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Editorials: Point and Counterpoint |

COUNTERPOINT: Do Randomized Controlled Trials Ignore Needed Patient Populations? No FREE TO VIEW

Glenn S. Tillotson, PhD, FCCP
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FINANCIAL/NONFINANCIAL DISCLOSURE: None declared.

CORRESPONDENCE TO: Glenn S. Tillotson, PhD, FCCP, GST Micro LLC, 227 Kayleen Ct, Durham NC 27713


Copyright 2016, . All Rights Reserved.


Chest. 2016;149(5):1130-1132. doi:10.1016/j.chest.2016.01.028
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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, unlike other sciences, has the benefit of enforcing a continual testing of theory by practice. The natural sequelae in therapeutics should be the clinical trial, which tests daily clinical impressions with a deliberate advance to therapy. Thus, it was on this basis that Avicenna, around the turn of the last millennium, suggested that “the trial of a remedy be used in its natural state upon uncomplicated disease.”(p89) He also acknowledged the need to ensure the reproducibility and safety of the test remedy, and he clearly recognized that animal studies are no substitute for studies in humans.

Perhaps one of the best, and earliest, documented clinical trials was conducted by General James Lancaster in 1600, when he sailed four ships to the East Indies. One of four ships was provided with lemon juice, and the other three were not; only the ship with lemon juice was free of scurvy. However, it was not until James Lind in the 18th century that this observation was re-examined. Lind took patients with scurvy who were “as similar as I could have them and they all stayed in one place.” Two received cider; two received elixir of vitriol; two received oranges and lemons; and two received an “electuary as recommended by the house surgeon.” As Lind noted, “the most sudden and visible good was seen in the oranges and lemons patients.” It took the British navy almost 100 years to introduce lemons to its ships, however.

The purpose of this historical perspective was to highlight that clinical research has been, to one extent or another, occurring for at least 2,000 years and has made significant progress. Clinical research in the form of RCTs has been the foundation of both drug development and therapeutic changes. A good example of a clinical trial for dropsy occurred in the 18th century by William Withering, when he studied digitalis and “decided the types of patients who would benefit from digitalis.” He used the patients as their own controls based on clinical history and detailed examination on a daily basis. He thus used loose inclusion and exclusion criteria and a retrospective cohort analysis some 150 years before we understood the principles of such approaches.

I was reminded of an old adage that applies to medical research, allegedly assigned to our surgical colleagues in consideration of sample size: “In my experience…” (N = 1), “In my series…” (n = 2), and “Time after time after time…” (n = 3). However, it is on the basis of clinical experience and developing statistical methods that we are now able to better understand the vagaries of mathematics and clinical research.

Current standards of clinical trials require that, whenever possible, the new therapy be compared with a standard of care, if one exists, and that all efforts be made to ensure that the two or more cohorts are similar in every respect. This latter point is essential if we are to be sure that any benefits are real and not a perception. Thus, to achieve the comparability of cohorts, it is essential to dictate inclusion and exclusion criteria to reduce the outlying cases that can confound the interpretation. In many clinical trials, the actual number of subjects enrolled is a fraction of those who are diagnosed with the same condition. Indeed, from personal experience, it is rare to observe recruitment of 30% to 40% of potential patients. Moreover, the number of evaluable cases diminishes even further as subjects fail to complete therapy or return for assessments or they drop out because of adverse events or death. The latter is perhaps something we cannot prepare for, but we must account for the other factors as we conduct sample size estimations. It is no surprise, therefore, that for a pharmaceutical company today to develop a new drug, it is estimated to cost more than $2.5 billion and take 8 to 10 years.

As an infectious disease/microbiologist, I focus my discussion on anti-infective agents mainly because it is my area of expertise but also because of the rich history of infectious disease studies in the last 150 years; we have learned a great deal from this history about how to study new remedies. First, a look back at diphtheria, a disease which has largely been eradicated in the developed world. Late in the 19th century, however, Behring et al studied 30 patients, six of whom died; using a historical control, the investigators noted that in the prior year, 21 of 32 died without the benefit of the therapeutic serum. Interestingly, the investigators said more cases would be needed to prove the efficacy of this therapy; these numbers were statistically significant, however. The following year, Roux et al reported a study of 300 patients with diphtheria treated with serum. They observed a mortality rate of 26% compared with 51% at the same hospital in the previous 4 years. Notably, the investigators stated “the series were compared as far as possible in respect of type of illness and severity.”(p609)

Another study of immunity in typhoid fever was conducted by Wright and Leishman. Dr Wright was an army surgeon who managed 11,000 soldiers; 3,000 received the inoculation and had a < 1% infection rate compared with a 2.5% infection rate in the remaining 8,000 soldiers. However, he noted a salient point in clinical research in that “these observers were army doctors who would vary in skill and interest in the trial.”(p123)

In the dawning of the antibiotic era, several classic studies were performed in pneumonia, including those of Evans and Gaisford. 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, 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.

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.

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. Interestingly, they quote Snodgrass and Anderson(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 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.

References

Crombie A.C. . Avicenna: Scientist and Philosopher.Wickens G.M..  :89- [PubMed]journal
 
Drummond J.C. .Wilbraham A. . The Englishman’s Food: a History of Five Centuries of English Diet.  1938;:- [PubMed] Jonathan Cape London, Englandjournal
 
Lind J. . A Treatise of the Scurvy.  1753;:- [PubMed] Sands, Murray & Cochran Edinburgh, Scotlandjournal
 
Withering W. . An Account of the Foxglove and Some of its Medical Uses With Practical Remarks on Dropsy and Other Diseases.  1785;:- [PubMed] GCJ & J Robinson Birminghamjournal
 
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.
 
Behring E. .Boer O. .Kossell H. . Zur behandlung diphtheriekranker menschen mit diphtherieheilserum. Deustche Med Wcneshr. 1893;19:389-392 [PubMed]journal
 
Roux E. .Martin L. .Chaillou A. . Trois cent cas de diphtheria traite par le serum antidiphtherique. Ann Inst Pasteur. 1894;8:540-661 [PubMed]journal
 
Wright A.E. .Leishman W.B. . 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 [PubMed]journal. [CrossRef] [PubMed]
 
Evans G.M. .Gaisford W.F. . Treatment of pneumonia with 2(p-aminobenzene sulphonamide) pyridine. Lancet. 1938;2:14-19 [PubMed]journal
 
Wagle P.M. .Sokhey S.H. .Dikshit B.B. .Ganapathy K. . Chemotherapy in plague. Indian M Gaz. 1941;76:29-32 [PubMed]journal
 
Corey G.R. .Stryjewski M.E. . 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:S469-S476 [PubMed]journal. [CrossRef] [PubMed]
 
Snodgrass W.R. .Anderson T. . Sulphanilamide in the treatment of erysipelas: a controlled series of 270 cases. Br Med J. 1937;2:1156-1159 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Crombie A.C. . Avicenna: Scientist and Philosopher.Wickens G.M..  :89- [PubMed]journal
 
Drummond J.C. .Wilbraham A. . The Englishman’s Food: a History of Five Centuries of English Diet.  1938;:- [PubMed] Jonathan Cape London, Englandjournal
 
Lind J. . A Treatise of the Scurvy.  1753;:- [PubMed] Sands, Murray & Cochran Edinburgh, Scotlandjournal
 
Withering W. . An Account of the Foxglove and Some of its Medical Uses With Practical Remarks on Dropsy and Other Diseases.  1785;:- [PubMed] GCJ & J Robinson Birminghamjournal
 
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.
 
Behring E. .Boer O. .Kossell H. . Zur behandlung diphtheriekranker menschen mit diphtherieheilserum. Deustche Med Wcneshr. 1893;19:389-392 [PubMed]journal
 
Roux E. .Martin L. .Chaillou A. . Trois cent cas de diphtheria traite par le serum antidiphtherique. Ann Inst Pasteur. 1894;8:540-661 [PubMed]journal
 
Wright A.E. .Leishman W.B. . 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 [PubMed]journal. [CrossRef] [PubMed]
 
Evans G.M. .Gaisford W.F. . Treatment of pneumonia with 2(p-aminobenzene sulphonamide) pyridine. Lancet. 1938;2:14-19 [PubMed]journal
 
Wagle P.M. .Sokhey S.H. .Dikshit B.B. .Ganapathy K. . Chemotherapy in plague. Indian M Gaz. 1941;76:29-32 [PubMed]journal
 
Corey G.R. .Stryjewski M.E. . 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:S469-S476 [PubMed]journal. [CrossRef] [PubMed]
 
Snodgrass W.R. .Anderson T. . Sulphanilamide in the treatment of erysipelas: a controlled series of 270 cases. Br Med J. 1937;2:1156-1159 [PubMed]journal. [CrossRef] [PubMed]
 
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