Can a Safety Study Support a Superiority Claim? Barely, FDA Advisors Say Sue Sutter [email protected]
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Pharma intelligence Pinkwww.ThePinkSheet.com SheetVol. 78 / No. 27 July 4, 2016 informa Can A Safety Study Support A Superiority Claim? Barely, FDA Advisors Say SUE SUTTER [email protected] sing a clinical trial originally designed in the design of studies with for safety to support an efficacy supe- the primary goal of estab- Uriority claim poses unique challenges lishing safety to something that can make reliance upon a single study that is looking at superior- yodiyim/shutterstock.com credit: Photo for regulatory purposes potentially risky. ity,” committee Chairman That was one take-home message from Robert Smith, an endocri- There are complexities in trying the FDA Endocrinologic and Metabolic Drugs nologist at Brown Universi- Advisory Committee’s June 28 review of the ty, said. “We’ve encountered to move from a trial intended to EMPA-REG OUTCOME trial’s results to support some of those difficulties.” establish safety “to something a cardiovascular mortality benefit claim for By a one-vote margin, Boehringer Ingelheim GMBH and Eli Lilly & the committee said EMPA- that is looking at superiority,” Co.’s diabetes drug Jardiance (empagliflozin). REG provided substantial EMPA-REG started out as a 4,000-patient evidence to establish that committee chairman Smith said. study aimed at excluding an excess risk pre- empagliflozin, an SGLT2 in- approval under FDA’s December 2008 guid- hibitor, reduced CV mortality in the high-risk agonist reduced the risks of MACE and CV ance on CV safety assessments for diabetes population studied in the trial (see box, p. 4). death by 13% and 22%, respectively (“Novo drugs. However, it evolved into a 7,000-patient Given the close vote and the fact that Jard- Will Go After MACE Indication For Victoza study powered to demonstrate non-inferior iance and Synjardy (empagliflozin/metfor- Based On LEADER” — “The Pink Sheet” DAILY, safety and superiority post-approval, all the min) would be the first type 2 diabetes drugs June 14, 2016). while undergoing numerous changes in de- labeled for a CV benefit, it’s still very much an Notably, LEADER was initiated after liraglu- sign, protocol and statistical analyses plans. open question how FDA will act on the sN- tide’s January 2010 approval and, therefore, This evolution raised questions for FDA re- DAs by their early September user fee date. may not face the same design change con- viewers and advisory committee members as cerns raised in the EMPA-REG review. to whether the study’s primary endpoint result LOOKING AHEAD TO LEADER If FDA takes the LEADER data to its ad- – a statistically significant benefit on the com- The committee may have an opportunity to visory committee, which seems likely, the posite endpoint of major adverse cardiovascu- revisit study design issues for diabetes drug panel also would have another chance to lar events (MACE) – was sufficiently robust to CV outcomes trials in the next year. opine on the appropriate CV endpoints “open the door” to consideration of a 38% re- Novo Nordisk AS plans to seek a broad for such trials (see related story, “Diabetes CV duced risk of CV death, a component of MACE. CV risk reduction claim for Victoza (liraglu- Endpoints Suffer Renewed Criticism At Empa- “There are complexities in trying to move tide) based on results from the LEADER gliflozin Meeting,” p. 6). from a guidance that was generated to help trial. In the 9,340-patient study, the GLP-1 CONTINUED ON PAGE 4 REGULATORY PUBLISHER’S SPOTLIGHT R&D Brexit Talks Must Prioritize Editor’s Note: Expanded Content Bristol’s Oncology Strategy: Patient Access, Avoid Regulatory Coming Soon, p. 11 Cover All The Bases To Keep Divergence – EFPIA, p. 9 The Lead, p. 12 Standard of Care Optimize clinical trial design with Trialtrove’s new Standard of Care service Minimize Risk: • Quickly access Standard of Care disease treatments by patient segment and country. • View Standards of Care by treatment regimen or individual drug views. Data is sourced directly from Datamonitor Healthcare’s expert and robust primary resource analyses. 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ERS Genomics, Juniper AdvisORY COMMITTEES @thepinksheet1 6 Diabetes CV Endpoints Suffer Renewed Criticism At Empagliflozin Meeting thepinksheet.com July 4, 2016 | Pink Sheet | 3 ADVISORY COMMITTEES CONTINUED FROM COVER AS STUDY FOCUS EVOLVED, SO In its advisory committee briefing document, DID PROTOCOL FDA contrasted EMPA-REG with some other diabetes For Jardiance and Synjardy, Boehringer seeks a new labeling claim for reduced incidence of drug CV outcomes trials in that it “was not CV death in patients with type 2 diabetes and established CV disease. The claim is narrower prospectively designed (i.e., sized) with the expressed than originally requested, with Boehringer deciding during the course of the review to intent of demonstrating a cardiovascular benefit of abandon its quest for all-cause mortality and the new antidiabetic therapy.” heart failure claims (“Jardiance Mortality Claim Narrowly Endorsed By FDA Advisory Committee” — “The Pink Sheet” DAILY, June 28, 2016). post-approval. Approximately 230 individuals In its advisory committee briefing docu- In EMPA-REG, patients at high CV risk were – mostly Boehringer personnel but also some ment, FDA contrasted EMPA-REG with some randomized to one of two empagliflozin dos- from outside the company – were unblinded other diabetes drug CV outcomes trials – es or placebo. The trial was originally planned to the interim analysis. specifically, Merck & Co. Inc.’s TECOS trial of as a 4,000-patient study intended to exclude Boehringer said access to unblinded data Januvia (sitagliptin) and the SAVOR trial of As- an 80% or greater increased CV risk pre-ap- was controlled by confidentiality agreements traZeneca PLC’s Onglyza (saxagliptin) – in that proval under the 2008 guidance. and only provided to the independent team it “was not prospectively designed (i.e., sized) FDA Division of Metabolism and Endocri- responsible for the interim database lock, statis- with the expressed intent of demonstrating a nology Products clinical reviewer Andreea tical analyses and reporting of the interim data. cardiovascular benefit of the new antidiabetic Lungu said the sponsor originally proposed therapy.” Both TECOS and SAVOR showed neu- to conduct a second CV outcomes trial, the ADEQUACY OF SINGLE STUDY tral CV effects with the DPP-4 inhibitors. results of which would be combined with QUESTIONED “There is no precedent on using these types EMPA-REG to exclude an excess CV risk of 30% When the final study results were published in of safety trials for efficacy since this is the first or greater post-approval pursuant to the guid- September 2015, it marked the first time a CV of the diabetes safety trials to be considered ance. However, FDA took the position that in- outcomes trial of a diabetes drug had demon- for an efficacy claim,” the briefing document’s creasing the enrollment of EMPA-REG would strated a benefit (“Empagliflozin’s CV Benefit Im- statistical review states. “It does remain an is- be more efficient. presses At EASD, But What Will FDA Say?” — “The sue on whether the results from a single study Under an amended study plan submit- Pink Sheet” DAILY, Sep. 17, 2015). initially designed for safety will be sufficient to ted to FDA in January 2012, the trial’s sample Empagliflozin demonstrated a 14% re- obtain efficacy claims.” size was increased by 3,000 patients. Protocol duced risk of MACE, a composite consisting FDA noted that as the study evolved, the changes to address this plan resulted in ad- of CV death, nonfatal myocardial infarction protocol, statistical analysis plan, Clinical equate power to independently exclude the and nonfatal stroke. The results, which nar- Endpoint Committee charter and endpoint 1.3 risk margin for MACE. Superiority testing rowly met the statistical criteria for superiority, definitions went through multiple changes, was to be conducted only after excluding this were driven entirely by the CV death compo- including specific exclusion of “silent” MIs from risk margin for MACE and a four-point MACE nent, with no benefit on nonfatal MI and an the primary endpoint. In addition, there were endpoint that also included unstable angina. unfavorable imbalance in nonfatal stroke that a large number of deaths considered to be An interim analysis was used to support the did not reach statistical significance.