Fed drug plan comes down to solving the conundrum’

Can we promote new drugs yet limit their use?

Nothing less than the future efficacy of antibiotics in the United States may be at stake over the next few years as a task force of 10 federal agencies implements a sweeping plan to stave off a much-feared "post-antibiotic" era.
The ambitious, recently finalized plan attacks the problem of antibiotic resistance from virtually every angle and, as previously reported, places infection control among the top priorities. (See related story, p. 42.)

The plan is essentially a blueprint for future interaction by the Centers for Disease Control and Prevention, the Food and Drug Administra-tion (FDA), the National Institutes of Health, and seven other federal agencies. It calls for a national system for antibiotic resistance surveillance that would include drug susceptibility data and patterns of antimicrobial use. The plan calls for prevention and control of drug-resistant infections by promoting the prudent use of antimicrobial drugs, improving diagnostic testing, and increasing vaccine use.

But amid the broad strategies for action lies an essential paradox that must be solved to preserve effective antibiotics against ever-evolving bacteria. The recurrent problem, as described in the task force report, begins when a pharmaceutical company makes a major investment in developing a new drug, shepherding the product through pre-clinical studies and expensive clinical trials. When the approved drug is then marketed and used widely, allowing recovery of costs and profitability, resistance develops more rapidly and shortens the effective life of the drug.

Conversely, clinical policies limiting use of the antibiotic may limit sales and profits for the company. Thus, pharmaceutical companies may be reluctant to invest extensive resources in the development of antimicrobials targeted at resistant organisms, which are often given for short time periods to small numbers of patients.

"That’s the fundamental conundrum regarding new drug development," says David Bell, MD, co-chairman of the federal task force and assistant to the director at the CDC center for infectious diseases.

"In truth, we need both approaches: We need the pipeline of new drugs to be constantly flowing; we also need to take steps to extend the useful life of the drugs we already have. We need a balance," he adds. "Neither approach is going to be sufficient, and we also need, of course, other approaches such as vaccines, infection control strategies, and measures to prevent infection transmission in the first place."

The problem most recently came up with the development of linezolid (Zyvox by Pharmacia and Upjohn in Kalamazoo, MI), which is approved for treatment of nosocomial infections due to methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Rather than cry "pass the ammunition," infection control professionals immediately warned that the new drug could be of little avail if hospitals don’t tighten their grip on clinical formularies.

William Schaffner, MD, chairman of the department of preventive medicine at Vanderbilt Univer-sity Medical School in Nashville, TN, advises, "Hold this in reserve until we have to use it — until we are faced with vancomycin resistance."

On the other hand, Robert Moellering, MD, professor of medicine at Harvard Medical School in Cambridge, MA, who conducted laboratory trials with linezolid, notes this is always a conflict, but pharmaceutical companies "are not nonprofit organizations." (See Hospital Infection Control, May 2000, pp. 69-71, under archives at HIConline.com.)

Enter the federal task force again, acknowledging the problem, but not yet specifying in
its plan how it will try to solve it. However, it comes tantalizing close to suggesting something akin to the old agricultural approach of giving farmers incentives to plant some crops and not grow others.

The report calls for consideration of "financial and/or other incentives or investments to promote the development and/or appropriate use
of priority [antimicrobial] products . . . for which market incentives are inadequate."

From carrot to stick

While that appears to be the carrot, the stick may come in the form of some of the overtures about regulatory action in the plan, including possible labeling changes on important drugs. But federal regulatory agencies such as the FDA and the Environmental Protection Agency could not circumvent their normal process and simply mandate requirements, Bell explains.

"They’re in a bit of a difficult position in terms of committing to specific regulatory actions in a framework like this," he says.

"[The regulatory agencies] have legally mandated procedures for developing regulations that could not be circumvented through the task force. So their action items often used the verb explore’ because that is the only way they could phrase it. In other words, explore going in a certain direction rather than commit to a specific regulation that they really legally couldn’t do in a document like this. But their heart’s in the right place, there is no doubt about it. I think having them onboard and having their issues addressed is an important component of the plan."

For example, the task force calls for exploring ways to periodically review and update antimicrobial drug susceptibility information included on drug labeling. In addition to possible labeling changes, the plan calls for "education and behavioral interventions" that may ultimately extend to changes in medical licensing content.

Special panel to be informed

Another key aspect of the plan is that a new federal advisory committee — most likely linked to the CDC or FDA — will develop a list of drug-pathogen combinations (i.e., MRSA/vancomycin) and select important drugs to be "preferentially used for the treatment of . . . organisms that are resistant to other drugs."

The advisory panel also will monitor the use
of selected important drugs, with "consideration of changes in product labeling by FDA and in
recommendations for use if increased resistance
is detected." Essentially, the idea is to address "drugs of last resort for which available treatment options are very limited or nonexistent," Bell says. But the task force must consider two categories
of important drugs. On the one hand, there is the older but still important drug showing signs of fading efficacy (i.e., vancomycin) and on the other, a newly developed drug such as linezolid.

"It’s a different situation because in one of them, the drug has been out for many years and the drug company that produced it has presumably recouped its investment," Bell says. "It’s off-patent. And the question is, Is there anything needed to protect that drug?’ The other [situation] is a new drug that has come out to treat organisms that were previously untreatable, but the drug company has not recouped
its investment.

"The drug companies are telling us if we unduly limit the use of those new drugs then there won’t be any more new drugs. They won’t have any incentive," he adds.

(Editor’s note: The final federal draft guidelines have been posted at www.cdc.gov/drugresistance/action plan.)

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