New Rules for Clinical Trials of Patients With Acute Bacterial Skin and Skin-Structure Infections: Do Not Let the Perfect Be the Enemy of the Good

Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina, USA.
Clinical Infectious Diseases (Impact Factor: 8.89). 06/2011; 52 Suppl 7(Supplement 7):S469-76. DOI: 10.1093/cid/cir162
Source: PubMed


Over the past decade, the United States has witnessed an epidemic of acute bacterial skin and skin-structure infections (ABSSSIs) caused primarily by community-acquired methicillin-resistant Staphylococcus aureus. To address this medical need as well as the ongoing threat of increasing resistance, new antibiotics are being developed. Clinical trials involving patients with complicated ABSSSI are being implemented to understand the efficacy and safety of these new antibiotic agents. Because antibiotics clearly have an effect on the resolution of the majority of these infections, placebo-controlled trials have been replaced by noninferiority studies. However, to conduct noninferiority trials a noninferiority margin must be determined on the basis of the effect size of the comparator antibiotic. The lack of modern-day placebo-controlled studies of ABSSSI makes determining effect size/noninferiority margin--and as a result, trial design--challenging. The US Food and Drug Administration (FDA) in collaboration with the Foundation for the National Institutes of Health (FNIH) have been working hard to resolve these issues and develop a new guidance to aid investigators in the conduct of these trials. In this article, we first review the 1998 guidance and its shortcomings. Next, we address the ongoing discussion of the new 2010 guidance as we understand it, along with its perceived strengths and weaknesses. Throughout this process, we wish to emphasize that the continued development of antibiotics is essential. Thus, we hope that as the FDA and FNIH move forward they will strike a balance between "The Perfect" statistical solution and "The Good" practical clinical realities.

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    • "To achieve this equal distribution of patients, we closed the enrollment earlier for cellulitis, since we reached the targeted number of patients sooner, and extended the enrollment period for SSI and DFI. After the start of the study, we reduced our target for enrollment for DSTA to 150 patients, in light of the November 2008 FDA Advisory Committee discussion highlighting the limited role of antibiotics in treating these infections [3,10]. "
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    ABSTRACT: Objective: To measure the incidence of treatment failure and associated costs in patients with methicillin-resistant Staphylococcus aureus skin and soft tissue infections (SSTIs). This was a prospective, observational study in 13 primary care clinics. Primary care providers collected clinical data, wound swabs, and 90-day follow-up information. Patients were considered to have "moderate or complicated" SSTIs if they had a lesion ≥5 cm in diameter or diabetes mellitus. Treatment failure was evaluated within 90 days of the initial visit. Cost estimates were obtained from federal sources. Overall, treatment failure occurred in 21% of patients (21 of 98) at a mean additional cost of $1,933.71 per patient. In a subgroup analysis of patients who received incision and drainage, those with moderate or complicated SSTIs had higher rates of treatment failure than those with mild or uncomplicated SSTIs (36% vs. 10%; P=.04). One in 5 patients presenting to a primary care clinic for a methicillin-resistant S. aureus SSTI will likely require additional interventions at an associated cost of almost $2,000 per patient. Baseline risk stratification and new treatment approaches are needed to reduce treatment failures and costs in the primary care setting.
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    ABSTRACT: The increasing concern of antibacterial resistance has been well documented, as has the relative lack of antibiotic development. This paradox is in part due to challenges with clinical development of antibiotics. Because of their rapid progression, untreated bacterial infections are associated with significant morbidity and mortality. As a consequence, placebo-controlled studies of new agents are unethical. Rather, pivotal development studies are mostly conducted using non-inferiority designs versus an active comparator. Further, infections because of comparator-resistant isolates must usually be excluded from the trial programme. Unfortunately, the placebo-controlled data classically used in support of non-inferiority designs are largely unavailable for antibiotics. The only available data are from the 1930s and 1940s and their use is associated with significant concerns regarding constancy and assay sensitivity. Extended public debate on this challenge has led to proposed solutions by some in which these concerns are addressed by using very conservative approaches to trial design, endpoints and non-inferiority margins, in some cases leading to potentially impractical studies. To compound this challenge, different Regulatory Authorities seem to be taking different approaches to these key issues. If harmonisation does not occur, antibiotic development will become increasingly challenging, with the risk of further decreases in the amount of antibiotic drug development. However with clarity on Regulatory requirements and an ability to feasibly conduct global development programmes, it should be possible to bring much needed additional antibiotics to patients.
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