10 januari: methodology

Question 1

Methodology is related to which guidelines in ICH?

Answer 1

ICH E9

Question 2

Direction of ICH-E9.
.... Bias
..... Precision
...... Robustness of results  & conclusion
Fit: Maximize, minimize, evaluate

Answer 2

minimize bias, maximize precision, evaluate robustness

Question 3

Define bias and describe its possible sources.

Answer 3

The systematic tendency of any factors associated with the design, conduct, analysis, and evaluation of the results of a clinical to make the estimate of treatment effect deviate from its true value.

• operational bias
• statistical bias

Question 4

Provide an example of possible bias in the design of the trials.

Answer 4

Assignment of treatments such that subjects at lower risk are systematically assigned to one treatment

Question 5

Provide two examples of possible bias during the conduct of the trial.

Answer 5

1) exclusion of subject from analysis based upon knowledge of subject outcomes
e. g. when blind is broken, bias (can) occur and subject is excluded

2) How a doctor asks the patient how he/she feels also contains bias

Question 6

How can you prevent measurement bias?

Answer 6

Having multiple investigational sites

Question 7

What is robustness?

Answer 7

Sensitivity of the overall conclusions to various limitations of the data, assumptions, and analytic approaches to data analysis

Question 8

What is the golden standard for a clinical trial design (4)

Answer 8

• Randomisation
• blinding
• trial design
• control group

Question 9

Name and describe when you use a certain type of randomisation (5) (give advantage/disadvantage when possible).

Answer 9

1) simple: e.g. flip a coin. could lead to unequal distribution
2) blocked: e.g. predefined n for each group. Not per site, but in total. Could potentially have consequences for amount of IPs per site (e.g. measurement error in site A could impact results). Not in trials with low recruitment.
3) unequal: e.g. 2xn drug 1, 1xn placebo. Applied when it is unethical to give placebo.
4) stratified: define subgroups (e.g. gender, age), then block randomisation for each subgroup. Is time-consuming.
5) responsive adaptive (solution for simple). 1st patient>A, then 2nd patient 95% of B. If 2nd and 3rd patient>B, then 4th patient 66% of A, etc.

Question 10

What type of bias does randomisation prevent?

Answer 10

Selection bias.

Question 11

What type of bias does blinding prevent?

Answer 11

Measurement and response bias.

Question 12

In what phase do you use open label?

Answer 12

Dose ranging trials, pilot trials, when blinding is not possible (e.g. in surgery)

Question 13

When do you use single blind?

Answer 13

When laboratory values/AEs give away treatment/control. E.g. in case of carcino drug A with hair loss, and drug B without hair loss.

Question 14

Explain how you would resolve problems when your comparator drug has another form/distribution method in comparison to IP.

Answer 14

Double dummy

Question 15

Explain difference between superiority and non-inferiority. When do you use each approach?

Answer 15

Superiority; in comparative to prove new treatment is better. non-inferiority; same results, but distribution method is less invasive, manufactoring is cheaper,

Question 16

Name and describe trial designs (5). When do you use each approach?

Answer 16

1) Parallel group. – variation between subjects
2) Paired design. within one subject, at one time (e.g. on left and right hand). not applicable for systematic interventions.
3) cross-over design. 1 subject: treatment A; cool-down period; treatment B.
4) factorial design: one subject, multiple treatments at the same design (e.g. HIV treatments with Beta blockers etc.) examine interaction between treatments.
5) prospective vs retrospective

Question 17

In which phase of CTs do you especially use the Golden Standard?

Answer 17

Phase III for MAA