Dangerous Antibiotics for the 21st Century

fda approved smallNo one can dispute that multidrug-resistant “superbugs” are a key public health concern for the 21st century. Better, safe and effective cures are needed. But the 21st Century Cures Act, legislation that will be voted on this week in the House, is not the solution to this problem.

Over 2 million people are infected with antibiotic-resistant bacteria each year, resulting in at least 23,000 deaths. New antibiotics have been slow in coming: No antibiotic with a truly novel mechanism of action has been discovered since the late 1980s. Yet this drought is not the fault of the Food and Drug Administration (FDA), which has long been under tremendous pressure to approve new antibiotics quickly. This pressure was increased even further by a 2012 law that accelerated review for qualifying antibiotics.

Thanks to the current review process for antibiotics, clinical development for these drugs is already quick by industry standards. A new antibiotic takes only seven years to get to market, compared with nine years for cancer drugs.

Quick approval is not without costs. Many of the antibiotics approved over the past decade have suffered from safety and effectiveness problems. For example, tigecycline (Tygacil), an antibiotic that received special accelerated FDA approval in 2005, was slapped with a black-box warning in 2013 stating that the drug increases the risk of death.

Bedaquiline (Sirturo), granted accelerated approval in 2012, also increases the risk of death. This antibiotic was approved based on the fact that it effectively reduced the amount of tuberculosis in research subjects’ sputum, a “surrogate endpoint” that does not actually benefit the patient but is thought to be a sign of potential benefit. Unfortunately in this case, improving the surrogate endpoint did not improve survival: Subjects who received bedaquiline during clinical trials were five times as likely to die as those who did not. Yet the FDA ultimately approved the drug anyway, with another black-box warning describing the mortality risk.

Other recently approved antibiotics, including dalbavancin (Dalvance) and ceftazidime-avibactam (Avycaz), gained approval by showing that they were no less effective than an existing antibiotic, rather than showing they were more effective than an existing drug or placebo. Such “non-inferiority” trials are notorious for providing misleading results if there are flaws in trial design or conduct.

This questionable string of antibiotics approvals should have triggered congressional oversight and possibly new legislation strengthening the FDA’s review of these drugs. Yet instead Congress appears poised to do the opposite: the 21st Century Cures Act, which will likely passed during the House vote this week, would create yet another accelerated approval pathway designed to speed antibiotics approvals. The bill, modeled on the Antibiotic Development to Advance Patient Treatment (ADAPT) Act, would pressure the FDA to approve new antibiotics based on even smaller clinical trials, more surrogate endpoints and potentially even more questionable forms of evidence.

Disturbingly, the bill would require the FDA to consider expanding this new approval pathway to other drugs beyond antibiotics within four years, without any further action required from Congress.

In addition to undermining approval standards, the 21st Century Cures Act includes a new Medicare payment system that would undermine recent federal efforts to encourage more careful stewardship of these drugs in hospitals and elsewhere. Overuse of antibiotics worsens the problem of multidrug resistance by accelerating the speed at which superbugs evolve to resist new drug treatments.

The new payment system proposed in 21st Century Cures would offer hospitals a financial bonus each time a patient receives certain new antibiotics during his or her hospital stay. Currently, antibiotics payments are included as part of a bundled hospital payment, so hospitals have little incentive to use antibiotics unless medically necessary, particularly expensive new antibiotics. The proposed payment system would create the opposite effect, offering strong financial incentives for hospitals to overuse new antibiotics.

Cutting review periods and squandering new antibiotics is not the right way to create better antibiotics for the 21st century. Instead, Congress should invest public resources into early-stage research targeted at expanding the available options at the start of the antibiotics development pipeline. Truly innovative science will lead to better products at the end of the pipeline, ones that will not require lower FDA standards to gain approval.

The 21st Century Cures Act ultimately comes up short when it comes to research funding. One of the most highly-publicized provisions of the bill would provide more funding to the National Institutes of Health (NIH), which offers grants for basic, early-stage research. But this research funding would be a temporary 4.5 percent increase to the annual NIH budget that will end abruptly after three years. An additional, smaller sum would be dedicated to a new “Innovation Fund” that would be available for infectious disease research and other priorities, but this fund also would expire, after five years.

On balance, the antibiotics provisions in 21st Century Cures will be bad for patients and public health. In exchange for an ephemeral boost in research funding, the bill will pressure the FDA to approve dangerous new antibiotics and institutionalize a hospital payment system that promotes antibiotics overuse and speeds the development of drug resistance.

The American public does need a bill to create and preserve safer, more effective antibiotics in the 21st century, but the 21st Century Cures Act is not it.