- Email: [email protected]
POINT: Do Randomized Controlled Trials Ignore Needed Patient Populations? Yes
[
Editorials Point and Counterpoint
]
POINT:
Do Randomized Controlled Trials Ignore Needed Patient Populations? Yes Katherine Courtright, MD Philadelphia, PA
EBM = evidence-based medicine; HF = heart failure; IPF = idiopathic pulmonary fibrosis; MS = multiple sclerosis; RCT = randomized controlled trials
ABBREVIATIONS:
Evidence-based medicine (EBM) is central to efforts to improve the quality, safety, and affordability of health care. Randomized controlled trials (RCTs) are generally considered the highest level of evidence for assessing the effectiveness of interventions, and they serve as a foundation for EBM practice standards and performance measurements. However, critics cite the limited usefulness of applying EBM to individual patients, partly because RCTs often fail to enroll subjects who are representative of patients seen in the community.1 This failure yields inequity in the provision of high-quality care and creates potential for patient harm. Trialists have come a long way since the landmark 1985 Physicians’ Health Study of low-dose aspirin for the primary prevention of cardiovascular disease enrolled > 90% white male subjects2; disparate enrollment still occurs, however, for important and prevalent patient subgroups.
Minority Groups Racial and ethnic minorities have received the most attention for their notable absence from clinical trials. Beyond the overt ethical issues, the neglect of racial and ethnic minorities from clinical trials has implications for the safety and efficacy of interventions among these 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 Published by Elsevier Inc under license from the American College of Chest Physicians. DOI: http://dx.doi.org/10.1016/j.chest.2016.01.029
1128 Point and Counterpoint
subgroups. Most experts believe that genetic variants partially explain racial variation in the incidence, severity, and outcomes of many diseases. Patients of different races may have a distinct drug response, such as with nitric oxide-mediated vasodilator therapies in heart failure (HF).3 Recent discoveries in sepsis and idiopathic pulmonary fibrosis (IPF) have revealed racial variation in the innate immune response and a mucosal defense protein in the lung,4,5 respectively, that seem to play an important role in these diseases. Black individuals in the United States experience the highest adjusted incidence of severe sepsis.6 However, the landmark Phase III trial that led to approval by the US Food and Drug Administration of recombinant human activated protein C for severe sepsis included < 20% black participants and did not prespecify race as an analytic.7 The racial demographic characteristics of IPF differ from sepsis in that it predominantly affects white subjects.5 Nonetheless, the recent Phase III trial of pirfenidone that solidified its approval by the US Food and Drug Administration for the treatment of IPF enrolled < 50 nonwhite patients,8 an insufficient number by any account for adequate evaluation of the efficacy and safety of pirfenidone among minority populations. Many researchers attribute persistent underenrollment of minorities to disproportionately high rates of mistrust of the health system and unwillingness to participate in research despite evidence to the contrary.9 More likely, racial and ethnic minorities with less frequent health system interactions have fewer opportunities to enroll in clinical trials. Also, linguistic barriers disproportionately prohibit inclusion of ethnic minorities. Other important contributing factors tightly entangled with race and ethnicity include low socioeconomic status, cultural beliefs, and health provider attitudes.10 After the Physicians’ Health Study,2 and many other trials like it at the time, the National Institutes of Health Revitalization Act of 1993 mandated sufficient inclusion of racial minority groups and women in their funded clinical trials. This necessary step has proven insufficient, and efforts continue with nationwide special interest groups (eg, Eliminating Disparities in Clinical Trials project) and protected National Institutes of Health funding mechanisms for disparities research.11
[
149#5 CHEST MAY 2016
]
Elderly Older adults assume a disproportionate burden of disease and health-care expenditures, but they are vastly underrepresented in clinical trials. Explicit age-based exclusion criteria may exist because of commonly held beliefs that the elderly are more subject to manipulation and exploitation. Although a noble intent, these assumptions instead leave elderly individuals vulnerable to harm from therapies without proven efficacy and safety.12,13 For example, cancer therapies are often toxic and difficult to tolerate, particularly among older adults with multiple comorbidities. However, among 15 years’ worth of National Cancer Institute-sponsored lung cancer trials, slightly more than one-third of patients enrolled were aged $ 65 years despite two-thirds of lung cancer cases occurring in this age group within the general population.14 This imbalance is not limited to therapeutic trials. The National Lung Screening Trial included only 25% of participants aged $ 65 years at randomization, and none was aged > 74 years.15 In a post hoc-stratified analysis, the significant reduction in mortality seen in the trial disappeared for the group aged $ 65 years.16 Moreover, the higher rate of false- positive findings and increased frequency of invasive procedures among this older subgroup should raise concerns about their risk-benefit ratio from lung cancer screening with low-dose CT scans. Nonetheless, the Centers for Medicare & Medicaid Services determined that “the evidence is sufficient” to cover screening for eligible beneficiaries up to 77 years.17 Finally, low enrollment of older adults in RCTs is not unique to cancer. Although > 80% of patients hospitalized for HF are aged > 65 years, one review of all HF trials from 1985 to 1999 reported the mean age of participants to be 61.4 years, and nearly one-third of the protocols explicitly excluded elderly patients.11 More recently, the mean age of participants enrolled in HF trials has been increasing but is not on pace with the projected doubling of the US population aged $ 65 years in the coming decades.
Multimorbidity A recently recognized patient subgroup missing from the EBM evidence base is aptly named multimorbidity; that is, the occurrence of $ 2 chronic conditions in one person. This missing subgroup poses a serious challenge for the conduct and applicability of clinical trials. Multimorbidity is associated with increased disability and diminished quality of life, and these patients are at risk for inadequate care and adverse treatment effects
journal.publications.chestnet.org
from polypharmacy.18 Further complicating matters, the incidence of multimorbidity increases with age, with a prevalence exceeding 65% in those aged $ 65 years. Medical care is often organized into silos that deal with individual diseases, and RCTs are similarly designed. Inclusion and exclusion criteria select for an “ideal” study population, in which patients have the target disease with minimal other risk factors and high protocol adherence. This approach minimizes the threat of residual confounding despite randomization that could diminish the observed treatment effect. However, this process leads to a study population that does not truly reflect the target population. For example, nearly one-half of patients who present with acute myocardial infarction have chronic renal disease; however, more than one-half of cardiovascular clinical trials explicitly excluded these patients.19 Patients with renal disease often experience an increased risk of bleeding due to platelet dysfunction, which has important implications for the safety of antiplatelet therapies used for the primary or secondary prevention of cardiovascular disease. For these individuals, bedside clinicians have to decide when and how to apply “the evidence” without much guidance.
Statistical and Practical Solutions Directly overcoming the barriers to equitable enrollment in clinical trials is not always feasible. Personnel and financial constraints limit the reach of study recruiters, and small community medical centers often lack the necessary infrastructure to be a clinical trial site. Traditional statistical methods used to address issues with external validity all have limitations. Subgroup analyses may demonstrate that study results are upheld, but they are often underpowered to make such claims and are prone to type II error. Alternatively, sensitivity analyses may show a large subgroup effect size, needed to alter the inference from the study population, but these are estimates and not based on actual patient data. Poststratification, or adjusted analysis, requires careful a priori selection of covariates or it risks introducing bias. Follow-up observational studies are sometimes advocated, but they are time-consuming, expensive, and can delay dissemination of effective therapies or recognition of harm. A mandatory national patient registry, such as that created for lung cancer screening, may serve as a reasonable middle-ground that allows for widespread dissemination of an efficacious intervention or drug
1129
while simultaneously tracking safety and effectiveness in populations not well represented in the original RCT. Pragmatic clinical trials are a high-quality alternative or supplement to RCTs and by definition include a diverse population from heterogeneous practice settings in an effort to bridge the gaps between EBM, patient-centered medicine, and efficient care. The ethicality of clinical research relies on an overarching goal of developing generalizable knowledge to improve human health or understand human biology. Coupled with evidence that suggests clinical trial participants may have better health outcomes,20 fulfilling this goal requires equitable participation in trials to avoid unnecessary harm or the provision of substandard care.
References 1. Cohen AM, Stavri PZ, Hersh WR. A categorization and analysis of the criticisms of evidence-based medicine. Int J Med Inform. 2004;73(1):35-43. 2. Hennekens CH, Eberlein K. A randomized trial of aspirin and betacarotene among US physicians. Prev Med. 1985;14(2):165-168. 3. Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail. 1999;5(3):178-187. 4. Ferguson JF, Patel PN, Shah RY, et al. Race and gender variation in response to evoked inflammation. J Transl Med. 2013;11:63. 5. Lederer DJ, Arcasoy SM, Barr RG, et al. Racial and ethnic disparities in idiopathic pulmonary fibrosis: a UNOS/OPTN database analysis. Am J Transplant. 2006;6(10):2436-2442. 6. Barnato AE, Alexander SL, Linde-Zwirble WT, Angus DC. Racial variation in the incidence, care, and outcomes of severe sepsis: analysis of population, patient, and hospital characteristics. Am J Respir Crit Care Med. 2008;177(3):279-284. 7. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699-709. 8. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-2092. 9. Wendler D, Kington R, Madans J, et al. Are racial and ethnic minorities less willing to participate in health research? PLoS Med. 2006;3(2):e19. 10. Hussain-Gambles M, Atkin K, Leese B. Why ethnic minority groups are under-represented in clinical trials: a review of the literature. Health Soc Care Community. 2004;12(5):382-388. 11. Heiat A, Gross CP, Krumholz HM. Representation of the elderly, women, and minorities in heart failure clinical trials. Arch Intern Med. 2002;162(15):1682-1688. 12. Herrera AP, Snipes SA, King DW, Torres-Vigil I, Goldberg DS, Weinberg AD. Disparate inclusion of older adults in clinical trials: priorities and opportunities for policy and practice change. Am J Public Health. 2010;100(suppl 1):S105-S112. 13. Scott IA, Guyatt GH. Cautionary tales in the interpretation of clinical studies involving older persons. Arch Intern Med. 2010;170(7):587-595. 14. Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS. Underrepresentation of patients 65 years of age or older in cancertreatment trials. N Engl J Med. 1999;341(27):2061-2067. 15. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5): 395-409.
1130 Point and Counterpoint
16. Pinsky PF, Gierada DS, Hocking W, Patz EF Jr, Kramer BS. National lung screening trial findings by age: Medicare-eligible versus under65 population. Ann Intern Med. 2014;161(9):627-633. 17. Medicare Coverage Database: Screening for Lung Cancer with Low Dose Computed Tomography (LDCT) (CAG-00439N) Feb 5 2015. Centers for Medicare & Medicaid Services website. https://www.cms. gov/medicare-coverage-database/details/nca-decision-memo.aspx? NCAId¼274. Accessed October 11, 2015. 18. Lehnert T, Heider D, Leicht H, et al. Review: health care utilization and costs of elderly persons with multiple chronic conditions. Med Care Res Rev. 2011;68(4):387-420. 19. Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease. JAMA. 2006;296(11):1377-1384. 20. Davis S, Wright PW, Schulman SF, et al. Participants in prospective, randomized clinical trials for resected non-small cell lung cancer have improved survival compared with nonparticipants in such trials. Cancer. 1985;56(7):1710-1718.
COUNTERPOINT:
Do Randomized Controlled Trials Ignore Needed Patient Populations? No Glenn S. Tillotson, PhD, FCCP Durham, NC
Deliberate experiments designed to assess the value and merits of therapeutic processes in patients are a critical part of modern medicine. These experiments are rarely easy, and they can be costly and time-consuming. If badly designed, they can even be a threat to patients. The efficiency of such experiments is very important. Over time, randomized controlled trials (RCTs) have been developed and have evolved to ensure clinical relevance, but it is impossible to ensure that everyone who has a disease is included in a study for reasons of scientific interpretation. I will use historical context and how research has evolved to explore this topic. We can go back to approximately 2000 BC to learn what the ancient Egyptians practiced in terms of treating certain lesions, obviously with a range of herbs and potions. Indeed, according to Herodotus, the ancient Babylonians used to exhibit their sick in public so that passersby might advise suitable treatment based on similar cases. However, due to the lack of records, we do not know if this method benefited medicine. Medicine, AFFILIATIONS:
GST Micro LLC.
None declared. Glenn S. Tillotson, PhD, FCCP, GST Micro LLC, 227 Kayleen Ct, Durham NC 27713; e-mail: gtillotsonconsult@ yahoo.com Copyright Ó 2016 Published by Elsevier Inc under license from the American College of Chest Physicians. DOI: http://dx.doi.org/10.1016/j.chest.2016.01.028 FINANCIAL/NONFINANCIAL DISCLOSURE: CORRESPONDENCE TO:
[
149#5 CHEST MAY 2016
]
Editorials Point and Counterpoint
]
POINT:
Do Randomized Controlled Trials Ignore Needed Patient Populations? Yes Katherine Courtright, MD Philadelphia, PA
EBM = evidence-based medicine; HF = heart failure; IPF = idiopathic pulmonary fibrosis; MS = multiple sclerosis; RCT = randomized controlled trials
ABBREVIATIONS:
Evidence-based medicine (EBM) is central to efforts to improve the quality, safety, and affordability of health care. Randomized controlled trials (RCTs) are generally considered the highest level of evidence for assessing the effectiveness of interventions, and they serve as a foundation for EBM practice standards and performance measurements. However, critics cite the limited usefulness of applying EBM to individual patients, partly because RCTs often fail to enroll subjects who are representative of patients seen in the community.1 This failure yields inequity in the provision of high-quality care and creates potential for patient harm. Trialists have come a long way since the landmark 1985 Physicians’ Health Study of low-dose aspirin for the primary prevention of cardiovascular disease enrolled > 90% white male subjects2; disparate enrollment still occurs, however, for important and prevalent patient subgroups.
Minority Groups Racial and ethnic minorities have received the most attention for their notable absence from clinical trials. Beyond the overt ethical issues, the neglect of racial and ethnic minorities from clinical trials has implications for the safety and efficacy of interventions among these 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 Published by Elsevier Inc under license from the American College of Chest Physicians. DOI: http://dx.doi.org/10.1016/j.chest.2016.01.029
1128 Point and Counterpoint
subgroups. Most experts believe that genetic variants partially explain racial variation in the incidence, severity, and outcomes of many diseases. Patients of different races may have a distinct drug response, such as with nitric oxide-mediated vasodilator therapies in heart failure (HF).3 Recent discoveries in sepsis and idiopathic pulmonary fibrosis (IPF) have revealed racial variation in the innate immune response and a mucosal defense protein in the lung,4,5 respectively, that seem to play an important role in these diseases. Black individuals in the United States experience the highest adjusted incidence of severe sepsis.6 However, the landmark Phase III trial that led to approval by the US Food and Drug Administration of recombinant human activated protein C for severe sepsis included < 20% black participants and did not prespecify race as an analytic.7 The racial demographic characteristics of IPF differ from sepsis in that it predominantly affects white subjects.5 Nonetheless, the recent Phase III trial of pirfenidone that solidified its approval by the US Food and Drug Administration for the treatment of IPF enrolled < 50 nonwhite patients,8 an insufficient number by any account for adequate evaluation of the efficacy and safety of pirfenidone among minority populations. Many researchers attribute persistent underenrollment of minorities to disproportionately high rates of mistrust of the health system and unwillingness to participate in research despite evidence to the contrary.9 More likely, racial and ethnic minorities with less frequent health system interactions have fewer opportunities to enroll in clinical trials. Also, linguistic barriers disproportionately prohibit inclusion of ethnic minorities. Other important contributing factors tightly entangled with race and ethnicity include low socioeconomic status, cultural beliefs, and health provider attitudes.10 After the Physicians’ Health Study,2 and many other trials like it at the time, the National Institutes of Health Revitalization Act of 1993 mandated sufficient inclusion of racial minority groups and women in their funded clinical trials. This necessary step has proven insufficient, and efforts continue with nationwide special interest groups (eg, Eliminating Disparities in Clinical Trials project) and protected National Institutes of Health funding mechanisms for disparities research.11
[
149#5 CHEST MAY 2016
]
Elderly Older adults assume a disproportionate burden of disease and health-care expenditures, but they are vastly underrepresented in clinical trials. Explicit age-based exclusion criteria may exist because of commonly held beliefs that the elderly are more subject to manipulation and exploitation. Although a noble intent, these assumptions instead leave elderly individuals vulnerable to harm from therapies without proven efficacy and safety.12,13 For example, cancer therapies are often toxic and difficult to tolerate, particularly among older adults with multiple comorbidities. However, among 15 years’ worth of National Cancer Institute-sponsored lung cancer trials, slightly more than one-third of patients enrolled were aged $ 65 years despite two-thirds of lung cancer cases occurring in this age group within the general population.14 This imbalance is not limited to therapeutic trials. The National Lung Screening Trial included only 25% of participants aged $ 65 years at randomization, and none was aged > 74 years.15 In a post hoc-stratified analysis, the significant reduction in mortality seen in the trial disappeared for the group aged $ 65 years.16 Moreover, the higher rate of false- positive findings and increased frequency of invasive procedures among this older subgroup should raise concerns about their risk-benefit ratio from lung cancer screening with low-dose CT scans. Nonetheless, the Centers for Medicare & Medicaid Services determined that “the evidence is sufficient” to cover screening for eligible beneficiaries up to 77 years.17 Finally, low enrollment of older adults in RCTs is not unique to cancer. Although > 80% of patients hospitalized for HF are aged > 65 years, one review of all HF trials from 1985 to 1999 reported the mean age of participants to be 61.4 years, and nearly one-third of the protocols explicitly excluded elderly patients.11 More recently, the mean age of participants enrolled in HF trials has been increasing but is not on pace with the projected doubling of the US population aged $ 65 years in the coming decades.
Multimorbidity A recently recognized patient subgroup missing from the EBM evidence base is aptly named multimorbidity; that is, the occurrence of $ 2 chronic conditions in one person. This missing subgroup poses a serious challenge for the conduct and applicability of clinical trials. Multimorbidity is associated with increased disability and diminished quality of life, and these patients are at risk for inadequate care and adverse treatment effects
journal.publications.chestnet.org
from polypharmacy.18 Further complicating matters, the incidence of multimorbidity increases with age, with a prevalence exceeding 65% in those aged $ 65 years. Medical care is often organized into silos that deal with individual diseases, and RCTs are similarly designed. Inclusion and exclusion criteria select for an “ideal” study population, in which patients have the target disease with minimal other risk factors and high protocol adherence. This approach minimizes the threat of residual confounding despite randomization that could diminish the observed treatment effect. However, this process leads to a study population that does not truly reflect the target population. For example, nearly one-half of patients who present with acute myocardial infarction have chronic renal disease; however, more than one-half of cardiovascular clinical trials explicitly excluded these patients.19 Patients with renal disease often experience an increased risk of bleeding due to platelet dysfunction, which has important implications for the safety of antiplatelet therapies used for the primary or secondary prevention of cardiovascular disease. For these individuals, bedside clinicians have to decide when and how to apply “the evidence” without much guidance.
Statistical and Practical Solutions Directly overcoming the barriers to equitable enrollment in clinical trials is not always feasible. Personnel and financial constraints limit the reach of study recruiters, and small community medical centers often lack the necessary infrastructure to be a clinical trial site. Traditional statistical methods used to address issues with external validity all have limitations. Subgroup analyses may demonstrate that study results are upheld, but they are often underpowered to make such claims and are prone to type II error. Alternatively, sensitivity analyses may show a large subgroup effect size, needed to alter the inference from the study population, but these are estimates and not based on actual patient data. Poststratification, or adjusted analysis, requires careful a priori selection of covariates or it risks introducing bias. Follow-up observational studies are sometimes advocated, but they are time-consuming, expensive, and can delay dissemination of effective therapies or recognition of harm. A mandatory national patient registry, such as that created for lung cancer screening, may serve as a reasonable middle-ground that allows for widespread dissemination of an efficacious intervention or drug
1129
while simultaneously tracking safety and effectiveness in populations not well represented in the original RCT. Pragmatic clinical trials are a high-quality alternative or supplement to RCTs and by definition include a diverse population from heterogeneous practice settings in an effort to bridge the gaps between EBM, patient-centered medicine, and efficient care. The ethicality of clinical research relies on an overarching goal of developing generalizable knowledge to improve human health or understand human biology. Coupled with evidence that suggests clinical trial participants may have better health outcomes,20 fulfilling this goal requires equitable participation in trials to avoid unnecessary harm or the provision of substandard care.
References 1. Cohen AM, Stavri PZ, Hersh WR. A categorization and analysis of the criticisms of evidence-based medicine. Int J Med Inform. 2004;73(1):35-43. 2. Hennekens CH, Eberlein K. A randomized trial of aspirin and betacarotene among US physicians. Prev Med. 1985;14(2):165-168. 3. Carson P, Ziesche S, Johnson G, Cohn JN. Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group. J Card Fail. 1999;5(3):178-187. 4. Ferguson JF, Patel PN, Shah RY, et al. Race and gender variation in response to evoked inflammation. J Transl Med. 2013;11:63. 5. Lederer DJ, Arcasoy SM, Barr RG, et al. Racial and ethnic disparities in idiopathic pulmonary fibrosis: a UNOS/OPTN database analysis. Am J Transplant. 2006;6(10):2436-2442. 6. Barnato AE, Alexander SL, Linde-Zwirble WT, Angus DC. Racial variation in the incidence, care, and outcomes of severe sepsis: analysis of population, patient, and hospital characteristics. Am J Respir Crit Care Med. 2008;177(3):279-284. 7. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699-709. 8. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-2092. 9. Wendler D, Kington R, Madans J, et al. Are racial and ethnic minorities less willing to participate in health research? PLoS Med. 2006;3(2):e19. 10. Hussain-Gambles M, Atkin K, Leese B. Why ethnic minority groups are under-represented in clinical trials: a review of the literature. Health Soc Care Community. 2004;12(5):382-388. 11. Heiat A, Gross CP, Krumholz HM. Representation of the elderly, women, and minorities in heart failure clinical trials. Arch Intern Med. 2002;162(15):1682-1688. 12. Herrera AP, Snipes SA, King DW, Torres-Vigil I, Goldberg DS, Weinberg AD. Disparate inclusion of older adults in clinical trials: priorities and opportunities for policy and practice change. Am J Public Health. 2010;100(suppl 1):S105-S112. 13. Scott IA, Guyatt GH. Cautionary tales in the interpretation of clinical studies involving older persons. Arch Intern Med. 2010;170(7):587-595. 14. Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr, Albain KS. Underrepresentation of patients 65 years of age or older in cancertreatment trials. N Engl J Med. 1999;341(27):2061-2067. 15. National Lung Screening Trial Research Team, Aberle DR, Adams AM, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5): 395-409.
1130 Point and Counterpoint
16. Pinsky PF, Gierada DS, Hocking W, Patz EF Jr, Kramer BS. National lung screening trial findings by age: Medicare-eligible versus under65 population. Ann Intern Med. 2014;161(9):627-633. 17. Medicare Coverage Database: Screening for Lung Cancer with Low Dose Computed Tomography (LDCT) (CAG-00439N) Feb 5 2015. Centers for Medicare & Medicaid Services website. https://www.cms. gov/medicare-coverage-database/details/nca-decision-memo.aspx? NCAId¼274. Accessed October 11, 2015. 18. Lehnert T, Heider D, Leicht H, et al. Review: health care utilization and costs of elderly persons with multiple chronic conditions. Med Care Res Rev. 2011;68(4):387-420. 19. Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease. JAMA. 2006;296(11):1377-1384. 20. Davis S, Wright PW, Schulman SF, et al. Participants in prospective, randomized clinical trials for resected non-small cell lung cancer have improved survival compared with nonparticipants in such trials. Cancer. 1985;56(7):1710-1718.
COUNTERPOINT:
Do Randomized Controlled Trials Ignore Needed Patient Populations? No Glenn S. Tillotson, PhD, FCCP Durham, NC
Deliberate experiments designed to assess the value and merits of therapeutic processes in patients are a critical part of modern medicine. These experiments are rarely easy, and they can be costly and time-consuming. If badly designed, they can even be a threat to patients. The efficiency of such experiments is very important. Over time, randomized controlled trials (RCTs) have been developed and have evolved to ensure clinical relevance, but it is impossible to ensure that everyone who has a disease is included in a study for reasons of scientific interpretation. I will use historical context and how research has evolved to explore this topic. We can go back to approximately 2000 BC to learn what the ancient Egyptians practiced in terms of treating certain lesions, obviously with a range of herbs and potions. Indeed, according to Herodotus, the ancient Babylonians used to exhibit their sick in public so that passersby might advise suitable treatment based on similar cases. However, due to the lack of records, we do not know if this method benefited medicine. Medicine, AFFILIATIONS:
GST Micro LLC.
None declared. Glenn S. Tillotson, PhD, FCCP, GST Micro LLC, 227 Kayleen Ct, Durham NC 27713; e-mail: gtillotsonconsult@ yahoo.com Copyright Ó 2016 Published by Elsevier Inc under license from the American College of Chest Physicians. DOI: http://dx.doi.org/10.1016/j.chest.2016.01.028 FINANCIAL/NONFINANCIAL DISCLOSURE: CORRESPONDENCE TO:
[
149#5 CHEST MAY 2016
]