PPHC 13: Evidence Evaluation (Epidemiology) – What are features of experimental studies?

Question 1

What is the big picture for experimental epidemiology?

Answer 1

is there a relationship (causation) between exposure and outcome

Question 2

What are experimental studies?

Answer 2

• evaluate specific intervention (exposure) – can be a new drug, device, healthcare service
• create a controlled environment such that the only thing that is different between study groups (exposed vs. comparison) is the exposure itself

Question 3

What are the 2 types of exposure assignment?

Answer 3

• randomized: assignment to study groups (exposed vs. unexposed) is by chance – not under the control of investigator
• assignment to study groups is under control of investigator – by hospital record, by day of study recruitment

Question 4

What are randomized controlled trials (RCTs)?

Answer 4

experimental study to assess the efficacy of an intervention in humans

Question 5

What is efficacy?

Answer 5

ability to achieve a desired effect (under highly controlled conditions)

Question 6

What is effectiveness?

Answer 6

do interventions work in circumstances that reflect real-world practice

Question 7

Drug Regulatory Approval Process

Phase I Clinical Trial

• question
• participants
• design
• goals

Answer 7

• question: is the drug safe
• participants: healthy volunteers
• design: open label (not blinded), uncontrolled (no comparison group)
• goals: safety (identify side effects), tolerability (degree to which side effects can be tolerated),
  pharmacokinetics (what body does to drug), pharmacodynamics (what drug does to the body)

Question 8

Drug Regulatory Approval Process

Phase II Clinical Trial

• question
• participants
• design
• goals

Answer 8

• question: does the drug work
• participants: patients (~30-300 patients)
• design: open label (not blinded), uncontrolled (no comparison group) /OR/ open label (not blinded), non-randomized controlled
• goals: safety, efficacy

Question 9

Drug Regulatory Approval Process

Phase III Clinical Trial

• question
• participants
• design
• goals

Answer 9

• question: is the drug better than what we have
• participants: patients (> 300) – often in multiple sites, countries
• design: randomized controlled trial
• goals: safety, efficacy

Question 10

What are the steps in the experimental study flow?

Answer 10

• assess for eligibility
• randomization
• concealment of allocation
• blinding
• exposure
• outcome
• analysis

Question 11

Experimental Study Flow

Assess for Eligibility

Answer 11

• generalizability – who can findings apply to
• inclusion and exclusion criteria to identify participants – broad (exclude few, more generalizable), restricted (exclude many, less generalizable)

Question 12

Experimental Study Flow

Randomization

Answer 12

• allocation to study groups (exposed group vs. comparison group) is by chance alone
• optimizes the equal distribution of measured characteristics between study groups
• increases the likelihood that unmeasured characteristics are equally distributed between study groups
• random assignment equitably ensures that every eligible participant has the same chance of receiving the intervention, free of subjective criteria or influence (by researchers)

Question 13

Experimental Study Flow

Concealment of Allocation

Answer 13

protecting the randomization before participants are entered into a trial

• researcher does not know if the next participants will get treatment or control
• if not done, results in error (‘bias’) such that certain patients may be more likely to enter into one study group over another – lose benefits of randomization
• concealment of allocation is always feasible in an RCT

Question 14

Experimental Study Flow

Blinding

Answer 14

masking of the allocation after randomization of participants

• not feasible in all RCTs (ie. cannot blind in RCT of coffee and ileus) but important in RCTs involving comparison to placebo

Question 15

What is a single-blinded study?

Answer 15

patient does not know which study group they are allocated to

Question 16

What is a double-blinded study?

Answer 16

patient and researcher do not know which study group patients are allocated to

Question 17

Experimental Study Flow

Exposure

Answer 17

• define all aspects of study treatment so uniform
• control is placebo (best to define efficacy of study therapy, but may not be ethical/practical/feasible) or active control (current standard)

Question 18

Experimental Study Flow

Outcome

Answer 18

what do you want to achieve with the new intervention

• primary endpoint – ie. time to first post-operative bowel movement (surrogate endpoint for duration of ileus)
• secondary, additional endpoints – ie. time to tolerance of solid food, time to first flatus, need for additional laxatives, safety, length of hospital stay

Question 19

What are the 2 approaches to analyzing RCTs?

Answer 19

• intention to treat analysis (ITTA)
• per protocol analysis

Question 20

What is intention to treat analysis (ITTA)?

Answer 20

all randomized patients are included in the final data analysis

Question 21

What is per protocol analysis?

Answer 21

only patients who complete the trial according to protocol are analyzed

Question 22

What is the measure of association for RCTs?

Answer 22

relative risk

(risk of outcome among exposed) / (risk of outcome among unexposed) = a/(a+b) / c/(c+d)

Question 23

What are the disadvantages of RCTs?

Answer 23

• expense – typically $ millions
• time – typically years
• only answer a single question
• may not be applicable to most patients in practice
• may not be practical, ethical
• hard to get funded
• time consuming and complex

Question 24

Experimental Studies

Answer 24

• researcher assigns the exposure in an experimental study
• randomization aims to avoid systematic errors in assigning the intervention
• randomization aims to make study groups comparable

Question 25

Concealment of Allocation vs. Blinding

Answer 25

• concealment is the procedure to protect the randomization process before participants are entered into a trial and is always feasible
• blinding is the procedure to mask allocation after randomization of participants and is not always feasible