Forging a new path

A patient balks at paying $50 for a dose of antibiotics. However, that same patient has no issue paying $50,000 for an oncology drug that may extend life for a few weeks.

This example, in one form or another, is recounted by drug manufacturers, physicians and patient groups that are advocating for changes in how antibacterial drugs are developed, approved, priced and monitored.

Few incentives exist for drugmakers developing antibiotics. The science is difficult, the regulatory process has challenging clinical requirements, and the prices of drugs on the market are low.

“Those three things combined put us into the antibiotic market failure that we have now,” said Dr. Brad Spellberg, associate professor of medicine at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, Calif.

Even as the excess healthcare costs for antibiotic-resistant infections have grown to $20 billion, drug development in this sector has declined.

A new law that provides financial incentives to manufacturers developing antibiotics and requires the Food and Drug Administration to issue new guidance on how certain antibiotics are approved has set the stage for a new regulatory pathway that may be similar to the successful orphan-drug development program.

The market for orphan drugs, which target rare diseases affecting fewer than 200,000 patients in the U.S., is booming. Nine of the 35 new drugs approved by the FDA during fiscal 2012 were orphan drugs, many of which cost $10,000 or more a month.

“It's not identical to orphan drugs, but many of the principles that define why we have orphan drug legislation do apply to areas of unmet need of antibacterial therapy,” Spellberg said.

The law, which passed in 2012 as a provision in the Food and Drug Administration Safety and Innovation Act, seeks to streamline development of certain antibacterial drugs. It also provides priority review, fast-track eligibility and extended exclusivity periods to manufacturers with drugs that are designated “qualified infectious disease products.”

Two drugs developed by Cubist Pharmaceuticals, a Lexington, Mass.-based biopharmaceutical company, received those designations in December. Both drugs are in phase 3 clinical trials.

“Although these infections are getting more and more common, and more and more worrisome, they're still not yet at the level of epidemic where industry can easily do a large phase 3 trial on that highly resistant group of organisms,” said Dr. Barry Eisenstein, senior vice president of scientific affairs for Cubist Pharmaceuticals. “The normal pathways to get approvals for new drugs, particularly new antibiotics, are not available” for drug-resistant infections.

Eisenstein and executives at six other drug companies proposed a new regulatory framework that they say will improve development of new antibacterial treatments for unmet needs, in part by allowing smaller populations in clinical trials.

The framework has four tiers, which would allow for varying indications, labels and efficacy requirements. Only one of the tiers would require two randomized, controlled clinical trials, the standard requirement for new drug approvals in the U.S.

“Although historically antibiotics have not qualified for orphan drug-based registration, we propose the application of successful ideas from registration of orphan drug products and other existing successful regulatory frameworks to address the challenges of antibiotic drug development,” the executives wrote in the January issue of the Lancet.

Price is another issue that may align the orphan drug and antibiotic markets. The prices of antibiotics approved to treat a narrow subset of patients will increase markedly, Robert Guidos, vice president of public policy and government relations for the Infectious Diseases Society of America, said during a meeting convened last week by the Pew Charitable Trusts.

“Creating scenarios in which there is a pricing premium placed on antibacterials is probably the single biggest financial incentive that one could create,” Spellberg said. “That would have a tremendous impact.”

The FDA plans to hold a hearing this week to gather information on developing a new approval pathway for drugs targeting serious or life-threatening conditions that address an unmet medical need, including antibiotics.

Even as the FDA evaluates a new pathway for antibiotics, a step that is likely to improve a weak pipeline of new drugs, other questions persist about postmarket monitoring, off-label prescribing and the agency's role in stemming further antimicrobial resistance.

“The challenge for public policy is how you incentivize new drugs but in a way that you don't recreate the problem of resistance all over again,” said Ramanan Laxminarayan, director of the Center for Disease Dynamics, Economics & Policy, a Washington-based not-for-profit that seeks to improve decisionmaking in health policy. “The FDA is now seriously starting to look at how we can manage drug effectiveness while at the same time trying to get some new drugs in the pipeline.”

Physicians have the discretion to prescribe off-label uses for drugs. High prices and better education of physicians and healthcare providers could deter some off-label use of drugs approved under a new pathway, drug executives said during the Pew meeting. However, hospital officials said physicians are often unaware of a drug's indication or have not read its label.

Dr. Pranita Tamma, director of pediatric antimicrobial stewardship at Johns Hopkins Hospital in Baltimore, said during the Pew meeting that special labeling and high prices are “not enough to ensure drugs are used judiciously.”