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Patient co-operation and the sensitivity of clinical trials
J. chron. Dis. Vol. 15, pp. 1025-1036. Pergamon
Press Ltd. Printed in Great Britain
PATIENT CO-OPERATION AND THE SENSITIVITY OF CLINICAL TRIALS C. R. B. JOYCE, M.A., B.Sc., Ph.D. The Department of Pharmacology, The London Hospital Medical College, Turner St., London, E. I. (Received 28 January 1962)
MANY clinicians, and many of those conerned with clinical trials, have doubts from time to time about the extent to which theirpatientsareobeying(orevenunderstanding) their therapeutic instructions [l-4]. Such doubts are usually ignored or rationalized, for there are few records of attempts to measure the extent of such failures of communication between patient and doctor. So far as is known, there are even fewer examinations of the effect of these failures upon interpretations of therapeutic success and failure, especially inferences from clinical trials. Most quantitative statements available apply to the single case of out-patient treatment of tuberculosis and are rather depressing: four separate estimates indicate a default-rate of between 22 and 50 per cent [5-81. Considerable attention has been paid recently to the presence of placebo reactors (or, for that matter, drug non-reactors) in clinical trials, and to their effect upon such trials [g-11], but the proportion of what may be called ‘participators’ and ‘non-participators’ seems a no less important question to raise and indeed a more fundamental one. A comparison of placebo with two analgesics in patients with inflammatory joint disease gave a useful opportunity to investigate methods of studying such questions and of examining their importance for the interpretation of results. Some observations have been briefly reported elsewhere [12, 131. It is proposed that there are in fact three basic ways of improving the sensitivity of clinical trials-technical, statistical, and psychological.Therelationshipof simple methods involving the first two will be considered here: the third is the subject of a separate paper. PROCEDURE
the out-patient clinic of the Department of Physical Medicine and Regional Rheumatism Centre at the London Hospital who were found to be suffering from ‘definite’ rheumatoid arthritis [14], were admitted to a double-blind trial if they were not already taking phenylbutazone. They were allowed to continue to take aspirin, codeine and related mixtures, as well as any physical treatment considered appropriate by the examining physician. The trial compared phenylbutazone (2 x 200 mg/day); C 20410 (Ciba) (1-phenyl- 2-methyl-4, dimethylamino-3, 6-dioxo-1, 2, 3, 6-tetrahydropyridazine) (2 X 375 mg/day) and a placebo (lactose, twice daily) in white sugar-coated pills of externally identical appearance. Sufficient pills (60 f 3) were issued to give full treatment for 28 days : on the 28th day the patient was to return for examination and change of treatment, but she was told to return earlier than that if Women
attending
1025
C. R. B. JOYCE
1026
she felt unable to continue the current treatment. In such cases, the next treatment was substituted. It was intended that each patient should take all three treatments, and that an equal number should take each of the six possible treatment sequences. All pills given to half the patients on each sequence also contained 10 mg of phenol red. Each pill-box was labelled : “One tablet to be swallowed whole twice daily after meals.” At the first, second, third and fourth (final) clinical examination, the examining physician completed a standard form for each patient, listing the visibly active joints, toxic signs, degree and nature of pain experienced, limbering-up time, functional state and treatments taken. At the second, third and fourth interviews the patient completed a questionnaire on symptoms experienced, and on being invited by the physician compared the treatment just received with the treatment that preceded it: on these occasions she also gave samples of blood for determination of haemoglobin (Hb), white blood cell count and (WBC), and erythrocyte sedimentation rate (ESR) and urine for detection of protein and phenol red. At the second interview, and before seeing the physician, the patient also completed a much more extensive ‘personality’ questionnaire about her family background, propensities for alcohol, tobacco, analgesics, hypnotics and purgatives; this questionnaire also contained the materials found to be useful in the prediction of the placebo reactor [9]. At the final interview she stated her overall preference (if any) for one of the three treatments. No questionnaire was completed in the doctor’s presence, but assistance (for the most part purely
TABLE1.
EXPERIMENTAL PROCEDURE
(28 days between consultations
unless patient chose to return earlier)
CONSULTATtON First
Second
Clinical assessments
‘Personality’ questionnaire Symptom questionnaire Clinical assessments Pathological tests
Third
Fourth
Symptom questionnaire Clinical assessments Pathological tests
Symptom questionnaire Clinical assessments Pathological tests
-~ Clinical assessments:
Active joints Number of toxic manifestations Pam experience Limbering-up time Functional capacity
‘Personality’ questionnaire :
Social background Drug habits Alcohol Smoking Maudsley neuroticism Maudsley extraversion/introversion Placebo-Reaction Scale Autonomic awareness Scale
Pathological
tests :
ESR WBC Hb
blood
protein marker
urine
Patient Co-operation TABLE 2.
and the Sensitivity of Clinical Trials
1027
NUMBER OF PATENTSNOT COMPLETING TRIAL ~_~
X
~~~~
__._~
Number leaving trial altogether
__
Y
2
Number unable to take drug for 28 days ~__
3 _____
TOTAL ~____
5
x2=9.455
Total patients involved
2
-.
2
4
8
I
15
22
9
19
30
P (2 d.f.)
X =Phenylbutazone (2 x 200 mg/day) Y =Placebo (lactose twice daily) Z =C 20410 (2 x 375 mg/day).
motor, in the actual marking of the papers, or purely sensory, in the reading of the questions for those patients who had not their spectacles with them) had not infrequently to be given by the physiotherapists or nursing staff. The ‘flow diagram’ of the experiment is shown in Table 1. In all, 78 patients were admitted to the trial between mid-April and mid-October 1960. Of these, 48 formed 8 replicates of a completely balanced block Latin Square design : all the pills of 4 replicates (i.e. 24 patients) contained phenol red. In the results these patients are referred to as ‘The 48.’ It was intended to admit a second set of 48 patients, but the slow admission rate and the number of patients having to be dismissed from the trial made this impossible to attain within a reasonable time. Patients completing the trial (i.e. all those who took all three treatments, including the 48 patients already mentioned) are referred to below as ‘Completers.’ RESULTS
Preliminary examination of d@erences between treatments Eight patients were unable to complete the trial. A further 22 returned to the clinic before 28 days had elapsed (3 on more than one occasion), and their treatment was therefore changed early (Table 2). The remaining patients gave no indication whatsoever to the physician that they had experienced difficulty in complying with the instructions, but it is clear from Table 2 that many patients were unable to complete the course of C 20410. Analysis of variance of the results from the 48 showed that C20410 significantly reduced the number of active joints in comparison with the I.
TABLE 3.
--
DIFFERENCES BETWEENMEASURES ~..__~ .___
No. of active joints
OF DRUG _~
EFFECTS
-__
IN THE
_~.
Y
z
Mean
3.1
3.9
2.6
3.2
X
Y
Z
1.2
1.4
1.7
-~ P CO.05
X =Phenylbutazone (2 x 200 mg/day) Y =Placebo (lactose twice daily) Z =C 20410 (2 x 375 mg/day).
P >0.2
Mean 1.4
GROUP OF 48
No. of symptoms
No. of toxic manifestations
x
BALANCED
X
Y
a.2
9.7
Z
9.8 -~P
Mean .._~_
9.2
C. R. B. JOYCE
1028 TABLE4.
OBSERVATIONS ON BLOODOF THEBALANCEDGROUPOF 48 PATIENTS (Values are means i- S.E.M.) ____ n
-
ESR
.-
WBC (counts/mm3)
(mm/hr) Phenylbutazone
40-41
29.4h3.73
12.3hO.33
8OOOf380
Placebo
44-45
31.1h3.37
12.4*0.22
74OOzt360
c 20410
30-39
24.1f2.82
12.4kO.23
68005380
Probability that the difference between any treatment observation >O.l. TABLET.
OCCURRENCEOFTOXICSIGNSAND
SYMPTOOMSINALLPATIL?NTS
Frequency of occurrence (%) Phenylbutawne
Placebo
Oedema 19 Dyspepsia 17 Anorexia 0* Diarrhoea 7 Vomiting 0 Nausea 0 Headache 10* Vertigo 7* Depression 3 4* Other C.N.S. disorders Increase in joint pain 0 Palpitations 4 Rash 5 Buccal ulcers 4 Stomatitis 3 Dry mouth 3 Sore throat 1 ____. _~~~ ___. No. of patients with 1 sign 41 No. of patients on treatment 73 *Probability
of difference between treatments
13 12 0* 3 1 4 12* 12* 8 8* 5 :
and placebo was due to chance is
No. of patients with sign
C 20410
Phenylbutazone
Both drugs
14 22 8” 4 6 4 25* 25*
13 11 0 5 0 0 7 5 2 3 0 3 4 3 2 2 1
2 2 0 0 0 0 3 3 0 0 0 1 0 0 0 0 0 _~ ._
1:* 3
1
3 3 1 5
5 4 0 3 0
34
49
72
74
-
< 0.05. No other differences significant (P > 0.05).
This substance also caused more toxic signs and more symptomatic reports, but these were not significantly different from those found with the placebo, Phenylbutazone gave fewer toxic signs and symptoms than placebo: the difference in the latter case was highly significant (Table 3). There were no significant differences among the three treatments in their effects on ESR and WBC count (Table 4). The pattern of toxicity differed between C 20410 and phenylbutazone: the former was more likely to cause dyspepsia and other gastric disturbances, as well as headache and other unpleasant central nervous effects. Very few patients experienced the same difficulties on both drugs (Table 5). However, it was clear from patients’ statements of preference, both during and at the completion of the trial, that they found C 20410 less pleasant to take than phenylbutazone (Table 6). The pre-trial treatment, regardless of
placebo.
Patient Co-operation TABLE 6. A.
and the Sensitivity of Clinical Trials
PAI-IENTS'TREATMENT
1029
PREFERENCES
PREFERENCE ATEACHCHANGEOFTREATMENT
Number of preferences for Phenylbutazone In preference to: Phenylbutazone Placebo c 20410 Pre-trial treatment
23 20.5 10
Total preferences As % of maximum possible
53.5 61 B.
PREFERENCESATEND
-
__~
Pre-trial treatment 8
Phenylbutazone 25
Pre-trial treatment 8
1st treatment 9
-~
Pre-trial treatment
Placebo
c 20410
9
11.5 19.5 9
-
40 50
19.5 41
12.5 9.5 -..__ 31 39
6 6.5 I
.~~___
OFTRIAL _~____~______
Placebo 6
c20410 ~9 -_ 2nd treatment 3rd treatment 10 21 ____.____~_. ~~_~~~_
was preferred to that in the first treatment period on 41 per cent of occasions, and this was not significantly different from the preferences for placebo. C 20410 was preferred on exactly half the occasions that it was compared with another treatment, but phenylbutazone was preferred on 2 out of every 3 occasions. When the three treatments were compared only with each other, the patterns of preferences were significantly different (for the monthly comparison, x2=7 .601, P (2 d.f.) < 0.025; for the final comparison, x2= 15.684, P (2 d.f.) < 0.001).
its nature,
Discussion. It appeared from the observations on the 48 patients that C 20410 was an active drug in inflammatory joint disease: at the doses used it was perhaps more effective than phenylbutazone, but it was also more toxic and less acceptable to patients. A lower dose might well give results comparable in both respects to a similar dose of phenylbutazone, and the rather different distribution of toxic effects suggests that the new drug would be worth trying in patients intolerant of phenylbutazone. It is also interesting that the patients’ preferences for treatment were similar whether obtained monthly or at the end of three months: this consistency over such long periods of time suggested that some response was being validly measured. It appeared to be related to the extent to which undesirable side-effects were avoided rather than to the reduction in the number of active joints-this latter effect was perhaps usually too small in relation to the total experiences of discomfort (20-30 per cent) to outweigh the disadvantages of treatment. In a conventional clinical trial it would perhaps be concluded at this point that the new substance had no decisive advantage over phenylbutazone: it would perhaps be lightly commended and referred back to ‘further study’-or oblivion. However, we were also interested in methods of estimating the extent to which patients comply with instructions in such trials and the results were therefore examined more closely.
C. R. B. JOYCE
1030 II.
Evidence of the extent of patient co-operation
There are at least three ways in which information on patient co-operation can be obtained. (i) Patients may be asked to assess the extent to which they observed instructions; (ii) the substance taken, or its metabolites, can be looked for in the urine; or (iii) the number of pills taken can be estimated-with what reliability remains to be seen-from the number issued minus the number returned. Information of the first kind is notorious for its unreliability and is embarrassing to collect if additional and obvious means of checking it are to be used. We therefore used methods (ii) and (iii). The urine of all patients was examined at each visit for the presence of phenol red and their unused pills were collected at the next visit and subsequently counted. Presence ofmarker in urine. The urine of 67 patients was examined for the presence of phenol red on each of their three visits (the pills of 33 of these patients had, in fact, contained marker). The urine of a further 6 patients (4 with marker) was examined on two visits, and of 2 (1 with marker) on one occasion each: 3 patients (1 with marker) failed at each of three attendances to give a sample of urine. Only 38 out of the 108 urine samples which should have contained marker gave positive readings. (On one occasion the urine of a patient whose pills had not contained marker was recorded as being positive on testing for phenol red. The composition of the returned pills of this patient was checked, as were those of 16 others chosen at random: all agreed with expectation, and this was therefore presumably a ‘true’ false positive.) The odds were about even that marker would be found in the urine of patients who took placebo pills containing marker. It was only two-thirds as likely as this that there would be
TABLE7. A.
BY
INCIDENCEOF MARKERIN THEURINEOF ALL PATIENTSWHO TOOKPILLSCONTAININO10 MO PHENOLRED
TREATMENT _I___
Treatment Placebo Marker present Marker absent
17 20
Total
37
Proportion of occasions that marker was present
0.46
Phenylbutazone
~~~___
c 20410
Total
11 25
10 25
38 70
36
35
108
0.31
0.29
0.35
-.__
Probability of chance difference:
P > 0.2
B. BY PERIOD Period
Marker present Marker absent Total
1
2
3
Total
16 21 37
13 24 37
9 25 34
38 70 108
Probability
of chance difference : P > 0.2
Patient Co-operation
1031
and the Sensitivity of Clinical Trials
marker in the urine of patients taking the other two treatments also containing marker (Table 7A). These differences are suggestive but not significant (P > 0.2 on comparison with the theoretical ~2 distribution). It may be that the marker is more liable to combine with drug than with lactose and so to be rendered undetectable : an alternative explanation is that the differences reflected true differences in default rates, and this is discussed later. The proportional difference showed a trend towards a decline with time (Table 7B), but this effect was not statistically significant. The choice of a marker to check the consumption of pills is extremelydifficult. Such a substance must be devoid of pharmacological and psychological action (e.g. it should not run the risk even of changing the appearance of the urine-that no patient complained of this or commented upon it is not evidence that it did not occur in the present case); and it must be easily detectable at low concentration in excretions (preferably urine) following administration of small amounts. Its ideal rate of TABLE 8.
APPARENT
MEAN
-... From attendance records From pill returns -_ Discrepancy
DURATION OF TREATMENT(IN DAYS)FOR RECORDS AND PILLSRETURNED
Placebo
c 20410
Mean
27.0 23.6
25.8 22.3
23.8 20.4
25.5 22.1
3.5
3.4
3.4
3.14
Ii!
1.
ATTENDANCE
Phenylbutazone
MIN. FIG.
ALL PATIENTS FROM
DAYS
lb
26
24
2;
MISSED
Histogram of minimum number of days of treatment missed, calculated from pills returned: all treatments and all patients.
-__
1032
C. TABLE
9.
R. B. JOYCE
NUMBER OF INSTANCES OF ‘OBEDIENT’ BEHAVIOUR
Number of ‘obedient’ occasions ..____
Completers
(3 attendances)
Non-completers Non-completers ____---
(2 attendances) (1 attendance)
0
1
2
3
Total
4
12
15
33
64
2 2
3 2
5
.-____
-
10 4 ____
excretion is almost impossible to specify if, as was necessary in the present case, the urine is tested only once in each treatment period, and always at the end: for it must be so rapidly excreted that defaulting can be detected, yet so slowly that its absence signifies default with certainty. There were no significant differences in the number of active joints, toxic signs or other observations between patients taking pills with or without the marker. Return of pills. Pills were collected back from 68 patients at each of their three visits, from 4 on two occasions, and from 3 on one occasion. Two patients produced no pills at any of their three visits, although being reminded by letter to do so. One patient on two occasions produced boxes that obviouslycontainedpillsotherthanthose issued; these resembled a standard preparation of phenylbutazone, and her results were excluded from the trial as a whole. The average apparent duration of each treatment for all completers, obtained from the recorded intervals between attendances, and the average number of days of treatment apparently missed, obtained by dividing the number of pills returned by 2 (Table S), show a remarkable agreement. The mean day discrepancies for each drug, assuming that 60 pills (or 30 days’ supply) were issued, are almost identical at 3.4 days each. This value is too large to be due to differences in the exact numbers of pills supplied, and, although small (it represents only about 13 per cent of the total treatment) it is obviously worth closer study. The frequency distribution of the discrepancies for all occasions is remarkable (Fig. 1): the range is almost maximal (O-26 days), with a median of 3.5 days. It is clear that the behaviour of individuals varies widely, and its consistency is of obvious importance. If the rather arbitrary but generous period of a 5-day discrepancy is allowed to separate the ‘obedient’ from the ‘disobedient,’ only 40 out of 78 individuals were ‘obedient’ to instructions on all possible occasions (Table 9) and eight never complied with the instructions. For the 64 completers alone, 33 could be classed as ‘obedient’ for each of their 3 visits and 4 could be classed as ‘disobedient’ on all 3 visits. This measure of patient ‘co-operation’, like that provided by the marker, is open to several, but different, objections. Patients may have disposed of the appropriate number of pills by routes other than the oral: indeed, since they were all given supplies slightly larger than those needed for the 28 day interval between treatments, one might regard the failure to return any pills as a rather unfavourable sign. In fact, this was observed only 13 times out of 218 possible occasions, and involved 9 patients; 7 of these were taking pills that included marker, and on 3 of their 11 occasions marker was also present in the urine. On 4 of the occasions when no pills were returned and marker was absent, the interval between attendances was 30 days or greater. Thus 4 of the 7 occasions when marker would have been expected remained to be accounted
Patient Co-operation TABLE 10. _____
and the Sensitivity of Clinical Trials
PRESENCE OF MARKER IN URINE OF ‘OBEDIENT’ AND ‘DISOBEDIENT PATIENTS TAKING PILLS CONTAINING PHENOL RED ~~~__. -.______~_ .._ _-._ n
_ .__._ ‘Obedient’ patients ‘Disobedient’ patients Total
Marker present
17 1.5
21 12
32
33
Marker absent _____~ _~ 27 30
~~___~._~~_
Total _.~~~ ~~_ 48 42
..~_~_ _
57
____ (P 10.05:
1033
_
90
l-tail)
for, and this proportion (57 per cent) is similar to that in which marker was absent from all the urines examined (65 per cent: Table 7). The sample is small and the point would perhaps scarcely have been worth making, had it not also applied to the patients who returned some pills. However, their attention was never drawn to the number of pills in the box, and one would probably be assuming a greater ingenuity than they possessed were one to suppose that they did not consume, but threw away, the correct number of pills on each occasion that this was required. The imperfect observations on the marker allow the validity of the pill returns as an indicator of patients’ behaviour to be checked further. The proportion of occasions on which marker was present in the urine of the 17 possible patients who were always ‘obedient’ to instructions was 44 per cent, whereas that for the corresponding 15 ‘disobedient’ patients was only 29 per cent and this difference in the proportions, in the predicted direction, is significant by a one-tailed test at the 0.05 level of probability (Table 10). The number of pills returned is meaningful in another way. The mean number of pills returned for the treatment preferred by each patient (regardless of which it was) was almost exactly half as great as that for all the non-preferred treatments (8.4 against 17.0), and this represents a mean day discrepancy of about 2 against 6.5. It thus seems that the pill discrepancy score has some validity in showing whether patients did or did not take their pills. We have therefore considered the effect of taking this into account in re-evaluating the treatments.
TABLE 11. _ _~
n
ASSOCIATION OF DIFFERENCESBETWEEN MEASURES OF DRUG EFFECTSAND DEGREE OF CO-OPERATION ~~~___ ._
Patient group ~~~ ~~~ ~~
33
Most co-operative
No. of active joints x
Y
Z
Mean
X
3.0
3.4
2.5
3.0
0.9
0.8 1.8
3.5
1.3
1.6 1.7 >0.2
P
27
Less co-operative P
No. of toxic manifestations ._____
so.05
3.0
4.4
3.1 5 0.1
X -Phenylbutazone (2 x 200 mg/day) Y ==Placebo (lactose twice daily) Z-C 20410 (2 x 375 mg/day)
Y
Z
No. of symptoms
Mean
X
1.2
7.4
~~__ 1.5
Y
Z
8.3 8.4 co.2
Mean 8.0
8.7 10.6 10.9 10.1
1034
C. R. B. JOYCE
III. Information obtained from results by use qf measures of patient co-operation The 33 ‘obedient’ patients amongst the 60 completers showed fewer active joints and fewer toxic signs, and reported fewer subjective side-effects than the 27 ‘less obedient’ patients (Table 11). These differences are significant (P < 0.05). But whereas for the ‘obedient’ group the differences between treatments are significant for the number of active joints and of toxic signs, for the ‘less obedient’ group only that for the numbers of symptoms is significant. The likely explanation is that because, as has already been seen, the less obedient patients stopped taking their pills earlier in the treatment period, clinical changes (activity of the disease or toxicity of the drugs) were no longer remarked-even if present at the start of the period-by the physicians: whereas memories of the subjective effects were still vivid and were elicited by the symptom questionnaire. (Incidentally, it is notable that for neither group was there a difference between the symptom scores on placebo and C 20410). However, it has already been pointed out that the division into ‘obedient’ and ‘disobedient’ groups is rather arbitrary, and it wastes less information to examine, by the analysis of covariance, the contribution to experimental error made by individual differences in pill consumption : or, to put it in another way, to see if differences between treatments may be more sensitively detected by allowing for variation in the number of pills taken. The number of pills consumed by 48 patients was used as the covariate in calculating revised estimates of the more important measures of between-treatment differences. The observations were insufficiently complete to allow this to be done for the ESR. The patients in this set were not identical with those in ‘the 48’: substitutions were made, of patients on the appropriate treatment sequences, in order to reduce the need to calculate missing values of the variates and covariate. There were nevertheless four such missing values in the latter, and these were estimated, as were the others, by the method of least-squared deviations from the individual patient and treatment means [15]. This, and the presence of substitutes, accounts for the differences between the unadjusted treatment means in Table 12 and those in Table 3. The adjusted means were calculated by the exact method [16] and the differences between treatments examined by a t-test of significance. The most striking effect of the covariance adjustments is to increase the number of active joints on phenylbutazone and to decrease that on the new drug. On the other hand, toxicity becomes a more serious problem with C 20410 and the reductions in limbering-up time and number of symptoms brought about by C 20410 are now less impressive. The possibility that patients unable to tolerate phenylbutazone may not be similarly sensitive to C 20410 is of course unaffected by this argument, and together with the fact that the most objective measure available of the effects of treatments shows a marked improvement suggests that C 20410 deserves further study. The only apology that seems to be necessary for presenting a result that is so agreeably acceptable to common-sense is that this device seems rarely if ever to have been reported. There are very few accounts of attempts to confirm that patients are following treatment in diverse conditions. It is possible that some studies, meticulously carried out, have not been published because the evidence that they provided about the co-operativeness of patients was depressing. The present work suggests that even under such conditions a good deal of useful information is still recoverable, and need not merely be restricted to statements about the reasons for the lack of co-operation
Patient Co-operation TABLE
(Unadjusted
.~_ .____
12. SIGNIFICANCE OF DIFFERENCES BETWEEN TREATMENT MEANS and adjusted for regression of variables on number of pills consumed)
Treatment Variable
_~~
.-__
~___
--__
Unadjusted
-~-
Pills consumed Phenylbutazone Placebo C 20410
50.63 46.00 42.60
Limbering-up time (min) Phenylbutazone Placebo c 20410
56.3 79.8 64.3
-
co.05 >O.l
1.04 1.13 1.81
>0.4
Symptoms Phenylbutazone Placebo C 20410
8.00 9.69 9.48
Active joints Phenylbutazone Placebo C 20410
2.79 4.02 2.65
__
.
P
Toxic signs Phenylbutazone Placebo c 20410
c =regression
1035
and the Sensitivity of Clinical Trials
>0.05
>0.3
Adjusted
P
-
-
c=-o.o90 52.1 79.9 68.4 c=-0.069 0.73 1.13 2.12 c=-O.o41 7.81 9.69 9.65 c=+o.154 3.49 4.03 1.47
~__
0.2
>0.2 co.01
10.001 >O.P
>0.2
coefficient of variable upon pills consumed [ 161.
itself. It is also possible that certain conventional studies of new (or old) drugs have failed to reveal the genuine usefulness of the proposed remedies for these reasons. Perhaps an understanding of the possible explanations for this may help to bridge the gap between the subjective optimists, who disbelieve trials because they imply that drugs are no good which everyone knows are clinically useful, and the objective pessimists who regard trials with too much relish because they prove that drugs are useless which others believe useful. A final point: it is possible, notwithstanding the arguments put forward above, that the sensitivity of trials might be further increased by using only those patients likely to co-operate. The arguments for and against this course resemble those about proper attitudes to the inclusion in trials of reactors and non-reactors to placebo substances, and have been discussed elsewhere [9]. As in the latter case, the basic question is the possibility of predicting aspects of human behaviour reliably enough and long enough before they happen to be useful in practice. This, a ‘psychological’ method of improving the sensitivity of clinical trials, will be discussed in another paper. SUMMARY
Phenylbutazone (400 mg/day) ; 1-phenyl-2-methyl-4, dimethylamino-3, 6-dioxo1,2, 3, 6-tetrahydropyridazine (C 20410, Ciba) (750 mg/day); and a placebo have been compared under double-blind conditions in 78 female out-patients with active inflammatory polyarthritis. C 20410 reduced the number of active joints, erythrocyte sedimentation rate, and limbering-up time below the values on the control treatment, as did phenylbutazone,
1036
C. R. B. JOYCE
but the new substance was significantly more‘ toxic’ and significantly less well liked by patients than the latter. These differences emerged more clearly when the information obtained by incorporating a urine-marking substance in the pills, and from counts of the number of pills returned unconsumed, was used in the analysis of the results. Some implications for the results of past and future research of such simple technical and statistical methods of increasing the sensitivity of clinical trials are discussed. am most grateful to DR. W. S. TEGNER for permitting this investigation to take to DR. R. M. MASONfor invaluable help and criticism at all times; to the other members of the Department of Physical Medicine, the London Hospital, for enthusiastic and meticulous attention to what was necessary; to members of the Department of Pharmacology, the London Hospital Medical College, for much dull routine work and more criticism; and to DR. C. D. Acknowledgements-I
place in his department;
FALCONER of Ciba Laboratories Ltd. and DR. W. STODDARTof Geigy Pharmaceuticals Ltd. for providing the materials used, and to their pharmaceutical colleagues for solving the problems involved
in making comparable
preparations
of the treatments.
REFERENCES 1. EVANS,W. : Faults in the diagnosis and management of cardiac pain, Brit. med. J. 1,249,1959. 2. FERGUSON,T. and MACPHAIL, A. N. : Hospitaland Community, Oxford University Press, London, 1954. 3. GOLDBERG, M.: The social worker in the ‘sixties: the impact of developing social policies on established practices and attitudes, Almoner 14, 96, 1961. 4. PRATT, L., SELIGMANN,A. and READER, G. : Physicians’ views on the level of medical information among patients, Amer. J. publ. Hlth. 47, 1277, 1957. 5. DD(ON, W. M., STRADLING,P. and WOOT~ON,I. D. P. : Outpatient P.A.S. therapy, Lancer 2, 871, 1957. 6. LEGGAT, P.O.: P.A.S. and the patient, Lancer 2, 1283, 1957. 7. SIMPSON,J. McD.: Simple tests for the detection of urinary PAS, Tubercle 37, 333, 1956. S., RAMAKRISHNAN, C. V. 8. VELU, S., ANDREWS, R. H., DEVADATTA,S., Fox, W., RADHAKRISHNA, SELKON,J. B., SOMASUNDARAM, P. R. and SUBBAIAH,T.V. : Progress in the second year of patients with quiescent pulmonary tuberculosis after a year of chemotherapy at home or in sanatorium, and influence of further chemotherapy on the relapse rate, Bull. Wld. Hlth. Org. 23, 511, 1960. 9. JOYCE, C. R. B.: Consistent differences in individual reactions to drugs and dummies, Brit. J.
Pharmacol. 14, 512, 1959. 10. JOYCE, C. R. B.: Experiments with control substances, Ann. rheum. Dis. 20,78, 1961. 11. LASAGNA,L., MOSTELLER,F., VONFELSINGER,J. M. and BEECHER, H. K. : A study of the placebo response, Amer. J. Med. 16,770, 1954. 12. JOYCE, C. R.B. and MASON, R. M.: Observations on the methodology of clinical trials in the rheumatic diseases using a known drug (phenylbutazone), a placebo and a test substance (C 2041O), Atti X Congr. Lega Int. c. Reum. 2,1255, 1961. 13. MASON,R. M. and JOYCE, C. R. B.: A controlled trial of l-phenyl-2-methyl_4,dimethyl-amino-3, 6-dioxo-1,2,3,6,-tetrahydro-pyridazine, (C 20410,Ciba), phenylbutazone and a placebo in rheumatoid arthritis, Atti X Congr. Lega Znt. c. Reum. 2, 1267, 1961. 14. ROPES, M. W., BENNETT, G. A., COBB, S., JACOX, R. and JESSAR, R. A.: 1958 revision of diagnostic criteria for rheumatoid arthritis, Bull. rheum. Dis. 9, 175, 1958. 15. FINNEY, D. J.: Statistical Method in Biological Assay, Gritfin, London, 1952. 16. COCHRANE,W. G. and Cox, G. M.: Experimental Designs, 2nd edn. Wiley, New York, 1957.
Press Ltd. Printed in Great Britain
PATIENT CO-OPERATION AND THE SENSITIVITY OF CLINICAL TRIALS C. R. B. JOYCE, M.A., B.Sc., Ph.D. The Department of Pharmacology, The London Hospital Medical College, Turner St., London, E. I. (Received 28 January 1962)
MANY clinicians, and many of those conerned with clinical trials, have doubts from time to time about the extent to which theirpatientsareobeying(orevenunderstanding) their therapeutic instructions [l-4]. Such doubts are usually ignored or rationalized, for there are few records of attempts to measure the extent of such failures of communication between patient and doctor. So far as is known, there are even fewer examinations of the effect of these failures upon interpretations of therapeutic success and failure, especially inferences from clinical trials. Most quantitative statements available apply to the single case of out-patient treatment of tuberculosis and are rather depressing: four separate estimates indicate a default-rate of between 22 and 50 per cent [5-81. Considerable attention has been paid recently to the presence of placebo reactors (or, for that matter, drug non-reactors) in clinical trials, and to their effect upon such trials [g-11], but the proportion of what may be called ‘participators’ and ‘non-participators’ seems a no less important question to raise and indeed a more fundamental one. A comparison of placebo with two analgesics in patients with inflammatory joint disease gave a useful opportunity to investigate methods of studying such questions and of examining their importance for the interpretation of results. Some observations have been briefly reported elsewhere [12, 131. It is proposed that there are in fact three basic ways of improving the sensitivity of clinical trials-technical, statistical, and psychological.Therelationshipof simple methods involving the first two will be considered here: the third is the subject of a separate paper. PROCEDURE
the out-patient clinic of the Department of Physical Medicine and Regional Rheumatism Centre at the London Hospital who were found to be suffering from ‘definite’ rheumatoid arthritis [14], were admitted to a double-blind trial if they were not already taking phenylbutazone. They were allowed to continue to take aspirin, codeine and related mixtures, as well as any physical treatment considered appropriate by the examining physician. The trial compared phenylbutazone (2 x 200 mg/day); C 20410 (Ciba) (1-phenyl- 2-methyl-4, dimethylamino-3, 6-dioxo-1, 2, 3, 6-tetrahydropyridazine) (2 X 375 mg/day) and a placebo (lactose, twice daily) in white sugar-coated pills of externally identical appearance. Sufficient pills (60 f 3) were issued to give full treatment for 28 days : on the 28th day the patient was to return for examination and change of treatment, but she was told to return earlier than that if Women
attending
1025
C. R. B. JOYCE
1026
she felt unable to continue the current treatment. In such cases, the next treatment was substituted. It was intended that each patient should take all three treatments, and that an equal number should take each of the six possible treatment sequences. All pills given to half the patients on each sequence also contained 10 mg of phenol red. Each pill-box was labelled : “One tablet to be swallowed whole twice daily after meals.” At the first, second, third and fourth (final) clinical examination, the examining physician completed a standard form for each patient, listing the visibly active joints, toxic signs, degree and nature of pain experienced, limbering-up time, functional state and treatments taken. At the second, third and fourth interviews the patient completed a questionnaire on symptoms experienced, and on being invited by the physician compared the treatment just received with the treatment that preceded it: on these occasions she also gave samples of blood for determination of haemoglobin (Hb), white blood cell count and (WBC), and erythrocyte sedimentation rate (ESR) and urine for detection of protein and phenol red. At the second interview, and before seeing the physician, the patient also completed a much more extensive ‘personality’ questionnaire about her family background, propensities for alcohol, tobacco, analgesics, hypnotics and purgatives; this questionnaire also contained the materials found to be useful in the prediction of the placebo reactor [9]. At the final interview she stated her overall preference (if any) for one of the three treatments. No questionnaire was completed in the doctor’s presence, but assistance (for the most part purely
TABLE1.
EXPERIMENTAL PROCEDURE
(28 days between consultations
unless patient chose to return earlier)
CONSULTATtON First
Second
Clinical assessments
‘Personality’ questionnaire Symptom questionnaire Clinical assessments Pathological tests
Third
Fourth
Symptom questionnaire Clinical assessments Pathological tests
Symptom questionnaire Clinical assessments Pathological tests
-~ Clinical assessments:
Active joints Number of toxic manifestations Pam experience Limbering-up time Functional capacity
‘Personality’ questionnaire :
Social background Drug habits Alcohol Smoking Maudsley neuroticism Maudsley extraversion/introversion Placebo-Reaction Scale Autonomic awareness Scale
Pathological
tests :
ESR WBC Hb
blood
protein marker
urine
Patient Co-operation TABLE 2.
and the Sensitivity of Clinical Trials
1027
NUMBER OF PATENTSNOT COMPLETING TRIAL ~_~
X
~~~~
__._~
Number leaving trial altogether
__
Y
2
Number unable to take drug for 28 days ~__
3 _____
TOTAL ~____
5
x2=9.455
Total patients involved
2
-.
2
4
8
I
15
22
9
19
30
P (2 d.f.)
X =Phenylbutazone (2 x 200 mg/day) Y =Placebo (lactose twice daily) Z =C 20410 (2 x 375 mg/day).
motor, in the actual marking of the papers, or purely sensory, in the reading of the questions for those patients who had not their spectacles with them) had not infrequently to be given by the physiotherapists or nursing staff. The ‘flow diagram’ of the experiment is shown in Table 1. In all, 78 patients were admitted to the trial between mid-April and mid-October 1960. Of these, 48 formed 8 replicates of a completely balanced block Latin Square design : all the pills of 4 replicates (i.e. 24 patients) contained phenol red. In the results these patients are referred to as ‘The 48.’ It was intended to admit a second set of 48 patients, but the slow admission rate and the number of patients having to be dismissed from the trial made this impossible to attain within a reasonable time. Patients completing the trial (i.e. all those who took all three treatments, including the 48 patients already mentioned) are referred to below as ‘Completers.’ RESULTS
Preliminary examination of d@erences between treatments Eight patients were unable to complete the trial. A further 22 returned to the clinic before 28 days had elapsed (3 on more than one occasion), and their treatment was therefore changed early (Table 2). The remaining patients gave no indication whatsoever to the physician that they had experienced difficulty in complying with the instructions, but it is clear from Table 2 that many patients were unable to complete the course of C 20410. Analysis of variance of the results from the 48 showed that C20410 significantly reduced the number of active joints in comparison with the I.
TABLE 3.
--
DIFFERENCES BETWEENMEASURES ~..__~ .___
No. of active joints
OF DRUG _~
EFFECTS
-__
IN THE
_~.
Y
z
Mean
3.1
3.9
2.6
3.2
X
Y
Z
1.2
1.4
1.7
-~ P CO.05
X =Phenylbutazone (2 x 200 mg/day) Y =Placebo (lactose twice daily) Z =C 20410 (2 x 375 mg/day).
P >0.2
Mean 1.4
GROUP OF 48
No. of symptoms
No. of toxic manifestations
x
BALANCED
X
Y
a.2
9.7
Z
9.8 -~P
Mean .._~_
9.2
C. R. B. JOYCE
1028 TABLE4.
OBSERVATIONS ON BLOODOF THEBALANCEDGROUPOF 48 PATIENTS (Values are means i- S.E.M.) ____ n
-
ESR
.-
WBC (counts/mm3)
(mm/hr) Phenylbutazone
40-41
29.4h3.73
12.3hO.33
8OOOf380
Placebo
44-45
31.1h3.37
12.4*0.22
74OOzt360
c 20410
30-39
24.1f2.82
12.4kO.23
68005380
Probability that the difference between any treatment observation >O.l. TABLET.
OCCURRENCEOFTOXICSIGNSAND
SYMPTOOMSINALLPATIL?NTS
Frequency of occurrence (%) Phenylbutawne
Placebo
Oedema 19 Dyspepsia 17 Anorexia 0* Diarrhoea 7 Vomiting 0 Nausea 0 Headache 10* Vertigo 7* Depression 3 4* Other C.N.S. disorders Increase in joint pain 0 Palpitations 4 Rash 5 Buccal ulcers 4 Stomatitis 3 Dry mouth 3 Sore throat 1 ____. _~~~ ___. No. of patients with 1 sign 41 No. of patients on treatment 73 *Probability
of difference between treatments
13 12 0* 3 1 4 12* 12* 8 8* 5 :
and placebo was due to chance is
No. of patients with sign
C 20410
Phenylbutazone
Both drugs
14 22 8” 4 6 4 25* 25*
13 11 0 5 0 0 7 5 2 3 0 3 4 3 2 2 1
2 2 0 0 0 0 3 3 0 0 0 1 0 0 0 0 0 _~ ._
1:* 3
1
3 3 1 5
5 4 0 3 0
34
49
72
74
-
< 0.05. No other differences significant (P > 0.05).
This substance also caused more toxic signs and more symptomatic reports, but these were not significantly different from those found with the placebo, Phenylbutazone gave fewer toxic signs and symptoms than placebo: the difference in the latter case was highly significant (Table 3). There were no significant differences among the three treatments in their effects on ESR and WBC count (Table 4). The pattern of toxicity differed between C 20410 and phenylbutazone: the former was more likely to cause dyspepsia and other gastric disturbances, as well as headache and other unpleasant central nervous effects. Very few patients experienced the same difficulties on both drugs (Table 5). However, it was clear from patients’ statements of preference, both during and at the completion of the trial, that they found C 20410 less pleasant to take than phenylbutazone (Table 6). The pre-trial treatment, regardless of
placebo.
Patient Co-operation TABLE 6. A.
and the Sensitivity of Clinical Trials
PAI-IENTS'TREATMENT
1029
PREFERENCES
PREFERENCE ATEACHCHANGEOFTREATMENT
Number of preferences for Phenylbutazone In preference to: Phenylbutazone Placebo c 20410 Pre-trial treatment
23 20.5 10
Total preferences As % of maximum possible
53.5 61 B.
PREFERENCESATEND
-
__~
Pre-trial treatment 8
Phenylbutazone 25
Pre-trial treatment 8
1st treatment 9
-~
Pre-trial treatment
Placebo
c 20410
9
11.5 19.5 9
-
40 50
19.5 41
12.5 9.5 -..__ 31 39
6 6.5 I
.~~___
OFTRIAL _~____~______
Placebo 6
c20410 ~9 -_ 2nd treatment 3rd treatment 10 21 ____.____~_. ~~_~~~_
was preferred to that in the first treatment period on 41 per cent of occasions, and this was not significantly different from the preferences for placebo. C 20410 was preferred on exactly half the occasions that it was compared with another treatment, but phenylbutazone was preferred on 2 out of every 3 occasions. When the three treatments were compared only with each other, the patterns of preferences were significantly different (for the monthly comparison, x2=7 .601, P (2 d.f.) < 0.025; for the final comparison, x2= 15.684, P (2 d.f.) < 0.001).
its nature,
Discussion. It appeared from the observations on the 48 patients that C 20410 was an active drug in inflammatory joint disease: at the doses used it was perhaps more effective than phenylbutazone, but it was also more toxic and less acceptable to patients. A lower dose might well give results comparable in both respects to a similar dose of phenylbutazone, and the rather different distribution of toxic effects suggests that the new drug would be worth trying in patients intolerant of phenylbutazone. It is also interesting that the patients’ preferences for treatment were similar whether obtained monthly or at the end of three months: this consistency over such long periods of time suggested that some response was being validly measured. It appeared to be related to the extent to which undesirable side-effects were avoided rather than to the reduction in the number of active joints-this latter effect was perhaps usually too small in relation to the total experiences of discomfort (20-30 per cent) to outweigh the disadvantages of treatment. In a conventional clinical trial it would perhaps be concluded at this point that the new substance had no decisive advantage over phenylbutazone: it would perhaps be lightly commended and referred back to ‘further study’-or oblivion. However, we were also interested in methods of estimating the extent to which patients comply with instructions in such trials and the results were therefore examined more closely.
C. R. B. JOYCE
1030 II.
Evidence of the extent of patient co-operation
There are at least three ways in which information on patient co-operation can be obtained. (i) Patients may be asked to assess the extent to which they observed instructions; (ii) the substance taken, or its metabolites, can be looked for in the urine; or (iii) the number of pills taken can be estimated-with what reliability remains to be seen-from the number issued minus the number returned. Information of the first kind is notorious for its unreliability and is embarrassing to collect if additional and obvious means of checking it are to be used. We therefore used methods (ii) and (iii). The urine of all patients was examined at each visit for the presence of phenol red and their unused pills were collected at the next visit and subsequently counted. Presence ofmarker in urine. The urine of 67 patients was examined for the presence of phenol red on each of their three visits (the pills of 33 of these patients had, in fact, contained marker). The urine of a further 6 patients (4 with marker) was examined on two visits, and of 2 (1 with marker) on one occasion each: 3 patients (1 with marker) failed at each of three attendances to give a sample of urine. Only 38 out of the 108 urine samples which should have contained marker gave positive readings. (On one occasion the urine of a patient whose pills had not contained marker was recorded as being positive on testing for phenol red. The composition of the returned pills of this patient was checked, as were those of 16 others chosen at random: all agreed with expectation, and this was therefore presumably a ‘true’ false positive.) The odds were about even that marker would be found in the urine of patients who took placebo pills containing marker. It was only two-thirds as likely as this that there would be
TABLE7. A.
BY
INCIDENCEOF MARKERIN THEURINEOF ALL PATIENTSWHO TOOKPILLSCONTAININO10 MO PHENOLRED
TREATMENT _I___
Treatment Placebo Marker present Marker absent
17 20
Total
37
Proportion of occasions that marker was present
0.46
Phenylbutazone
~~~___
c 20410
Total
11 25
10 25
38 70
36
35
108
0.31
0.29
0.35
-.__
Probability of chance difference:
P > 0.2
B. BY PERIOD Period
Marker present Marker absent Total
1
2
3
Total
16 21 37
13 24 37
9 25 34
38 70 108
Probability
of chance difference : P > 0.2
Patient Co-operation
1031
and the Sensitivity of Clinical Trials
marker in the urine of patients taking the other two treatments also containing marker (Table 7A). These differences are suggestive but not significant (P > 0.2 on comparison with the theoretical ~2 distribution). It may be that the marker is more liable to combine with drug than with lactose and so to be rendered undetectable : an alternative explanation is that the differences reflected true differences in default rates, and this is discussed later. The proportional difference showed a trend towards a decline with time (Table 7B), but this effect was not statistically significant. The choice of a marker to check the consumption of pills is extremelydifficult. Such a substance must be devoid of pharmacological and psychological action (e.g. it should not run the risk even of changing the appearance of the urine-that no patient complained of this or commented upon it is not evidence that it did not occur in the present case); and it must be easily detectable at low concentration in excretions (preferably urine) following administration of small amounts. Its ideal rate of TABLE 8.
APPARENT
MEAN
-... From attendance records From pill returns -_ Discrepancy
DURATION OF TREATMENT(IN DAYS)FOR RECORDS AND PILLSRETURNED
Placebo
c 20410
Mean
27.0 23.6
25.8 22.3
23.8 20.4
25.5 22.1
3.5
3.4
3.4
3.14
Ii!
1.
ATTENDANCE
Phenylbutazone
MIN. FIG.
ALL PATIENTS FROM
DAYS
lb
26
24
2;
MISSED
Histogram of minimum number of days of treatment missed, calculated from pills returned: all treatments and all patients.
-__
1032
C. TABLE
9.
R. B. JOYCE
NUMBER OF INSTANCES OF ‘OBEDIENT’ BEHAVIOUR
Number of ‘obedient’ occasions ..____
Completers
(3 attendances)
Non-completers Non-completers ____---
(2 attendances) (1 attendance)
0
1
2
3
Total
4
12
15
33
64
2 2
3 2
5
.-____
-
10 4 ____
excretion is almost impossible to specify if, as was necessary in the present case, the urine is tested only once in each treatment period, and always at the end: for it must be so rapidly excreted that defaulting can be detected, yet so slowly that its absence signifies default with certainty. There were no significant differences in the number of active joints, toxic signs or other observations between patients taking pills with or without the marker. Return of pills. Pills were collected back from 68 patients at each of their three visits, from 4 on two occasions, and from 3 on one occasion. Two patients produced no pills at any of their three visits, although being reminded by letter to do so. One patient on two occasions produced boxes that obviouslycontainedpillsotherthanthose issued; these resembled a standard preparation of phenylbutazone, and her results were excluded from the trial as a whole. The average apparent duration of each treatment for all completers, obtained from the recorded intervals between attendances, and the average number of days of treatment apparently missed, obtained by dividing the number of pills returned by 2 (Table S), show a remarkable agreement. The mean day discrepancies for each drug, assuming that 60 pills (or 30 days’ supply) were issued, are almost identical at 3.4 days each. This value is too large to be due to differences in the exact numbers of pills supplied, and, although small (it represents only about 13 per cent of the total treatment) it is obviously worth closer study. The frequency distribution of the discrepancies for all occasions is remarkable (Fig. 1): the range is almost maximal (O-26 days), with a median of 3.5 days. It is clear that the behaviour of individuals varies widely, and its consistency is of obvious importance. If the rather arbitrary but generous period of a 5-day discrepancy is allowed to separate the ‘obedient’ from the ‘disobedient,’ only 40 out of 78 individuals were ‘obedient’ to instructions on all possible occasions (Table 9) and eight never complied with the instructions. For the 64 completers alone, 33 could be classed as ‘obedient’ for each of their 3 visits and 4 could be classed as ‘disobedient’ on all 3 visits. This measure of patient ‘co-operation’, like that provided by the marker, is open to several, but different, objections. Patients may have disposed of the appropriate number of pills by routes other than the oral: indeed, since they were all given supplies slightly larger than those needed for the 28 day interval between treatments, one might regard the failure to return any pills as a rather unfavourable sign. In fact, this was observed only 13 times out of 218 possible occasions, and involved 9 patients; 7 of these were taking pills that included marker, and on 3 of their 11 occasions marker was also present in the urine. On 4 of the occasions when no pills were returned and marker was absent, the interval between attendances was 30 days or greater. Thus 4 of the 7 occasions when marker would have been expected remained to be accounted
Patient Co-operation TABLE 10. _____
and the Sensitivity of Clinical Trials
PRESENCE OF MARKER IN URINE OF ‘OBEDIENT’ AND ‘DISOBEDIENT PATIENTS TAKING PILLS CONTAINING PHENOL RED ~~~__. -.______~_ .._ _-._ n
_ .__._ ‘Obedient’ patients ‘Disobedient’ patients Total
Marker present
17 1.5
21 12
32
33
Marker absent _____~ _~ 27 30
~~___~._~~_
Total _.~~~ ~~_ 48 42
..~_~_ _
57
____ (P 10.05:
1033
_
90
l-tail)
for, and this proportion (57 per cent) is similar to that in which marker was absent from all the urines examined (65 per cent: Table 7). The sample is small and the point would perhaps scarcely have been worth making, had it not also applied to the patients who returned some pills. However, their attention was never drawn to the number of pills in the box, and one would probably be assuming a greater ingenuity than they possessed were one to suppose that they did not consume, but threw away, the correct number of pills on each occasion that this was required. The imperfect observations on the marker allow the validity of the pill returns as an indicator of patients’ behaviour to be checked further. The proportion of occasions on which marker was present in the urine of the 17 possible patients who were always ‘obedient’ to instructions was 44 per cent, whereas that for the corresponding 15 ‘disobedient’ patients was only 29 per cent and this difference in the proportions, in the predicted direction, is significant by a one-tailed test at the 0.05 level of probability (Table 10). The number of pills returned is meaningful in another way. The mean number of pills returned for the treatment preferred by each patient (regardless of which it was) was almost exactly half as great as that for all the non-preferred treatments (8.4 against 17.0), and this represents a mean day discrepancy of about 2 against 6.5. It thus seems that the pill discrepancy score has some validity in showing whether patients did or did not take their pills. We have therefore considered the effect of taking this into account in re-evaluating the treatments.
TABLE 11. _ _~
n
ASSOCIATION OF DIFFERENCESBETWEEN MEASURES OF DRUG EFFECTSAND DEGREE OF CO-OPERATION ~~~___ ._
Patient group ~~~ ~~~ ~~
33
Most co-operative
No. of active joints x
Y
Z
Mean
X
3.0
3.4
2.5
3.0
0.9
0.8 1.8
3.5
1.3
1.6 1.7 >0.2
P
27
Less co-operative P
No. of toxic manifestations ._____
so.05
3.0
4.4
3.1 5 0.1
X -Phenylbutazone (2 x 200 mg/day) Y ==Placebo (lactose twice daily) Z-C 20410 (2 x 375 mg/day)
Y
Z
No. of symptoms
Mean
X
1.2
7.4
~~__ 1.5
Y
Z
8.3 8.4 co.2
Mean 8.0
8.7 10.6 10.9 10.1
1034
C. R. B. JOYCE
III. Information obtained from results by use qf measures of patient co-operation The 33 ‘obedient’ patients amongst the 60 completers showed fewer active joints and fewer toxic signs, and reported fewer subjective side-effects than the 27 ‘less obedient’ patients (Table 11). These differences are significant (P < 0.05). But whereas for the ‘obedient’ group the differences between treatments are significant for the number of active joints and of toxic signs, for the ‘less obedient’ group only that for the numbers of symptoms is significant. The likely explanation is that because, as has already been seen, the less obedient patients stopped taking their pills earlier in the treatment period, clinical changes (activity of the disease or toxicity of the drugs) were no longer remarked-even if present at the start of the period-by the physicians: whereas memories of the subjective effects were still vivid and were elicited by the symptom questionnaire. (Incidentally, it is notable that for neither group was there a difference between the symptom scores on placebo and C 20410). However, it has already been pointed out that the division into ‘obedient’ and ‘disobedient’ groups is rather arbitrary, and it wastes less information to examine, by the analysis of covariance, the contribution to experimental error made by individual differences in pill consumption : or, to put it in another way, to see if differences between treatments may be more sensitively detected by allowing for variation in the number of pills taken. The number of pills consumed by 48 patients was used as the covariate in calculating revised estimates of the more important measures of between-treatment differences. The observations were insufficiently complete to allow this to be done for the ESR. The patients in this set were not identical with those in ‘the 48’: substitutions were made, of patients on the appropriate treatment sequences, in order to reduce the need to calculate missing values of the variates and covariate. There were nevertheless four such missing values in the latter, and these were estimated, as were the others, by the method of least-squared deviations from the individual patient and treatment means [15]. This, and the presence of substitutes, accounts for the differences between the unadjusted treatment means in Table 12 and those in Table 3. The adjusted means were calculated by the exact method [16] and the differences between treatments examined by a t-test of significance. The most striking effect of the covariance adjustments is to increase the number of active joints on phenylbutazone and to decrease that on the new drug. On the other hand, toxicity becomes a more serious problem with C 20410 and the reductions in limbering-up time and number of symptoms brought about by C 20410 are now less impressive. The possibility that patients unable to tolerate phenylbutazone may not be similarly sensitive to C 20410 is of course unaffected by this argument, and together with the fact that the most objective measure available of the effects of treatments shows a marked improvement suggests that C 20410 deserves further study. The only apology that seems to be necessary for presenting a result that is so agreeably acceptable to common-sense is that this device seems rarely if ever to have been reported. There are very few accounts of attempts to confirm that patients are following treatment in diverse conditions. It is possible that some studies, meticulously carried out, have not been published because the evidence that they provided about the co-operativeness of patients was depressing. The present work suggests that even under such conditions a good deal of useful information is still recoverable, and need not merely be restricted to statements about the reasons for the lack of co-operation
Patient Co-operation TABLE
(Unadjusted
.~_ .____
12. SIGNIFICANCE OF DIFFERENCES BETWEEN TREATMENT MEANS and adjusted for regression of variables on number of pills consumed)
Treatment Variable
_~~
.-__
~___
--__
Unadjusted
-~-
Pills consumed Phenylbutazone Placebo C 20410
50.63 46.00 42.60
Limbering-up time (min) Phenylbutazone Placebo c 20410
56.3 79.8 64.3
-
co.05 >O.l
1.04 1.13 1.81
>0.4
Symptoms Phenylbutazone Placebo C 20410
8.00 9.69 9.48
Active joints Phenylbutazone Placebo C 20410
2.79 4.02 2.65
__
.
P
Toxic signs Phenylbutazone Placebo c 20410
c =regression
1035
and the Sensitivity of Clinical Trials
>0.05
>0.3
Adjusted
P
-
-
c=-o.o90 52.1 79.9 68.4 c=-0.069 0.73 1.13 2.12 c=-O.o41 7.81 9.69 9.65 c=+o.154 3.49 4.03 1.47
~__
>0.2 co.01
10.001 >O.P
>0.2
coefficient of variable upon pills consumed [ 161.
itself. It is also possible that certain conventional studies of new (or old) drugs have failed to reveal the genuine usefulness of the proposed remedies for these reasons. Perhaps an understanding of the possible explanations for this may help to bridge the gap between the subjective optimists, who disbelieve trials because they imply that drugs are no good which everyone knows are clinically useful, and the objective pessimists who regard trials with too much relish because they prove that drugs are useless which others believe useful. A final point: it is possible, notwithstanding the arguments put forward above, that the sensitivity of trials might be further increased by using only those patients likely to co-operate. The arguments for and against this course resemble those about proper attitudes to the inclusion in trials of reactors and non-reactors to placebo substances, and have been discussed elsewhere [9]. As in the latter case, the basic question is the possibility of predicting aspects of human behaviour reliably enough and long enough before they happen to be useful in practice. This, a ‘psychological’ method of improving the sensitivity of clinical trials, will be discussed in another paper. SUMMARY
Phenylbutazone (400 mg/day) ; 1-phenyl-2-methyl-4, dimethylamino-3, 6-dioxo1,2, 3, 6-tetrahydropyridazine (C 20410, Ciba) (750 mg/day); and a placebo have been compared under double-blind conditions in 78 female out-patients with active inflammatory polyarthritis. C 20410 reduced the number of active joints, erythrocyte sedimentation rate, and limbering-up time below the values on the control treatment, as did phenylbutazone,
1036
C. R. B. JOYCE
but the new substance was significantly more‘ toxic’ and significantly less well liked by patients than the latter. These differences emerged more clearly when the information obtained by incorporating a urine-marking substance in the pills, and from counts of the number of pills returned unconsumed, was used in the analysis of the results. Some implications for the results of past and future research of such simple technical and statistical methods of increasing the sensitivity of clinical trials are discussed. am most grateful to DR. W. S. TEGNER for permitting this investigation to take to DR. R. M. MASONfor invaluable help and criticism at all times; to the other members of the Department of Physical Medicine, the London Hospital, for enthusiastic and meticulous attention to what was necessary; to members of the Department of Pharmacology, the London Hospital Medical College, for much dull routine work and more criticism; and to DR. C. D. Acknowledgements-I
place in his department;
FALCONER of Ciba Laboratories Ltd. and DR. W. STODDARTof Geigy Pharmaceuticals Ltd. for providing the materials used, and to their pharmaceutical colleagues for solving the problems involved
in making comparable
preparations
of the treatments.
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