While an advisory committee will weigh design of the clinical program for an investigational aspirin substitute for heart bypass patients, a Food and Drug Administration official says a noninferiority trial may not be adequate.
The FDA’s Cardiovascular and Renal Drugs Advisory Committee will likely deliberate on the required size of a clinical study for Portola Pharmaceuticals’ drug PRT061103 when the panel reviews the product on Dec. 8.
Portola would like to use 64-slice computed tomography scans as a measure of "graft patency" – the degree to which the veins transplanted from a coronary artery bypass surgery patient’s arms or legs remain open following the operation, which in turn the company wishes to use as a surrogate end point for the efficacy of PRT061103, which is about to enter the clinic. The compound is meant to prevent cardiovascular problems in bypass patients who cannot take aspirin due to severe adverse reactions in their gastrointestinal lining.
But there are two major problems with this proposed study design, FDA Division of Cardiovascular and Renal Products Director Norman Stockbridge wrote in a briefing document for the upcoming committee meeting.
The company itself admits that the CT scans have lower sensitivity and specificity than invasive coronary angiography, which, however, carries risks of infrequent but major complications including stroke or death.
"As long as what is contemplated is a difference-finding study, I would have no issue with the loss of discriminatory power; it simply means that the trial needs to be a little larger to make up for missed or misclassified events," Dr. Stockbridge wrote. "How to compensate for this in a noninferiority trial is more complicated, as these features of CT make the two groups tend to look more similar."
Portola declined to comment on whether it is planning a noninferiority study of PRT061103 versus aspirin, citing the imminence of the advisory committee meeting.
CT Sensitivity Also Is a Worry
An even bigger problem with the company’s plans than the CT sensitivity issue is the usefulness of saphenous vein graft patency as a surrogate end point. The "FDA has questioned the adequacy of SVG patency as a surrogate (how likely it is to predict CV events)," Dr. Stockbridge wrote.
That’s because of a confounding effect in the supporting data Portola cites in its background package. The company uses data from the Coronary Artery Surgery Study Registry, a database of 24,959 patients from 1974-1979 at 15 centers across North America, to show that they had a better chance of survival if they had all three vessels bypassed.
"However, this is, of course, not a randomized comparison," Dr. Stockbridge said. "There is a reason relating to the patient’s underlying disease why all three vessels were not amenable to treatment, and these factors may well be responsible for poor outcome." The same applies to Portola’s attempt to show the same thing regarding reduction in the risk bypass recipients ran of contracting angina, the FDA reviewer added.
So while bypass surgery is itself an undoubted good, and the degree to which the grafts remain open may have something to do with the risks that patients will later have a heart attack or angina – which may seem intuitively obvious – "the strength of that relationship is not very strong," Dr. Stockbridge said.
Beyond PRT061103
The advisory committee’s recommendations may have implications for future product sponsors as well, since the stated purpose of the first part of the advisory panel’s deliberations is a general discussion of how to study thromboxane receptor antagonists such as PRT061103 for prevention of cardiovascular adverse events in CABG patients. The afternoon session will focus more specifically on Portola’s planned trial and will be closed to the public.
PRT061103 has completed preclinical studies, and Portola expects to start the phase I trial very soon. The firm also has more advanced anti-thrombotic candidate drugs in its pipeline – elinogrel and betrixaban, both of which have completed phase II studies.
Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.