Medical Device Daily Washington Editor

ALEXANDRIA, Virginia – The topic of one of the morning sessions on the second day of this week’s Cardiac Safety Assessment Summit was strategic planning for cardiac safety testing and if the presenter has his facts right, companies can comply with modern regulatory requirements and still get new drug or drug/device combination from point A to point B without breaking the bank or taking an eternity to make the trip.

Daniel Goodman, MD, a senior scientific consultant for Cardiocore (Bethesda, Maryland), a clinical trial consultancy, said that the E14 guidance on QT-interval assessment for non-antiarrhythmic drugs, promulgated by the International Conference on Harmonization (ICH) is in use at FDA, and he urged attendees to “think of E14 as the government’s transportation strategy for the U.S.”

The irony of the metaphor was not lost on attendees, who braved some of the nation’s worst traffic to attend the session.

“Our cars have really become very safe, and fuel efficiency is dramatically better,” Goodman said. “The only trouble is you get on the highway and you’re driving one mile-per-hour.”

Goodman said that “few organizations have established an overall strategic plan” to test a product for its impact on the QT interval – the period when the ventricles recharge in preparation for the next contraction – but “there are ways to plan for cardiac safety so that you can do it efficiently and cost effectively.” However, he warned that it’s not necessarily a linear approach.

Goodman said that for preclinical and early clinical studies, sponsors should always conduct analyses of risks and potential gains and explore flexible approaches to data acquisition, especially in terms of timing. He said that firms should not forget to identify any other risks to cardiac health.

“Cardiac safety is not just QT,” Goodman said, noting that “ischemia risk and unanticipated myopathy risk” are critical issues.

“Do your thorough QT study early, but not too early,” he said, adding that it is difficult “to tailor a [QT study] recipe to all compounds.” And sponsors should employ “a flexible approach at all times” and “anticipate the answer of your QT studies before you do it.”

Smart planning for the collection of data in QT studies maximizes both the amount of data collected as well as the utility of that data, and it also can reduce the number of tests that are not pertinent to the eventual use of the drug. This, Goodman said, allows companies to reduce the likelihood that labeling will affect a drug’s market potential.

Goodman said a number of firms have internal QT resource teams, and that FDA also has stockpiled a considerable amount of expertise. “You don’t want to go from challenge to challenge without a plan,” he said, implicitly suggesting that a company contact FDA with open questions.

“You need to start to think right away where cardiac safety will place the compound” in the market, Goodman said. He said that Phase I studies allow patient exposure to doses “you will never give again ... for timeframes you will never have again.” This allows a firm to pull in abundant pharmacokinetic data. Also during Phase I, a sponsor might screen for QT effects over extended periods. Such archives of data can support a drug’s applications and also be useful for examination of a different drug. A sponsor might also engage in additional ECG tracking for high-risk patients.

Efficacy, Goodman said, “is usually a determining factor in the safety liability you can tolerate,” adding that there is “competitive safety as well.”

“Your QT signal might not be great, but it might be better than the competition’s,” Goodman said, urging the audience to not dismiss a drug that shows some potential QT interference if the drug is an improvement over those currently available.

Lest sponsors become engulfed in concerns over potential interference in ventricular repolarization, Goodman noted other possible cardiac disorders.

“QT [pathology] is a terrible problem,” he said, “but in terms of sheer numbers of deaths, it is dwarfed by cardiac ischemic complications” and cardiac death.

“We all got shocked with the fenfluramine experience, then the COX-2 experience,” and the similar problems with the “glitazone” class of diabetes drugs, Goodman said, adding that this area needs much more development. However, he also reminded the audience that oncology compounds create additional issues in terms of the execution of a thorough QT study, among these that one will have to use patients rather than volunteers due to the severe effects of anticarcinogenics. Such studies will, of course, include no placebo arm. The toxicity of most cancer drugs also rules out the use of an arm of the study that would employ a dose higher than is thought to be therapeutic.

As was the case with the first day’s discussions, panelists admitted that biologics are less well understood in terms of their impact on cardiac health, but perhaps not so much for QT interval distortion.

“I think the biologics are the big question mark for other cardiac complications” but not so much for QT, Goodman said.

Study: Seniors could see health security decline

A new study by Marilyn Moon, VP and director of health programs at the American Institutes for Research (Washington) concluded that if policy changes aren’t made to strengthen Medicare and Social Security, millions of seniors will experience serious declines in their financial and health security. “Low-income seniors often don’t have access to private pension plans like 401Ks so they rely on Medicare and Social Security. Medicare and Social Security need to be strongly supported in order for our parents and grandparents to have financial stability. Even seniors who have access to retirement plans like 401Ks are at risk when the market changes suddenly — look at the recent housing credit problems.

Moon says that other experts agree that a health crisis can wipe out even relatively generous savings, and healthcare burdens are projected to command an ever larger share of the resources for the coming wave of retirees. “The need for these programs to bolster financial status and to protect against risk will only increase over time; these institutions are critical sources of financial stability,” said Moon.

Judith Stein, executive director of the Center for Medicare Advocacy, a leading national expert on Medicare, said, “Medicare eases financial and emotional stress on families and beneficiaries and makes a significant difference in people’s health and quality of life... . Having made healthcare available and accessible to older people and those with disabilities, Medicare provides a model for a national healthcare program.” Moon says that any proposed policy changes to Medicare and Social Security must take into account seniors of modest means. Rather than attempting to keep these programs strong by reducing benefits, or privatizing them, “The system needs to become more progressive over time, and it must remain public so that seniors do not have to choose between inadequate protection and a lesser quality of care.”