ArticleStatistical methods in medical research
Adaptive non-inferiority margins under observable non-constancy.
Article in Statistical methods in medical research. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed.
- Evaluating group-sequential non-inferiority clinical trials following interim stopping: The HIV Prevention Trials Network 083 trial.Clinical trials (London, England) · 2022Trial
- Using the adherence-efficacy relationship of emtricitabine and tenofovir disoproxil fumarate to calculate background hiv incidence: a secondary analysis of a randomized, controlled trial.Journal of the International AIDS Society · 2021Trial
- Comparing Approaches for Estimating Counterfactual HIV Incidence Among Populations With High Vulnerability to HIV in Lima, Peru: A Multi-Study Comparative Analysis.Journal of the International AIDS Society · 2026Article
- Indirect Treatment Comparison of Long-Acting Injectable Cabotegravir as Pre-exposure Prophylaxis When Compared with no Pre-exposure Prophylaxis for HIV Prevention.Infectious diseases and therapy · 2025Article
- Exploring different objectives in non-inferiority trials.BMJ (Clinical research ed.) · 2024Article
- Estimating counterfactual placebo HIV incidence in HIV prevention trials without placebo arms based on markers of HIV exposure.Clinical trials (London, England) · 2024Article
- Generalizing the intention-to-treat effect of an active control from historical placebo-controlled trials: A case study of the efficacy of daily oral TDF/FTC in the HPTN 084 study.Journal of the American Statistical Association · 2024Article
- Article
- Counterfactual estimation of efficacy against placebo for novel PrEP agents using external trial data: example of injectable cabotegravir and oral PrEP in women.Journal of the International AIDS Society · 2023Article
- Estimating the impact of HIV PrEP regimens containing long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate/emtricitabine among men who have sex with men in the United States: a mathematical modelling study for HPTN 083.Lancet regional health. Americas · 2023Article
- Ethical issues in establishing the efficacy and safety of long-acting injectable pre-exposure prophylaxis for HIV prevention: the HPTN 083 trial.The lancet. HIV · 2021Review
- Sample size calculation for active-arm trial with counterfactual incidence based on recency assay.Statistical communications in infectious diseases · 2021Article
- A Bayesian averted infection framework for PrEP trials with low numbers of HIV infections: application to the results of the DISCOVER trial.The lancet. HIV · 2020Review
- Article
- Statistical approaches to accelerate the development of long-acting antiretrovirals for HIV pre-exposure prophylaxis.Current opinion in HIV and AIDS · 2020Review
- Advancing Novel PrEP Products - Alternatives to Non-Inferiority.Statistical communications in infectious diseases · 2019Article
- The Connection between the Averted Infections Ratio and the Rate Ratio in Active-control Trials of Pre-exposure Prophylaxis Agents.Statistical communications in infectious diseases · 2019Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
A central assumption in the design and conduct of non-inferiority trials is that the active-control therapy will have the same degree of effectiveness in the planned non-inferiority trial as in the prior placebo-controlled trials used to define the non-inferiority margin. This is referred to as the 'constancy' assumption. If the constancy assumption fails, decisions based on the chosen non-inferiority margin may be incorrect, and the study runs the risk of approving an inferior product or failing to approve a beneficial product. The constancy assumption cannot be validated in a trial without a placebo arm, and it is unlikely ever to be met completely. When there are strong, observable predictors of constancy, such as dosing and adherence to the active-control product, we can specify conditions where the constancy assumption will likely fail. We propose a method for using measurable predictors of active-control effectiveness to specify non-inferiority margins targeted to the planned study population characteristics. We describe a pre-specified method, using baseline characteristics or post-baseline predictors in the active-control arm, to adapt the non-inferiority margin at the end of the study if constancy is violated. Adaptive margins can help adjust for constancy violations that will inevitably occur in real clinical trials, while maintaining pre-specified levels of Type I error and power.
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