Planning and Design of Clinical Trials: 3rd Articulation


  1. Phase I and II Trials
    1. No optimal design for phase I trials can be recommended. The knowledge and intuition of the investigator is very important as in the choice of patients and in close observations. Very sick patients should not be selected for phase I studies since they have very low tolerance to toxicity and are likely to show it at very low doses, thus giving misleading results. However, this may not always be the situation. In many cancer clinical trials, patients who are no longer amenable to other treatments are recruited for phase I studies. Patient’s age should also be considered. Studies have shown that patients less than 18 years may tolerate higher doses of a drug than those older than 18 years. In cancer patients, younger (< 50 years) patient’s tumour may be more sensitive to chemotherapy than older (≥ 50 years) patient’s. Intervals between prior drug therapy and the administration of the phase I drug should be long enough to allow the toxic effect of the prior therapy to disappear. Other considerations for patient selection include concomitant medications and life expectancy long enough to complete the phase I study. The effect of concomitant drugs is often difficult to evaluate. Therefore, if possible, phase I patients should not be on medications other than the one being studied.
    2. The schedule and route of administration are determined on the basis of the type of drugs, mechanism of drug’s activity, patient convenience and preclinical animal pharmacokinetic information. A measure of response or effectiveness has to be determined, for example, a decrease of tumour cells to one-half the starting volume. In addition, changes in other relevant characteristics of patients should be used in determining the effectiveness of treatment. In a two-stage procedure, if no effect is noted in phase I, a phase IIA trial could be under-planning. After a treatment is found to be effective in phase IIA, a phase IIB trial should be conducted. If the treatment is found to be ineffective again in phase IIB, it would be considered unworthy of further study.
    3. The objective of a phase IIA or preliminary trial is to decide if a particular therapeutic regimen is effective enough to warrant further study. The decision to be reached at the end of the preliminary trial is one of the two possibilities:
      1.                                                               i.      The treatment is unlikely to be effective in x percent of patients or more.
      2.                                                             ii.      The treatment could be effective in x percent of patients or more.
    4. One would like to reject an ineffective treatment as quickly as possible and investigate further those treatments with a higher likelihood of effectiveness. The preliminary trial is designed so that a minimum possible number of consecutive failures is observed before the study is terminated. Suppose that the relevant percentage of effectiveness is 30 (x=30). Then the possible decisions for a preliminary trial are:
      1.                                                               i.      The treatment is unlikely to be effective in 30% of patients or more.
      2.                                                             ii.      The treatment could be effective in 30% of patients or more.


Consecutive patients

False Treatment’s Probability




0.7 X 0.7 = 0.49


0.7 X 0.7 X 0.7 = 0.343






  1. Thus if the treatment were at least 30% effective, there would be more than a 95% (1-0.0404) chance that one or more successes would be obtained in nine consecutive patients. If nine consecutive failures are observed, the treatment is unlikely to be effective in 30% of patients. Following this logic, Gehan (1961) gives the minimum number of patients necessary to decide whether a treatment is not of a given effectiveness or not worthy of further trial at a given level of rejection error (rejection error is defined as the chance of rejecting the treatment for further trial when it should have been accepted). The table below gives the sample size required for a preliminary trial of a new treatment for various levels of therapeutic effectiveness (percent) and two rejection error levels. For example, if one is interested in a treatment of 25% effectiveness and is willing to accept 5% rejection error, a sample of 11 patients is necessary. If one or more patients show response (effect of treatment), the treatment receives further trial.


Therapeutic Effectiveness

Rejection Error


































  1. The definition of therapeutic effectiveness requires careful assessment. In diseases for which previous procedures or therapies have been completely ineffective, the definition may pose no serious difficulties, and any objective benefit to the patient can be considered as a therapeutic effect. But if partial benefits are frequently observed, it is reasonable to require pronounced objective improvement in the patient’s disease. The preliminary trial will eliminate regimens having little or no effectiveness.
  2. When a regimen has passed a Phase II preliminary trial or has been sufficiently effective in a phase I trial, then a phase IIB or follow-up trial is recommended in order to provide a precise estimate of its effectiveness. An estimate of true effectiveness is the proportion of patients in the sample who are treated successfully. For example, if a sample of 11 patients had been taken in a preliminary trial (with a 10% rejection error) in search of a 20% positive effect of treatment, and one treatment success was observed, then 60 additional patients would be required to guarantee an estimate of the true percentage effectiveness with a standard error of about 5%. If the required standard error was about 10% then 7 additional patients would be needed.
  3. The sampling plan described above for the preliminary and follow-up trials is a two-stage procedure known as double sampling (Cox 1958). The initial sample is calculated to meet the probability of further trial. It requires at least a single treatment success before the second sample is taken. A complete phase II trial requires completion of both IIA and IIB if this sampling method is used, not just IIA. Although response rate is often used as the criterion for treatment success, it is not the only desirable statistic that can be obtained from phase II trials. Many phase II trials also estimate remission duration and survival time when applicable.

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