| Auteur||Mustapha Setta|
|Titel||Sequential Designs in Phase II Clinical Trials|
|Begeleider||B. van Es|
|Faculteit||Faculteit der Natuurwetenschappen, Wiskunde en Informatica|
|Instituut/afd.||FNWI: Korteweg-De Vries Instituut|
|Samenvatting||In order to create new medicines clinical trials are needed. A clinical trial is a research study to answer specific questions about vaccines, new therapies or new ways of using known treatments. It is also used to determine whether new drugs or treatments are both safe and effective.
In most clinical trials one group of participants is given an experimental drug, while another group is given either a standard treatment for the disease or a placebo (the short hand term is two-armed). However, in earlier stages of development, clinical trials may also have only one ‘arm’ which means that all participants gets the same experimental drug. Clinical trials can be divided into three categories: phase I, II and III.
Phase I studies are primarily concerned with the drug's safety, and are the first time the drug is tested in humans. These studies are typically done in a small number of healthy volunteers (20-100), usually in a hospital setting where they can be closely monitored and treated if there are any side effects. The purpose of these studies is to determine how the experimental drug is absorbed, metabolized, and excreted in humans. Additionally, they seek to determine what types of side effects occur as the dosage of the drug is increased. Any beneficial effects of the drug are also noted.
Phase II: Once an experimental drug has been proven to be safe and well-tolerated in healthy volunteers, it must be tested in the patients that have the disease or condition that the experimental drug is expected to improve/cure. In addition to ensuring that the experimental drug is safe and effective in the patient population of interest, Phase II studies are also designed to evaluate the effectiveness of the drug. The second phase of testing may last from several months to a few years and may involve up to several hundred patients.
Phase III: is a study where an experimental drug is tested in several hundred to several thousand patients with the disease/condition of interest. Most Phase III studies are well controlled, randomized trials. That is, one group of patients (subjects) receives the experimental drug, while a second "control" group receives a standard treatment or placebo. Placement of the subject into the drug treatment or placebo group is random in a binary context (as if by the flip of a coin). Often these studies are "double-blinded", that is, neither the patient nor the researchers know who is getting the experimental drug. The large-scale testing provides the pharmaceutical company, as well as the FDA, with a more thorough understanding of the drug's effectiveness, benefits/risks, and range/severity of possible adverse side effects.
In this research the focus will be on designs for Phase II studies, different designs will be inventoried, evaluated and programmed (in SAS) to make them available. A ‘real-life’ example of a design that may be applied to an actual Organon study is presented.
The two-stage designs that are evaluated can be divided into two groups: One-armed and Two-armed. In both cases, data is used to make a decision about whether to reject or ’accept’(not reject) a statistical hypothesis -usually stated as a null hypothesis H0- in favor of an alternative hypothesis HA. One has then the following setting:
H0: p<=p0 where the true response p of the treatment is less than some uninteresting level p0.
HA: p>p1 where the true response probability is at least some desirable target level p1.
For the one-armed trials, we have first evaluated the one-stage design where a pre-specified number of patients are enrolled. The treatment is then tested only once, namely at the end of the trial. Two methods are evaluated, the normal approximation which is based at the normal distribution and the exact binomial method where the binomial distribution is used.
However, in order to reduce the number of patients that are used for a trial, a two and three-stage designs that are introduced by Herson (1979) and later by Fleming (1982) and Simon (1989) are explored. Further, a multi-stage design of Thall and Simon is reviewed.
In Fleming’s design the treatment may be declared ‘promising’ as well as ‘unpromising’ at the end of the trial. However in order to reduce the number of patients, in case of early evidence of (in) efficacy, Fleming introduces also interim analyses. After every interim analysis one can also declare the treatment ‘promising’ as well as ‘unpromising’.
Simon’s design is slightly different from Fleming’s design. In this design the trial will be stopped, only because of the lack of the effect (i.e. the treatment is then declared ‘unpromising’ not only at the end of the trial but also after every interim analysis).
Further, the characteristics of both designs are derived assuming a fixed value of the response rate of the treatment p. Obvious choices are then p=p0 (the response under the null hypothesis) and p=p1 (the response rate under the alternative hypothesis).
Similarly to Simon’s design is Herson’s design (1979), again after each interim analysis the treatment may only be declared ‘unpromising’, the only difference is that the characteristics of this design are derived in a different way then in Fleming’s. Here one chose the response rate of the treatment to follow a certain distribution the ‘prior’. Usually the Beta distribution is taken.
Thall and Simon’s design (1994) includes both possibilities ‘promising’ as well as ‘unpromising’. Further is this design a multi-stage design which means that the data is monitored continuously until the total number of patients is reached. The designs properties are derived using a fixed value of the response rate of the treatment.
For ‘two-armed’ trials, an approach based on conditional power is developed (i.e. the probability to reject the null hypothesis of ‘no difference between treatments’ at the end of the trial). If the conditional power is ‘low’ the trial will be stopped and the new treatment will be declared ‘unpromising’ as compared to the control.
For both one-armed and two-armed trials, restriction was made to binary outcomes, i.e and design properties were derived using the binomial distribution. However, for continuous outcomes the designs are similar. The only difference is that the properties will be derived under a continuous distribution. Furthermore, clinicians often prefer a binary outcome like response or bleeding.
For ‘two-armed’ trials we have not considered stopping after an interim analysis and followed by declaring the new treatment ‘promising’. This topic has, however, extensively been discussed in the statistical literature. See, for example, O’Brien and Fleming (1979).
Finally, a case study was reviewed. Deep venous thrombosis (DVT) is a condition where there is a blood clot in a deep vein (a vein that accompanies an artery). For years the standard has been an anticoagulant medication called Heparin which was given through the vein. This results in relatively immediate anticoagulation and treatment of the clot. Along with heparin an oral medication called warfarin is given. The main side effect of heparin and warfarin is bleeding.
Some time ago a new treatment was introduced for the prevention of DVT: Hirulog. To explore the potential of Hirulog in the prevention of DVT, a phase II dose ranging study was preformed in patients undergoing major knee or hip surgery (Ginsberg et al, 1994).
The study objective was to identify a Hirulog dose associated with:
• an overall DTV rate 15%
• a bleeding rate < 5%
These values represent the approximate rates of the standard treatment heparin. Five dosage regimens were investigated in a sequential fashion using the designs presented above, where each dose was evaluated independently. For each dose it was planned to monitor the rates of bleeding and thrombosis in every 10 patients up to a maximum of 50. Hence, this study may be considered as a sequence of five one-armed trials.
A dose-finding study was not fully covered. If doses are investigated in a sequential fashion, then the methods of the case study can be applied. If only two doses are investigated in parallel, then the design for two-armed trial can be applied. However, for more than two doses, other methods should be developed. See, for example, Whitehead et al for a recent reference.|
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