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Editorials: Point and Counterpoint |

Rebuttal From Dr Courtright FREE TO VIEW

Katherine Courtright, MD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

CORRESPONDENCE TO: Katherine Courtright, MD, Gates Bldg, 5048, 3400 Spruce St, Hospital of the University of Pennsylvania, Philadelphia, PA 19104


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(5):1132-1133. doi:10.1016/j.chest.2016.01.031
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“Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.” Sir William Osler taught that a great physician practiced the art, not just the science, of medicine. Dr Tillotson analogously reasons that statistical and scientific principles oblige the exclusion of patient variability from randomized controlled trials (RCTs), and thus the application of their results to individual patients must rely on the art of medicine. Although this scenario is true to some extent, it should not absolve the biomedical researcher from seeking to continually improve the conduct of clinical research.

Dr Tillotson elegantly portrays the evolution of medical experimentation since ancient Egypt, but why should the progress stop at the present-day RCT model? The biomedical research community has shown that it is possible to improve upon the status quo. Since the National Institutes of Health Revitalization Act of 1993, the inclusion of more women in cardiovascular clinical trials has led to the recognition of sex differences in the risk and manifestations of heart failure, which may have important treatment implications. However, women remain underrepresented in cardiovascular trials, although far less so than three decades ago.

Indeed, there is still much work to be done to improve on the current RCT approach. For example, there has been growing appreciation for the importance of heterogeneity of treatment effects, which reflects the variability in patients’ baseline risk for an outcome of interest and its effect on the risk-benefit balance for a given therapy. The potential implications of heterogeneity of treatment effects were highlighted by a reanalysis of a clinical trial that favored carotid endarterectomy over aspirin for reducing stroke risk. When reanalyzed according to baseline stroke risk, the data revealed that surgery was beneficial in high-risk patients but potentially increased the stroke risk in low-risk patients. Importantly, this distinction is not appreciable from the original trial’s reported average treatment effect, which is most often what physicians bring to the bedside for individual patient decision-making. Although post hoc statistical methods exist for parsing out this heterogeneity, they are often ignored or done incorrectly.

The solution is not to create blanket trial exclusion criteria based on variability in age, sex, or race. Rather, the focus should be on innovative approaches that allow clinical trials to preserve narrow eligibility criteria but in a patient-centered manner. Predictive or prognostic enrichment of trial enrollment, whereby eligibility is based on patients’ likelihood of response to therapy or risk for the outcome, is a promising mechanism for increasing the efficiency, safety, and interpretability of clinical trials. This enrichment strategy has been advocated by the US Food and Drug Administration for therapeutic trials since 2012, and it is particularly appealing for evaluating the effectiveness of interventions for the highly heterogeneous syndromes of acute respiratory distress and sepsis.

Voltaire warned that perfect is the enemy of good. This axiom may well be true when scraping the vascular intima during a carotid endarterectomy, but it should not apply to scientists striving to improve the quality of their research such that it better informs bedside physicians trying to deliver high-quality, evidence-based care.

References

Osler W. . On the educational value of the medical society. Yale Med J. 1903;IX:325- [PubMed]journal
 
Tillotson G.S. . Counterpoint: Do randomized controlled trials ignore needed patient populations? No. Chest. 2016;149:1130-1132 [PubMed]journal
 
Mezu U. .Bott-Silverman C. .Hsich E. . Heart failure in women is different than in men; Should treatment be different? Cleve Clin J Med. 2007;74:423-424 [PubMed]journal. [CrossRef] [PubMed]
 
Melloni C. .Berger J.S. .Wang T.Y. .et al Representation of women in randomized clinical trials of cardiovascular disease prevention. Circ Cardiovasc Qual Outcomes. 2010;3:135-142 [PubMed]journal. [CrossRef] [PubMed]
 
Kent D.M. .Rothwell P.M. .Ioannidis J.P. .Altman D.G. .Hayward R.A. . Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal. Trials. 2010;11:85- [PubMed]journal. [CrossRef] [PubMed]
 
Rothwell P.M. . Can overall results of clinical trials be applied to all patients? Lancet. 1995;345:1616-1619 [PubMed]journal. [CrossRef] [PubMed]
 
Burke J.F. .Sussman J.B. .Kent D.M. .Hayward R.A. . Three simple rules to ensure reasonably credible subgroup analyses. BMJ. 2015;351:h5651- [PubMed]journal. [PubMed]
 
Gabler N.B. .Duan N. .Liao D. .Elmore J.G. .Ganiats T.G. .Kravitz R.L. . Dealing with heterogeneity of treatment effects: Is the literature up to the challenge? Trials. 2009;10:43- [PubMed]journal. [CrossRef] [PubMed]
 
Temple R. . Enrichment of clinical study populations. Clin Pharmacol Ther. 2010;88:774-778 [PubMed]journal. [PubMed]
 
Guidance for Industry: Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products. US Food and Drug Administration website.http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm332181.pdf. Accessed January 11, 2016.
 
Voltaire. “La Begueule”. Contes (Tales) 1772.
 

Figures

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References

Osler W. . On the educational value of the medical society. Yale Med J. 1903;IX:325- [PubMed]journal
 
Tillotson G.S. . Counterpoint: Do randomized controlled trials ignore needed patient populations? No. Chest. 2016;149:1130-1132 [PubMed]journal
 
Mezu U. .Bott-Silverman C. .Hsich E. . Heart failure in women is different than in men; Should treatment be different? Cleve Clin J Med. 2007;74:423-424 [PubMed]journal. [CrossRef] [PubMed]
 
Melloni C. .Berger J.S. .Wang T.Y. .et al Representation of women in randomized clinical trials of cardiovascular disease prevention. Circ Cardiovasc Qual Outcomes. 2010;3:135-142 [PubMed]journal. [CrossRef] [PubMed]
 
Kent D.M. .Rothwell P.M. .Ioannidis J.P. .Altman D.G. .Hayward R.A. . Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal. Trials. 2010;11:85- [PubMed]journal. [CrossRef] [PubMed]
 
Rothwell P.M. . Can overall results of clinical trials be applied to all patients? Lancet. 1995;345:1616-1619 [PubMed]journal. [CrossRef] [PubMed]
 
Burke J.F. .Sussman J.B. .Kent D.M. .Hayward R.A. . Three simple rules to ensure reasonably credible subgroup analyses. BMJ. 2015;351:h5651- [PubMed]journal. [PubMed]
 
Gabler N.B. .Duan N. .Liao D. .Elmore J.G. .Ganiats T.G. .Kravitz R.L. . Dealing with heterogeneity of treatment effects: Is the literature up to the challenge? Trials. 2009;10:43- [PubMed]journal. [CrossRef] [PubMed]
 
Temple R. . Enrichment of clinical study populations. Clin Pharmacol Ther. 2010;88:774-778 [PubMed]journal. [PubMed]
 
Guidance for Industry: Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products. US Food and Drug Administration website.http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm332181.pdf. Accessed January 11, 2016.
 
Voltaire. “La Begueule”. Contes (Tales) 1772.
 
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