Sex 'Superbugs' and Antibiotics
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The discovery of a new drug-resistant strain of gonorrhea - now being called a "superbug", should worry policymakers. This is only the latest (and certainly not the last) instance where antibiotic-resistant bacteria threaten public health. The last line of antibiotics that treat gonorrhea - cephalosporins - are beginning to fail worldwide (a recently developed antibiotic in this class ceftobiprole medocaril, however, has shown some efficacy against a methicillin-resistant staphylococcus aureus (MRSA) - though the FDA rejected approval in 2008). 

Among all drug classes, antibiotics are known to have among the lowest risk-adjusted net present value (NPV: the discounted future revenue minus discounted costs) - around $100 million; compare this to an estimated $300 million NPV for cancer drugs or $1.15 billion for drugs treating musculoskeletal conditions. In effect, this means that antibiotics fall fairly low on drug companies' lists of new projects. Though there are many reasons for antibiotics' poor value for companies, it is widely agreed upon that FDA clinical trial regulations (particularly as they affect antibiotic development) contribute significantly. 

Just like any other drug candidate, when a new drug application (NDA) is filed for an antibiotic, there needs to be supporting evidence demonstrating its safety, correct dosage, and efficacy using the FDA's 3-phase clinical trial approach. But antibiotics have to face yet another hurdle - traditionally, drugs are tested against a placebo to establish efficacy. However, when it comes to putting antibiotics through clinical trials (usually patients are signed up in a hospital setting) using a placebo in the control arm of the study presents an ethical dilemma of offering someone with a serious infection a simple placebo (more importantly, the point of a placebo is to verify that particular conditions won't clear up on their own - while simple upper respiratory infections very well might, it's hard to argue that a MRSA infection will). Because of this, antibiotics are put into what are known as "non-inferiority" trials; drug sponsors have to show that new antibiotics are - within a certain margin - no worse than existing treatments.

The problem here is twofold - first, the FDA's clinical trial designs require very large patient samples, and place restrictions on previous antibiotic use (the patient can't have taken another antibiotic within a certain time period before being entered into the trial). For antibiotics, which have very specialized markets (these markets tend to have higher than average mortality rates because they are usually in a hospital setting), large sample sizes are often unrealistic, and neither is the expectation of no prior antibiotic use (because patients are often given an antibiotic immediately when being admitted for an infection). Second, while the FDA has (thankfully) moved away from imposing pre-defined non-inferiority margins and has given investigators more discretion in doing so, the guidance is still relatively stringent and has not helped spur antibiotic development. In particular, the guidance still favors a "fixed margin" approach, where the non-inferiority margin is identified based on historical placebo trials (the alternative, the "synthesis" method is less conservative but more nuanced - it combines estimates for effect versus a comparator drug as well as versus a placebo). The preference for placebo-focused trials undoubtedly causes confusion when placebo trials are unavailable or impractical.

Besides the FDA regulations, other issues with antibiotics development are inherent to the market - antibiotics are short-term therapies, with a course of therapy typically lasting around a week. By contrast, cancer therapies can last for months, or statins for a lifetime, giving drugmakers a much longer time frame to recoup their costs and generate profits.

But is there really a pressing need for new antibiotics? Or is the drug-resistant strain of gonorrhea a one-off finding? A few statistics should answer this:

  • More Americans die from MRSA every year than from AIDS. 
  • Growing antibiotic resistance has led to doctors using old, highly toxic antibiotics like collistin, which may often kill the patient just as well as the infection.
  • The number of new antibacterial agents approved in the U.S. is at an all-time low.

The need for antibacterial drugs is undeniable. A growing number of pathogens are becoming resistant to all but the most toxic antibiotics in our armamentarium - many of these (like gonorrhea) used to be highly susceptible to available antibiotics but developed resistance over time. All is not doom and gloom however - the reauthorization, last year, of the Prescription Drug User Fee Act (PDUFA V) included a provision known as the GAIN Act. This established an additional five years of Hatch-Waxman exclusivity for antibiotic NDA-filers, resulting in a total of 10 years of market exclusivity with or without a patent. The law also gives antibiotics priority review and fast track status to reduce the review period and speed up the path from Phase I testing to NDA filing. While there may be marginal benefits for drugmakers, because the market exclusivity runs concurrently with patent life, the impact of an additional five years of Hatch-Waxman exclusivity is unlikely to be a game-changer.

Even more importantly, however, the law mandated that the FDA create a new pathway for approval of antibiotics. A specialized designation (with complete and thorough guidance) for antibiotics that simplified the development process and peeled back unnecessary regulations would be the best step that the FDA could take in helping spur antibiotic development. Since PDUFA V, the Infectious Diseases Society of America (IDSA) and the President's Council of Advisors on Science and Technology (PCAST) have proposed a "special population, limited medical use" pathway, which has received some FDA support. However, antibiotics approved under such a pathway would be very restricted to only the subpopulation for which trials establish an adequate benefit-risk ratio (though at the same time, this would hopefully make approval more predictable). Nevertheless, this seems to be a moot point for the time being, since no official draft guidance has been issued from the FDA, and the idea is still in the discussion stages with industry groups.

An adequate supply of antibiotics, and the ability to fend off ever-evolving bacteria is crucial to a future rife with chronic diseases and a generally "older" population. FDA regulations are hampering the ability of pharmaceutical companies to provide this supply. Policymakers should pressure the FDA to make good on its PDUFA obligations and to re-examine its antibiotic trial guidance. The limited use designation, when FDA takes action on it, may be valuable for the industry - a streamlined, focused pathway would help justify higher prices for antibacterial drugs, increasing the class's NPV for drugmakers. And while some may clamor about pharmaceutical companies profiteering from people's sickness, think of it this way - if we're willing to pay tens of thousands (even hundreds of thousands) of dollars for a cancer treatment that offers a few extra months of life, we should be willing to pay at least as much for an antibiotic that unquestionably saves a life.

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