June News and Events

Abstract

Articles for News and Events are selected each month by the editor, from the online Current News and Events, accessible from the CID home page ( http://www.journals.uchicago.edu/CID ). All articles are provided by ican prevent ( http://www.icanprevent.com ).

Task Force Studying Significance of Drug-Related QT Interval

Does the 6-ms increase in the QT interval associated with moxifloxacin (Avelox) or the 3-ms average increase associated with gatifloxacin (Tequin) predict torsades de pointes? The two newly approved fluoroquinolones are not recommended for patients with preexisting QT prolongation or those currently taking other agents that prolong the QT interval.

Torsades de pointes (literally “twists of points”) was first described in 1966 by Dessertenne in France and is a potentially fatal polymorphic ventricular tachycardia characterized by the finding of a long QT interval on an electrocardiogram.

The average increase in QT interval associated with either moxifloxacin or gatifloxacin is considered a small increase, according to Robert Temple, director of the office of medical policy in the Center for Drug Evaluation and Research at the US Food and Drug Administration (FDA). “Everybody knows that a substantial increase in QT intervals predicts a risk for torsades de pointes and is a very damaging finding for a drug—no debate. What we're trying to come to grips with and agonizing over is small increases,” explained Temple, who is heading a joint FDA-Pharmaceutical Research and Manufacturers of America task force on drug-associated QT prolongation. But, the FDA needs more data before it can issue a policy, said Temple.

Another fluoroquinolone, grepafloxacin (Razar), was withdrawn in November 1999 after Glaxo Wellcome received reports of 7 cardiac-related fatalities worldwide. A safety-related label change was added in October 1999 for a third fluoroquinolone, sparfloxacin (Zagam); this postmarketing change includes a contraindication for patients with preexisting QT prolongation.

The FDA had hoped that measuring the effect of a drug on the rapid potassium channel would be a good predictor of torsades de pointes and sudden death. “However, additional information has shown that this correlation is not as complete as we had thought,” Temple said. Both grepafloxacin and sparfloxacin had very little effect on the rapid potassium channel. According to Temple, one of the goals of the joint task force is to determine whether a constellation of animal and in vitro studies can predict QT prolongation in vivo.

Macrolide antibiotics, such as erythromycin and clarithromycin, prolong the QT interval. However, torsades de pointes is a rare event. “There is an intention to collect some data on previously approved drugs, such as erythromycin and clarithromycin, but, based upon their extensive marketing experience, the magnitude of danger does not appear to be very large,” said Mark Goldberger, MD, associate director for quality assurance at the FDA Center for Drug Evaluation and Research. “Ultimately, the goal is to get companies to run more tests and provide comparative data between these drugs and others to build a body of data,” Goldberger said.

Another goal of the task force is to identify people with preexisting sodium- and potassium-channel problems and determine whether they are at increased risk for torsades de pointes, said Temple.

According to the FDA, QT interval prolongation has been associated with the following types of drugs: antiarrhythmics, antibiotics, antimalarials, antifungals, antihistamines, and tricyclic antidepressants.

“For any drug the FDA thinks has an important QT effect, it will be extremely conspicuous in the labeling,” said Temple. He added that the drugs known to cause significant increases in the QT interval are being withdrawn from the market at a rapid rate. Goldberger concurred: “It also might be that a product may actually not be developed, if the drug prolongs the QT interval and has a predilection for drug interaction. As offending drugs are removed, QT prolongation may also become less of a problem.”

Recently Approved Antibacterial Agents Offer New Treatment Options

The inventory of tools for combating a variety of stubborn infections, including those caused by antibiotic resistant organisms, has expanded significantly in the past several months with the approval, by the US Food and Drug Administration (FDA), of 4 new antibacterial agents. Approval of anti-infective drugs by the FDA doubled in 1999, compared with the previous 2 years.

According to Janice Soreth, MD, medical team leader at the FDA's Center for Drug Evaluation and Research, Division of Anti-infective Drug Products, the makers of levofloxacin (Levaquin) set a precedent when they applied for a new indication: treatment of community-acquired pneumonia caused by penicillin-resistant Streptococcus pneumoniae . This application, approved in February 2000, was the first drug application to address specifically the treatment of resistant organisms.

Soreth said that pharmaceutical companies had been asking the FDA what number of successfully treated infections caused by a drug-resistant organism in clinical trials would be enough to garner FDA approval of a drug for that indication. According to Soreth, it wasn't a number that the FDA wanted but a body of evidence, which was provided with the levofloxacin new-indication submission in 1998.

Levofloxacin, a fluoroquinolone, was first approved by the FDA in 1997. Soreth said that evidence gathered across 8 clinical trials on community-acquired pneumonia included 15 patients with community-acquired pneumonia caused by penicillin-resistant S. pneumoniae who were treated with levofloxacin, of whom 6 had bacteremia and 5 had severe disease. All 15 recovered after treatment with levofloxacin. “This big picture provided strong and robust evidence for the approval of levofloxacin for the treatment of community-acquired pneumonia caused by penicillin-resistant S. pneumoniae ,” said Soreth.

Linezolid (Zyvox) joined the armamentarium to treat infections caused by antibiotic resistant organisms in April. The FDA approved linezolid for the treatment of adult patients with vancomycin-resistant Enterococcus faecium (VREF) infections, nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA), and complicated skin and skin-structure infections caused by MRSA.

Linezolid is the first oxazolidinone approved by the FDA for clinical use. The oxazolidones, first discovered in 1987, are synthetic antibiotics that inhibit bacterial protein synthesis at a very early stage.

Additional approved indications for linezolid include the treatment of nosocomial and community-acquired pneumonia caused by methicillin-susceptible S. aureus and penicillin-susceptible S. pneumoniae , and complicated and uncomplicated skin and skin-structure infections caused by methicillin-susceptible S. aureus and Streptococcus pyogenes . Linezolid is supplied for either intravenous or oral administration. No adjustment is necessary for oral dosing.

Last September, quinupristin/dalfopristin (Synercid) was approved for treating patients with life-threatening infections associated with VREF bacteremia, under the FDA's accelerated approval process. Quinupristin/dalfopristin also was approved for the treatment of complicated skin and skin-structure infections caused by S. aureus (methicillin-susceptible) or S. pyogenes; the drug is delivered intravenously.

Two new fluoroquinolones, gatifloxacin (Tequin) and moxifloxacin (Avelox), were approved in December 1999 for the treatment of community-acquired pneumonia, acute sinusitis, and acute bacterial exacerbation of chronic bronchitis caused by indicated susceptible organisms. Gatifloxacin was also approved for treating complicated and uncomplicated urinary tract infections, pyelonephritis, and uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae and acute, uncomplicated rectal infections in women that are due to N. gonorrhoeae .

SmithKline Beecham filed a new drug application on December 15, 1999, for another fluoroquinolone, gemifloxacin (Factive), for the treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute sinusitis, acute pyelonephritis, and uncomplicated urinary tract infections. The evaluation of gemifloxacin by the FDA's Anti-Infective Drugs Advisory Group is not expected until late this year or in 2001.

New drug-approval labels (listed alphabetically by proprietary name) are available at the FDA's Center for Drug Evaluation and Research Web site: http://www.fda.gov/cder/approval/index.htm .

Risks and Benefits of Direct-to-Consumer Advertising Evaluated by the Food and Drug Administration

Broadcast television advertising of prescription drugs typically includes a rundown of the featured drug's risks and adverse events by the voice-over narrator, often as a toll-free phone number or Web site address is rolling on the screen. The Food and Drug Administration (FDA) will evaluate whether this simultaneous broadcast of warnings and promotional information, in voice-over and visual format, interferes with consumers' absorption of the information about the risks associated with the advertised drug.

According to the FDA's Division of Drug Marketing, Advertising, and Communications (DDMAC), more than 50 consumer-directed prescription drug advertisements have reached television viewers or radio listeners in the United States. The FDA will issue final comments on the effects of direct-to-consumer (DTC) promotion on the public health by August 2001.

“The DTC advertisements let people know that there are treatments available for their health problems. The FDA is not convinced this is such a bad thing,” said Nancy Ostrove, PhD, a branch chief in the DDMAC at the FDA's Center for Drug Evaluation and Research (CDER).

In the FDA's August 1999 draft guidance for industry concerning consumer-directed (i.e., DTC) broadcast advertisements, the agency said that a balanced communication of the benefits and risks of advertised products outweighed the postulated but not demonstrated disadvantages.

“We have concerns about DTC advertising as it relates to certain types of products, antibiotics among them,” said Ostrove. The agency also has concerns about DTC ads for controlled substances and antipsychotic drugs, she said. In general, manufacturers have not chosen drugs with major side effects for DTC promotion.

The FDA also would like to know if DTC advertising leads to more inappropriate prescribing, but this information is tough to get, Ostrove said. The FDA has no special funding for the assessment of DTC advertising and, in its evaluation, is relying on publicly available data from consumer surveys (e.g., American Association of Retired Persons, Time Warner Inc., National Consumers League, Prevention magazine) and from published studies.

Violative advertisements are found through post hoc surveillance by the DDMAC. For example, the FDA has objected to the risk disclosure being presented too rapidly in broadcast television ads, said Ostrove. “Television ads submitted under the required process [for post hoc surveillance] are reviewed by DDMAC in 1 to 2 days,” said Ostrove. Often advertisers will seek out voluntary comment and review before releasing their advertisement for broadcast. The FDA responds to these presubmitted television ads within 20 days. “To pull the ad because it's violative is an expensive proposition for pharmaceutical companies, and it doesn't look good,” she said. Most complaints about advertisements come from consumers, health care providers, and competitors of prescription drug companies. “The FDA watches television, too,” she added.

Some DTC ad campaigns never mention the proprietary name of a drug or product. For example, SmithKline Beecham is currently running what Advertising Age magazine calls an “unbranded” campaign for the Lyme disease vaccine. “I never thought I was a target for Lyme disease, until I found out you can get it in your local park, in your own backyard, or even mowing the lawn,” says the voice-over in one of the campaign ads. Such unbranded ads are not required to carry warnings. The advertisements fall outside the FDA's jurisdiction, provided the drug involved is not identifiable.

Ostrove said that the FDA calls these “help-seeking” ads and that they have appeared for 2 decades in the prescription drug advertising area. “There is a public benefit. We have always encouraged those types of ads if they are done correctly,” she said. However, if it is clearly a disguised drug ad, then the FDA would consider it violative, she added.

Help-seeking DTC campaigns also have been used in the past to promote vaccines: influenza and chickenpox vaccine manufacturers have used this form of promotion, according to Bill Purvis, chief of the Advertising and Promotional Labeling (APL) branch at the FDA's Center for Biologics Research and Evaluation (CBER). CBER's APL reviews all DTC biologics advertising and selectively reviews traditional biologics advertising to health care professionals. “All help-seeking ads are reviewed to ensure the sponsors do not cross the line and provide so much information about their specific product that they unintentionally create a regulated product advertisement,” he said.

The manufacturer will not be violating any FDA advertising and marketing rules in the Lyme disease vaccine campaign if both prevention and treatment are included in the discussion, Ostrove said.

Internet-based product promotion is also subject to post hoc surveillance by the FDA. According to FDA spokesperson Crystal Wyand, all Web site advertisements for prescription drugs and biologics also need to be submitted to the FDA, under the postmarketing requirements. Most recently, a notice of violation letter regarding misleading information on the promotional Web site for gatifloxacin (Tequin; www.Tequin.com ) was sent to Bristol-Myers Squibb Company. This was discovered through routine surveillance by the DDMAC, Wyand said.