The FDA's (long overdue) reboot for antibiotic drug development.

For a science-based agency that prides itself as being the world's "gold standard" for drug and medical device regulation, the FDA's approach to antibiotic drug development has been - for the lack of a better word - mystifying for the better part of a decade. As Infectious Diseases Society of America (IDSA) president Thomas Slama noted in a letter to HHS Secretary Kathleen Sebelius in August "...regulatory disincentives resulting from the lack of clear and feasible antibacterial clinical guidance for industry has become a towering impediment to antibiotic development."

How did the FDA become a "towering impediment to antibiotic development"? It's a long story, but starts with Congress (especially Senator Chuck Grassley and Representative Ed Markey) attacking the agency's approval of the antibiotic Ketek in 2004 - basically accusing the FDA of being in cahoots with drugmakers to foist a dangerous drug on the public.

The Congressional assault gave cover to a clique of regulators at the FDA who wanted to enforce draconian new clinical trials requirements for antibiotics that sharply increased the cost and time required to bring new medicines to market. (It's also worth noting that experts agree that the FDA's European equivalent, the EMA, is way ahead of the agency in terms of creating a more practical and financially attractive environment for antibiotic drug development.)

As a result, since 2006 the FDA has insisted on clinical trial designs for new antibiotics that they were warned (then and since) were totally impractical and unfeasible by outside clinical and industry experts.

Now, after the problem of antibiotic drug resistance has grown to near crisis levels and antibiotic drug development is in free fall, the agency has said that they are willing to rethink their previously inflexible standards. (The whole story is detailed in an excellent article in the current issue of BioCentury: "Antibiotics Reset", subscription required.)

MRSA deaths v AIDS.png

Indeed, in 2005, the latest year for which data is available from the CDC, deaths from methicillin-resistant Staphylococcus aureus (MRSA) significantly outpaced AIDs-related deaths, yet the drug availability for HIV/AIDs treatments is much more robust than the few and far between treatments for MRSA.

Thankfully, the recent PDUFA V reauthorization contained some important provisions that have pushed the FDA to revamp its antibiotic drug standards and improved (at least marginally) financial incentives for drugmakers. For instance, the GAIN Act adds market exclusivity for new antibiotics, and mandates Priority Reviews for antibiotic New Drug Applications (NDAs), making the field marginally more attractive for drug developers.

The law also mandates that the FDA create a "pathogen focused antibacterial drug development pathway," so multiple clinical trials of the same infection but at different parts of the body can be used in support of the same new drug application. The law also requires the FDA to provide advice for developers of drugs for "limited spectrum" pathogens, i.e., drug resistant bacteria like MRSA.

Both provisions should provide a modest but welcome boost for antibiotic focused companies. The FDA is also working with stakeholders to develop new legislation for a Limited Population Antibacterial Drug approval pathway that would essentially allow orphan-drug style approvals - in smaller, faster clinical trials - for antibiotics in narrow populations. This would allow companies to quickly target emerging pathogens and drug resistant strains before they become widespread.

BioCentury notes that "senior FDA officials say the agency is committed to rapidly replacing infeasible requirements for antibiotics with pragmatic standards based on the realities of clinical practice at a pace commensurate with the public health threat posed by rapidly evolving pathogens." This is great news, and long overdue.

But more important questions still have to be answered. Here are three questions Congress should ask the agency:

Why did the agency create "infeasible" antibiotic drug development standards that were so wide of the mark in the first place?

Why did it take the agency so long - six years and counting - to recognize and correct the problem?

How is the agency going to ensure that the same flawed decision making process doesn't happen again, and isn't happening now for other disease indications?

Better yet, the agency's antibiotic "reboot" should be used by Congress to implement a total review of the agency's management procedures, practices, and policies for incorporating new scientific information into regulatory guidance for industry.

It would also be helpful to create an outside scientific board of advisors that would both help the agency keep abreast of the latest scientific developments, and provide regular reports to Congress on FDA's performance. This would go beyond PDUFA requirements, which are focused on relatively narrow procedural metrics, and examine the FDA's performance in advancing innovation through regulatory reforms, instituting consistent management practices across centers, and working more collaboratively with the FDA's scientific partners in industry, the NIH, and academic medicine to develop sensible regulatory standards.

As part of a top-down FDA review, Congress also shouldn't ignore its own impact on the agency. As long as the FDA is used by Congress as a convenient punching bag, FDA staff will continue to produce overly cautious regulations - even if it is at the expense of public health.

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