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Year of Publication
1.  Noninferiority trials: clinical understandings and misunderstandings 
Clinical investigation  2013;3(3):215-218.
doi:10.4155/cli.12.157
PMCID: PMC3929272  PMID: 24563733
active control; informed consent; noninferiority margin; preservation of effect
2.  Discordant MIC Analysis: A New Path to Licensure for Anti-infective Drugs 
Clinical trials (London, England)  2013;10(6):10.1177/1740774513507503.
Summary
Background
Evaluation of anti-infective drugs for licensure often relies on a noninferiority (NI) design where new drug B is noninferior to comparator drug A if the difference in success rates is reliably not worse than some fixed margin. The margin must be based on historical studies that estimate the magnitude of the benefit of drug A over placebo. This approach hampers drug development because the obligatory evidence for margin determination is often nonexistent.
Purpose
To develop a new method for licensure of anti-infective drugs when there is no historical evidence for reliable construction of the NI margin.
Methods
The MIC measures the minimum amount of drug that it takes to inhibit growth of bacteria in vitro. Patients who are infected with bacteria that have a low MIC to a given drug are expected to have good outcome when treated with that drug. Thus a differential effect of drug B versus drug A, if it exists, is likely to occur in patients whose pathogens have discordant MICs (e.g. low MIC for drug B, high MIC for drug A, or vice versa). A new paradigm for licensure of anti-infective drugs is proposed where a clinically acceptable NI margin is selected and licensure supported if the NI margin is met and B is reliably demonstrated superior to A in a subset of patients whose paired MICs favor B. The requirement for some evidence of superiority encourages a study that is carefully designed and executed.
Results
Simulations indicate the approach shows promise in realistic settings provided adequate data are available. A simulated example illustrates use of the methods.
Limitations
If the data have small sample size, weak MIC/success relationship, or high correlation between MIC-A, MIC-B, this procedure will have poor power.
Conclusion
Discordant MIC analysis may offer a novel path to licensure for certain anti-infective drugs.
doi:10.1177/1740774513507503
PMCID: PMC3845416  PMID: 24287133
AUC:MIC ratio; Interaction Test; Logistic Regression; Licensure
3.  Beyond Intuition: Patient Fever Symptom Experience 
Journal of pain and symptom management  2013;46(6):10.1016/j.jpainsymman.2013.02.012.
Context
Fever is an important sign of inflammation recognized by health care practitioners and family caregivers. However, few empirical data obtained directly from patients exist to support many of the long-standing assumptions about the symptoms of fever. Many of the literature-cited symptoms, including chills, diaphoresis, and malaise, have limited scientific bases, yet they often represent a major justification for antipyretic administration.
Objectives
To describe the patient experience of fever symptoms for the preliminary development of a fever assessment questionnaire.
Methods
Qualitative interviews were conducted with 28 inpatients, the majority (86%) with cancer diagnoses, who had a recorded temperature of ≥38°C within approximately 12 hours before the interview. A semi-structured interview guide was used to elicit patient fever experiences. Thematic analyses were conducted by three independent research team members, and the data were verified through two rounds of consensus building.
Results
Eleven themes emerged. The participants reported experiences of feeling cold, weakness, warmth, sweating, nonspecific bodily sensations, gastrointestinal symptoms, headaches, emotional changes, achiness, respiratory symptoms, and vivid dreams/hallucinations.
Conclusion
Our data not only confirm long-standing symptoms of fever but also suggest new symptoms and a level of variability and complexity not captured by the existing fever literature. Greater knowledge of patients’ fever experiences will guide more accurate assessment of symptoms associated with fever and the impact of antipyretic treatments on patient symptoms in this common condition. Results from this study are contributing to the content validity of a future instrument that will evaluate patient outcomes related to fever interventions.
doi:10.1016/j.jpainsymman.2013.02.012
PMCID: PMC3830719  PMID: 23742739
Fever; symptoms; qualitative research; content validity
5.  Biomarkers and Surrogate Endpoints In Clinical Trials 
Statistics in medicine  2012;31(25):2973-2984.
One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures and radiological tests, often are considered as replacement endpoints or “surrogates” for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. .
doi:10.1002/sim.5403
PMCID: PMC3551627  PMID: 22711298
validation; accelerated approval; correlate; indirect measure; clinically meaningful endpoint; replacement endpoint; clinical efficacy measure; effect modifiers
6.  Progress on Developing Endpoints for Registrational Clinical Trials of Community-Acquired Bacterial Pneumonia and Acute Bacterial Skin and Skin Structure Infections: Update From the Biomarkers Consortium of the Foundation for the National Institutes of Health 
Potential endpoints for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections trials were evaluated. Review of historical and modern data led to the conclusion that antimicrobial treatment effects are most apparent early in therapy. Later outcomes provide important supportive information.
Efficacy endpoints for previous registrational trials of antimicrobials for acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP) were based on nonstandardized, clinician-based observations and decisions, as well as on patient reports. More quantifiable, reproducible, and externally verifiable endpoints could improve the design of future noninferiority trials. At the request of the Food and Drug Administration, the Foundation for the National Institutes of Health convened a broadly representative scientific project team to evaluate potential endpoints for such registrational trials. Review of historical and modern data led to the conclusion that antimicrobial treatment effects are most apparent early in therapy; later outcomes provide important supportive information. Although evidence is incomplete, early response endpoints can anchor noninferiority hypotheses in ABSSSI and CABP registrational trials, thereby allowing evidence-based drug development to continue. Further research is underway to establish which short- and long-term outcomes are well-defined, reliable, and reflective of how patients feel, function, or survive.
doi:10.1093/cid/cis566
PMCID: PMC3529608  PMID: 22744885
7.  Recommendations for Improving the Design, Conduct, and Analysis of Clinical Trials in Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia 
Overall decisions on the clinical use of new antimicrobials depend on the validity and reliability of the evidence from appropriately designed, conducted, and analyzed clinical trials. Because pneumonia is the sixth leading cause of death in the United States and the leading cause of infectious disease–related death, appropriate design of trials in hospital-acquired pneumonia and ventilator-associated pneumonia are an important public health issue. Several issues with the current design of trials in hospital-acquired pneumonia and/or ventilator-associated pneumonia potentially bias their results and raise questions about their validity. These issues are magnified in the context of noninferiority trials, in which bias can make interventions appear more similar, giving false-positive results of safety and effectiveness. The goal of this article is to provide a scientific basis for improving the validity, reliability, and efficiency of clinical trials in hospital-acquired pneumonia and/or ventilator-associated pneumonia to provide better information for decision making for patients, clinicians, regulators, and other stakeholders.
doi:10.1086/653036
PMCID: PMC3016845  PMID: 20597667
8.  Clinical, demographic and laboratory parameters at HAART initiation associated with decreased post-HAART survival in a U.S. military prospective HIV cohort 
Background
Although highly active antiretroviral therapy (HAART) has improved HIV survival, some patients receiving therapy are still dying. This analysis was conducted to identify factors associated with increased risk of post-HAART mortality.
Methods
We evaluated baseline (prior to HAART initiation) clinical, demographic and laboratory factors (including CD4+ count and HIV RNA level) for associations with subsequent mortality in 1,600 patients who began HAART in a prospective observational cohort of HIV-infected U.S. military personnel.
Results
Cumulative mortality was 5%, 10% and 18% at 4, 8 and 12 years post-HAART. Mortality was highest (6.23 deaths/100 person-years [PY]) in those with ≤ 50 CD4+ cells/mm3 before HAART initiation, and became progressively lower as CD4+ counts increased (0.70/100 PY with ≥ 500 CD4+ cells/mm3). In multivariate analysis, factors significantly (p < 0.05) associated with post-HAART mortality included: increasing age among those ≥ 40 years (Hazard ratio [HR] = 1.32 per 5 year increase), clinical AIDS events before HAART (HR = 1.93), ≤ 50 CD4+ cells/mm3 (vs. CD4+ ≥ 500, HR = 2.97), greater HIV RNA level (HR = 1.36 per one log10 increase), hepatitis C antibody or chronic hepatitis B (HR = 1.96), and HIV diagnosis before 1996 (HR = 2.44). Baseline CD4+ = 51-200 cells (HR = 1.74, p = 0.06), and hemoglobin < 12 gm/dL for women or < 13.5 for men (HR = 1.36, p = 0.07) were borderline significant.
Conclusions
Although treatment has improved HIV survival, defining those at greatest risk for death after HAART initiation, including demographic, clinical and laboratory correlates of poorer prognoses, can help identify a subset of patients for whom more intensive monitoring, counseling, and care interventions may improve clinical outcomes and post-HAART survival.
doi:10.1186/1742-6405-9-4
PMCID: PMC3320559  PMID: 22339893
Highly active antiretroviral therapy; mortality; CD4+ lymphocyte count
9.  Issues in Noninferiority Trials: The Evidence in Community-Acquired Pneumonia 
When investigators hypothesize that experimental interventions provide advantages other than improved effectiveness, they can use noninferiority (NI) trials to determine whether one can rule out the possibility that those interventions have unacceptably worse effectiveness than the standard “active control” regimen. To conduct valid NI trials, there must be evidence from historical studies that provides reliable, reproducible, and precise estimates of the effect of the active control, compared with that of placebo, on the specific outcomes investigators plan to use in the NI trial; this effect should be of substantial magnitude, and the estimates of the active control’s effect from historical studies must represent its effect in the planned NI trial had a placebo group been included. These conditions allow formulation of an NI margin such that, if the NI trial establishes that the effectiveness of the experimental intervention is not worse than the effectiveness of the active control by more than the NI margin, then one can conclude that the experimental regimen (1) preserves a substantial fraction of the effect of the active control and (2) will not result in a clinically meaningful loss of effectiveness. After general discussion of NI trial design issues, we consider the design of NI trials to evaluate antimicrobials in the treatment of community-acquired pneumonia. We present an extensive literature review, allowing estimation of the historical effect of active control regimens in community-acquired pneumonia primarily on the basis of evidence related to use of sulfonamides or penicillin. This review allows formulation of NI margins that are specific to age and bacteremia status of patients.
doi:10.1086/591390
PMCID: PMC2673530  PMID: 18986275
12.  Antimicrobial Drug Resistance, Regulation, and Research1 
Emerging Infectious Diseases  2006;12(2):183-190.
Research models and regulatory measures could aid in developing antimicrobial drugs to address bacterial resistance.
Innovative regulatory and legislative measures to stimulate and facilitate the development of new antimicrobial drugs are needed. We discuss research approaches that can aid regulatory decision making on the treatment of resistant infections and minimization of resistance selection. We also outline current and future measures that regulatory agencies may employ to help control resistance and promote drug development. Pharmacokinetic/pharmacodynamic research models offer promising approaches to define the determinants of resistance selection and drug doses that optimize efficacy and reduce resistance selection. Internationally, variations exist in how regulators use drug scheduling, subsidy restrictions, central directives, educational guidelines, amendments to prescribing information, and indication review. Recent consultations and collaborations between regulators, academics, and industry are welcome. Efforts to coordinate regulatory measures would benefit from greater levels of international dialogue.
doi:10.3201/eid1202.050078
PMCID: PMC3373116  PMID: 16494740
Antibiotic resistance; Bacterial infections; Clinical trials; Drug approval; Drug industry; Drug resistance, microbial; Outcome assessment; Pharmacology; Pharmacokinetics

Results 1-14 (14)