Fight Resistance - Pharmaceutical Executive


Fight Resistance
Doomsayers predict that the post-antibiotic age is coming. But rising rates of antimicrobial resistance show that in many parts of the world, it is already here.

Pharmaceutical Executive

Systems Failing

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.

The intervals between Antibiotic discovery and the development of resistance
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 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.

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
"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."

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.


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