Recent regulatory events in the United States clearly highlight the vagaries of developing antibiotics. The medical need for new antimicrobial drugs is driven by the continuing development of bacterial resistance to existing marketed agents. The Infectious Disease Society of America (IDSA) has identified specific target pathogens for which we need new therapeutic agents in their "Bad Bugs; No Drugs" white article.1,2 Moreover, the government's response to the threat of bioterrorism was the creation of Project Bioshield, a $5.6-billion program to seemingly foster private development and subsequent government stockpiling of new vaccines and treatment of specific microbial pathogens. However, this excellent intention has hardly been a raging success for a variety of reasons.
Against this backdrop has been the shifting fortunes of various recent antibiotic submissions for community respiratory tract infections. The sequence of rejections began quietly in the summer of 2005 with both azithromycin and levofloxacin not being approved for new dosages for acute exacerbations of chronic bronchitis (AECB) based on the belief of Food and Drug Administration (FDA) that noninferiority study designs did not permit either drug to show a benefit of antibiotic therapy over no treatment. Contrary to published meta-analyses by Saint et al3 and, more recently, a Cochrane review,4 as well as a large well-conducted placebo-controlled clinical trial showing that antibiotics do provide a clinical benefit in certain patients with AECB, the FDA determined that the margin of benefit over placebo had not been established; consequently, noninferiority trials were not adequate for the approval of the AECB indication. Importantly, both drugs rejected for AECB were approved for another indication, acute bacterial sinusitis (ABS). Even as the FDA was making these precedent setting decisions, no public announcement was made regarding the regulatory suitability of noninferiority trials for either AECB or ABS. Then, a year later in the fall of 2006, 2 antibiotics were rejected for ABS on similar grounds.5,6 Food and Drug Administration reasoned that as more than 60% of ABS infections resolved spontaneously, there was no clear margin of benefit from antibiotic therapy. All 4 pharmaceutical companies followed the published FDA clinical trial guidance7 only to be told that "new" guidance was in effect, and they now had to show superiority of new agents in these 2 infections. In December 2006, the FDA went 1 step further when it convened a joint advisory committee (composed of panels from Anti-Infective Drug Advisory Committee and Office of Drug Safety and Risk Management) to review the benefit-risk ratio of telithromycin. This advisory committee ultimately recommended withdrawal of telithromycin's indications for ABS and AECB based on risks of adverse events outweighing any potential benefits.8,9 The panel did vote for continued marketing of the same drug for community-acquired pneumonia, although a patient medication guide was strongly urged. These recommendations came on the back of recent congressional criticism of the 2004 approval of telithromycin which highlighted not only the safety concerns regarding that product but also the fact that FDA approval was based on noninferiority clinical trials.10,11 When asked whether other currently marketed drugs with indications for AECB or ABS based on this same type of noninferiority trials would have these indications retracted, the FDA stated that old drugs currently labeled for AECB and ABS would not be reviewed unless "significant safety concerns are raised."8 These drugs would not be approved today because of inadequate study design.
The clinical development of antibacterial drugs has long accepted the fact that use of placebo in the treatment of an active infection is not ethical, a position accepted in the FDA's 1992 "Points to Consider" document.12 Over the past 15 years, efforts have been made to ensure that new anti-infective products were not less effective than the current standard of care by establishing narrow definitions of noninferiority (ie, for a properly sized study, a lower 95% confidence limit of 10% means that the observed difference is not more than 6%). What the FDA is now requesting in their insistence for superiority studies is essentially to return to the preantibiotic era and prove that antibiotics are better than placebo in non-life-threatening infections.
The current state of "community antibiotic" drug development can best be described as a state of confusion. Larger pharmaceutical companies, with a few exceptions, have ceased major discovery efforts to identify new classes of antibiotics needed to tackle the increasing problem of antibiotic resistance. Concurrently, a number of small biotechnology or biopharmaceutical companies have used capital investment to continue the search for new antibiotics. Several of these projects are based on "shelved" research programs from big pharmaceutical companies and are being continued in the hope of creating new valuable agents. A good example was the development of daptomycin that was discovered by Eli Lilly but developed and marketed by Cubist.13 Clearly, the big pharmaceutical pipeline of shelved or discarded programs will soon dissipate, and it is unclear how successful the biotech efforts at their own innovation will be.
A vital component for both scientists and investors is to have a clear understanding of the regulatory requirements for drug approval. More than a decade ago, the IDSA collaborated with the FDA to develop specific clinical trial guidelines for many common bacterial infections. These guidelines were published in 1998 and remain posted on the FDA Web site. Similar guidelines are still in use by the European Medicines Agency.14 The FDA's departure from these established guidelines was largely driven by the FDA without the kind of thoughtful input provided by the IDSA in the 1990s. In the absence of new clinical trial guidelines, sponsors of new anti-infective drugs are dependent on nonpublic discussions with the agency that ultimately are not binding. The FDA did establish a Special Protocol Assessment in 200315 to provide a more structured agreement on clinical development; however, for the products recently reviewed and not approved for study design issues, the Special Protocol Assessment process was not available. Until new guidelines are presented and found acceptable, there will be a chilling effect on investor confidence for new community respiratory tract antibiotics.
So have recent changes of course been based on sound science? Are AECB and ABS trivial self-resolving infections that do not require antibiotic therapy?
The AECB affects many millions of patients each year, costing some $18 billion in health care annually. Properly selected patients with AECB have underlying chronic obstructive pulmonary disease which is the fourth leading cause of death in the United States.16 The impact of these acute episodes is alarmingly high, with lost work time, outpatient clinical visits, hospitalizations, and some mortality-all being associated with AECB. In several well-controlled studies, a bacterial causality has been shown in more than 50% of acute exacerbations.17,18 Efforts to differentiate bacterial from viral causes of AECB are not possible at the time the patient presents to a physician, and many episodes are associated with both viral and bacterial pathogens. Thus, it is entirely appropriate to treat most cases of acute episodes of chronic bronchitis with antibiotics because untreated infections can, and do, progress to more severe infections including pneumonia. Repetitive episodes are the norm and have been shown to contribute to diminishing lung function with associated depression and other ancillary but debilitative conditions.19,20 Patients fulfilling the cardinal symptoms of chronic bronchitis know that they will benefit from a course of antibiotics. Indeed, Allegra et al,21 more than 15 years ago, demonstrated that a short course of antibiotics yielded significantly better clinical outcomes when compared with placebo in a well-defined patient cohort of chronic obstructive pulmonary disease patients with acute exacerbations. This was the last placebo-controlled antibiotic study in AECB; however, because the study was conducted in Italy and published in an Italian medical journal, the results have been excluded from the aforementioned meta-analyses.3,4 Recent attempts to conduct a new placebo-controlled AECB trial have met considerable resistance from US and foreign ethics committees and some Ministries of Health because they considered the study unethical, given that established treatment guidelines supported the use of antibiotics in AECB (R. Echols, MD, oral communication).
At the September 2006 Anti-Infective Drugs Advisory Committee meeting, when the committee reviewed Oscient's Factive (gemifloxacin) New Drug Application for ABS, the FDA struck a similar note to their determination for AECB when they clearly stated that noninferiority studies in ABS, although consistent with the FDA's published guidelines and their prior agreement with the sponsor, were no longer acceptable to establish the efficacy of an antibiotic for the treatment of ABS. Although ABS does not have the underlying morbidity of AECB, there are well-known serious complications of bacterial infections involving the sinuses.22 The analysis of previously conducted placebo-controlled ABS trials, used by the FDA and used to support their position that the benefit of antibiotic treatment had not been established, included a hodgepodge of poorly designed studies, most of which had not established a bacteriologic or even a radiographic diagnosis of the disease being studied.23 Indeed, the lack of diagnostic definitions makes the evaluation of ABS studies difficult, which is why the FDA's clinical trial guidelines required antral puncture of the maxillary sinus to establish a specific etiology. Such data were included in the Factive New Drug Application and have been used in the approval of all antibiotics for ABS since the early 1990s.
Going forward, will placebo-controlled superiority studies be acceptable to ethics committees, investigators, or their patients? Although ABS does not have the same level of morbidity as AECB, the trivialization of the condition seems inappropriate because more than 30 million primary care office visits each year attest to the patients' burden of the condition. Similar to AECB, established treatment guidelines do support the use of antibiotic treatment in properly selected patients.24-26 Ongoing efforts to conduct a placebo-controlled study in ABS where subjects are required to undergo an antral tap have not been well received. Although the sample size is considerably smaller in this superiority study compared with noninferiority studies, enrollment has with 2 to 3 times longer. A fundamental irony is that the very patients most likely to benefit from antibiotics, those with actual bacterial infection, are less likely to enroll in placebo-controlled studies because their symptoms are more likely to be worse than those with a viral infection. Thus, if future placebo-controlled studies do not capture the right patients, the results are likely to be less compelling.
These considerations then lead to the last question, should more investments be made in the arena of community-focused antibiotics? Christoffersen27 recently reviewed the market opportunities relating to antibiotics for the pharmaceutical industry and capital investors. The global sales of antibiotics in 2005 was more than $25 billion, of which, $8.5 billion was in the United States. The number of prescriptions had also increased by around 8% to 10% in 2005. Additionally, the emergence of resistant pathogens can potentially further enhance such market opportunities. There remains the question of whether this in vitro resistance leads to poorer clinical outcomes and the necessity for new antibiotics.28 A glimpse into the future may come from the United Kingdom where efforts to reduce antibiotic prescribing to combat resistance development have led to a substantial decline in antibiotic prescribing for lower respiratory tract infections. However, when Price et al29 examined the trends in hospitalization and deaths due to pneumonia or influenza for 2 periods (ie, before the enforced reduction of antibiotic prescribing and the subsequent 2-year period), they suggested that patients who failed to receive outpatient antibiotics were more likely to be admitted to the hospital or die because of respiratory-related illness. Notwithstanding evidence for the future medical need for antibiotic treatments, Christoffersen27 comments that, despite a relatively rich investing history, the huge medical need, and the very large potential markets, it is evident that a significant change has occurred in the landscape for antibiotic investment. A confluence of issues has now made investing in antibiotics a tough sell.
Do we really understand the consequences of overprescribing antibiotics? Although direct costs, adverse events, and development of resistance can be associated with any amount of antibiotic use, what are the consequences of under use? Who can predict what the consequence of no new community antibiotics will be?
The leadership of the IDSA has recently addressed the lack of regulatory guidance in a letter to the then acting commissioner.30 We can only hope that these new guidelines will provide a reasonable framework and guidance to permit the development of new agents and will not create insurmountable obstacles that further confound the process. If not, we may be facing a future similar to that of our grandparents who personally experienced the loss of siblings and friends to community respiratory tract infections we now consider easily cured.
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15. US Food and Drug Administration/Center for Drug Evaluation and Research. Guidance for industry for Special protocol assessment (FDA/CDER, Rockville, MD, 2002). Available at: http://www.fda.gov/cder/guidance/3764fnl.htm
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