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Research Study Designs Experimental Design
Experimental Study Design n Best design for determining efficacy of treatment: n n Randomized, controlled, double blinded, experimental designed study. Experimental study can be controlled or noncontrolled. Randomized or non-randomized Double blinded, single blinded or no blinding A randomized controlled trial (study) may be described as prospective, longitudinal, follow-up, and experimental.
Randomized Controlled Trial n Patients are assigned to one of two or more groups that receive a treatment or intervention and are followed over time for a measured outcome. n Some patients are designated as the control group which serves as the comparison group and which a placebo or sugar pill or a comparison drug is given n Both groups are compared on the outcomes and treatment effectiveness is determined.
Randomized Controlled Trial n Advantages n Utilizes a control group (strongest evidence) n Bias is minimized n Extraneous factors being responsible for outcomes is minimized. n Most reliable technique for evaluating treatments n Most statistically powerful study design
Randomized Controlled Trial n Disadvantages n Expensive n Patient enrollment can be difficult (time length) n Drop out rate is higher because of long term follow-up (required by FDA) n Ethical problems in testing new therapies in humans n Time necessary to perform study can be long. n Most complex to interpret.
Experimental Controlled Study Example n To determine whether Retin A cream can reduce wrinkle formation, investigators recruited 100 healthy subjects from 65 -70 y. o. and randomized them to receive Retin A or placebo. They applied the cream 2 x daily for 1 year. A dermatologist rated the degree of facial wrinkles using a scale from 1 -10 at the beginning and end of the study for all participants and compared the two groups.
Randomized Controlled Trial (RCT) Summary n The RCT design is suitable for most types of pharmaceutical research. n It is considered to be the most statistically powerful study design. n The major difference between the clinical trial and other designs is the ability of the investigator to actively intervene, rather than simply observe.
Non-controlled experimental Study n Does not utilized a control group. n The drug treatment procedure to be studied is administered to a single group of patients. n Outcome measures are determined in this group.
Non-controlled experimental Study Example n A study to determine the efficacy of Zofran in prevention and treatment of Cisplatin induced nausea and vomiting (N&V) was done. 50 patients receiving Cisplatin for ovarian cancer were given Zofran at the start of Cisplatin therapy. The number of episodes of nausea and vomiting were recorded. Only 10% rated the N&V as severe. Investigators concluded that Zofran is effective in minimizing Cisplatin induced N&V.
Design Types of Controlled Experimental Studies n Parallel design n Crossover design n Time series design (Before and After)
Differences between types of controlled experimental designs n Different outcomes can be measured more accurately with different designs. n Different statistical tests are applied to different study designs. n Different bias risks are inherent in each design
Parallel Design n A parallel design includes independent study groups and each group receives a different treatment regimen or intervention n Randomized Controlled Trials are often parallel design n Parallel design is more useful for studying conditions which are prone to change over time (pain, acute exacerbations of a disease, remissions) n Example: In a study to evaluate the efficacy of beta blockers for hypertension, 24 patients are randomized into two groups of 12 patients. One group is then treated with a beta blocker and the other treated with placebo.
Crossover Design n A crossover design may have just one study group that receives all of the treatments (ie. Drug and placebo). n It is more statistically sensitive and efficient, using fewer patients. n Fewer patients can lead to a more homogenous group with less variability in measurement. (Less variability between groups implies a measured difference is more likely to be due to treatment effects instead of interpatient variability.
Cross-Over Design Example n In a study to evaluate the efficacy of beta blockers for hypertension patients, 12 patients would be enrolled into the study and 6 patients would be assigned to treatment with the beta blocker first, followed by placebo treatment and the other 6 patients would receive the same treatments in reverse order, all having a washout period in-between treatments.
Cross-Over Design n Advantages n n Smaller number of patients are required since the same patient groups receive both treatments The ability to analyze patients both within groups as well as between groups n Within groups: baseline factors (age, gender differences) which could influence the results are eliminated because patients serve as their own control group. n Between groups: Evaluate the effect of time on the results (we can see what the patient does during the placebo time period as well as what he does during treatment period)
Cross-Over Design n Disadvantages n Time involved for a crossover design is longer than other design types n More drop outs because of time involved. n Study design is very sensitive to drop outs since small number of patients involved. n Period effects n Sequence effects n Carry over effects
Period Effects n Differences between treatment groups over passages of time. n Period effects occur because patients are observed at least twice and their condition may change between the first and second observation. n Period effects increase within-person variability, which reduces the power of the design and decreases the advantage of a cross-over design study
Period Effect Variables n Depressed patients may be less depressed during n n the 2 nd treatment period simply because depression tends to improve over time. Learned effects Development of tolerance or resistance Changes in the disease state Psychological variables: pain syndromes, exacerbation of exzema, multiple sclerosis acute flare ups, etc.
Sequence Effects n Changes in the effectiveness of the drug treatment produced by the order in which the drugs were administered. n Appear statistically as interactions. Interactions affect the interpretation of the results because the magnitude of the treatment differences is not consistent.
Carry-over effect n When the effects of the drug given during the first period persists into the second period. n Carryover effects only affect the treatment response in the 2 nd time period. n Can be eliminated by using a washout period between treatments. This allows the patient to return to baseline levels before the 2 nd treatment is started.
Carry-over effects n The ability to remove the influence of carryover effects through the use of a washout period differentiates carry-over and period effects. n Period effects represent long term or permanent changes in the subject that are unlikely to be eliminated with a washout period. n Carry-over effects represent temporary changes secondary to continued presence of the drug in the system, such as for a drug with a long half-life persisting into the 2 nd treatment period, but the effects of the drug with a short half-life not persisting
Cross-Over Design n One risk is that this design is not powerful enough to detect a clinically important interaction of period, sequence or carry-over effect. n If the interaction is clinically significant, then you must transform the crossover study into a parallel design to do the statistical analysis. (defeats purpose of using less subjects and saving money) n Types of studies good for cross-over design are: n bioavailability studies (interactions would be less likely since the patients serve as their own controls)
Time Series (Before and After) Design n Patients are studied before the experimental drug is given. After the drug is given for a certain amount of time, the patients are evaluated again to determine the effects of the drug. n More than one drug can be tested with this type of study design by continuing to administer drugs in sequence.
Times Series (Before and After) n Advantages n Certain factors which could influence the study are eliminated (age, gender differences, etc) n Patients serve as their own controls so smaller number of patients are needed (as compared to parallel design)
Times Series (Before and After) n Disadvantages The disease/condition being treated can change over time, unrelated to the drug treatment. n Carry-over effects could occur. n Things that cause a carry-over effect n Drugs with a long elimination half-life n Drugs with active metabolites (esp. active metabolites with long half-lives) n Drugs whose effects on the disease state being treated persist after the drugs themselves are eliminated from the body (lipophillic drugs) n