Designing Studies to Find Early Signals of Efficacy

Brown, Michael; Chuang‐Stein, Christy; Kirby, Simon

doi:10.1080/10543406.2011.570466

Cited by 16 publications

(11 citation statements)

References 15 publications

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“…Recent reports have introduced clinical development models and decision algorithms that could incorporate our conclusions to improve outcomes by adjusting the choice of error rates to the cost of the errors, and quantifying the corresponding successes and profits. 5,46,47 A recent analysis by Lindborg et al supports the general notion that higher-powered early-phase trials may increase treatment development productivity. 48 Using different assumptions (e.g., a higher probability of success), methodology, and outcomes (e.g., using cost of development alone instead of including value of "false-negatives"), they reach similar conclusions.…”

Section: Preventative Minimizing and Mitigating Approachesmentioning

confidence: 91%

“…This, however, will allow testing of only the “side” of benefit while knowledge of the countereffects or harmful effects, also of public health and drug development relevance, will be missed (for example, if a drug for hypertension increased blood pressure instead of reducing it). Strategic approach . Recent reports have introduced clinical development models and decision algorithms that could incorporate our conclusions to improve outcomes by adjusting the choice of error rates to the cost of the errors, and quantifying the corresponding successes and profits …”

Section: Preventative Minimizing and Mitigating Approachesmentioning

confidence: 99%

“…Strategic approach . Recent reports have introduced clinical development models and decision algorithms that could incorporate our conclusions to improve outcomes by adjusting the choice of error rates to the cost of the errors, and quantifying the corresponding successes and profits …”

Section: Preventative Minimizing and Mitigating Approachesmentioning

confidence: 99%

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The Burden of the “False‐Negatives” in Clinical Development: Analyses of Current and Alternative Scenarios and Corrective Measures

Burt¹,

Button

Thom

et al. 2017

Clinical Translational Sci

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The "false-negatives" of clinical development are the effective treatments wrongly determined ineffective. Statistical errors leading to "false-negatives" are larger than those leading to "false-positives," especially in typically underpowered early-phase trials. In addition, "false-negatives" are usually eliminated from further testing, thereby limiting the information available on them. We simulated the impact of early-phase power on economic productivity in three developmental scenarios. Scenario 1, representing the current status quo, assumed 50% statistical power at phase II and 90% at phase III. Scenario 2 assumed increased power (80%), and Scenario 3, increased stringency of alpha (1%) at phase II. Scenario 2 led, on average, to a 60.4% increase in productivity and 52.4% increase in profit. Scenario 3 had no meaningful advantages. Our results suggest that additional costs incurred by increasing the power of phase II studies are offset by the increase in productivity. We discuss the implications of our results and propose corrective measures. Clin Transl Sci (2017) 10, 470-479; doi:10.1111/cts.12478; published online on 4 July 2017. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?✔ Early-phase clinical development studies are usually underpowered, with little knowledge about the extent, magnitude, and economic impact of the consequent "falsenegatives." Only one brief previous report, using different methodology, has studied the topic. 48 WHAT QUESTION DID THIS STUDY ADDRESS?✔ Our simulations aimed to study the impact of statistical error thresholds on clinical development productivity. WHAT THIS STUDY ADDS TO OUR KNOWLEDGE ✔ Underpowered phase II studies result in unacceptably high rates of "false-negatives." The burden of "falsenegatives" on clinical development productivity is potentially enormous, leading to loss of effective treatments and associated commercial profits. Increasing the power of early-phase trials is worth the investment in larger sample sizes. HOW THIS MIGHT CHANGE CLINICAL PHARMACOL-OGY OR TRANSLATIONAL SCIENCE ✔ Increasing power of early-phase clinical trials could improve productivity of drug development with increased profits due to reduction in frequency of "false-negatives" compensating the costs of larger sample-sized studies.Clinical development is increasingly a complex, risky, lengthy, failure-prone, and costly process with considerable healthcare benefits and commercial profits at stake.1-4 Contributing to the costs and delays are statistical errors that lead to "false-positive" and "false-negative" results. The "falsepositives" are the treatments that appear promising but in fact are not. These errors can lead to expensive followup testing, exposure to unnecessary risks and ineffective treatments, and potentially costly delays in development of promising back-up treatments. The "false-negatives" are the effective treatments wrongly eliminated, leading to missed healthcare and economic opportunities and are the subject of our investigation. While the "falseness" o...

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Section: Preventative Minimizing and Mitigating Approachesmentioning

confidence: 91%

Section: Preventative Minimizing and Mitigating Approachesmentioning

confidence: 99%

See 1 more Smart Citation

The Burden of the “False‐Negatives” in Clinical Development: Analyses of Current and Alternative Scenarios and Corrective Measures

Burt¹,

Button

Thom

et al. 2017

Clinical Translational Sci

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“…Otherwise, a No‐Go decision will be made. This decision rule is displayed in Figure (a) for a Go decision. Finding an early signal of efficacy approach (ESOE)The approach of finding an early signal of efficacy allows three possible decisions: a decision to kill (stop development of) a compound, a decision to continue with staged development and a decision to accelerate development. Two critical values, C 1 and C 2 (C 1 < C 2 ), are pre‐specified.…”

Section: Five Approaches To Decision‐making In Early Phase Clinical Tmentioning

confidence: 99%

“…The approach of finding an early signal of efficacy allows three possible decisions: a decision to kill (stop development of) a compound, a decision to continue with staged development and a decision to accelerate development. Two critical values, C 1 and C 2 (C 1 < C 2 ), are pre‐specified.…”

Section: Five Approaches To Decision‐making In Early Phase Clinical Tmentioning

confidence: 99%

A comparison of five approaches to decision‐making for a first clinical trial of efficacy

Kirby

Chuang‐Stein²

2016

Pharmaceutical Statistics

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The first trial of clinical efficacy is an important step in the development of a compound. Such a trial gives the first indication of whether a compound is likely to have the efficacy needed to be successful. Good decisions dictate that good compounds have a large probability of being progressed and poor compounds have a large probability of being stopped. In this paper, we consider and contrast five approaches to decision-making that have been used. To illustrate the use of the five approaches, we conduct a comparison for two plausible scenarios with associated assumptions for sample sizing. The comparison shows some large differences in performance characteristics of the different procedures. Which decision-making procedures and associated performance characteristics are preferred will depend on the focus of interest and the decision maker's attitude to risk. Copyright © 2016 John Wiley & Sons, Ltd.

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JPEN Journal Club 89. Signal‐finding studies

Koretz

2024

J Parenter Enteral Nutr

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Designing Studies to Find Early Signals of Efficacy

Cited by 16 publications

References 15 publications

The Burden of the “False‐Negatives” in Clinical Development: Analyses of Current and Alternative Scenarios and Corrective Measures

The Burden of the “False‐Negatives” in Clinical Development: Analyses of Current and Alternative Scenarios and Corrective Measures

A comparison of five approaches to decision‐making for a first clinical trial of efficacy

JPEN Journal Club 89. Signal‐finding studies

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