates for CABG (13,17,19,24,25,26,27,28,29,30,31,32). (Level of Evidence: B)

Advantages of Single Arm Studies Allow device iteration Allow label expansion Allow more predictable timelines Reduce clinical trial barriers (randomization) Allow timely evaluation of new therapy Detect adverse effects earlier

Mitigating Risks Consider whether there is adequate control for change in concomitant medical practice Ensure uniform data collection, adjudication Patient level adjustment (propensity score) may be more desirable than fixed OPC to minimize impact of known risk factors that may vary between trials Consider likelihood of unanticipated risks of new therapy How stents might differ from heart valves

Single Arm Studies for DES Device iteration for improvement is desirable The field is mature Rich, contemporary, global data available >140,000 patient observations from US FDA approved stents in ~100 prospective trials Agreement is present on endpoint definitions, methods of adjudication Risk factors for major endpoints are well-understood