0
Editorials: Point and Counterpoint |

POINT: Do Randomized Controlled Trials Ignore Needed Patient Populations? Yes 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, . All Rights Reserved.


Chest. 2016;149(5):1128-1130. doi:10.1016/j.chest.2016.01.029
Text Size: A A A
Published online

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. 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 subjects; disparate enrollment still occurs, however, for important and prevalent patient subgroups.

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 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). 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,, 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. 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. The racial demographic characteristics of IPF differ from sepsis in that it predominantly affects white subjects. 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, 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. 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. After the Physicians’ Health Study, 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.

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., 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.

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. In a post hoc-stratified analysis, the significant reduction in mortality seen in the trial disappeared for the group aged ≥ 65 years. 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.

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. 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.

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 from polypharmacy. 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. 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.

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 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, fulfilling this goal requires equitable participation in trials to avoid unnecessary harm or the provision of substandard care.

Cohen A.M. .Stavri P.Z. .Hersh W.R. . A categorization and analysis of the criticisms of evidence-based medicine. Int J Med Inform. 2004;73:35-43 [PubMed]journal. [CrossRef] [PubMed]
 
Hennekens C.H. .Eberlein K. . A randomized trial of aspirin and beta-carotene among US physicians. Prev Med. 1985;14:165-168 [PubMed]journal. [CrossRef] [PubMed]
 
Carson P. .Ziesche S. .Johnson G. .Cohn J.N. . 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;5:178-187 [PubMed]journal. [CrossRef] [PubMed]
 
Ferguson J.F. .Patel P.N. .Shah R.Y. .et al Race and gender variation in response to evoked inflammation. J Transl Med. 2013;11:63- [PubMed]journal. [CrossRef] [PubMed]
 
Lederer D.J. .Arcasoy S.M. .Barr R.G. .et al Racial and ethnic disparities in idiopathic pulmonary fibrosis: a UNOS/OPTN database analysis. Am J Transplant. 2006;6:2436-2442 [PubMed]journal. [CrossRef] [PubMed]
 
Barnato A.E. .Alexander S.L. .Linde-Zwirble W.T. .Angus D.C. . 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;177:279-284 [PubMed]journal. [CrossRef] [PubMed]
 
Bernard G.R. .Vincent J.L. .Laterre P.F. .et al Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699-709 [PubMed]journal. [CrossRef] [PubMed]
 
King T.E. Jr..Bradford W.Z. .Castro-Bernardini S. .et al A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083-2092 [PubMed]journal. [CrossRef] [PubMed]
 
Wendler D. .Kington R. .Madans J. .et al Are racial and ethnic minorities less willing to participate in health research? PLoS Med. 2006;3:e19- [PubMed]journal. [PubMed]
 
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;12:382-388 [PubMed]journal. [CrossRef] [PubMed]
 
Heiat A. .Gross C.P. .Krumholz H.M. . Representation of the elderly, women, and minorities in heart failure clinical trials. Arch Intern Med. 2002;162:1682-1688 [PubMed]journal. [PubMed]
 
Herrera A.P. .Snipes S.A. .King D.W. .Torres-Vigil I. .Goldberg D.S. .Weinberg A.D. . Disparate inclusion of older adults in clinical trials: priorities and opportunities for policy and practice change. Am J Public Health. 2010;100:S105-S112 [PubMed]journal. [CrossRef] [PubMed]
 
Scott I.A. .Guyatt G.H. . Cautionary tales in the interpretation of clinical studies involving older persons. Arch Intern Med. 2010;170:587-595 [PubMed]journal. [PubMed]
 
Hutchins L.F. .Unger J.M. .Crowley J.J. .Coltman C.A. Jr..Albain K.S. . Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med. 1999;341:2061-2067 [PubMed]journal. [CrossRef] [PubMed]
 
Aberle D.R. .Adams A.M. . National Lung Screening Trial Research Teamet al Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409 [PubMed]journal. [CrossRef] [PubMed]
 
Pinsky P.F. .Gierada D.S. .Hocking W. .Patz E.F. Jr..Kramer B.S. . National lung screening trial findings by age: Medicare-eligible versus under-65 population. Ann Intern Med. 2014;161:627-633 [PubMed]journal. [CrossRef] [PubMed]
 
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?NCAId=274. Accessed October 11, 2015.
 
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;68:387-420 [PubMed]journal. [CrossRef] [PubMed]
 
Coca S.G. .Krumholz H.M. .Garg A.X. .Parikh C.R. . Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease. JAMA. 2006;296:1377-1384 [PubMed]journal. [CrossRef] [PubMed]
 
Davis S. .Wright P.W. .Schulman S.F. .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;56:1710-1718 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Cohen A.M. .Stavri P.Z. .Hersh W.R. . A categorization and analysis of the criticisms of evidence-based medicine. Int J Med Inform. 2004;73:35-43 [PubMed]journal. [CrossRef] [PubMed]
 
Hennekens C.H. .Eberlein K. . A randomized trial of aspirin and beta-carotene among US physicians. Prev Med. 1985;14:165-168 [PubMed]journal. [CrossRef] [PubMed]
 
Carson P. .Ziesche S. .Johnson G. .Cohn J.N. . 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;5:178-187 [PubMed]journal. [CrossRef] [PubMed]
 
Ferguson J.F. .Patel P.N. .Shah R.Y. .et al Race and gender variation in response to evoked inflammation. J Transl Med. 2013;11:63- [PubMed]journal. [CrossRef] [PubMed]
 
Lederer D.J. .Arcasoy S.M. .Barr R.G. .et al Racial and ethnic disparities in idiopathic pulmonary fibrosis: a UNOS/OPTN database analysis. Am J Transplant. 2006;6:2436-2442 [PubMed]journal. [CrossRef] [PubMed]
 
Barnato A.E. .Alexander S.L. .Linde-Zwirble W.T. .Angus D.C. . 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;177:279-284 [PubMed]journal. [CrossRef] [PubMed]
 
Bernard G.R. .Vincent J.L. .Laterre P.F. .et al Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699-709 [PubMed]journal. [CrossRef] [PubMed]
 
King T.E. Jr..Bradford W.Z. .Castro-Bernardini S. .et al A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2083-2092 [PubMed]journal. [CrossRef] [PubMed]
 
Wendler D. .Kington R. .Madans J. .et al Are racial and ethnic minorities less willing to participate in health research? PLoS Med. 2006;3:e19- [PubMed]journal. [PubMed]
 
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;12:382-388 [PubMed]journal. [CrossRef] [PubMed]
 
Heiat A. .Gross C.P. .Krumholz H.M. . Representation of the elderly, women, and minorities in heart failure clinical trials. Arch Intern Med. 2002;162:1682-1688 [PubMed]journal. [PubMed]
 
Herrera A.P. .Snipes S.A. .King D.W. .Torres-Vigil I. .Goldberg D.S. .Weinberg A.D. . Disparate inclusion of older adults in clinical trials: priorities and opportunities for policy and practice change. Am J Public Health. 2010;100:S105-S112 [PubMed]journal. [CrossRef] [PubMed]
 
Scott I.A. .Guyatt G.H. . Cautionary tales in the interpretation of clinical studies involving older persons. Arch Intern Med. 2010;170:587-595 [PubMed]journal. [PubMed]
 
Hutchins L.F. .Unger J.M. .Crowley J.J. .Coltman C.A. Jr..Albain K.S. . Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med. 1999;341:2061-2067 [PubMed]journal. [CrossRef] [PubMed]
 
Aberle D.R. .Adams A.M. . National Lung Screening Trial Research Teamet al Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409 [PubMed]journal. [CrossRef] [PubMed]
 
Pinsky P.F. .Gierada D.S. .Hocking W. .Patz E.F. Jr..Kramer B.S. . National lung screening trial findings by age: Medicare-eligible versus under-65 population. Ann Intern Med. 2014;161:627-633 [PubMed]journal. [CrossRef] [PubMed]
 
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?NCAId=274. Accessed October 11, 2015.
 
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;68:387-420 [PubMed]journal. [CrossRef] [PubMed]
 
Coca S.G. .Krumholz H.M. .Garg A.X. .Parikh C.R. . Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease. JAMA. 2006;296:1377-1384 [PubMed]journal. [CrossRef] [PubMed]
 
Davis S. .Wright P.W. .Schulman S.F. .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;56:1710-1718 [PubMed]journal. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543