Deflecting the Post-Antibiotic Era
Synopsis: The lack of new antibiotic development necessitates novel regulatory approaches.
It has been suggested that we may be entering into a "post-antibiotic era." Disaster has so far been averted by the continuing development of new antimicrobial agents. It is now, however, clear that this flow of new agents, especially ones directed at resistant Gram-negative pathogens, has slowed to a trickle. In response to this and other related issues, representatives of the Infectious Disease Society of America (IDSA), the Pharmaceutical Research and Manufacturers Association (PhRMA), and the FDA recently met in a 2-day public workshop to discuss new antimicrobial drug development.
A major reason for this limited development of novel antibacterial agents is economic. Simply put, it costs a pharmaceutical company as much to develop an antihypertensive as it does an antibiotic, but a patient may take the former for the rest of their lives, while they may take an antibiotic for only a few days. Furthermore, the target population for a drug such as an antihypertensive is very large, while that aimed at a resistant Gram-negative pathogen is small. This small target population also directly affects drug development since FDA approval currently requires successful completion of 2 large, randomized, controlled trials. In the development of an antibiotic for an indication that affects a relatively small population, the small target population makes patient accrual difficult and, therefore, prolonged and costly. Also affecting sample size is the degree of required demonstrated "non-inferiority" (the "delta") in comparisons of test agents with standard therapy, an issue that was discussed at length. The major focus of the meeting was to address means of overcoming these interrelated regulatory and economic disincentives to novel antibiotic development.
The discussions also covered a number of related topics. The need for a placebo-controlled trial in future trials of acute exacerbations of chronic bronchitis was addressed, given the uncertain benefit of such therapy. The need for quantitative bacteriology in the diagnosis of ventilator-associated pneumonia was also discussed. The acceptance of bacteriologic end points as sufficient for approval in order to increase the statistical power of clinical trials was also addressed. The acceptance of bacteriologic end points in lieu of clinical end points would thus markedly reduce the number of patients required for completion of clinical trials. This would be especially beneficial in relatively low frequency infections such as bacterial meningitis. There was agreement that the use of pharmacokinetic and pharmacodynamic (PK/PD) data could be used to reduce required sample sizes. Expedited review of selected agents could also be considered, as was the possibility of requiring only a single phase 3 randomized trial or of noncomparative trials, using historical matched controls. The development of a federally funded consortium for clinical trials of critical drugs active against agents on a priority list was also discussed.
Perhaps the most novel suggestion was "wild card exclusivity." Patents for prescription drugs are normally issued for 20 years, but various laws grant pharmaceutical companies a patent extension or market exclusivity period beyond the normal patent period. All patent extensions and periods of market exclusivity effectively delay the introduction of generic versions of the prescription drugs. For instance, in return for agreeing to do pediatric testing of a specific drug, a manufacturer is given a 6-month extension of the patent on that drug—meaning the pharmaceutical company can continue to set the market price and generic forms of the drug cannot enter the market. Straightforward application of this exclusivity would, however, provide limited incentive when applied to a critical antibiotic with a limited market and, therefore, limited economic return during the extension period. If, however, wild card exclusivity were awarded for the development of a novel antibiotic, the exclusivity could be applied to any pharmaceutical in the company’s portfolio, thus potentially increasing its economic value. Such a change would, however, require legislation.
It has been pointed out that antimicrobial agents are the only class of drugs with built-in obsolescence. The very use of such agents exerts a selective pressure that inevitably leads to the emergence of resistant microbial strains. The effect of this resistance is to render the antimicrobial progressively less effective. Optimal use strategies can only slow, but not prevent, this progression. As a consequence, we are dependent on the continued development of novel antimicrobials, in an attempt to keep ahead of the evolutionary curve. The continuation of the dialog that took place at this meeting and the implementation of some of these strategies provide hope that the post-antibiotic era never occurs.