Historical Controls

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COMMENTARIES 145

Age

Figure. Comparison of 95th percentile values for sys-tolic pressure of male youths by age among selected studies. Heavy line represents values reported by NHLBI Task Force on Blood Pressure Control in Children. Ab-breviation used is: NHS, National Health Survey. (Re-printed with permission from Fixler’#{176}).

intake) as general health measures. I recommend restraint in this area until we can have reasonable assurance that the long-term cost/benefit ratio is favorable.

. WALLACE W. MCCRORY, MD

Division of Pediatric Nephrology

New York Hospital-Cornell Medical Center New York

REFERENCES

1. Adams FH, Landaw EM: What are healthy blood pressures for children? Pediatrics 68:268, 1981

2. Blumenthal 5, Epps RP, Heavenrich R, et al: Report of the task force on blood pressure control in children. Pediatrics.

59(supp):7

3. Szklo M.: Epidemiologic patterns of blood pressure in chil-then. Epidemiologic Rev 1:143, 1979

4. Voors AW, Webber LS, Fredrichs RR, et al: Body weight and body mass as determinants of basal blood pressure in children: The Bogalusa heart study. Am J Epidemiol

106:101, 1977

5. Gutgesell M, Terrell G, Labarthe D: Pediatric blood pres-sure: Ethnic comparisons in a primary care center. H,per-tension 3:39, 1981

6. Higgins MW, Keller JB, Metzner HL, et al: Studies of blood pressure in Tecumseh, Michigan. II. Antecedents in child-hood of high blood pressure in young adults. Hypertension

2(suppl 1):1, 1980

7. Katz SH, Hediger ML, Schall JI, et al: Blood pressure growth and maturation from childhood through adolescence. Hyper-tension 2(suppl):55, 1980

8. Rosner B, Hennekens CH, Kass EH, et al: Age-specific correlation analysis of longitudinal blood pressure data. Am J Epidemiol 103:306, 1977

9. Zinner SH, Margolius HS, Rosner B, et al: Stability of blood pressure rank and urinary kallikrein concentration in child-hood: An eight-year follow-up. Circulation 58:908, 1978 10. Fixler DE, Kautz JA, Dana K: Systolic blood pressure

dif-ferences among pediatric epidemiological studies. Hyperten. sion 2(suppl):1, 1980

11. Grim CE, Luft FC, Miller JZ, et al: Effects ofsodium loading and depletion in normotensive first-degree relatives of essen-tial hypertensives. J Lab Clin Med 94:764, 1979

Historical

Controls

The use of concurrent controls in clinical trials has been advocated for a considerable period of time and by a large number of researchers. Never-theless, the nature of clinical investigations appears to lead to continuing interest in the use of historical controls. The two opposing views are enunciated in papers by Byar et al’ and Gehan and Freireich.2

When a clinical trial is viewed as a scientific experiment, the use of concurrent controls, and especially randomized concurrent controls, is to be preferred based on long-standing principles of ex-perimental design. There is little doubt that the ethics of clinical experimentation rightly impose constraints on what might otherwise be viewed as ideal experimental design. The concern with histor-ical controls is that they satisfy some of these constraints but at the price of possibly being unable to answer the scientific question that the clinical trial is undertaken to answer.

The relative importance of historical and concur-rent controls is a complex, controversial issue. The situation was summarized well by the widely re-spected British statistician, D. R. Cox,3 following a conference concerned with clinical trials;

. . . other things being equal the arguments for concur-rent controls are overwheLming, but when the number of available patients is limited, or when relatively large quantities of high quality recent historical data are avail-able, critical use ofthe historical data instead of or as well as concurrent controls may be wise. Further empirical

evidence on the stability of comparisons involving histor-ical controls is desirable.

Farewell and D’Angio4 considered empirical evi-dence from the National Wilma’ Tumor Study Group. In the first National Wilms’ Tumor Study (NWTS-1), group II and III patients were randomly assigned into three treatment groups, two single-drug chemotherapy regimens, A and B, and a

American Academy of Pediatrics.

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146 PEDIATRICS Vol. 70 No. 1 July 1982 ble-drug regimen, C, which used both

actinomycin-D and

vincristine.

The

conclusions of the study

indicated that regimen C was the better treatment with respect to both relapse and survival; in the second National Wilms’ Tumor Study (NWTS-2), regimen C was compared with a three-drug regi-men, D, which added adriamycin.

In the second study the regimen C group from NWTS-1 could have been used for an historical control group and all patients might have received regimen D. A comparison of the historical data on regimen C with the data on regimen D from

NWTS-2resulted in an estimated relative risk of relapse of 0.81 for regimen D, which was not significantly different from 1.0

(P

= .47). In contrast, a compar-ison of the NWTS-2 randomized controls on regi-men C with the patients receiving regimen D re-suited in an estimated relative risk of relapse of 0.56 for regimen D, which was significantly different from 1.0

(P

= .03). Both analyses adjusted for the

prognostic factors of nodal involvement, histology, tumor weight, and patient age.

These data were also used to simulate various strategies in the design of NWTS-2. This included the compromise suggestion of Pocock5 that random-ization take place between the new and old treat-ments in a ratio of 2:1 or 3:1. The argument for this

strategy is that the availability of some concurrent controls serves as a check on the suitability of the historical comparison group. If there are no signif-icant and important differences between the ran-domized and historical controls, then the historical data might be included in comparisons with a new treatment group. A simulation of a 2:1 randomiza-tion, however, failed to identify a significant differ-ence between the two control groups, and the com-parison of the combined control groups with the patients receiving regimen D was not significant. The problem with an imbalanced randomization may be that there is an insufficient number of randomized controls to make the comparisons of interest effective.

The advent of statistical procedures that can adjust the comparison of two treatments for differ-ing distributions of other prognostic factors has been used to support more extensive use of histor-ical controls. This is because there appears to be no need to use randomization to ensure comparability of the treatment arms. The weak point in this reasoning is that absolute faith is placed in the mathematical form and the choice of prognostic factors in the statistical methodology chosen. Changes in patients and patient care from one period to another may be quite subtle but may generate an apparent treatment effect because the proper adjustment for such changes is unknown. In the analysis of the NWTS data, an analysis of the

extensive data collected on NWTS-1 and NWTS-2 patients receiving regimen C could not identify any prognostic factors that might have accounted for the difference found between the results based on the historical controls and those based on the con-current controls.

The use of historical controls is often advocated when a series of studies for treatment of a particular disease is planned. The best treatment group in the most recent study becomes the control group for the following study. Such an approach may be particularly prone to problems because by choosing the results of the best treatment in one study the efficacy of the treatment will probably be overesti-mated, and therefore in a subsequent study the results using historical controls and those using randomized controls could be different. This prin-cipie is best illustrated when, in fact, there is no real difference between two treatments but in a partic-ular trial one treatment will by chance produce better results. The same treatment applied in a subsequent trial will be likely to produce poorer results than in the first trial. Even when there is a real difference between treatments, the danger of an optimistic estimate of the best treatment’s effi-cacy is present.

A

final clinical decision that regimen D should be used in preference to regimen C does not result from NWTS-2. Such a decision depends on many factors involved in total patient care, eg, short- and long-term treatment complications. In fact, the de-sign of NWTS-3 reflects a conclusion that some advantage to regimen D, measured in disease-free survival, has been established but that questions about the potentially lethal, delayed cardiotoxicity of the regimen remain to be answered. The new study, therefore, compares a modified, more inten-sive regimen C with a modified regimen D.

What has been suggested here, as in many other places, is that the use of historical controls can be a potentially misleading approach to undertaking treatment comparisons. This fact and the evident scientific advantages to concurrent randomized controls must be given heavy weight, together with the ethical issues, in designing clinical trials.

V. T. FAREWELL, PHD

Program in Epidemiology and Biostatistics Fred Hutchinson Cancer Research Center 1124 Columbia Street

Seattle

REFERENCES

1. Byar DP, Simon RM, Friedewald WT, et al: Randomized clinical trials, N EngI J Med 295:74, 1976

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COMMENTARIES 147

2. Gehan EA, Freireich EJ: Non-randomized controls in cancer

clinical trials. N Engi J Med 290:198, 1974

3_ Cox DR: Summary views: A statistician’s perspective. Can-cer Treat Rep 64:533, 1980

4. Farewell VT, D’Angio, GJ: A simulated study of historical

controls using real data. Biometrics 37:169, 1981

5_ Pocock SJ: The combination of randomized and historical controls in clinical trials. J Chronic Din 29:175, 1976

REFERENCE

1. Fazen LE III, Felizberto P1: Baby walker injuries. Pediatrics

70:106, 1982

Injuries

to Baby

Walkers

The Consumer Products Safety Commission is-sued a report on baby-walker related injuries at approximately the same time that an article on the same subject was accepted for publication in

Pedi-atrics. ‘ The latter study of the risks and problems

of baby walkers as seen in a private practice accu-rately expresses the problem as most practicing pediatricians see it. However, only a portion of users who are sufficiently injured to require treatment will be observed or treated by pediatricians. Thus, the CPSC report of 23,900 walker injuries requiring treatment in one year, 1980, indicates a much greater problem than might be inferred from the experience of a single pediatric practice. If the CPSC figures are correct, the study by Fazen and Felizberto assumes added importance. The impli-cation is that the need, emphasized by the authors, for informing and educating the public about the risks of using a baby walker, is so much the greater. Pediatricians and other child health advocates should assume this role. Regulatory agencies should promote safer products, clearer labeling, and so forth, for whatever helpful result that can be achieved in that manner. Manufacturers of walkers should voluntarily look at and reevaluate their product as to its safety in the age group for which it is intended. In this area, as in others, pediatricians also could offer their expertise as volunteer consul-tants to industry; the end result would be better and safer products.

H. JAMES HOLROYD, MD

Chairman, AAP Committee on Accident and Poison Prevention,

1346 Foothill Boulevard, La Canada, California

Cerebral

Blood

Flow

Velocity

in the

Human

Newborn:

The

Value

of Its Determination

The anterior fontanel of the newborn has been utilized to great advantage for imaging the intracra-nial contents by real-time ultrasound scan, for de-termining intracranial pressure by appropriate sur-face sensors, and for measuring the velocity of blood in the anterior cerebral artery by a Doppler ultra-sonic technique. Because the pathogenesis of much of the neuropathology encountered in the neonatal brain appears to relate to derangements of cerebral blood flow and because most procedures for assess-ing the cerebral circulation are technically difficult and invasive, the latter technique has provoked considerable interest and study. A recent commen-tar)’ by Bejar et al’ has been critical of both the technique and some of the data obtained with it. We believe that the technique is valuable and that the data obtained are generally useful; in this com-mentary we discuss our view of the issues raised by Bejar et al)

DOPPLER METHOD FOR ASSESSMENT OF

BLOOD FLOW VELOCITY

Basic Principle

Measurement of blood flow velocity by the ultra-sonic technique makes use of the Doppler effect2 (named for its discoverer, Christian Doppler, who described the phenomenon in 1842). Thus, the fre-quency of sound waves reflected from a moving object is shifted by an amount proportional to the velocity of the object. When ultrasound is used for measurement of blood flow velocity, the sound waves emitted by the transducer are reflected and their frequency is shifted by red blood cells.2 The Doppler signals are dependent not only on the velocity of the red blood cells, but also on the angle of the probe to the axis of blood flow; other factors that may affect the frequency shift, eg, the fre-quency of the transmitted ultrasound and the ye-locity of sound in the medium, are, for practical

American Academy of Pediatrics.

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1982;70;145

Pediatrics

V. T. Farewell