Medical Device Daily 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.”

Medical Device Daily asked Grant about combination products that involve a non-antiarrhythmic drug.

The Office of Combination Products will send an application involving a drug/device combination to CDER if the primary mechanism of action is pharmacological, so any such product would obviously be subject to the kind of scrutiny described above.

Conversely, a combo product relying mainly on mechanical action would go to the Center for Devices and Radiological Health, but CDER reviewers would still examine the drug portion of any such application. The question posed was whether this kind of scrutiny would hold for products that rely principally on a mechanical action rather than on a pharmacological action.

“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.

However, the QT/IRT team would closely examine a combo product that relies primarily on mechanical function – but which includes a drug that is new or not well characterized – because “you would be concerned about the drug portion,” Grant said.

Personal care rule changes proposed by CMS

A proposed rule that would allow more Medicaid beneficiaries to be in charge of their own personal assistance services, including personal care services, instead of having those services delivered by an agency, has been issued by the Centers for Medicare & Medicaid Services.

Published in the Federal Register, CMS is requesting public comment on how states could allow Medicaid beneficiaries who need help with the activities of daily living to hire, direct, train or fire their own personal care workers rather than working with personnel employed by an agency. Beneficiaries could even hire qualified family members who may already be familiar with the individual’s needs to perform personal assistance (not medical) services.

“This proposal would give Medicaid beneficiaries significant new freedom to determine how their personal assistance services are delivered and by whom,” said Kerry Weems, CMS acting administrator. “As healthcare is not simply an economic transaction, this proposal represents a fundamental shift that restores a person’s ability to improve their overall health by taking greater control of his or her own decisions.”

If a state adopts a self-directed personal assistance services state plan option, beneficiaries could receive a cash allowance to hire their own workers to help with such activities as bathing, preparing meals, household chores and other related services that help a person to live independently. Allotments could also be used to purchase items that help foster independence such as a wheelchair ramp or microwave oven.

The proposal would put into place a provision of the Deficit Reduction Act of 2005 that allows states to elect a state plan option to provide care in ways that previously required “waivers” of previous Medicaid laws. Such waivers are subject to certain budgetary requirements and are temporary in nature.

Before a state could request this change to its state plan, the state must have an existing personal care services benefit, or be operating a home or community-based services waiver program.

Enrollment in this state plan option is voluntary, and the state must also provide traditional agency-delivered services if the beneficiary wishes to discontinue self-directed care.

States choosing this option must have necessary quality assurances and other safeguards in place to assure the health and welfare of participants. States must also train potential participants in ways to manage their budgets and assess their personal care needs.

Comments on the proposal are due Feb. 19, 2008.