Study Designs Pt1: Parallel Group and Cross over EXAM 2

Question 1

What are two common designs using two or more groups of patients?

Answer 1

-Parallel group (non-crossover)
-Cross-over

Question 2

What is a Parallel group design?

Answer 2

Comparing relative effects of drugs or treatments on 2 or more groups

Most common: Drug vs. placebo
-could also be Drug vs. placebo vs. standard of care
or
-Drug 1 VS Drug 2 VS Drug 3 VS Placebo

Question 3

Why is the Parallel group design considered robust?

Answer 3

Because it is tolerant to many types of problems such as missing data, missing visits, etc.)

Question 4

What are the advantages of a Parallel group design?

Answer 4

-easy to conduct and it takes less time to achieve objectives bc the study in other groups run simultaneously, whereas in cross-over they have to switch
-Patients are enrolled for a shorter time and only exposed to one drug (in cross-over there is only one group of patients receiving the drug and placebo - enrolled longer and exposed to two treatments)

-A more diverse set of patients (patients in placebo or drug group (cross-over has only one group)

-suitable for phase 1, 2, and 3 trials

Question 5

Disadvantages of a Parallel group design

Answer 5

-possibility that the experimental and placebo group is different - but this is minimized by random assignment

-requires more patients than in the cross-over design -> more expensive

Question 6

What is a Run-in Period?

Answer 6

-Period of time before running a trial where the treatment or NO treatment is given

-incorporated to detect and exclude a subgroup of the study population (non-adherent patient - they are not taking their meds as prescribed, or look for outliers of placebo response when they get placebo in the run-in-period)

Question 7

How can the data collected in the Run-in Period be helpful to optimize a study?

Answer 7

-Screen out non-compliant patients
-Screen for placebo response (placebo response is expected from any pt, they screen for a significantly higher placebo response)

-Ensure that the patients have the same baseline
-Exclude pt who are likely to have adverse effects

Question 8

What is a Cross-over design?

Answer 8

-The same patients (e.g. n=500) receive both the investigational and control treatment during separate periods
-pt serves as their own control -> their reaction to each treatment is compared

-Less variability due to a smaller number of pt

-Data are highly affected by dropouts
(when dropping out early; X2 bc a pt is enrolled in drug and placebo group)

Question 9

Timeline of Crossover

Answer 9

1. Search for eligible patients
2. Random Assignment of patients to control and placebo group

-2 groups: one group starts with the drug group and changes to the placebo group and vice versa

3. Washout -> Pt cross-over from drug to placebo group and vice versa

Question 10

What is the Washout period?

Answer 10

To avoid the Carryover Effect

If the drug works during a trial, you want the effect of the drug to stop before cross-over, to avoid carrying over the effects into the next phase

-> It might seem like the placebo effect is working but in reality, it is still the drug from the previous phase

Question 11

What affects the length of the Washout period?

Answer 11

-The drug’s half-life (usually 5 half-lives)
-biological effect -> could be longer than the half-life (f.e. steroids have prolonged pharmacological effect days after elimination)

Question 12

When should a Washout period be conducted?

Answer 12

-Before the Run-in-period ( creating Baseline levels)

-Between the swap of groups

Question 13

When should the Baseline level of drug in patients be accomplished?

Answer 13

After the Washout period and right before random assignment into the groups

Is there a Run-in Period before the first phase of a Cross-over design??

Question 14

What is the Period effect?

Answer 14

Conditions/diseases fluctuate in severity during the trial
-> It goes up during one phase of the study, but after cross-over, it doesn’t -> mask the actual patient’s response

Question 15

What is a disease that is associated with the Period effect?

Answer 15

Osteoarthritis

Question 16

What study design should be used to investigate disease with fluctuations?

Answer 16

Parallel Group study design preferred

Question 17

What is the Sequence effect?

Answer 17

It happens when the sequence (order) may have an impact on the efficacy of a drug (f.e. Albuterol causes bronchodilation when the lungs are constricted -> if a steroid is tested and given previous to albuterol, it lowers inflammation and albuterol is able to penetrate the lung much better and cause much more dilation than it would be w/o the steroid -> the effect of albuterol is unintentionally improved

-To avoid this effect half of the patients are randomly assigned to the sequence (order) of the drug

-referred to as a 2-sequence study (during Cross-over)

Question 18

Advantages of a Cross-over design

Answer 18

-minimize variability of drug response (bc the same patients for both groups)
-more efficient use of patients (same patients for both groups)
-smaller number of patients -> lower cost

Question 19

Disadvantages of a Cross-over design

Answer 19

Patients are longer enrolled in a study (1 period in the drug group and 1 in the placebo group)

-the risk of dropout
-Dropout may be high -> f.e. in a study with 2 drugs -> twice as likely to experience adverse effects -> more likely to drop out
A single dropout can represent X2 bc one pt goes through 2 periods

Question 20

More Disadvantages of Cross-over Design

Answer 20

-More exposure to drugs: In a study with active treatment (standard treatment), the patients are exposed to 2 drugs, composed to half of the patients being exposed to one drug each

-More exposure to placebo: reduces the likelihood of adverse effects, but patients are also untreated for a longer time (ethic?)

-Possibility of variation in patient’s disease (Period effect)

Question 21

When are Cross-over designs appropriate?

Answer 21

-Condition is relatively stable (no fluctuations, no period effect)
-The treatment period is not too long (if treatment takes a year, we do not want to cross over and wait for another year)
-effects of the drug are reversible (drug effect is easy to wash away - to prevent the carry-over effect)
-when the carryover effect is not considered a problem

Question 22

When are Cross-over designs inappropriate?

Answer 22

-Self-limited disease with a short duration bc the disease might go away before the cross-over

-> better to use a Parallel group design

Question 23

When looking at a graph showing the sequence of a cross-over-design; What do Period and Sequence mean?

RECOGNIZE how different designs would look like
3 sequence 2 sequence, 1 period, 2 period

Answer 23

Period: Period where a drug is tested (could be the drug 1 in period 1 and the drug 2 in period 2)

Sequence: Describing the different types of treatment (drug 1, drug 2, drug 3, placebo)
??
Number of groups: f.e. concurrent treatment: Drug and Placebo -> then both swap

Question 24

What would be a reason to use an Extra-Period Crossover?

Answer 24

An extra period is added to the second phase

-to investigate for side effects that may appear at a later phase of drug therapy

-the drug doesn’t work as well as expected in the short-term -> requires a longer time to manifest its beneficial effect

Question 25

What are the problems with an Open-label Crossover without Randomization?

Answer 25

-open to Period effect
-open to sequence effect
-potential Bias

Question 26

What does an “Invalid Initiation” in Cross-over-trial mean?

Answer 26

Starting at different Baseline points

Question 27

Invalid Initiation in the Second part of the Cross-over-trial

Answer 27

There is no sufficient washout-time
so the placebo and medication have a different Baseline at the end of treatment II (makes Treatment III invalid)

Question 28

What does the graph of the Valid Trial imply?

Answer 28

1. sufficient washing out time -> both groups start Baseline
2. Placebo and meds perform well in Period I, -> Washout and CROSS-OVER -> In Period II the meds perform well the placebo doesn’t

-> This is likely due to the period effect, fluctuation in period II which does not occur in period I (looks like the placebo doesn’t work in period II)

Shouldn’t the placebo not be working at all???

Question 29

Ideal Collected Data from a cross-over-trial

Answer 29

1. Both groups start at Baseline -> placebo doesn’t perform well, the meds do
2. Sufficient washing time and cross-over
3. Both start at the Baseline in period II placebo doesn’t perform well, and the meds do