It hasn’t acquired numerous media consideration however on Tuesday the FDA approved an expansion of the canagliflozin (Invokana, Janssen) label to incorporate a discount within the danger of coronary heart assault, stroke, or CV dying in adults with sort 2 diabetes and established CV illness.
Canagliflozin, an oral SGLT2 inhibitor, thus turns into the third diabetes drug accepted for CV danger discount on this inhabitants. One other SGLT2 inhibitor, empagliflozin (Jardiance, Lilly and Boehringer Ingelhiem) is accepted for CV dying discount whereas liraglutide (Victoza, Novo Nordisk), an injectable GLP-1 RA, is accepted for the discount of main hostile cardiovascular occasions.
I’m not now commonly updating CardioBrief (I could resume subsequent yr) however I acquired an nameless message elevating questions concerning the approval that prompted me to ask Sanjay Kaul (Cedars Sinai) for extra perspective. I assumed my readers can be curious about these messages.
Right here is the unique message I acquired:
“Off the report: Canagliflozin will get FDA approval to assert MACE danger discount in response to firm press launch. The premise for approval was a meta-analysis of two detrimental trials that differed considerably in design, one in every of which (CANVAS) was unblinded. Interim outcomes for this trial had been introduced to the general public within the 2012 FDA Endocrinologic and Metabolic Medication Advisory Committee. Is that this a brand new bar for substantial proof for a CV danger discount declare at FDA? How was bias excluded for something aside from mortality? Is that this the primary time FDA grants a CV danger discount declare based mostly on a meta-analysis?”
Right here is Sanjay Kaul’s response:
Lengthy story!
Due to the potential hostile influence of public disclosure of the interim evaluation outcomes of CANVAS Cohort A research in the course of the AdCom panel in January 2013, FDA thought-about two choices, both reject the CANVAS Cohort-A outcomes and ask the sponsor to conduct a brand new massive and adequately powered trial to deal with CV security (rule out 1.3 danger margin) or to borrow ‘legitimate’ unbiased information from CANVAS Cohort-A and mix with a medium-sized CANVAS Cohort A-like new CVOT. The pooling was to be completed in a blinded style and all trial conduct points had been to be ensured to be prime quality and standardized. Thus, due to the extenuating circumstances associated to the general public launch of outcomes from interim evaluation of CANVAS Cohort-A, the FDA accepted an built-in evaluation plan whereby information from prolonged follow-up of CANVAS Cohort-A post-Nov 20, 2012 (date of final public disclosure to EMA) can be mixed with new information from the CANVAS-R trial (initially designed to guage therapy influence on albuminuria) to deal with CV security as assessed by exclusion of post-marketing HR of 1.30. One of many important necessities for information integration was that the two trials be very comparable in design and conduct; have comparable main and secondary endpoints and occasion adjudication (each trials had been to be adjudicated by a typical CEC). This was completed to attenuate bias and maximize statistical energy to permit dependable estimation of CV, kidney and security outcomes. The prespecified statistical hierarchical testing technique, collectively agreed by the FDA and the investigators, included a stepwise analysis of the endpoints. Of notice, superiority for MACE was not prespecified within the testing sequence, although the investigators said within the Statistical Evaluation Plan (SAP) that if the null speculation was rejected and the higher certain of the HR is
Personally, I can argue in opposition to approval for CV efficacy indication, as a result of superiority for MACE was not prespecified within the hierarchical testing plan; impact measurement was not c/w substantial effectiveness criterion; and in sensitivity analyses, 4 out of 6 analyses did not be vital. I’m typically supportive of FDA selections, however there are legit causes for my disagreement on this case! Whatever the FDA-approved indication, I’d argue that the amputation hazard renders the benefit-risk stability undesirable relative to empagliflozin. I don’t see the expanded label having a cloth influence on the downward trajectory on canagliflozin gross sales.
Hope this helps!
