- Email: [email protected]
Rebuttal From Dr Courtright
In the dawning of the antibiotic era, several classic studies were performed in pneumonia, including those of Evans and Gaisford.9 They tried to ensure “comparability of patients in sex and age distribution,”(p15) although there would be patients who could not be treated due to their disease severity or underlying conditions. One of the first studies that actually excluded patients who were microbiologically negative was reported by Wagle et al,10 in which they studied bubonic plague in India. They compared antiplague serum, iodine, and sulfonamide. All negative cases were excluded from the analysis, thus beginning the “modified intention-to-treat” analytical process. A cohort that is unique to infectious diseases, as almost all other diseases or conditions, has a clinical confirmation prior to recruitment.
therapeutic benefit to these patients is the “art of being a physician.” Thus, in conclusion, RCTs do not ignore needed populations but provide valuable data to enable the better treatment of these patients with new therapies.
The field of antibiotic research and development has been a checkered one over the past 10 years. There have been many regulatory changes during this period, some of which have served to deter industry from investing in this area. Among the changes has been a tightening of patient eligibility to ensure that we are comparing like with like populations. In parallel, the agencies have defined the various indications much more tightly, thus restricting possible subject enrollment.
6. Behring E, Boer O, Kossell H. Zur behandlung diphtheriekranker menschen mit diphtherieheilserum. Deustche Med Wcneshr. 1893;19:389-392.
Presently, there are activities supported by the US Food and Drug Administration and the Foundation for the National Institutes of Health that are applying some of the critical assessments of infections at time points which are clinically meaningful. For example, there are clear rules for examination of specific infection signs and symptoms at day 3 to 5 as well as usual test of cure, which is 3 to 5 days after the end of therapy. It is these early evaluations that show a difference, if one exists, between therapies. Typically, by day 14, a therapy has either worked, been switched, or the patient/participant has died. Nevertheless, Corey and Stryjewski asked that such regulatory advances be tested before instant implementation.11 Interestingly, they quote Snodgrass and Anderson12(p1157): “clinical judgment, however, is not statistically assessable.” Randomized trials are usually superior to nonrandomized observational studies because randomization is the basis for statistical inference. The subjects enrolled are, by definition, similar, and excluded patients are considered to be likely to skew the outcomes. Thus, today’s RCTs are undertaken to better understand a therapy as it applies to most patients with the same condition. Inevitably, there will be some patients who are sicker, older, or have comorbid conditions, but the ability to infer the
1132 Point and Counterpoint
References 1. Crombie AC. Avicenna: Scientist and Philosopher. In: Wickens GM, ed. London, England: Luzac & Company Ltd; 1952:89. 2. Drummond JC, Wilbraham A. The Englishman’s Food: a History of Five Centuries of English Diet. London, England: Jonathan Cape; 1938. 3. Lind J. A Treatise of the Scurvy. Edinburgh, Scotland: Sands, Murray & Cochran; 1753. 4. Withering W. An Account of the Foxglove and Some of its Medical Uses With Practical Remarks on Dropsy and Other Diseases. Birmingham: GCJ & J Robinson; 1785. 5. New approaches to patient recruitment and retention anticipate structural change in the clinical research enterprise. Tufts Center for the Study of Drug Development website. http://csdd.tufts.edu/news/ complete_story/pr_tufts_csdd_2014_cost_study. Accessed October 14, 2015.
7. Roux E, Martin L, Chaillou A. Trois cent cas de diphtheria traite par le serum antidiphtherique. Ann Inst Pasteur. 1894;8:540-661. 8. Wright AE, Leishman WB. Remarks on the results which have been obtained by the antityphoid inoculations and on the methods which have been employed in the preparation of the vaccine. Br Med J. 1900;1:122-129. 9. Evans GM, Gaisford WF. Treatment of pneumonia with 2(p-aminobenzene sulphonamide) pyridine. Lancet. 1938;2:14-19. 10. Wagle PM, Sokhey SH, Dikshit BB, Ganapathy K. Chemotherapy in plague. Indian M Gaz. 1941;76:29-32. 11. Corey GR, Stryjewski ME. New rules for clinical trials of patients with acute bacterial skin and skin-structure infections: Do not let the perfect be the enemy of the good. Clin Infect Dis. 2011;52(suppl 7):S469-S476. 12. Snodgrass WR, Anderson T. Sulphanilamide in the treatment of erysipelas: a controlled series of 270 cases. Br Med J. 1937;2:1156-1159.
Rebuttal From Dr Courtright Katherine Courtright, MD Philadelphia, PA
“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.”1 Sir William Osler taught that a great physician practiced the art, not just the science, of medicine. Dr Tillotson2 analogously reasons AFFILIATIONS: From the Pulmonary, Allergy and Critical Care Division, Hospital of the University of Pennsylvania. 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; e-mail: [email protected] Copyright Ó 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2016.01.031
[
149#5 CHEST MAY 2016
]
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.3 However, women remain underrepresented in cardiovascular trials, although far less so than three decades ago.4 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.5 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.6 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 decisionmaking. Although post hoc statistical methods exist for parsing out this heterogeneity,7 they are often ignored or done incorrectly.8 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.9 This enrichment
journal.publications.chestnet.org
strategy has been advocated by the US Food and Drug Administration for therapeutic trials since 2012,10 and it is particularly appealing for evaluating the effectiveness of interventions for the highly heterogeneous syndromes of acute respiratory distress and sepsis. Voltaire11 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 1. Osler W. On the educational value of the medical society. Yale Med J. 1903;IX:325. 2. Tillotson GS. Counterpoint: Do randomized controlled trials ignore needed patient populations? No. Chest. 2016;149(5):1130-1132. 3. 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(6):423-424, 426, 429-435. 4. Melloni C, Berger JS, Wang TY, et al. Representation of women in randomized clinical trials of cardiovascular disease prevention. Circ Cardiovasc Qual Outcomes. 2010;3:135-142. 5. Kent DM, Rothwell PM, Ioannidis JP, Altman DG, Hayward RA. Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal. Trials. 2010;11:85. 6. Rothwell PM. Can overall results of clinical trials be applied to all patients? Lancet. 1995;345:1616-1619. 7. Burke JF, Sussman JB, Kent DM, Hayward RA. Three simple rules to ensure reasonably credible subgroup analyses. BMJ. 2015;351:h5651. 8. Gabler NB, Duan N, Liao D, Elmore JG, Ganiats TG, Kravitz RL. Dealing with heterogeneity of treatment effects: Is the literature up to the challenge? Trials. 2009;10:43. 9. Temple R. Enrichment of clinical study populations. Clin Pharmacol Ther. 2010;88:774-778. 10. 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. 11. Voltaire. “La Begueule”. Contes (Tales) 1772.
Rebuttal From Dr Tillotson Glenn S. Tillotson, PhD, FCCP Durham, NC
Dr Courtright1 raises some excellent and valid points regarding the debate, and clearly this is an important aspect of improving medical practice. In essence, AFFILIATIONS:
GST Micro LLC.
FINANCIAL/NONFINANCIAL DISCLOSURE:
None declared. Glenn S. Tillotson, PhD, FCCP, GST Micro LLC, 227 Kayleen Ct, Durham NC 27713; e-mail: gtillotsonconsult@ yahoo.com Copyright Ó 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2016.01.027 CORRESPONDENCE TO:
1133
therapeutic benefit to these patients is the “art of being a physician.” Thus, in conclusion, RCTs do not ignore needed populations but provide valuable data to enable the better treatment of these patients with new therapies.
The field of antibiotic research and development has been a checkered one over the past 10 years. There have been many regulatory changes during this period, some of which have served to deter industry from investing in this area. Among the changes has been a tightening of patient eligibility to ensure that we are comparing like with like populations. In parallel, the agencies have defined the various indications much more tightly, thus restricting possible subject enrollment.
6. Behring E, Boer O, Kossell H. Zur behandlung diphtheriekranker menschen mit diphtherieheilserum. Deustche Med Wcneshr. 1893;19:389-392.
Presently, there are activities supported by the US Food and Drug Administration and the Foundation for the National Institutes of Health that are applying some of the critical assessments of infections at time points which are clinically meaningful. For example, there are clear rules for examination of specific infection signs and symptoms at day 3 to 5 as well as usual test of cure, which is 3 to 5 days after the end of therapy. It is these early evaluations that show a difference, if one exists, between therapies. Typically, by day 14, a therapy has either worked, been switched, or the patient/participant has died. Nevertheless, Corey and Stryjewski asked that such regulatory advances be tested before instant implementation.11 Interestingly, they quote Snodgrass and Anderson12(p1157): “clinical judgment, however, is not statistically assessable.” Randomized trials are usually superior to nonrandomized observational studies because randomization is the basis for statistical inference. The subjects enrolled are, by definition, similar, and excluded patients are considered to be likely to skew the outcomes. Thus, today’s RCTs are undertaken to better understand a therapy as it applies to most patients with the same condition. Inevitably, there will be some patients who are sicker, older, or have comorbid conditions, but the ability to infer the
1132 Point and Counterpoint
References 1. Crombie AC. Avicenna: Scientist and Philosopher. In: Wickens GM, ed. London, England: Luzac & Company Ltd; 1952:89. 2. Drummond JC, Wilbraham A. The Englishman’s Food: a History of Five Centuries of English Diet. London, England: Jonathan Cape; 1938. 3. Lind J. A Treatise of the Scurvy. Edinburgh, Scotland: Sands, Murray & Cochran; 1753. 4. Withering W. An Account of the Foxglove and Some of its Medical Uses With Practical Remarks on Dropsy and Other Diseases. Birmingham: GCJ & J Robinson; 1785. 5. New approaches to patient recruitment and retention anticipate structural change in the clinical research enterprise. Tufts Center for the Study of Drug Development website. http://csdd.tufts.edu/news/ complete_story/pr_tufts_csdd_2014_cost_study. Accessed October 14, 2015.
7. Roux E, Martin L, Chaillou A. Trois cent cas de diphtheria traite par le serum antidiphtherique. Ann Inst Pasteur. 1894;8:540-661. 8. Wright AE, Leishman WB. Remarks on the results which have been obtained by the antityphoid inoculations and on the methods which have been employed in the preparation of the vaccine. Br Med J. 1900;1:122-129. 9. Evans GM, Gaisford WF. Treatment of pneumonia with 2(p-aminobenzene sulphonamide) pyridine. Lancet. 1938;2:14-19. 10. Wagle PM, Sokhey SH, Dikshit BB, Ganapathy K. Chemotherapy in plague. Indian M Gaz. 1941;76:29-32. 11. Corey GR, Stryjewski ME. New rules for clinical trials of patients with acute bacterial skin and skin-structure infections: Do not let the perfect be the enemy of the good. Clin Infect Dis. 2011;52(suppl 7):S469-S476. 12. Snodgrass WR, Anderson T. Sulphanilamide in the treatment of erysipelas: a controlled series of 270 cases. Br Med J. 1937;2:1156-1159.
Rebuttal From Dr Courtright Katherine Courtright, MD Philadelphia, PA
“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.”1 Sir William Osler taught that a great physician practiced the art, not just the science, of medicine. Dr Tillotson2 analogously reasons AFFILIATIONS: From the Pulmonary, Allergy and Critical Care Division, Hospital of the University of Pennsylvania. 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; e-mail: [email protected] Copyright Ó 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2016.01.031
[
149#5 CHEST MAY 2016
]
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.3 However, women remain underrepresented in cardiovascular trials, although far less so than three decades ago.4 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.5 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.6 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 decisionmaking. Although post hoc statistical methods exist for parsing out this heterogeneity,7 they are often ignored or done incorrectly.8 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.9 This enrichment
journal.publications.chestnet.org
strategy has been advocated by the US Food and Drug Administration for therapeutic trials since 2012,10 and it is particularly appealing for evaluating the effectiveness of interventions for the highly heterogeneous syndromes of acute respiratory distress and sepsis. Voltaire11 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 1. Osler W. On the educational value of the medical society. Yale Med J. 1903;IX:325. 2. Tillotson GS. Counterpoint: Do randomized controlled trials ignore needed patient populations? No. Chest. 2016;149(5):1130-1132. 3. 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(6):423-424, 426, 429-435. 4. Melloni C, Berger JS, Wang TY, et al. Representation of women in randomized clinical trials of cardiovascular disease prevention. Circ Cardiovasc Qual Outcomes. 2010;3:135-142. 5. Kent DM, Rothwell PM, Ioannidis JP, Altman DG, Hayward RA. Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal. Trials. 2010;11:85. 6. Rothwell PM. Can overall results of clinical trials be applied to all patients? Lancet. 1995;345:1616-1619. 7. Burke JF, Sussman JB, Kent DM, Hayward RA. Three simple rules to ensure reasonably credible subgroup analyses. BMJ. 2015;351:h5651. 8. Gabler NB, Duan N, Liao D, Elmore JG, Ganiats TG, Kravitz RL. Dealing with heterogeneity of treatment effects: Is the literature up to the challenge? Trials. 2009;10:43. 9. Temple R. Enrichment of clinical study populations. Clin Pharmacol Ther. 2010;88:774-778. 10. 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. 11. Voltaire. “La Begueule”. Contes (Tales) 1772.
Rebuttal From Dr Tillotson Glenn S. Tillotson, PhD, FCCP Durham, NC
Dr Courtright1 raises some excellent and valid points regarding the debate, and clearly this is an important aspect of improving medical practice. In essence, AFFILIATIONS:
GST Micro LLC.
FINANCIAL/NONFINANCIAL DISCLOSURE:
None declared. Glenn S. Tillotson, PhD, FCCP, GST Micro LLC, 227 Kayleen Ct, Durham NC 27713; e-mail: gtillotsonconsult@ yahoo.com Copyright Ó 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2016.01.027 CORRESPONDENCE TO:
1133