Diagnostics & Imaging Week Washington Editor

ALEXANDRIA, Virginia – The first day of the second annual Cardiac Safety Assessment Summit, sponsored by the Center for Business Intelligence (Woburn, Massachusetts), included a session on assessing the safety of non-antiarrhythmic drugs that might affect ventricular function despite the fact that they are usually administered to treat atrial fibrillation.

FDA has adopted an international standard for making such determinations, but an FDA staffer at the meeting said that these standards might apply to any combination devices that deploy drugs with similar properties, especially when the drug in question is not well characterized.

Philip Sager, MD, the director of cardiovascular research at AstraZeneca (London), emcee for the afternoon session, said that an international standard developed for this consideration “has had a significant impact on drug development,” but “a few key issues” remain.

Among these issues is the question of which design elements FDA sees as key to a study of how such a drug affects the ability of the ventricles to recharge for another contraction. Other issues include determination of sampling size and the sensitivity of the assay employed to pick up serum drug concentrations.

Stephen Grant, MD, a reviewer at the division of cardiovascular and renal products at FDA’s Center for Drug Evaluation and Review (CDER), gave attendees an update on study design for non-antiarrhythmic drugs that may affect the heart’s QT interval, the time period during which the ventricles repolarize to execute the next beat.

FDA uses an interdisciplinary review team (IRT) to evaluate drugs that may have some effect on this function of the heart. Grant said that when CDER assembled the QT interdisciplinary review team (QT-IRT) in June of 2006, “the hope was to provide reliable and consistent advice” to advance studies of QT. This office also looks at alternate ways to assess QT effect of pharmaceuticals.”

Grant said that there were “some non-arrhythmic drug withdrawals in the 1990s due to TdP” — TdP being the acronym for a condition described as torsade de pointes, a French term that translates as “twisting of the points,” and in reference to the distortion of the QT portion of an electrocardiograph.

These problems led to development of a joint paper published by FDA and Health Canada in 2002 and eventually to the E14 guidance on QT studies, published by the International Conference on Harmonization (ICH) in 2005 (ICH being an effort to align pharmaceutical development regulations across nations.

Grant said that ICH proposed in the E14 guidance that “any [non-antiarrhythmic] drugs not known to prolong the QT undergo thorough studies.” He said that sponsors would be well advised to conduct such studies only after gaining meaningful information on the pharmacokinetics of the drug.

“The goal is to characterize the QT effects at peak concentrations,” he said, adding that these parameters are usually obtained by electrocardiography (ECG) and plasma sampling. The ICH E14 recommends double blinding and the use of identical procedures in both arms of the study, Grant said, and that the control arm should receive a placebo.

Grant noted that moxifloxacin should be used as a positive control for most such studies, which would make them three-arm studies. Moxifloxacin, a fluoroquinolone antibiotic that sells by the name Avelox, lengthens the QT interval, a feature common to a number of drugs in this class. Among these is grepafloxacin (Raxar), which Glaxo Wellcome (Middlesex, UK) pulled from the U.S. market in October 1999 because of QT interval distortion, but moxifloxacin is available in the U.S.

Studies “can be crossover or parallel, depending on the pharmacokinetics,” Grant said, such as accumulation of the drug substance, or patient tolerance for the drug. He recommended that sponsors use healthy subjects for such studies unless the positive control drug’s side effects are serious.

Grant said some of the review teams are handy with the functions of the personal computer, as demonstrated by the replication of the language employed by the QT-IRT office.

“A few divisions [at FDA] appear to be very good at the cut-and-paste function,” Grant quipped, but some FDA divisions modify the recommendations of the QT-IRT office substantially.

Some QT studies proposed by sponsors, Grant said, were fairly thorough but nonetheless fell short for any one of several reasons, the most common being that “assay sensitivity hasn’t been established.”

“We’ve seen several in which the dose was too low,” and ‘we’ve also seen several that lacked pharmacokinetic data,” he said.

As for assay sensitivity, Grant said, “what E14 states is that the positive control should have an effect on the mean QT interval of about five milliseconds.”

Diagnostics & Imaging Week asked Grant about combination products that involve a non-antiarrhythmic drug.

“When you’re worried about safety, if it has both a drug and device and the drug has a potential” to create problems, CDER reviewers would look at such a product closely, Grant said.

On the other hand, he noted that when he has seen such applications in the past, “the serum drug concentrations are usually so vanishingly small” that any impact on repolarization would be of no clinical significance.