Replies to post #126189 on Biotech Values

[jq1234]

NEJM Aug 2011 editorial pointed out some of these issues:

http://www.nejm.org/doi/full/10.1056/NEJMe1107516

One interesting point is how the interpretation of ROCKET AF depends on the results from the three different protocol-specified analyses of the primary outcome of stroke or systemic embolism. The primary analysis included only patients who were treated according to protocol and were followed for outcome events only for the period during which they were actually receiving the assigned treatment (or within 2 days after the last dose). This analysis, designated the “per-protocol, as-treated” analysis, resulted in a conservative test for noninferiority5 and showed that rivaroxaban was significantly noninferior to warfarin. The authors also tested for superiority using an intention-to-treat analysis, which did not show superiority for rivaroxaban over warfarin.

Between these two analyses, the authors conducted another analysis in the “as-treated safety population.” Here, they included all patients who received at least one dose of a study drug and were followed for events while receiving the drug (or within 2 days after the last dose), regardless of adherence to protocol. It is not surprising that the annual event rates in the two study groups in this analysis were much closer to those of the per-protocol analysis than to those in the intention-to-treat analysis. As a consequence, in the safety analysis, the between-group P value was significant, even though the results do not show superiority for rivaroxaban over warfarin, since the intention-to-treat analysis was negative. Thus, the multiple analyses have muddied the waters regarding rivaroxaban's efficacy and effectiveness over warfarin.

Trials comparing new oral antithrombotic agents with warfarin are dependent on the quality of the management of the warfarin cohort. Overall compliance varies. Trials like ROCKET AF and RE-LY use algorithms for imputing the dummy INR of the warfarin placebo in patients who are not receiving warfarin in order to maintain blinding. They also use the concept of “time in therapeutic range” to assess the quality of warfarin management. Such trials typically use a method described by Rosendaal et al.,6 in which the measured INR values and the interval between INR tests are both taken into account. On the basis of this approach, INR values were within the therapeutic range a mean of 55% of the time in ROCKET AF and 64% in the RE-LY trial. So the interpretation of noninferiority in a given trial may also depend both on the homogeneity and treatment accuracy of the warfarin cohort and on the dummy INR algorithm that is used.

[bladerunner1717]

FDA drops a bomb on Bayer/JNJ


1. FDA review drops a bombshell on Bayer, J&J anti-clotting drug Xarelto

By John Carroll Comment | Forward | Twitter | Facebook | LinkedIn

The FDA dropped a bombshell on the anti-clotting drug Xarelto (rivaroxaban) this morning, noting in an agency review that Bayer ($BAYN) and Johnson & Johnson ($JNJ) had offered insufficient data on safety as well as efficacy for preventing strokes among atrial fibrillation patients, urging an advisory committee to send researchers back to the clinic for another study. In a review peppered with comments that sometimes verged on outright scorn, the FDA reviewer cited numerous reasons for a complete response letter. Just by itself, the potential for unnecessarily endangering patients offered a chilling conclusion for a drug which had been widely billed as a likely blockbuster.

In a matter of minutes shares of Bayer dropped 12%, an enormous bite for a big cap pharma company. One of the reasons for the sudden reversal is that analysts had given the drug good chances for a positive review at an upcoming advisory committee meeting. Reuters cited those feelings just days ago, noting that one of the biggest worries was whether the treatment would be relegated to a secondary position behind an anti-clotting drug from Bistol-Myers Squibb and Pfizer. But based on the review, the agency is unlikely to let Xarelto to get close to the multibillion-dollar market without a battery of additional supporting data.

"If rivaroxaban is approved," notes the review, "patients taking it might be at greater risk of harm from stroke and/or bleeding than if they were treated with warfarin (the standard drug) used skillfully. In the opinion of this reviewer, rivaroxaban should not be approved unless the sponsor submits convincing information that it is as safe and effective for its target indication as warfarin when it is used skillfully (e.g., in the subgroup of patients at centers where TTR = ~67%), or that it is as safe and effective as another approved agent, such as dabigatran."

At best, the review suggests, "it seems advisable to make rivaroxaban a third-line agent, behind both warfarin and dabigatran (Pradaxa, from Boehringer Ingelhem)."

Analysts are likely to start revising their figures on the prospects for the new drugs looking to replace warfarin, a longtime standard anti-clotting therapy that presents a number of worrying risks for doctors and patients. One likely beneficiary is Eliquis (or apixaban), a new drug being advanced by Pfizer and Bristol-Myers Squibb. Investigators released upbeat safety and efficacy data just days ago.

An advisory committee review of Xarelto is coming up on Thursday.


Bladerunner

[genisi]

(e.g., TTR >~68%, near the midpoint of center based TTR in the RE-LY study, and the US median TTR of 65% in ROCKET).

Made me check the data from the ARISTOTLE trial and it had a "median TTR of 65.7% (interquartile limits 58.0% and 72.2%). Across centres’ TTR quartiles there were consistently lower rates of stroke and systemic embolism and major bleeding with apixaban than warfarin. In the lowest and highest centres’ TTR quartiles, hazard ratios (HR) were respectively 0.77 (95%CI 0.56 – 1.06) and 0.81 (95%CI 0.52 - 1.26) for stroke or systemic embolism and 0.53 (95%CI 0.39 - 0.72) and 0.72 (95%CI 0.55 - 0.93) for major bleeding."

http://www.escardio.org/congresses/esc-2011/congress-reports/Pages/709-3-ARISTOTLE.aspx