Research Study Designs

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Research Study Designs

• Experimental Design

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Experimental 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-randomized
• Double blinded, single blinded or no blinding
• A randomized controlled trial (study) may be
  described as prospective, longitudinal,
  follow-up, and experimental.

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Randomized 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
  given
• Both groups are compared on the outcomes and
  treatment effectiveness is determined.

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Randomized Controlled Trial

• Advantages
• Utilizes a control group (strongest evidence)
• Bias is minimized
• Extraneous factors being responsible for outcomes
  is minimized.
• Most reliable technique for evaluating treatments
• Most statistically powerful study design

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Randomized Controlled Trial

• Disadvantages
• Expensive
• Patient 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
  humans
• Time necessary to perform study can be long.
• Most complex to interpret.

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Experimental Controlled Study Example

• 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 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.

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Randomized 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.

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Non-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.

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Non-controlled experimental Study Example

• A study to determine the efficacy of Zofran in
  prevention and treatment of Cisplatin induced
  nausea and vomiting (NV) 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 NV as severe.
  Investigators concluded that Zofran is effective
  in minimizing Cisplatin induced NV.

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Design Types of Controlled Experimental Studies

• Parallel design
• Crossover design
• Time series design (Before and After)

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Differences 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

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Parallel Design

• A parallel design includes independent study
  groups and each group receives a different
  treatment regimen or intervention
• Randomized Controlled Trials are often parallel
  design
• Parallel design is more useful for studying
  conditions which are prone to change over time
  (pain, acute exacerbations of a disease,
  remissions)
• ExampleIn 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.

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Crossover Design

• A 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.

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Cross-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.

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Cross-Over Design

• Advantages
• 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
• Within 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)

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Cross-Over Design

• Disadvantages
• Time involved for a crossover design is longer
  than other design types
• More drop outs because of time involved.
• Study design is very sensitive to drop outs since
  small number of patients involved.
• Period effects
• Sequence effects
• Carry over effects

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Period Effects

• Differences 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

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Period Effect Variables

• Depressed patients may be less depressed during
  the 2nd 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.

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Sequence Effects

• Changes 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.

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Carry-over effect

• When 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.

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Carry-over effects

• The 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

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Cross-Over Design

• One 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)

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Time 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.

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Times Series (Before and After)

• Advantages
• Certain 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)

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Times Series (Before and After)

• Disadvantages
• The disease/condition being treated can change
  over time, unrelated to the drug treatment.
• Carry-over effects could occur.
• Things that cause a carry-over effect
• Drugs with a long elimination half-life
• Drugs 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)