FinalExamReview

Question 1

What are the benefits and drawbacks of rule-based design for Phase 1 Trials?

Answer 1

(3+3 Design):

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Question 2

What are the benefits and drawbacks of Model based design for Phase 1 Trials? (Give examples of specific models)

Answer 2

Continual Reassessment Method (CRM):
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Bayesian logistic Regression Model (BLRM):
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Question 3

What are the benefits and drawbacks of Hybrid design for Phase 1 Trials?

Answer 3

Modified Toxicity Probability Interval (mTPI):

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Question 4

Define Dose Limiting Toxicity.

Answer 4

DLT:
This describes the side effect that limits the dose amount that can be safely given.

• a serious or life-threatening side effect
• can be reversible
• definition depends on clinical setting

(Side effects that are defined in the study that tell us when to stop increasing the dose, or when a maximum tolerated dose is reached by a subject)

Question 5

Define Maximum Tolerated Dose.

Answer 5

MTD:
*Every person has a unique Maximum Tolerated Dose before reaching a Dose Limiting Toxicity

• Ratios/Proportions of people at each dosage level for which that dose is their MTD
• We look for the MTD that has a ratio of some target percentage (say 25%)

Question 6

What is the underlying purpose of a Phase I Trial?

Answer 6

The goal of Phase I drug trial is often to determine which does of the drug is SAFE and MOST LIKELY to show benefit.

*Maximum tolerated dose (max dose before unacceptable toxicity is experienced)

Question 7

Explain why type II error is more serious in a pilot study than type I error?

Answer 7

The purpose of a pilot study is to identify potentially effective treatments, so we do not want to discard potentially useful treatments. (Later studies are focused on type I error so we don’t have to be too concerned about it)

Question 8

What is the relationship between a Pilot study and a Phase II study?

Answer 8

Pilot study and Phase II studies have overlapping definitions, a Phase II studies are pilot studies focused on either efficacy or optimal dosage.

Question 9

Describe the key statistical features of a Futility Design study.

Answer 9

Futility Design:
*Formulation of null and alternative hypothesis are reversed from the norm
(smaller sample size):
-Single Arm Study
-More liberal Alpha
- one sided hypothesis
*Historical controls +/- Calibration/masking controls (Single arm studies in which subjects in the study receive experimental agent except in calibration/masking controls)

Question 10

What is the purpose of a futility design study?

Answer 10

The purpose is that if the new treatment mean effect is less than the control mean effect (cx) + delta, then we don’t move on to Phase III.

Basically, this means that the new treatment
(Reject the null means we don’t move to Phase III)

Question 11

Define a noninferiority Trial

Answer 11

A trial with the primary objective of showing that the response to the investigational product is NOT CLINICALLY INFERIOR to a comparative agent.

Question 12

Describe the possible scenarios of a non-inferiority trial.

Answer 12

“superior” - the entire confidence interval of the new treatment lies on the “superior” side of the null (no difference in treatment effect of new and old treatment).

“non-inferior” - the confidence interval of the new treatment covers the null (no difference) but NOT the null plus delta

“Inconclusive” - the confidence interval of the new treatment covers the null AND the null plus delta.

“inconclusive” - the upper bound of the new treatment is below the null, but the confidence interval covers the null plus delta delta.

“inferior” - the entire confidence interval of the new treatment is on the “inferior” side of the null plus delta

(NOTE: we can think of “null plus delta” could be number of bad outcomes if we are considering ‘plus delta’ to be a negative direction)

Question 13

What is the motivation behind performing noninferiority trials?

Answer 13

typically efficacy but can be for safety

we want to know if the new intervention is ‘as good as’ its comparator

OFTEN the intention is to claim overall superiority based on consideration of something other than efficacy

• fewer side effects
• simpler dosing
• less invasive
• lower cost

Question 14

What is an active control trial?

Answer 14

A trial in which an experimental intervention is compared with an accepted standard intervention.

Objectives:

1) Superior to active control OR
2) as good as active control

Question 15

How do we choose the margin of non-inferiority delta?

Answer 15

• maximum difference in responses that is considered to be clinically unacceptable (retain some % of active control’s effect)
• smaller than differences observed in superiority trials of the active comparator

Aim:
New intervention is better than placebo and similar to active control

Question 16

Describe what is meant by sub-group analyses.

Answer 16

a subset of participants in a clinical trial defined by a baseline characteristic (men/women; old/young; aspirin use (yes/no))

DO NOT DEFINE BY POST-BASELINE AS IT CAN BE AFFECTED BY TREATMENT

Always test for interaction with treatment (does the treatment work better in certain groups)

Consider linear model, test for interaction in the linear model and then if it is significant in the linear model then don’t look inside. If there is a significant interaction then we will examine treatment effect in each group.

Assessing an effect modifier.

Question 17

What are some administrative reasons for conducting a interim analyses?

Answer 17

• Ensure the study is being executed as planned.
• ensure that only appropriate patients are enrolled
• uncover the presence of unanticipated problems such as non-compliance
• check on assumptions made in designing the trial such as patient accrual rate and sample size parameters

Question 18

What are some economic reasons for conducting a interim analyses?

Answer 18

• Early stopping for negative results prevents wasting of resources, abandoning lost cause.
• Allows for informed management decisions re: allocation of limited R&D funds

Question 19

Describe the differences between (1) Haybittle & Peto (2) Pococok and (3) O’Brien and Fleming sequential boundaries with respect to the likelihood of stopping early and for the final look.

Answer 19

(1) Haybittle & Peto - constant until last time point and then increased change to reject null
(2) Pocock - constant throughout
(3) O’Brien and Fleming Increasing probability of rejecting null at every look

Question 20

What is the advantage of alpha spending designs over group sequential designs?

Answer 20

Group sequential designs are cumbersome and alpha spending designs are less cumbersome.

• Group sequential designs can have restrictive monitoring times that require equal increments of information (# patients) and sometimes causes administrative difficulties
• Alpha spending are more flexible than group sequential designs so the idea is to spend(distribute) the total probability of false positive risk (Type I error) as a continuous function of the information time (alpha spending function)