Futility in clinical research: Difference between revisions
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==Futility Stopping Rule for a Clinical Trial== | ==Futility Stopping Rule for a Clinical Trial== | ||
Periodically a | Periodically a Clinical Trial is reviewed through '''Interim Monitoring''' and if the treatment difference is smaller than some pre-established value, the clinical trial is stopped; meaning a trial that would not have shown statistical significance if they had gone onto completion. A DMC guided by a pre-specified statistical monitoring plan acceptable to both the DMC and the study leadership, will generally be in charge with recommending early termination on the basis of a positive result only when the data are truly compelling and the risk of a false positive conclusion is low. 1 In the past some clinical trials have been stopped for futility. Example of this were large trials in critical care medicine. <ref name="pmid1065108">{{cite journal |author= |title=Dentistry--and the world outside |journal=[[Tic]] |volume=34 |issue=4 |pages=1–6 |year=1975 |month=April |pmid=1065108 |doi= |url= |accessdate=2013-04-11}}</ref> | ||
There are various approaches that have been proposed to assess futility, including stochastic curtailment | There are various approaches that have been proposed to assess futility, including stochastic curtailment asymmetric stopping boundaries, predictive power, predictive probability, and group sequential methods.[5] | ||
1. One based on stochastic curtailment which was used in early trials | 1. One based on '''stochastic curtailment''' which was used in early trials when a Committee reviews the results of a trial (assuming about actual success rates of the treatments) and calculates the probability that the trial will give a significant result if finished. If this probability was small the trial should be terminated. A safe way to do this is to use the original difference that was used initially to calculate the sample size.<ref name="urlwww.fda.gov">{{cite web |url=http://www.fda.gov/downloads/Regulatoryinformation/Guidances/ucm127073.pdf |title=www.fda.gov |format= |work= |accessdate=2013-04-11}}</ref> | ||
2. The second method is to use asymmetric stopping boundaries. The futility boundary can be based on how quickly you want to stop the trial if the treatment is ineffective. The faster you stop for an ineffective treatment, however, the larger the sample size needs to be to detect a difference if it is there.<ref name="urlwww.fda.gov">{{cite web |url=http://www.fda.gov/downloads/Regulatoryinformation/Guidances/ucm127073.pdf |title=www.fda.gov |format= |work= |accessdate=2013-04-11}}</ref> | 2. The second method is to use '''asymmetric stopping boundaries'''. The futility boundary can be based on how quickly you want to stop the trial if the treatment is ineffective. The faster you stop for an ineffective treatment, however, the larger the sample size needs to be to detect a difference if it is there.<ref name="urlwww.fda.gov">{{cite web |url=http://www.fda.gov/downloads/Regulatoryinformation/Guidances/ucm127073.pdf |title=www.fda.gov |format= |work= |accessdate=2013-04-11}}</ref> | ||
===Disadvantages of Futility Stopping=== | ===Disadvantages of Futility Stopping=== | ||
Stopping a trial after obtaining data that suggests Futility originates several disadvantages<ref name="pmid1065108">{{cite journal|author= |title=Dentistry--and the world outside |journal=[[Tic]] |volume=34 |issue=4 |pages=1–6 |year=1975 |month=April |pmid=1065108 |doi= |url= |accessdate=2013-04-11}}</ref>, such as: | |||
- Leaves the primary research question without a definitive answer. | |||
- Difficult interpretation of a negative result. | |||
- Wider confidence bounds than if the study was finished which leads to the estimated treatment difference to be biased downward. | |||
- Increases the risk of imbalance in prognostic factors. | |||
- Alters the analyses of secondary outcomes | |||
Researchers will unlikely conduct the trial stopped again. | - Adverse events data is limited | ||
Clinical investigators have a responsibility to consider the effects of their research upon the totality of literature in their field. | - Researchers will unlikely conduct the trial stopped again. | ||
- Clinical investigators have a responsibility to consider the effects of their research upon the totality of literature in their field. | |||
===Advantages of Futility Stopping=== | ===Advantages of Futility Stopping=== | ||
Nevertheless, stopping a trial due to Futility might have positive consequences or advantages, for example<ref name="pmid1065108">{{cite journal|author= |title=Dentistry--and the world outside |journal=[[Tic]] |volume=34 |issue=4 |pages=1–6 |year=1975 |month=April |pmid=1065108 |doi= |url= |accessdate=2013-04-11}}</ref>: | |||
- Time saving | |||
- Appropriate use of research funding | |||
- Reducing the participants exposure to the harmful treatment | |||
These resources can be used towards more promising research studies that might generate important discoveries. | |||
==Conditional Power== | ==Conditional Power== | ||
Revision as of 14:13, 12 April 2013
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Gonzalo Romero
Overview
During the conduction of a clinical trial several interim analysis are performed in order to obtain data that could be used for early termination of the trial or adjusting the study's protocol due to futility, adverse effects profiles or insignificant statistical efficacy of the intervention being studied. This data is reported to the Data Monitoring Committee (DMC) which can help in decision making of the trial.
Interim Analysis
It s the implementation of sequential testing in clinical trials which gives important information in regards to the study progress. The frequency of this analysis is variable. Their intention is to monitor Safety, Efficacy and Futility analysis.
- Safety is assessed to determine a specific number of serious adverse events towards one group. Some adverse effects appear only in larger studies. [1]
- Efficacy to determine the difference between the intervention being studied and the control. [2]
- Futility to determine if the novel drug is not more efficacious than the control. If this is the scenario the trial should be stopped. [2]
Futility Definition
Futile is used to describe any intervention to achieve a result that is possible, but experience suggests that cannot be systematically obtained. A futile action is one that cannot achieve the intended goals. It is important to distinguish it from hopelessness; futility refers to the objective quality of an action, hopelessness is a subjective term. [3]
Medical Futility
In medicine a treatment or intervention is considered futile if it does not improve prognosis, comfort, well-being or general state of health or any other clinical end-point. Example of futile treatments could be the ones used in vegetative state patients and children with leukemia or Hodgkin lymphoma which are often described as "pushing ahead with futile therapies". Some futile treatments are used in terminally ill patients to facilitate their well being. It is important to highlight that carefully analyzing some futile treatments could eventually lead to clinical studies that might contribute to medicine in knowledge. [3]
Data Monitoring Committee
The Data Monitoring Committees (DMCs), also known as Data and Safety Monitoring Boards (DSMBs) or Data and Safety Monitoring Committees (DSMCs) is a group of subjects with important experience which reviews on a periodically basis accumulating data from ongoing clinical trials.
They have several responsibilities such as monitoring that the study continues until the planned completion of follow-up, regardless of the duration of treatment. Their members assess for safety of trial participants through Interim Monitoring. Also they monitor effectiveness, monitor study conduct, make recommendations, maintain meeting records.
The DMC establish a Charter describing the Operational procedures which includes meetings scheduling, data presentation, interim data access, assessment of conflict of interest, and methods of interim reports to the DMC.
The FDA recommends that a DMC should have access to the treatment assignment for each group, but other authors recommend that the information should be coded to avoid the introduction of bias by unblinding the DMC, assuring a greater objectivity of the interim review. They may recommend termination of a study if a group shows a significant adverse event when compared to control or if the investigated treatment shows to be futile (futility analysis) through the interim assessment and statistical methods used. The Sponsor and DMC should establish a process to unblind the treatment codes to the DMC members when needed in case of an emergency.
Futility Stopping Rule for a Clinical Trial
Periodically a Clinical Trial is reviewed through Interim Monitoring and if the treatment difference is smaller than some pre-established value, the clinical trial is stopped; meaning a trial that would not have shown statistical significance if they had gone onto completion. A DMC guided by a pre-specified statistical monitoring plan acceptable to both the DMC and the study leadership, will generally be in charge with recommending early termination on the basis of a positive result only when the data are truly compelling and the risk of a false positive conclusion is low. 1 In the past some clinical trials have been stopped for futility. Example of this were large trials in critical care medicine. [2]
There are various approaches that have been proposed to assess futility, including stochastic curtailment asymmetric stopping boundaries, predictive power, predictive probability, and group sequential methods.[5]
1. One based on stochastic curtailment which was used in early trials when a Committee reviews the results of a trial (assuming about actual success rates of the treatments) and calculates the probability that the trial will give a significant result if finished. If this probability was small the trial should be terminated. A safe way to do this is to use the original difference that was used initially to calculate the sample size.[1]
2. The second method is to use asymmetric stopping boundaries. The futility boundary can be based on how quickly you want to stop the trial if the treatment is ineffective. The faster you stop for an ineffective treatment, however, the larger the sample size needs to be to detect a difference if it is there.[1]
Disadvantages of Futility Stopping
Stopping a trial after obtaining data that suggests Futility originates several disadvantages[2], such as: - Leaves the primary research question without a definitive answer. - Difficult interpretation of a negative result. - Wider confidence bounds than if the study was finished which leads to the estimated treatment difference to be biased downward. - Increases the risk of imbalance in prognostic factors. - Alters the analyses of secondary outcomes - Adverse events data is limited - Researchers will unlikely conduct the trial stopped again. - Clinical investigators have a responsibility to consider the effects of their research upon the totality of literature in their field.
Advantages of Futility Stopping
Nevertheless, stopping a trial due to Futility might have positive consequences or advantages, for example[2]:
- Time saving
- Appropriate use of research funding
- Reducing the participants exposure to the harmful treatment
These resources can be used towards more promising research studies that might generate important discoveries.