What is the team's concern about biocreep in a noninferiority trial comparing a new antibiotic with the standard of care (existing antibiotic) for treating pneumonia?

Biocreep in Noninferiority Trials for Pneumonia Antibiotics

In a noninferiority trial comparing antibiotics for pneumonia, "biocreep" refers to the phenomenon where each successive noninferiority trial may support the noninferiority of a less-effective treatment, potentially leading to gradual erosion of treatment efficacy over time. 1

Understanding Biocreep

Biocreep occurs through the following mechanism:

• In a noninferiority trial, a new treatment is considered acceptable if it is "not unacceptably worse" than the standard treatment (within a predefined noninferiority margin)
• When a slightly less effective treatment is accepted as the new standard of care
• This new, slightly less effective treatment then becomes the comparator in future trials
• The process repeats with each successive trial potentially approving treatments with incrementally reduced efficacy 2, 3

This is particularly concerning for pneumonia treatments because:

• Pneumonia is the sixth leading cause of death in the United States and the leading cause of infectious disease-related death 1
• Even small reductions in treatment efficacy could have significant mortality implications

Key Factors Contributing to Biocreep Risk

Several factors increase the risk of biocreep in noninferiority trials:

1. Active control selection method: Using suboptimal comparators rather than the best available treatment 2
2. Noninferiority margin selection: Overly generous margins that allow for greater efficacy differences 2
3. Bias in active control effect estimates: Inaccurate estimates of the standard treatment's efficacy 2
4. Violation of the constancy assumption: Changes in the effect of the active comparator from one trial to the next 3

Clinical Implications and Prevention Strategies

To minimize biocreep risk in pneumonia antibiotic trials:

• Always use the best available treatment as the standard comparator 2
• Set appropriate noninferiority margins based on careful estimation of the control treatment's effect 2
• Account for variability and likely sources of bias in effect estimates 2
• Ensure preservation of a meaningful portion of the standard treatment's effect 2
• Monitor for violations of the constancy assumption across trials 3

Common Pitfalls in Noninferiority Trial Interpretation

• Failing to recognize that treatments meeting noninferiority criteria may still be statistically inferior to the standard treatment in conventional analysis 4
• Not accounting for the lack of a placebo arm, making it difficult to determine absolute efficacy when the new treatment is less effective than the standard 4
• Overlooking the ethical considerations of potentially accepting less effective treatments 5

The concern about biocreep is distinct from concerns about bacterial resistance developing during the trial or changes in antibiotic efficacy due to resistance, which are separate issues in antibiotic research.