S U P P L E M E N T A R T I C L E
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
G. Ralph Corey1,2and Martin E. Stryjewski2,3
1Division of Infectious Diseases; and2Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina; and3Centro de
Educacio ´n Me ´dica e Investigaciones Cli´nicas, Buenos Aires, Argentina
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the majority of these infections, placebo-controlled trials have been replaced by noninferiority studies.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.
Acute bacterial skin and skin-structure infections
(ABSSSIs; formerly cSSSIs) are among the most common
infections encountered in clinical practice. During 2001–
2003, there were 11.6 million outpatients visits for
ABSSSI in the United States .The visit rate for ABSSSI
was estimated to be .400 outpatient visits per 10,000
persons. More than one-half of these infections were
abscesses and cellulitis, most probably caused by Staph-
ylococcus aureus .
S. aureus is an evolving pathogen . Rates of
have been increasing at an alarming rate during the past
2 decades [3–5]. As an example, rates of MRSA isolated
from intensive care units in the United States increased
clone of community-associated MRSA (CA-MRSA;
usually USA 300) has spread rapidly and predominates
in previously healthy patients with ABSSSI [6–9]. CA-
MRSA has also become a nosocomial pathogen ,
causing both noninvasive and invasive infections [11–
13]. This epidemic has been complicated by the emer-
gence of MRSA strains displaying both partial and
complete resistance to vancomycin [14–18] as well as
Correspondence: G. Ralph Corey, MD, Duke Clinical Research Institute, 2400
Pratt St, Rm 7021, Durham, NC 27705 (email@example.com).
Clinical Infectious Diseases
? The Author 2011. Published by Oxford University Press on behalf of the
Infectious Diseases Society of America. All rights reserved. For permissions,
please e-mail: firstname.lastname@example.org.
ABSSSI Clinical Trial Design
d CID 2011:52 (Suppl 7)
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