CardioExchange Archive

FDA reviewers presented two dramatically different views of The Medicines Company’s investigational new drug cangrelor. One reviewer says the drug should not be approved without a new trial and even states that the CHAMPION trials “were conducted unethically” and provide sufficient reason to “refuse approval…on that fact alone.”  But two other reviewers recommend approval.

On Wednesday the FDA’s Cardiovascular and Renal Drugs Advisory Committee will meet to discuss two proposed indications for cangrelor. The first is for the reduction of thrombotic cardiovascular events including stent thrombosis in patients undergoing PCI. The second is for the maintenance of antiplatelet therapy in patients with acute coronary syndromes or patients with stents who have discontinued antiplatelet therapy because they are awaiting surgery and are at high risk for thrombotic events.

The negative perspective comes from the often outspoken and controversial FDA reviewer Tom Marciniak. (He has been a leading critic of rosiglitazone and rivaroxaban and has not hesitated in the past to disagree with fellow FDA staff members.)  Marciniak maintains that the CHAMPION trials did not demonstrate that cangrelor was either superior or noninferior to clopidogrel in the CHAMPION trials. Some of his chief points are:

• Clopidogrel was not administered optimally (too late and with an inadequate loading dose) in the control arm.
• Much higher rates of bleeding in cangrelor patients.
• Cangrelor was better only in the subgroup of patients with stable angina.
• No comparison with the newer antiplatelet agents prasugrel or ticagrelor.

But two other FDA clinical reviewers deliver a more generous recommendation, though it may not inspire much confidence among the panel members. The reviewers note that the primary efficacy endpoint was “carefully crafted following post-hoc analyses” of two previous failed trials. Their recommendation appears based more on technical points than a view of the results as robust. For instance, they agree with Marciniak that fewer control patients received the higher 600 mg dose of clopidogrel, but don’t believe the results should be discounted because the higher dose is still not mandated by labeling or guidelines.

The negative viewpoint was also shared by the FDA statistical reviewer, who noted that after adjusting for the imbalance in the loading dose the primary endpoint would no longer be significant in favor of cangrelor.

Marciniak did not review the second bridging indication. The two other reviewers recommended a complete response letter due to the absence of clinical data supporting the indication.

In a second report, Marciniak argues that cangrelor should not be approved for ethical reasons because the clinical trials were imbalanced because clopidogrel was not used optimally. CHAMPION PHOENIX, he writes:

was unethical because it delayed use of clopidogrel until after coronary angiography or later and because it prohibited routine use of prasugrel, ticagrelor, and glycoprotein IIb/IIIa inhibitors (GPIs). The PHOENIX informed consent documents (ICDs) failed to inform patients regarding the advantages of earlier use of clopidogrel and the use of prasugrel, ticagrelor, and GPIs. The patients in PHOENIX were not informed about ‘appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject’…”