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The qualification period
0895-4356/91$3.00+ 0.00 Copyright 0 1991Pergamon Press plc
J Clin EpidemiolVol. 44, No. 6, pp. 461-464, 1991 Printed in Great Britain. All rights reserved
Commentary THE QUALIFICATION PAUL KNIPSCHILD,‘*
PERIOD
PIETER LEFFERS’and ALVAN R. FEINSTEIN’
‘Department of Epidemiology/Health Care Research, Rijksuniversiteit Limburg, P.O. Box 616, 6200 MD Maastricht, The Netherlands and ‘Clinical Epidemiology Unit, Yale University School of Medicine, New Haven, CT 06510, U.S.A. (Received 3 October 1990)
Abstract-For randomized trials that do not require prompt onset of therapy, a pre-admission preparation, called the qualzjication period, can deal with certain customary difficulties in design, analysis, and ethics. For the patients’ baseline state, the qualification period can be used to “wash out” effects of previous treatment, to verify admission criteria, and to identify or stratify suitable prognostic indicators. For treatment, the qualification period can be used to test and adjust therapeutic dosages, to exclude placebo responders, and to confirm early responsiveness to long-term active therapy. For intention-to-treat analyses, the qualification period can allow special stratifications for patients who are therapeutically difficult to regulate or who comply imperfectly. By offering the cited improvements as well as a brief “pilot exposure” for each patient, the qualification period can also enhance the “informed consent” and general ethics of a trial.
1. INTRODUCTION
When therapeutic efficacy is evaluated with a randomized trial, treatment must be started promptly for urgent situations, such as patients with an acute myocardial infarction or an asthmatic attack. After the investigator has rapidly checked the general admission criteria, such patients are immediately randomized and allocated to the compared treatments. The haste may produce certain problems: the patient may not fulfil specific details of the admission criteria, or may have other features that require subsequent “de-admission” or special analytic adjustments. Unfortunately, these later corrections are often inadequate and leave ambiguity in the interpretation of the trial results.
In many other circumstances, however, patients seek help for clinical conditions that do *Author for correspondence. CE U/S-A
not require
urgent
treatment.
Therapy
may be
aimed at persistently enduring symptoms, such as insomnia or musculoskeletal pain, or at levels of symptomless “factors”, such as ocular hypertension or hyperlipidemia, that increase the long-term risk of developing certain diseases. In the non-urgent situations, patients need not be hastily entered into the randomized part of the trial. Before randomization itself, a period of time can be used for preparations that can eliminate certain problems in design, prevent other problems in analysis, and improve the general relevance, validity, efficiency, and ethics of the trial. This pre-admission preparation, for which we suggest the name the qualiJcation period, can serve four important
roles that are discussed in this essay. They refer to identifying suitable baseline characteristics in the admitted patients, checking for suitable adjustments and responses for the proposed treatment, determining special therapeutic
462
stratifications, and improving informed consent. 2. BASELINE
the ethics of
CHARACTERISTICS
During the qualification period the investigator has ample time to determine the baseline characteristics of each patient. These characteristics may require a “washout” of previous treatments, a re-check of suitability for admission, and plans for ensuring comparability. 2.1. Washout period The ideal goal of admitting only previously untreated patients may be impractical for clinical conditions that have a low incidence. Therefore, patients are often admitted to a trial even though they were previously treated or are currently receiving a different treatment for the same condition. Effective earlier treatment, however, may alter the patient’s eligibility for admission by influencing the baseline level of the target symptom or risk factor. The effect of a previous treatment may also interfere with the action of the proposed new treatment. The qualification period can be used as a “washout” interval, intended to eliminate the residual effect of previous treatment, and to allow a recurrence of the original level of the target symptom or risk factor. The washout may also allow a more accurate measurement of prognostic indicators (discussed later) whose level may have been affected by previous treatment. 2.2. Admission criteria Before entering patients into the qualification period, the investigator can check for rough, easy-to-determine features of the inclusion and exclusion criteria such as (probable) diagnosis, age, and sex. During the qualification period, additional data (including post-washout status) can be obtained to identify patients who are best suited for the subsequent trial. Because the patient’s clinical history, physical examination, and routine laboratory tests may not give enough information about either the particular condition under study or contraindications to the proposed treatment, the qualification period can be used to repeat measurements, check medical records, and do additional tests. To help improve validity, the admitted patients should be a reasonably homogeneous group. This goal can be attained by restricting the study population to those with demarcated
levels of prognostic indicators. To help improve efficiency, admission may be restricted to patients who could most benefit from the treatment, i.e. those with unfavourable levels of the prognostic indicators. All of these distinctions can be carefully checked during the qualification period, so that admission criteria can be applied accurately. 2.3. Comparability Despite prognostic restrictions in the admission criteria, many other prognostic indicators may have different levels among the admitted patients. Investigators usually hope that the random allocation of treatment will distribute these distinctions equitably, and produce prognostic comparability in the contrasted groups. This hope will always depend on the “luck of the draw”, and is particularly threatened if the trial contains a relatively small number of patients. Therefore the investigator should ensure a balanced distribution of levels of prognostic indicators over the contrasted groups. This balance can be attained by randomization within patient groups who are stratified on their estimated level of prognosis. If several investigators or institutions evaluate the outcome in the trial patients, the comparability of outcome measurements can be aided by additional stratification according to the site of observation. Such stratification by “center” is especially valuable in multi-center trials, and it also augments the comparability of external circumstances in situations where the treatment is difficult to standardize. The qualification period gives the investigator time to get accurate data for all of the known and putative prognostic indicators, and to use this information for a stratified randomization procedure. Any residual confounding by insufficiently balanced prognostic indicators can then be adjusted in a multivariable analysis afterwards.
3. THERAPEUTIC ADJUSTMENTS RESPONSES
AND
All of the activities just cited refer to identifying the baseline state of the patients before treatment begins. A different role for the qualification period is to adjust dosage for treatments that must be regulated for an appropriate response, to remove “placebo responders” whose results may make the trial less efficient, and to
463
Commentary
check patients for early responsiveness to longterm active treatment of symptoms. 3.1. Adjustment of dosage The dose of treatment must often be individually adjusted to achieve a particular response, such as lowering blood pressure, sugar, or lipids, or attaining a desirable tissue (or serum) concentration of the drug. The desired dosage may be difficult to establish after the patient has been randomized and the actual treatment begins. The qualification period can be used to determine the exact dosage needed for each patient’s optimum regulation. At randomization, the patient can then be assigned either to this optimum dosage or to an equivalent amount of placebo. (If two active drugs are being compared, the qualification period can be used to determine the appropriate dosage for each.) The adjustment process would enhance both the validity and the ethics of the trial, since the investigators can determine (and exclude) patients who may be unresponsive to the active treatment, and can ensure that an optimum dosage is prescribed. 3.2. Exclusion of “placebo responders” If treatment is aimed at relieving symptoms, the untreated group may have a high success rate due to “placebo effects” and spontaneous regression. In clinical trials, as opposed to regular patient care, this high success rate becomes “noise” that may obscure the efficacy of the active treatment, thereby making the trial less efficient. For example, suppose 30% of patients improve with placebo and 65% with active treatment. For the 35% difference in success rates, the variance of the estimate depends on the level of the success rates themselves. If the qualification period can eliminate enough placebo responders to reduce the success rate to 10% in the placebo group, the corresponding result in the treated group can be determined as follows: the success rate among placebo non-responders in the previous example was (65-30%)/(100 - 30%) = 50%. With the assumption that this success rate will remain the same in the new study, the treated group will have a 100% success rate in the 10% proportion of placebo responders, and a 50% success rate in the remaining 90% of non-placebo responders. The overall success rate will be 10% + 45% = 55%. Because the placebo group will have a success rate of lo%, the difference in success rates will be 45% between the two groups.
With this larger difference, and a lower success rate in the placebo-treated group, the trial will be more efficient. An equally stable estimate can be achieved with a smaller sample size. 3.3. Early responsiveness to active treatment If the trial is aimed at evaluating efficacy for a long course of symptomatic treatment, e.g. ultrasound for low back pain, the qualification period can be used to determine the immediate (but temporary) treatment response for every patient. This response can be used for a stratified randomization to increase prognostic comparability, and to discriminate between patients in whom the treatment may or may not be efficacious in the long run. Patients who show no evidence of any positive response to the active treatment might be excluded from admission. The qualification period thus offers an opportunity to do any or all of three activities: determining the appropriate dose of an active treatment that must be regulated; identifying and removing patients who respond particularly well to placebo treatment; and identifying the early response of patients for whom a long course of active treatment is planned. In the second instance, all patients must have an interval of placebo therapy during the qualification period; this interval can also serve for estimating compliance (as discussed later). In the third instance, all patients would have a brief interval of long-term active therapy. 4. SPECIAL
THERAPEUTIC
STRATIFICATIONS
The qualification period can also be used to anticipate and help solve a different problem that occurs in the analysis of results after a randomized trial is completed. The problem refers to the management of data for patients whose treatment was given in a non-proficient manner. If this problem arises from the patient’s misunderstanding, the qualification period can be used to correct ambiguous instructions. In most instances, however, the problems will arise from difficulties in regulation, or defects in compliance. 4.1. D@cult regulation The satisfactory regulation of a particular treatment may be particularly difficult for certain patients such as “brittle” diabetics or “resistant” hypertensives. These patients may have other prognostic disadvantages that are
464
Commentary
identified only by the problem of maintaining adequate dosage after treatment begins. A separate appraisal of results in the “poorly regulated” group is not permitted, however, by the current principles of “intention-to-treat” analysis. The problem can be eliminated by using the qualification period to identify the patients who can be well regulated with ease or difficulty. Treatment can then be randomly assigned within the “easy” or “difficult” strata, and the results can then be analyzed within strata without violating the intention-to-treat principle. 4.2. Poor compliance ‘Poor compliance can be a serious problem especially if the efficacy of a drug is tested outside the hospital. Some patients who have given consent to follow the protocol may change their mind and become poor compliers, or may drop out of the study altogether. The investigator is then confronted with a difficult dilemma. If the data of poor compliers are included in an intention-to-treat analysis, the prognostic comparability of treated groups remains intact, but the data may yield a biased estimate (underestimation) of the treatment effect. If the data of poor compliers are excluded in a per-protocol analysis, the groups may become prognostically incomparable, again leading to a biased estimate (probably overestimation) of the treatment effect. The solution would be to do both analyses and hope that there is no large discrepancy. For dropouts, however, the problem has no good solution. Because an intention-to-treat analysis is impossible for participants with no outcome data, the investigators may resort to an often frustrating “assuming-the-worst” analysis. For these reasons, vigorous efforts should be made before randomization to identify and exclude future poor compliers or potential dropouts. Unfortunately, not enough is known about the determinants of compliance and dropout behavior to make this decision on prior knowledge. The qualification period can be used, however, as a test. The presumption is that good compliers during the qualification period will be good compliers afterwards and will not drop out of the study. At the start of the qualification period, patients who admit that they cannot follow the protocol suitably may be eliminated from the study. Other patients can be rigorously examined during the qualification period, using an indicator substance for drugs or some other
monitoring system. Before randomization occurs, the investigators may want to exclude patients with particularly defective compliance. The remaining patients may then be stratified into good and non-good compliance groups, with treatment randomly assigned within the two strata. The subsequent results could then be checked within the two compliance groups in an intention-to-treat analysis that provides for differences in compliance, without violating prognostic comparability. 5. ETHICS OF INFORMED
CONSENT
By offering the cited improvements in relevance, validity, and efficiency of the trial, the qualification period would help improve the general ethical background for the trial. The trial will be more relevant because of the better identification of both patients and dosages, and more valid because it reduces non-comparability in prognosis, external circumstances, and measurement of effects. The trial will also be more efficient because “significant” differences may be obtained with smaller sample sizes. A separate virtue of the qualification period, however, is its role as a “pilot study” for each patient. During that time, patients have direct exposure to the procedures and requirements of the study. If uncertain about whether to continue, patients can withdraw before randomization. The trial itself will then be restricted to patients who are highly motivated to contribute to further knowledge of medical treatment. As noted earlier, a qualification period cannot be used when treatment must be started almost immediately. In most other therapeutic situations, however, activities conducted during the qualification period can improve the methodological quality of the trial, while enhancing its clinical pertinence and ethics. In particular, the qualification period can be used to determine and make suitable adjustments for problems that otherwise cannot be discerned until after the randomized part of the trial has begun. The advance discernment of these problems will allow suitable adjustment of treatment and suitable evaluation of results, without affecting the rigorous standards of clinical trials. Acknowledgemenrs-The
authors would like to thank Olli S. Miettinen for suggesting some of the ideas in this paper. After this manuscript was completed, we found that some of the ideas had been mentioned by J. M. Lang and the discussants of her manuscript, ‘The use of a run-in to enhance compliance” [Statistics in Medicine 1990; 9: 87-951.
J Clin EpidemiolVol. 44, No. 6, pp. 461-464, 1991 Printed in Great Britain. All rights reserved
Commentary THE QUALIFICATION PAUL KNIPSCHILD,‘*
PERIOD
PIETER LEFFERS’and ALVAN R. FEINSTEIN’
‘Department of Epidemiology/Health Care Research, Rijksuniversiteit Limburg, P.O. Box 616, 6200 MD Maastricht, The Netherlands and ‘Clinical Epidemiology Unit, Yale University School of Medicine, New Haven, CT 06510, U.S.A. (Received 3 October 1990)
Abstract-For randomized trials that do not require prompt onset of therapy, a pre-admission preparation, called the qualzjication period, can deal with certain customary difficulties in design, analysis, and ethics. For the patients’ baseline state, the qualification period can be used to “wash out” effects of previous treatment, to verify admission criteria, and to identify or stratify suitable prognostic indicators. For treatment, the qualification period can be used to test and adjust therapeutic dosages, to exclude placebo responders, and to confirm early responsiveness to long-term active therapy. For intention-to-treat analyses, the qualification period can allow special stratifications for patients who are therapeutically difficult to regulate or who comply imperfectly. By offering the cited improvements as well as a brief “pilot exposure” for each patient, the qualification period can also enhance the “informed consent” and general ethics of a trial.
1. INTRODUCTION
When therapeutic efficacy is evaluated with a randomized trial, treatment must be started promptly for urgent situations, such as patients with an acute myocardial infarction or an asthmatic attack. After the investigator has rapidly checked the general admission criteria, such patients are immediately randomized and allocated to the compared treatments. The haste may produce certain problems: the patient may not fulfil specific details of the admission criteria, or may have other features that require subsequent “de-admission” or special analytic adjustments. Unfortunately, these later corrections are often inadequate and leave ambiguity in the interpretation of the trial results.
In many other circumstances, however, patients seek help for clinical conditions that do *Author for correspondence. CE U/S-A
not require
urgent
treatment.
Therapy
may be
aimed at persistently enduring symptoms, such as insomnia or musculoskeletal pain, or at levels of symptomless “factors”, such as ocular hypertension or hyperlipidemia, that increase the long-term risk of developing certain diseases. In the non-urgent situations, patients need not be hastily entered into the randomized part of the trial. Before randomization itself, a period of time can be used for preparations that can eliminate certain problems in design, prevent other problems in analysis, and improve the general relevance, validity, efficiency, and ethics of the trial. This pre-admission preparation, for which we suggest the name the qualiJcation period, can serve four important
roles that are discussed in this essay. They refer to identifying suitable baseline characteristics in the admitted patients, checking for suitable adjustments and responses for the proposed treatment, determining special therapeutic
462
stratifications, and improving informed consent. 2. BASELINE
the ethics of
CHARACTERISTICS
During the qualification period the investigator has ample time to determine the baseline characteristics of each patient. These characteristics may require a “washout” of previous treatments, a re-check of suitability for admission, and plans for ensuring comparability. 2.1. Washout period The ideal goal of admitting only previously untreated patients may be impractical for clinical conditions that have a low incidence. Therefore, patients are often admitted to a trial even though they were previously treated or are currently receiving a different treatment for the same condition. Effective earlier treatment, however, may alter the patient’s eligibility for admission by influencing the baseline level of the target symptom or risk factor. The effect of a previous treatment may also interfere with the action of the proposed new treatment. The qualification period can be used as a “washout” interval, intended to eliminate the residual effect of previous treatment, and to allow a recurrence of the original level of the target symptom or risk factor. The washout may also allow a more accurate measurement of prognostic indicators (discussed later) whose level may have been affected by previous treatment. 2.2. Admission criteria Before entering patients into the qualification period, the investigator can check for rough, easy-to-determine features of the inclusion and exclusion criteria such as (probable) diagnosis, age, and sex. During the qualification period, additional data (including post-washout status) can be obtained to identify patients who are best suited for the subsequent trial. Because the patient’s clinical history, physical examination, and routine laboratory tests may not give enough information about either the particular condition under study or contraindications to the proposed treatment, the qualification period can be used to repeat measurements, check medical records, and do additional tests. To help improve validity, the admitted patients should be a reasonably homogeneous group. This goal can be attained by restricting the study population to those with demarcated
levels of prognostic indicators. To help improve efficiency, admission may be restricted to patients who could most benefit from the treatment, i.e. those with unfavourable levels of the prognostic indicators. All of these distinctions can be carefully checked during the qualification period, so that admission criteria can be applied accurately. 2.3. Comparability Despite prognostic restrictions in the admission criteria, many other prognostic indicators may have different levels among the admitted patients. Investigators usually hope that the random allocation of treatment will distribute these distinctions equitably, and produce prognostic comparability in the contrasted groups. This hope will always depend on the “luck of the draw”, and is particularly threatened if the trial contains a relatively small number of patients. Therefore the investigator should ensure a balanced distribution of levels of prognostic indicators over the contrasted groups. This balance can be attained by randomization within patient groups who are stratified on their estimated level of prognosis. If several investigators or institutions evaluate the outcome in the trial patients, the comparability of outcome measurements can be aided by additional stratification according to the site of observation. Such stratification by “center” is especially valuable in multi-center trials, and it also augments the comparability of external circumstances in situations where the treatment is difficult to standardize. The qualification period gives the investigator time to get accurate data for all of the known and putative prognostic indicators, and to use this information for a stratified randomization procedure. Any residual confounding by insufficiently balanced prognostic indicators can then be adjusted in a multivariable analysis afterwards.
3. THERAPEUTIC ADJUSTMENTS RESPONSES
AND
All of the activities just cited refer to identifying the baseline state of the patients before treatment begins. A different role for the qualification period is to adjust dosage for treatments that must be regulated for an appropriate response, to remove “placebo responders” whose results may make the trial less efficient, and to
463
Commentary
check patients for early responsiveness to longterm active treatment of symptoms. 3.1. Adjustment of dosage The dose of treatment must often be individually adjusted to achieve a particular response, such as lowering blood pressure, sugar, or lipids, or attaining a desirable tissue (or serum) concentration of the drug. The desired dosage may be difficult to establish after the patient has been randomized and the actual treatment begins. The qualification period can be used to determine the exact dosage needed for each patient’s optimum regulation. At randomization, the patient can then be assigned either to this optimum dosage or to an equivalent amount of placebo. (If two active drugs are being compared, the qualification period can be used to determine the appropriate dosage for each.) The adjustment process would enhance both the validity and the ethics of the trial, since the investigators can determine (and exclude) patients who may be unresponsive to the active treatment, and can ensure that an optimum dosage is prescribed. 3.2. Exclusion of “placebo responders” If treatment is aimed at relieving symptoms, the untreated group may have a high success rate due to “placebo effects” and spontaneous regression. In clinical trials, as opposed to regular patient care, this high success rate becomes “noise” that may obscure the efficacy of the active treatment, thereby making the trial less efficient. For example, suppose 30% of patients improve with placebo and 65% with active treatment. For the 35% difference in success rates, the variance of the estimate depends on the level of the success rates themselves. If the qualification period can eliminate enough placebo responders to reduce the success rate to 10% in the placebo group, the corresponding result in the treated group can be determined as follows: the success rate among placebo non-responders in the previous example was (65-30%)/(100 - 30%) = 50%. With the assumption that this success rate will remain the same in the new study, the treated group will have a 100% success rate in the 10% proportion of placebo responders, and a 50% success rate in the remaining 90% of non-placebo responders. The overall success rate will be 10% + 45% = 55%. Because the placebo group will have a success rate of lo%, the difference in success rates will be 45% between the two groups.
With this larger difference, and a lower success rate in the placebo-treated group, the trial will be more efficient. An equally stable estimate can be achieved with a smaller sample size. 3.3. Early responsiveness to active treatment If the trial is aimed at evaluating efficacy for a long course of symptomatic treatment, e.g. ultrasound for low back pain, the qualification period can be used to determine the immediate (but temporary) treatment response for every patient. This response can be used for a stratified randomization to increase prognostic comparability, and to discriminate between patients in whom the treatment may or may not be efficacious in the long run. Patients who show no evidence of any positive response to the active treatment might be excluded from admission. The qualification period thus offers an opportunity to do any or all of three activities: determining the appropriate dose of an active treatment that must be regulated; identifying and removing patients who respond particularly well to placebo treatment; and identifying the early response of patients for whom a long course of active treatment is planned. In the second instance, all patients must have an interval of placebo therapy during the qualification period; this interval can also serve for estimating compliance (as discussed later). In the third instance, all patients would have a brief interval of long-term active therapy. 4. SPECIAL
THERAPEUTIC
STRATIFICATIONS
The qualification period can also be used to anticipate and help solve a different problem that occurs in the analysis of results after a randomized trial is completed. The problem refers to the management of data for patients whose treatment was given in a non-proficient manner. If this problem arises from the patient’s misunderstanding, the qualification period can be used to correct ambiguous instructions. In most instances, however, the problems will arise from difficulties in regulation, or defects in compliance. 4.1. D@cult regulation The satisfactory regulation of a particular treatment may be particularly difficult for certain patients such as “brittle” diabetics or “resistant” hypertensives. These patients may have other prognostic disadvantages that are
464
Commentary
identified only by the problem of maintaining adequate dosage after treatment begins. A separate appraisal of results in the “poorly regulated” group is not permitted, however, by the current principles of “intention-to-treat” analysis. The problem can be eliminated by using the qualification period to identify the patients who can be well regulated with ease or difficulty. Treatment can then be randomly assigned within the “easy” or “difficult” strata, and the results can then be analyzed within strata without violating the intention-to-treat principle. 4.2. Poor compliance ‘Poor compliance can be a serious problem especially if the efficacy of a drug is tested outside the hospital. Some patients who have given consent to follow the protocol may change their mind and become poor compliers, or may drop out of the study altogether. The investigator is then confronted with a difficult dilemma. If the data of poor compliers are included in an intention-to-treat analysis, the prognostic comparability of treated groups remains intact, but the data may yield a biased estimate (underestimation) of the treatment effect. If the data of poor compliers are excluded in a per-protocol analysis, the groups may become prognostically incomparable, again leading to a biased estimate (probably overestimation) of the treatment effect. The solution would be to do both analyses and hope that there is no large discrepancy. For dropouts, however, the problem has no good solution. Because an intention-to-treat analysis is impossible for participants with no outcome data, the investigators may resort to an often frustrating “assuming-the-worst” analysis. For these reasons, vigorous efforts should be made before randomization to identify and exclude future poor compliers or potential dropouts. Unfortunately, not enough is known about the determinants of compliance and dropout behavior to make this decision on prior knowledge. The qualification period can be used, however, as a test. The presumption is that good compliers during the qualification period will be good compliers afterwards and will not drop out of the study. At the start of the qualification period, patients who admit that they cannot follow the protocol suitably may be eliminated from the study. Other patients can be rigorously examined during the qualification period, using an indicator substance for drugs or some other
monitoring system. Before randomization occurs, the investigators may want to exclude patients with particularly defective compliance. The remaining patients may then be stratified into good and non-good compliance groups, with treatment randomly assigned within the two strata. The subsequent results could then be checked within the two compliance groups in an intention-to-treat analysis that provides for differences in compliance, without violating prognostic comparability. 5. ETHICS OF INFORMED
CONSENT
By offering the cited improvements in relevance, validity, and efficiency of the trial, the qualification period would help improve the general ethical background for the trial. The trial will be more relevant because of the better identification of both patients and dosages, and more valid because it reduces non-comparability in prognosis, external circumstances, and measurement of effects. The trial will also be more efficient because “significant” differences may be obtained with smaller sample sizes. A separate virtue of the qualification period, however, is its role as a “pilot study” for each patient. During that time, patients have direct exposure to the procedures and requirements of the study. If uncertain about whether to continue, patients can withdraw before randomization. The trial itself will then be restricted to patients who are highly motivated to contribute to further knowledge of medical treatment. As noted earlier, a qualification period cannot be used when treatment must be started almost immediately. In most other therapeutic situations, however, activities conducted during the qualification period can improve the methodological quality of the trial, while enhancing its clinical pertinence and ethics. In particular, the qualification period can be used to determine and make suitable adjustments for problems that otherwise cannot be discerned until after the randomized part of the trial has begun. The advance discernment of these problems will allow suitable adjustment of treatment and suitable evaluation of results, without affecting the rigorous standards of clinical trials. Acknowledgemenrs-The
authors would like to thank Olli S. Miettinen for suggesting some of the ideas in this paper. After this manuscript was completed, we found that some of the ideas had been mentioned by J. M. Lang and the discussants of her manuscript, ‘The use of a run-in to enhance compliance” [Statistics in Medicine 1990; 9: 87-951.