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Dose Response Studies

The dose response of a drug is important in pharmacology, pharmacokinetics, toxicology and clinicalresearch. Dose response studies may be part of larger research to develop new treatments or tosupplement existing knowledge of a drug whose benefits may have already been established.

The study should aim to address the following key questions.

1. Is there evidence of a drug effect?2. What dose is required to produce a response different from the control response?3. What is the nature of the dose response relationship?

(eg. Does doubling the dose double the response?)4. What is the optimal dose?

(Is there a level at which a drug becomes harmful, or below which there is no benefit or harm?)

Parallel Designs

Typically, patients are randomised to one of several active dose groups or placebo in the same way as

with a RCT. However, if the efficacy of a particular treatment has been established it may be unethicalto have a placebo group. Equally, a placebo group may be unnecessary if the placebo response rate isvery low (such as spontaneous cure from cancer).

Dose titration is often used, especially in early drug development, where the safety is of greaterconcern. Trial patients are started at low doses, which may be increased at intervals to achieve aresponse. It may require fewer patients to assess a drug effect since within-patient variability is used,but dose and time effects cannot be completely separated, which may obscure the real drug effect.Titration studies are most appropriate when the ultimate use of the drug will be in a titration scheme.

Crossover Designs

Crossover studies aim to reduce between-subject variability (heterogeneity) by exposing the studyparticipants to both the drug and the placebo at different times. In this situation, the differences inresponse are more meaningful because each participant acts as his own control.

In the example design, patients are allocated to one of four sequences, during which they are crossedover to different doses each week. Study participants are increasingly exposed to the study drug,making the design safer and more appealing to clinicians. The use of the placebo group in eachperiod maintains the double blind nature of the trial and allows for the separation of treatment andtime period effects.

Period Group 1 Group 2 Group 3 Group 4

Week 1 Placebo 10mg 10mg 10mg 75% lowest dose

Week 2 10mg Placebo 20mg 20mg 50% middle dose

Week 3 20mg 20mg Placebo 40mg 25% highest dose

Week 4 40mg 40mg 40mg Placebo 75% highest dose

Table 1. Dose escalation crossover study

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Factorial Designs

Factorial designs are useful for studying two factors simultaneously to find optimal dosage regimens,or studying the effects of two drugs to be used in combination. Examples of possible designs below.Equal numbers are usually allocated to each group, but the statistical power may be improved byincreasing the size of the placebo and highest dose-by-frequency group. Because of the highernumber of groups, factorial designs require larger samples.

Dose Duration of IV infusion

Route Placebo 10mg 20mg 40mg Dose 0 15 m 30 m 60 m

Oral 0

IV 10mg

20 mg

Tables 2&3. Factorial designs for comparing two variables in a dose response study.

Key issues with dose response studies

Often studies aim to identify the minimum effective dose for a drug. A particular dose may produce astatistically significant (p