There are two broad approaches to managing antimicrobial resistance: managing behavior to maintain drugs' effectiveness and
ensuring a robust pipeline of new antimicrobial treatments. On both these fronts, it's fair to say that the systems-based
approaches to stop resistance have been given a lot of lip service, but have largely failed.
Managing behavior Antimicrobial resistance shouldn't have gotten this far. Back in 2001, WHO issued its Global Strategy for Containment of
Antimicrobial Resistance. Through a set of 67 recommendations, it called for a massive overhaul of the way public health systems
respond to AMR. In particular, it recommended the implementation of national programs to promote rational use of medicines—programs
that generally don't exist in most developing nations.
The intervals between Antibiotic discovery and the development of resistance
The plan made sense, but countries failed to implement it. WHO tried again with resolution WHA58.27, which recommended speeding
implementation of the 2001 working plan, and then again in May 2007 with resolution WHA60.16, which once again recommended
creating national bodies to run rational drug-use programs. This initiative lies at the heart of empowering local governments
to maintain their supply of effective antibiotics to fight infection. The price tag for the program? Just $30 million over
six years. A bargain—if only someone were willing to support it.
Drug development Meanwhile, regulators and government officials can't seem to coordinate the range of issues to align public health guidelines
with market incentives and inspire drug development.
Experts in infectious-disease control have tried to combat AMR by coaching physicians to prescribe fewer antibiotics, and
to "save" newer therapies for patients who have failed on others. This can slow the time before resistance develops—but it
also depresses sales when an innovative antibiotic is on patent, undercutting profitability and giving companies minimal incentive
to develop additional products.
"It's somewhat of a self-limiting occurrence," says John Lebbos, MD, an analyst for Decision Resources. "The more innovative
you are, the more limited market you get."
Antibiotic Pipeline: The late-stage antibiotic pipeline shows a glut of treatments for particular conditions, but a lack of
drugs appropriate for the developing world
Other industry insiders say the real problem is the changing regulatory environment for antibiotics. "The success rates of
approvals went down," says Robert Reynolds, MD, director of drug discovery technology for the nonprofit Southern Research
Institute. "The perception was that FDA had much more stringent requirements, which changed the net-present-value calculations
on developing new antibiotics."
After safety issues were spotted with Pfizer's Trovan and GSK's Raxar in 1999, the standards for antibiotics changed. The
following year, Sanofi-Aventis submitted its ketolide antibiotic drug Ketek for FDA review. But with a higher safety bar,
FDA wanted more testing. The company spent an additional three years—and $518 million, according to Paul Rubin, an economics
professor for Emory University—conducting Phase III trials with a whopping 24,000 patients (on top of the initial 7,000 patients
it had already tested).
Part of the problem with Ketek was that Sanofi-Aventis had used the noninferiority trial design at a time when the agency
began to question its value. Noninferiority trials were previously considered the gold standard, testing a drug's rough equivalence
to treatments already on the market. FDA decided to approve the drug anyway—a decision that would come under attack in 2006,
when the drug was linked to liver damage and failure.
Since then, FDA has encouraged superiority trials for antibiotics. The result is predictable: more studies, bigger trials,
and a number of new antibiotics shelved or delayed. Recently, FDA required additional testing from Replidyne and Forest's
antibiotic candidate faropenem and Pfizer's dalbavancin, developed to fight the deadly MRSA infection, although neither of
these drugs showed safety issues.