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RTSM (Randomization and Trial Supply Management) for Early Phase Studies
Abstract and Figures
Phase I and early Phase II studies generally have the aim of establishing the safety, tolerability and pharmacokinetics of one or more doses and formulations. Traditionally many of these studies have tended to be conducted at a single site so that the randomization, dosing, dispensing, blood sampling procedures and progression between successive cohorts could be tightly managed. Allowing competitive recruitment may be particularly important in patient studies in populations where it is difficult to recruit. RTSM (Randomization and Trial Supply Management) technology allows management of the recruitment to each cohort which would be difficult, if not impossible, to coordinate with many centers. Examples are given in this letter to show how RTSM technology can be used to manage randomization, cohort progression and dosing in multicentre early phase trials. Additionally, a sample survey of the incidence and types of early phase cohort studies performed by Perceptive Informatics was undertaken. The survey of our database showed that many early phase studies are conducted in multiple sites and countries with fairly low numbers of patients per site; this reflects the need for speed on the critical path for drug development.
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Calcitonin gene-related peptide (CGRP) may have a causative role in migraine. We therefore hypothesized that a CGRP-receptor antagonist might be effective in the treatment of migraine attacks.
In an international, multicenter, double-blind, randomized clinical trial of BIBN 4096 BS, a highly specific and potent nonpeptide CGRP-receptor antagonist, 126 patients with migraine received one of the following: placebo or 0.25, 0.5, 1, 2.5, 5, or 10 mg of BIBN 4096 BS intravenously over a period of 10 minutes. A group-sequential adaptive treatment-assignment design was used to minimize the number of patients exposed.
The 2.5-mg dose was selected, with a response rate of 66 percent, as compared with 27 percent for placebo (P=0.001). The BIBN 4096 BS group as a whole had a response rate of 60 percent. Significant superiority over placebo was also observed with respect to most secondary end points: the pain-free rate at 2 hours; the rate of sustained response over a period of 24 hours; the rate of recurrence of headache; improvement in nausea, photophobia, phonophobia, and functional capacity; and the time to meaningful relief. An effect was apparent after 30 minutes and increased over the next few hours. The overall rate of adverse events was 25 percent after the 2.5-mg dose of the drug and 20 percent for the BIBN 4096 BS group as a whole, as compared with 12 percent for placebo. The most frequent side effect was paresthesia. There were no serious adverse events.
The CGRP antagonist BIBN 4096 BS was effective in treating acute attacks of migraine.
Proper randomisation rests on adequate allocation concealment. An allocation concealment process keeps clinicians and participants unaware of upcoming assignments. Without it, even properly developed random allocation sequences can be subverted. Within this concealment process, the crucial unbiased nature of randomised controlled trials collides with their most vexing implementation problems. Proper allocation concealment frequently frustrates clinical inclinations, which annoys those who do the trials. Randomised controlled trials are anathema to clinicians. Many involved with trials will be tempted to decipher assignments, which subverts randomisation. For some implementing a trial, deciphering the allocation scheme might frequently become too great an intellectual challenge to resist. Whether their motives indicate innocent or pernicious intents, such tampering undermines the validity of a trial. Indeed, inadequate allocation concealment leads to exaggerated estimates of treatment effect, on average, but with scope for bias in either direction. Trial investigators will be crafty in any potential efforts to decipher the allocation sequence, so trial designers must be just as clever in their design efforts to prevent deciphering. Investigators must effectively immunise trials against selection and confounding biases with proper allocation concealment. Furthermore, investigators should report baseline comparisons on important prognostic variables. Hypothesis tests of baseline characteristics, however, are superfluous and could be harmful if they lead investigators to suppress reporting any baseline imbalances.
Minimization is a largely nonrandom method of treatment allocation for clinical trials. We conducted a systematic literature search to determine its advantages and disadvantages compared with other allocation methods. Minimization was originally proposed by Taves and by Pocock and Simon. The latter paper introduces a family of allocation methods of which Taves' method is the simplest example. Minimization aims to ensure treatment arms are balanced with respect to predefined patient factors as well as for the number of patients in each group. Further extensions of the method have also been proposed by other authors. Simulation studies show that minimization provides better balanced treatment groups when compared with restricted or unrestricted randomization and that it can incorporate more prognostic factors than stratified randomization methods such as permuted blocks within strata. Some more computationally complex methods may give an even better performance. Concerns over the use of minimization have centered on the fact that treatment assignments may be predicted with certainty in some situations and on the implications for the analysis methods used. It has been suggested that adjustment should always be made for minimization factors when analyzing trials where minimization is the allocation method used. The use of minimization may sometimes result in added organizational complexity compared with other methods. Minimization has been recommended by many commentators for use in clinical trials. Despite this it is still rarely used in practice. From the evidence presented in this review, we believe minimization to be a highly effective allocation method and recommend its wider adoption in the conduct of randomized controlled trials.
The trial objective was to test whether a new mechanism of action would effectively treat migraine headaches and to select a dose range for further investigation. The motivation for a group sequential, adaptive, placebo-controlled trial design was (1) limited information about where across the range of seven doses to focus attention, (2) a need to limit sample size for a complicated inpatient treatment and (3) a desire to reduce exposure of patients to ineffective treatment. A design based on group sequential and up and down designs was developed and operational characteristics were explored by trial simulation. The primary outcome was headache response at 2 h after treatment. Groups of four treated and two placebo patients were assigned to one dose. Adaptive dose selection was based on response rates of 60% seen with other migraine treatments. If more than 60% of treated patients responded, then the next dose was the next lower dose; otherwise, the dose was increased. A stopping rule of at least five groups at the target dose and at least four groups at that dose with more than 60% response was developed to ensure that a selected dose would be statistically significantly (p=0.05) superior to placebo. Simulations indicated good characteristics in terms of control of type 1 error, sufficient power, modest expected sample size and modest bias in estimation. The trial design is attractive for phase 2 clinical trials when response is acute and simple, ideally binary, placebo comparator is required, and patient accrual is relatively slow allowing for the collection and processing of results as a basis for the adaptive assignment of patients to dose groups. The acute migraine trial based on this design was successful in both proof of concept and dose range selection.
A regulatory perspective of the statistician's role in the data verification and inspection process
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