Analyzing phase III studies in hospice/palliative care. A solution that sits between intention-to-treat and per protocol analyses: The palliative-modified ITT analysis

Currow, DC; Plummer, JL; Kutner, JS; Samsa, GP; Abernethy, AP

Analyzing phase III studies in hospice/palliative care. A solution that sits between intention-to-treat and per protocol analyses: The palliative-modified ITT analysis

Currow, DC

Plummer, JL Kutner, JS Samsa, GP Abernethy, AP

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Publication Type:: Journal Article
Citation:: Journal of Pain and Symptom Management, 2012, 44 (4), pp. 595 - 603
Issue Date:: 2012-01-01

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Field	Value	Language
dc.contributor.author	Currow, DC https://orcid.org/0000-0003-1988-1250	en_US
dc.contributor.author	Plummer, JL	en_US
dc.contributor.author	Kutner, JS	en_US
dc.contributor.author	Samsa, GP	en_US
dc.contributor.author	Abernethy, AP	en_US
dc.date.available	2011-10-12	en_US
dc.date.issued	2012-01-01	en_US
dc.identifier.citation	Journal of Pain and Symptom Management, 2012, 44 (4), pp. 595 - 603	en_US
dc.identifier.issn	0885-3924	en_US
dc.identifier.uri	http://hdl.handle.net/10453/115508
dc.description.abstract	Intention-to-treat (ITT) analyses are the standard way to evaluate randomized controlled trials (RCTs) to minimize Type I errors related to differential rates of noncompletion from one study arm. People in palliative care often die sooner than predicted as a direct result of disease progression, some of whom will be participating in RCTs and who will, therefore, withdraw or die after randomization for reasons unrelated to the intervention. This proportion of withdrawals is statistically negligible in other clinical disciplines, but commonplace in hospice/palliative care, creating a systematic bias away from the true effect. ITTanalyses in hospice/palliative care that deem all withdrawals to be treatment failures or that impute data from deteriorating participants systematically underestimate the benefits of interventions, reducing the power of these studies. Equally unacceptable would be a per protocol analysis that excludes all withdrawals after randomization as this will underestimate toxicity. A modified analytic approach is needed on a continuum between ITTand per protocol analyses. To address data after randomization where there is a high rate of withdrawals because of death or deterioration, criteria need to include being: 1) prespecified in the original protocol; 2) clinically absolutely the result of disease progression; 3) identified by the blinded Independent Data Monitoring Committee as being unrelated to the intervention(s); and 4) accounted for in the study's CONSORT diagram. Such data should not be included in the analysis of the primary outcome. This article aims to define a better way of balancingType I andType II errors in hospice/palliative care RCTanalyses using the palliative-modified ITT analysis. Arguably, the palliative-modified ITT analysis should be the primary evaluation of hospice/palliative care Phase III studies but, as a minimum, should routinely be the key sensitivity analysis. © 2012 U.S. Cancer Pain Relief Committee.	en_US
dc.relation.ispartof	Journal of Pain and Symptom Management	en_US
dc.relation.isbasedon	10.1016/j.jpainsymman.2011.10.028	en_US
dc.subject.classification	Anesthesiology	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Palliative Care	en_US
dc.subject.mesh	Research Design	en_US
dc.subject.mesh	Randomized Controlled Trials as Topic	en_US
dc.subject.mesh	Clinical Trials, Phase III as Topic	en_US
dc.subject.mesh	Intention to Treat Analysis	en_US
dc.title	Analyzing phase III studies in hospice/palliative care. A solution that sits between intention-to-treat and per protocol analyses: The palliative-modified ITT analysis	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	44	en_US
utslib.for	1110 Nursing	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/IMPACCT
utslib.copyright.status	closed_access
pubs.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	44	en_US

Abstract:

Intention-to-treat (ITT) analyses are the standard way to evaluate randomized controlled trials (RCTs) to minimize Type I errors related to differential rates of noncompletion from one study arm. People in palliative care often die sooner than predicted as a direct result of disease progression, some of whom will be participating in RCTs and who will, therefore, withdraw or die after randomization for reasons unrelated to the intervention. This proportion of withdrawals is statistically negligible in other clinical disciplines, but commonplace in hospice/palliative care, creating a systematic bias away from the true effect. ITTanalyses in hospice/palliative care that deem all withdrawals to be treatment failures or that impute data from deteriorating participants systematically underestimate the benefits of interventions, reducing the power of these studies. Equally unacceptable would be a per protocol analysis that excludes all withdrawals after randomization as this will underestimate toxicity. A modified analytic approach is needed on a continuum between ITTand per protocol analyses. To address data after randomization where there is a high rate of withdrawals because of death or deterioration, criteria need to include being: 1) prespecified in the original protocol; 2) clinically absolutely the result of disease progression; 3) identified by the blinded Independent Data Monitoring Committee as being unrelated to the intervention(s); and 4) accounted for in the study's CONSORT diagram. Such data should not be included in the analysis of the primary outcome. This article aims to define a better way of balancingType I andType II errors in hospice/palliative care RCTanalyses using the palliative-modified ITT analysis. Arguably, the palliative-modified ITT analysis should be the primary evaluation of hospice/palliative care Phase III studies but, as a minimum, should routinely be the key sensitivity analysis. © 2012 U.S. Cancer Pain Relief Committee.

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http://hdl.handle.net/10453/115508