Tuesday, May 2, 2006

Even as we speculate about the likelihood of a pandemic of avian flu and anticipate the beginning of the season of West Nile virus infections, the United States is experiencing another perilous epidemic. As many as 2 million patients nationwide contract bacterial infections in hospitals each year, and 90,000 die, according to the Centers for Disease Control and Prevention (CDC). The death rate in such cases is alarmingly high not because the patients are initially very ill, but because hospital germs increasingly are resistant to multiple antibiotics. Thus, the infections are difficult to treat.

The CDC has adopted four main strategies: prevent infection, diagnose and treat infection, use antimicrobials wisely, and prevent transmission. However, federal officials have paid little attention to the flip side of the problem: the shortage of new antibiotics. For decades we’ve relied largely on new variations on old tricks to combat rapidly evolving pathogens: Most antibiotics in use today are chemically related to earlier ones discovered between 1941 and 1968. During the last 37 years, only two antibiotics with truly novel modes of action have been introduced — Zyvox in 2000 and Cubicin in 2003, the latter of which is used only against skin infections.

Marketing considerations and regulatory costs have exacerbated the antibiotics drought. Until about a decade ago, all major pharmaceutical makers had antibacterial research programs, but they have dramatically trimmed or eliminated these efforts, focusing instead on more lucrative drugs that treat chronic ailments and lifestyle issues.

Think Lipitor and Levitra. Whereas antibiotics cure a patient in days, and may not be required again for years, someone with high cholesterol or erectile dysfunction might pop expensive pills every day for decades. Moreover, drug development has become hugely expensive, with the cost to bring a drug to market now averaging more than $800 million.

Congressional remedies are needed, but have been elusive. Last year, Sens. Joe Lieberman, Connecticut Democrat, and Orrin Hatch, Utah Republican, introduced BioShield II, legislation that, if enacted, would have created tax incentives for companies that develop new antibiotics and would have limited their liability for side effects, as has been done for vaccines. It would also have extended patents on antibiotics to compensate for time lost while awaiting FDA approval.

The bill’s most controversial provision was “wild-card exclusivity,” which would have allowed a drug company that markets a new antibiotic to extend the patent on any product in its portfolio by up to two years, with the approval of federal officials. If Pfizer were to discover an important new antibiotic, for example, the company might be granted more time to market Viagra before generic manufacturers were permitted to produce the drug.

We like the concept of a wild-card, but as proposed, it was a little too wild. It would have permitted federal officials to grant a wild-card patent extension whenever a pharmaceutical maker developed an antibiotic that met the FDA’s broad definition of a “new chemical entity.” Under this language, were Bayer to chemically alter its already-marketed antibiotic ciprofloxacin (Cipro), the company might qualify for a lucrative patent extension on Levitra, even if the new antibiotic wasn’t significantly better than its precursor.

We propose a more appropriate standard: To qualify for wild-card exclusivity, a drug company’s new antibiotic would have to meet FDA’s criteria for “fast track” designation during development — a product that “is intended for the treatment of a serious or life-threatening condition and [that] demonstrates the potential to address unmet medical needs.” Thus, a new antibiotic would qualify if it were intended for serious infections; and if it were active against bacteria widely resistant to existing antibiotics, or if it were more easily administered — for example, orally — or had fewer side effects than alternatives. Under this proposal, a chemically altered Cipro would trigger the wild-card option only if it met these criteria.

We need also to adopt the kinds of critical FDA reforms suggested by the Infectious Disease Society of America. Among them: expediting publication of updated guidelines for clinical trials of antibiotics, including a clear definition of what constitutes acceptable surrogate markers as endpoints; encouraging “imaginative clinical trial designs that lead to a better understanding” of antibiotics’ efficacy; exploration of animal models of infection and microbiologic surrogate markers to reduce the efficacy studies required; and the FDA’s granting of accelerated review status to priority antibiotics.

The two novel antibiotics introduced since 2000 won’t be enough to keep rapidly mutating pathogens at bay for long, and once resistance appears, it will spread rapidly. Unless we create economic incentives for companies to develop antibiotics, it’s unlikely we’ll see many more wonder drugs in the near future. That’s something to think about next time you or a loved one contracts bronchitis, or is hospitalized with a flesh-eating bacterial infection.

Henry I. Miller, a physician, is a fellow at the Hoover Institution and a former FDA official. Barron’s selected his most recent book, “The Frankenfood Myth,” as one of the 25 Best Books of 2004. David Longtin is a free-lance writer.

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