2Experimental Study Design Best design for determining efficacy of treatment: Randomized, controlled, double blinded, experimental designed study.Experimental study can be controlled or non-controlled.Randomized or non-randomizedDouble blinded, single blinded or no blindingA randomized controlled trial (study) may be described as prospective, longitudinal, follow-up, and experimental.
3Randomized Controlled Trial 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.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 givenBoth groups are compared on the outcomes and treatment effectiveness is determined.
4Randomized Controlled Trial AdvantagesUtilizes a control group (strongest evidence)Bias is minimizedExtraneous factors being responsible for outcomes is minimized.Most reliable technique for evaluating treatmentsMost statistically powerful study design
5Randomized Controlled Trial DisadvantagesExpensivePatient enrollment can be difficult (time length)Drop out rate is higher because of long term follow-up (required by FDA)Ethical problems in testing new therapies in humansTime necessary to perform study can be long.Most complex to interpret.
6Experimental Controlled Study Example To determine whether Retin A cream can reduce wrinkle formation, investigators recruited 100 healthy subjects from y.o. and randomized them to receive Retin A or placebo. They applied the cream 2x 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.
7Randomized Controlled Trial (RCT) Summary The RCT design is suitable for most types of pharmaceutical research.It is considered to be the most statistically powerful study design.The major difference between the clinical trial and other designs is the ability of the investigator to actively intervene, rather than simply observe.
8Non-controlled experimental Study Does not utilized a control group.The drug treatment procedure to be studied is administered to a single group of patients.Outcome measures are determined in this group.
9Non-controlled experimental Study Example 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.
10Design Types of Controlled Experimental Studies Parallel designCrossover designTime series design (Before and After)
11Differences between types of controlled experimental designs Different outcomes can be measured more accurately with different designs.Different statistical tests are applied to different study designs.Different bias risks are inherent in each design
12Parallel DesignA parallel design includes independent study groups and each group receives a different treatment regimen or interventionRandomized Controlled Trials are often parallel designParallel design is more useful for studying conditions which are prone to change over time (pain, acute exacerbations of a disease, remissions)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.
13Crossover DesignA crossover design may have just one study group that receives all of the treatments (ie. Drug and placebo).It is more statistically sensitive and efficient, using fewer patients.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.
14Cross-Over Design Example 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.
15Cross-Over Design Advantages Smaller number of patients are required since the same patient groups receive both treatmentsThe ability to analyze patients both within groups as well as between groupsWithin groups: baseline factors (age, gender differences) which could influence the results are eliminated because patients serve as their own control group.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)
16Cross-Over Design Disadvantages Time involved for a crossover design is longer than other design typesMore drop outs because of time involved.Study design is very sensitive to drop outs since small number of patients involved.Period effectsSequence effectsCarry over effects
17Period EffectsDifferences between treatment groups over passages of time.Period effects occur because patients are observed at least twice and their condition may change between the first and second observation.Period effects increase within-person variability, which reduces the power of the design and decreases the advantage of a cross-over design study
18Period Effect Variables Depressed patients may be less depressed during the 2nd treatment period simply because depression tends to improve over time.Learned effectsDevelopment of tolerance or resistanceChanges in the disease statePsychological variables: pain syndromes, exacerbation of exzema, multiple sclerosis acute flare ups, etc.
19Sequence EffectsChanges in the effectiveness of the drug treatment produced by the order in which the drugs were administered.Appear statistically as interactions. Interactions affect the interpretation of the results because the magnitude of the treatment differences is not consistent.
20Carry-over effectWhen the effects of the drug given during the first period persists into the second period.Carryover effects only affect the treatment response in the 2nd time period.Can be eliminated by using a washout period between treatments. This allows the patient to return to baseline levels before the 2nd treatment is started.
21Carry-over effectsThe ability to remove the influence of carryover effects through the use of a washout period differentiates carry-over and period effects.Period effects represent long term or permanent changes in the subject that are unlikely to be eliminated with a washout period.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 2nd treatment period, but the effects of the drug with a short half-life not persisting
22Cross-Over DesignOne risk is that this design is not powerful enough to detect a clinically important interaction of period, sequence or carry-over effect.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)Types of studies good for cross-over design are:bioavailability studies (interactions would be less likely since the patients serve as their own controls)
23Time Series (Before and After) Design 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.More than one drug can be tested with this type of study design by continuing to administer drugs in sequence.
24Times Series (Before and After) AdvantagesCertain factors which could influence the study are eliminated (age, gender differences, etc)Patients serve as their own controls so smaller number of patients are needed (as compared to parallel design)
25Times Series (Before and After) DisadvantagesThe disease/condition being treated can change over time, unrelated to the drug treatment.Carry-over effects could occur.Things that cause a carry-over effectDrugs with a long elimination half-lifeDrugs with active metabolites (esp. active metabolites with long half-lives)Drugs whose effects on the disease state being treated persist after the drugs themselves are eliminated from the body (lipophillic drugs)