FDA/PhRMA Task Force To Assess QT Risk By Preclinical Markers

FDA and the Pharmaceutical Research & Manufacturers of America are forming a joint task force to define a preclinical threshold to serve as a predictor for the risk of drug-associated QT prolongation.

"A joint FDA/PhRMA task force is forming to review all available data," FDA Associate Director for Medical Policy Robert Temple, MD, told an Oct. 21 meeting of the Anti-Infective Drugs Advisory Committee. The group is hoping to agree on "what an appropriate preclinical/clinical work-up would be" for assessing QT-related risks.

Temple is part of the group, joined by representatives from the agency's Division of Cardio-Renal Drugs and industry members. The group, which is still forming, has begun discussions via conference calls.

The advisory committee where Temple discussed the task force was convened to review Bayer's fluoroquinolone antibiotic Avelox (moxifloxacin).

FDA asked the committee specifically to consider the therapeutic risks associated with a mean 6 msec QT prolongation observed in the clinical trials of the antibiotic. The majority of the committee determined the QT prolongation was not of clinical concern (¹ (Also see "Bayer Avelox Cardiac Safety Studies Recommended By FDA Committee" - Pink Sheet, 25 Oct, 1999.)).

However, FDA's regulatory decision may be complicated by Glaxo Wellcome's decision to withdraw another quinolone antibiotic Raxar (grepafloxacin). The company made the decision to remove the product in the U.S. and EU markets less than a week after the Avelox meeting.

Raxar, which carried a label warning for QT prolongation, was implicated in seven cardiac-event related deaths and three cases of torsade de pointes observed from 2.7 mil. prescriptions, Glaxo said (² (Also see "Glaxo Withdraws Raxar Following Seven Fatal Cardiovascular AEs" - Pink Sheet, 1 Nov, 1999.)).

Prolonged QT has been seen with other quinolone antibiotics and has been linked to clinical adverse events. At the Avelox meeting, FDA Division of Drug Risk Evaluation I medical officer Allen Brinker, MD, estimated from post-marketing surveillance that Rhone-Poulenc Rorer's Zagam (sparfloxacin) may produce 145 cardiac events per 10 mil. prescriptions.

Seven other quinolones have also been implicated in cardiac events, in the range of 3-30 per 10 mil. prescriptions, Brinker said (³ see chart: QT-Related Cardiac Event Reports For Antibiotics).

Raxar was not on Brinker's list, but 10 events that led to its withdrawal would indicate a cardiac-related event rate of 38 per 10 mil. prescriptions.

In light of the forming task force, FDA also asked the committee for input regarding recommendations which might aid FDA and drug companies in determining the risk of QT prolongation earlier in the development process.

"Preclinical data is critical," committee cardiology consultant Jeremy Ruskin, MD, Massachusetts General Hospital, offered. "Most of the studies would suggest that if you don't affect IKR [the fast potassium channel] you are probably pretty safe....The likelihood of having a significant clinical problem if you don't affect human IKR is pretty miniscule," he continued.

The fast potassium channel is one of three genetic loci which cause long QT syndrome if blocked. IKR appears to be the locus affected in most drug-induced long QT syndrome. Individuals with congenital long QT syndrome may have blockage of the slow potassium channel (IKS) or the calcium channel as well.

The task force hopes to gather more information about the significance of small changes in mean QT. Temple commented that it is very difficult to tell "where the problem gets very small or disappears...but we are thinking actively about this," he said. As of now, he observed, agency determinations regarding risk associated with a long QT are case-by-case.

Temple said that currently only broad guidelines make sense. "A 1 msec increase probably is not a problem. A 20 msec increase probably is a problem."

Temple pointed out there is some evidence that IKR inhibition correlates with drug concentration. If the task force could confirm that correlation and the relationship could be ascertained preclinically, "our dream, our hope, is that you find a cut-off point above which you are not worried, because the [drug] concentration needed is so large. There is at least some sense that it is breaking down that way," Temple said.

During the committee meeting, Bayer stressed that moxifloxacin is not metabolized by the cytochrome P450 enzyme, thus sidestepping potential trouble which could be caused by high concentrations of drug in the 7%-8% of the population that does not have the CYP 2D6 isozyme.

That issue led to the withdrawal of Hoechst Marion Roussel's Seldane (terfenadine), which caused clinically significant QT prolongation at concentrations above therapeutic levels. Seldane patients taking P450 inhibitor drugs or patients without a CYP 2D6 isozyme could build up cardiotoxic concentrations of the drug.

Bayer consultant Joel Morganroth, MD, University of Pennsylvania, cautioned FDA and industry against assuming that preclinical IKR data is simple to obtain or consistent. "It is concentration-dependent, model-dependent, and [dependent on] whose hands it is in."

Morganroth suggested that assessments of QT prolongation risk should be modeled on liver function testing which is done before commercializing a drug, and suggested that electrocardiographs should be a standard part of all clinical trials.

"If you screen for toxicity, and you don't think a drug affects the liver, how many of you would be comfortable going into a drug development program and not obtaining, in man, liver function tests?" he asked the committee.

"In the past, we have not done electrocardiograms on every single drug even taken into man in the non-cardiac field, because they don't affect the heart...they are non-cardiac. But we have now learned that so many drugs appear to affect the QT interval that were unexpected, that I simplistically would suggest that the EKG [be done] during, at least, acute dosing and... chronic exposure" clinical trials, Morganroth said.

FDA and industry also have a task force to assess drug-related liver injury in both preclinical and clinical trials.

A guidance for industry could result from the QT assessment task force, depending on how certain the task force is about the value of preclinical data, FDA indicated.

The EU's Committee for Proprietary Medicinal Products has published a "points for consideration" document outlining a standard for determining the implications associated with QT interval changes, Bayer's Morganroth told the advisory committee.

The CPMP advises that there is no need for concern if the QTc interval is less than 30 msec; a change between 31 msec and 60 msec suggests a possibility that the drug will cause clinical cardiac effects; and concern about cardiac events (arrhythmias) should be raised if the QTc interval is greater than 60 msec, Morganroth explained.

During the company presentation, Bayer noted that the QT interval associated with moxifloxacin would raise no concern based on the CPMP standards.

"The real issue is not that the numbers you are striving for tell you that is a danger level versus a safe level," Morganroth said. "It is really an outlier cut point that suggests the drug is causing that QT increase rather than spontaneous variability."

"When you make that judgment, 60 msec turns out to be very good at that," he continued.

Ruskin suggested that "the important issue is if you see a signal of an effect on a QT, go back and do an IKR screen and then look at single cells...so that you look at a number of different models over a very wide range of drug concentrations and heart rates, very careful to screen for metabolites and make sure that clinical data are collected in a very careful and rigorous way."

"What Bayer has done might serve as a model for working up a drug that affects the QT interval. This is really a lovely evaluation all the way from the preclinical through the clinical," he said. "I think this really is a package, and I would have to say that this is really the best of them that I've seen."