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November 16, 1984, Vol 252, No. 19 >
ARTICLE | November 16, 1984

Scientific Challenges in the Application of Randomized Trials FREE

Michael S. Kramer, MD; Stanley H. Shapiro, PhD
[+] Author Affiliations

Reprint requests to Department of Epidemiology and Health, McGill University, Purvis Hall, 1020 Pine Ave W, Montreal, Quebec, Canada H3A 1A2 (Dr Kramer).


JAMA. 1984;252(19):2739-2745. doi:10.1001/jama.1984.03350190041017
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References

In recent years, scientific challenges in the application of randomized trials have become more apparent, especially with the extension of such trials to the assessment of nondrug treatments, such as health education, psychotherapy, and health care provision. Six issues (individual v group randomization, blinding and unblinding, the effect of trial participation on outcome, selective subject participation, treatment compliance, and standardized v individualized treatment) are discussed in terms of their impact on internal validity, generalizability (external validity), and clinical relevance. Specific design strategies may be necessary to enhance these methodological and clinical desiderata. Attention to these challenges should lead to improvements in future randomized trials.

(JAMA 1984;252:2739-2745)

REFERENCES

1 +
Fisher RA: The Design of Experiments , ed 8. New York, Hafner, 1966;.
2 +
Hill AB: Statistical Methods in Clinical and Preventive Medicine . Edinburgh, Churchill Livingstone, 1962;.
3 +
Shapiro SH, Louis TA (eds): Clinical Trials: Issues and Approaches . New York, Marcel Dekker Inc, 1983;.
4 +
Fletcher RH, Fletcher SW:  Clinical research in general medical journals . N Engl J Med 1979;;301:180-183.
5 +
Schwartz D, Lellouch J:  Explanatory and pragmatic attitudes in therapeutic trials . J Chronic Dis 1967;;20:637-648.
6 +
Sackett DL, Gent M:  Controversy in counting and attributing events in clinical trials . N Engl J Med 1979;;301:1410-1412.
7 +
Louis TA, Shapiro SH:  Critical issues in the conduct and interpretation of clinical trials . Annu Rev Public Health 1983;;43:25-46.
8 +
Ederer F:  Practical problems in collaborative clinical trials . Am J Epidemiol 1975;;102:111-118.
9 +
Feinstein AR:  Clinical biostatistics XXIV: The role of randomization in sampling, testing, allocation, and credulous idolatry (conclusion) . Clin Pharmacol Ther 1973;;14:1035-1051.
10 +
Schafer A:  The ethics of the randomized clinical trial . N Engl J Med 1982;;307:719-724.
11 +
Lebacqz K:  Ethical aspects of clinical trials , in Shapiro SH, Louis TA (eds): Clinical Trials: Issues and Approaches . New York, Marcel Dekker Inc, 1983;, pp 81-98.
12 +
Thomson ME, Kramer MS:  Methodological standards for controlled clinical trials of early contact and maternal-infant behavior . Pediatrics 1984;;73:294-300.
13 +
Cornfield J, Mitchell S:  Selected risk factors in coronary disease: Possible intervention effects . Arch Environ Health 1969;;19:382-394.
14 +
Buck C, Donner A:  The design of controlled experiments in the evaluation of non-therapeutic interventions . J Chronic Dis 1982;; 35:531-538.
15 +
Louis TA, Lavori PW, Bailar JC, et al:  Crossover and self-controlled designs in clinical research . N Engl J Med 1984;;310:24-31.
16 +
Gray-Donald K, Kramer MS, Munday S, et al:  Effect of in-hospital formula supplementation on the duration of breast feeding: A controlled clinical trial . Pediatrics , in press.
17 +
 Multiple Risk Factor Intervention Trial Research Group: Multiple risk factor intervention trial: Risk factor changes and mortality results . JAMA 1982;;248:1465-1477.
18 +
Rickels K, Downing RW:  Side reactions in neurotics: II. Can patients judge which symptoms are caused by their medication? J Clin Pharmacol 1970;;10:298-305.
19 +
Karlowski TR, Chalmers TC, Frenkel LD, et al:  Ascorbic acid for the common cold: A prophylactic and therapeutic trial . JAMA 1975;; 231:1038-1042.
20 +
Jenkins CD:  Recent evidence supporting psychological and social risk factors for coronary disease . N Engl J Med 1976;;294:987-994, 1033-1038.
21 +
Vaillant GE:  Natural history of male psychological health: Effects of mental health on physical health . N Engl J Med 1979;;301:1249-1254.
22 +
Cassell J:  The contribution of the social environment to host resistance . Am J Epidemiol 1976;;104:107-123.
23 +
Cobb S:  Social support as a moderator of life stress . Psychosom Med 1976;;38:300-314.
24 +
Kaplan BH, Cassel JC, Gore S:  Social support and health . Med Care 1977;;15( (suppl 5) ):47-57.
25 +
Martin AR, Wolf MA, Thibodeau LA, et al:  A trial of two strategies to modify the test-ordering behavior of medical residents . N Engl J Med 1980;;303:1330-1336.
26 +
Bergevin Y, Dougherty C, Kramer MS:  Do infant formula samples shorten the duration of breast-feeding? Lancet 1983;;1:1148-1151.
27 +
Garceau AJ, Donaldson RM, O'Hara ET, et al:  A controlled trial of prophylactic portacavalshunt surgery . N Engl J Med 1964;;270:496-500.
28 +
 Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension: Results in patients with diastolic blood pressures averaging 115 through 128 mm Hg . JAMA 1967;;202:1028-1034.
29 +
 The Coronary Drug Project Research Group: The Coronary Drug Project: Design, methods, and baseline results . Circulation 1973;; 47( (suppl 1) ):I1-I50.
30 +
 The Coronary Drug Project Research Group: Influence of adherence to treatment and response of cholesterol on mortality in the Coronary Drug Project . N Engl J Med 1980;; 303:1038-1041.
31 +
 University Group Diabetes Program: A study of the effects of hypoglycemic agents on vascular complications in patients with adultonset diabetes: I. Design, methods, and baseline results. II. Mortality results . Diabetes 1970;; 19( (suppl 2) ):747-830.
32 +
Feinstein AR:  Clinical biostatistics VIII: An analytic appraisal of the University Group Diabetes Program (UGDP) study . Clin Pharmacol Ther 1971;;12:167-191.
33 +
Seaman AJ, Griswold HE, Reaume R, et al:  Long-term anticoagulant prophylaxis after myocardial infarction: Final report . N Engl J Med 1969;;281:115-119.
34 +
Mosteller F, Gilbert JP, McPeek B:  Controversies in design and analysis of clinical trials , in Shapiro SH, Louis TA (eds): Clinical Trials: Issues and Approaches . New York, Marcel Dekker Inc, 1983;, pp 13-64.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Fisher RA: The Design of Experiments , ed 8. New York, Hafner, 1966;.
2 +
Hill AB: Statistical Methods in Clinical and Preventive Medicine . Edinburgh, Churchill Livingstone, 1962;.
3 +
Shapiro SH, Louis TA (eds): Clinical Trials: Issues and Approaches . New York, Marcel Dekker Inc, 1983;.
4 +
Fletcher RH, Fletcher SW:  Clinical research in general medical journals . N Engl J Med 1979;;301:180-183.
5 +
Schwartz D, Lellouch J:  Explanatory and pragmatic attitudes in therapeutic trials . J Chronic Dis 1967;;20:637-648.
6 +
Sackett DL, Gent M:  Controversy in counting and attributing events in clinical trials . N Engl J Med 1979;;301:1410-1412.
7 +
Louis TA, Shapiro SH:  Critical issues in the conduct and interpretation of clinical trials . Annu Rev Public Health 1983;;43:25-46.
8 +
Ederer F:  Practical problems in collaborative clinical trials . Am J Epidemiol 1975;;102:111-118.
9 +
Feinstein AR:  Clinical biostatistics XXIV: The role of randomization in sampling, testing, allocation, and credulous idolatry (conclusion) . Clin Pharmacol Ther 1973;;14:1035-1051.
10 +
Schafer A:  The ethics of the randomized clinical trial . N Engl J Med 1982;;307:719-724.
11 +
Lebacqz K:  Ethical aspects of clinical trials , in Shapiro SH, Louis TA (eds): Clinical Trials: Issues and Approaches . New York, Marcel Dekker Inc, 1983;, pp 81-98.
12 +
Thomson ME, Kramer MS:  Methodological standards for controlled clinical trials of early contact and maternal-infant behavior . Pediatrics 1984;;73:294-300.
13 +
Cornfield J, Mitchell S:  Selected risk factors in coronary disease: Possible intervention effects . Arch Environ Health 1969;;19:382-394.
14 +
Buck C, Donner A:  The design of controlled experiments in the evaluation of non-therapeutic interventions . J Chronic Dis 1982;; 35:531-538.
15 +
Louis TA, Lavori PW, Bailar JC, et al:  Crossover and self-controlled designs in clinical research . N Engl J Med 1984;;310:24-31.
16 +
Gray-Donald K, Kramer MS, Munday S, et al:  Effect of in-hospital formula supplementation on the duration of breast feeding: A controlled clinical trial . Pediatrics , in press.
17 +
 Multiple Risk Factor Intervention Trial Research Group: Multiple risk factor intervention trial: Risk factor changes and mortality results . JAMA 1982;;248:1465-1477.
18 +
Rickels K, Downing RW:  Side reactions in neurotics: II. Can patients judge which symptoms are caused by their medication? J Clin Pharmacol 1970;;10:298-305.
19 +
Karlowski TR, Chalmers TC, Frenkel LD, et al:  Ascorbic acid for the common cold: A prophylactic and therapeutic trial . JAMA 1975;; 231:1038-1042.
20 +
Jenkins CD:  Recent evidence supporting psychological and social risk factors for coronary disease . N Engl J Med 1976;;294:987-994, 1033-1038.
21 +
Vaillant GE:  Natural history of male psychological health: Effects of mental health on physical health . N Engl J Med 1979;;301:1249-1254.
22 +
Cassell J:  The contribution of the social environment to host resistance . Am J Epidemiol 1976;;104:107-123.
23 +
Cobb S:  Social support as a moderator of life stress . Psychosom Med 1976;;38:300-314.
24 +
Kaplan BH, Cassel JC, Gore S:  Social support and health . Med Care 1977;;15( (suppl 5) ):47-57.
25 +
Martin AR, Wolf MA, Thibodeau LA, et al:  A trial of two strategies to modify the test-ordering behavior of medical residents . N Engl J Med 1980;;303:1330-1336.
26 +
Bergevin Y, Dougherty C, Kramer MS:  Do infant formula samples shorten the duration of breast-feeding? Lancet 1983;;1:1148-1151.
27 +
Garceau AJ, Donaldson RM, O'Hara ET, et al:  A controlled trial of prophylactic portacavalshunt surgery . N Engl J Med 1964;;270:496-500.
28 +
 Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension: Results in patients with diastolic blood pressures averaging 115 through 128 mm Hg . JAMA 1967;;202:1028-1034.
29 +
 The Coronary Drug Project Research Group: The Coronary Drug Project: Design, methods, and baseline results . Circulation 1973;; 47( (suppl 1) ):I1-I50.
30 +
 The Coronary Drug Project Research Group: Influence of adherence to treatment and response of cholesterol on mortality in the Coronary Drug Project . N Engl J Med 1980;; 303:1038-1041.
31 +
 University Group Diabetes Program: A study of the effects of hypoglycemic agents on vascular complications in patients with adultonset diabetes: I. Design, methods, and baseline results. II. Mortality results . Diabetes 1970;; 19( (suppl 2) ):747-830.
32 +
Feinstein AR:  Clinical biostatistics VIII: An analytic appraisal of the University Group Diabetes Program (UGDP) study . Clin Pharmacol Ther 1971;;12:167-191.
33 +
Seaman AJ, Griswold HE, Reaume R, et al:  Long-term anticoagulant prophylaxis after myocardial infarction: Final report . N Engl J Med 1969;;281:115-119.
34 +
Mosteller F, Gilbert JP, McPeek B:  Controversies in design and analysis of clinical trials , in Shapiro SH, Louis TA (eds): Clinical Trials: Issues and Approaches . New York, Marcel Dekker Inc, 1983;, pp 13-64.

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