Jonathon Hopkins Course Module 1

Question 1

Phase 1 of clinical trials -how many people are involved?

Answer 1

10-30 healthy volunteers or people with disease

Question 2

The goal of phase 1?

Answer 2

The goal of phase one trials is to identify a tolerable dose, and also to provide information on drug metabolism and excretion and really gather information on toxicities.

Question 3

Phase 2 clinical trials?

Answer 3

Phase two studies are slightly larger, they usually have 30 to 100 people. And in phase two we start to collect preliminary information on efficacy, but we continue to collect information on side effects and safety. Phase two trials are sometimes controlled and sometimes uncontrolled.

Question 4

Phase 3?

Answer 4

Phase three trials are the final approval stage for drug trials. They usually involve a 100 or more people, and the goal is to assess both efficacy and safety. Phase three trials are controlled and almost always randomized.

Question 5

Phase 4?

Answer 5

Phase four studies are frequently observational, but sometimes they are control trials.

Question 6

Type of trials that are covered in this course?

Answer 6

• parallel designs
• crossover designs
• group allocation
• factorial designs
• large sample
• equivalency
• non inferiority
• adaptive designs

Question 7

Comparison structure of a trial?

Answer 7

Thats means that experimental group are beeing compared with a control group.
In that gruop fall parallel, crossover and group allocation.

Question 8

Why is randomization good in parallel design?

Answer 8

We use randomization to allocate patients because it removes bias in the allocation process which is called selection bias.

Question 9

What is randomized in crossover design?

Answer 9

in a crossover design we randomize whether they receive A first and then B or B and then A.

Question 10

The most importatnt sentence for crossover desihn?

Answer 10

each patient serves as his or her own control. This is a nice feature because variability is almost always higher between measurements of an outcome taken on different people, than in repeated measurements taken on the same person.

Question 11

The result in a reduction of a variability in crossover design?

Answer 11

As a result of the reduction in variability, we need fewer patients to test the hypothesis of interest. So the crossover design is more efficient than the comparable parallel design.

Question 12

Disadvantages of a crossover design?

Answer 12

1. They can not be used for treatments that provide permanent cure.
2. Potential carryover effect if washout period is not long enough
3. Testing to make sure that there is no carryover effect, which is not powerful test
4. Dropouts could be problematic
5. Complicated analysis, because you correlate outcomes on the individuals

Question 13

Examples of crossover designs?

Answer 13

So examples of chronic diseases for which this design is used are asthma, hypertension and sometimes arthritis or other pain relief studies. The treatments in a crossover design as I mentioned must have short term effects and relieve only the signs and symptoms of the disease, but they really shouldn’t have any permanent effect on the underlying disease process

-Crossover designs are also used sometimes when we are in the early phases of studying a drug and we are looking at the metabolic bioavailability or tolerability of a new product.

Question 14

What could be randomization unit?

Answer 14

Usually we think that a person could be randomized only but for instance, eyes of the same indivual could be radnomized to recieve treatment A or B.

Question 15

What is group allocation design?

Answer 15

In a group allocation design, the randomization unit is a whole group of individuals, such as a community, or a school, or a clinic. The entire group of individuals is allocated to the same intervention. This type of randomization is also sometimes called cluster randomization.

Question 16

when we use cluster randomization?

Answer 16

• When individual randomization is not feasable
• contamination
• It’s also important to recognize that if there’s correlation in the responses within a group, and there usually is, this design, the group allocation design, loses some efficiency. In other words, the group allocation design requires more individuals to address a given hypothesis, as compared to a parallel or a crossover design.

Question 17

Factorial design?

Answer 17

In the factorial design we are testing two or sometimes more experimental interventions simultaneously. So we test treatment A versus the control for treatment A, and we test treatment B versus the control for treatment B.

Question 18

Reeasons to do factorial designs?

Answer 18

Usually for a economical reasons, rarely to see if there is an interaction.

Question 19

When we look at a table for factroial design how do we estimate main effecs assuming that there is no interaction and what we do if we want to look for an interaction?

Answer 19

when we do a factorial design we are usually interested in the estimation of the main effects assuming that the treatments do not have an interaction. To make these comparisons, we use the responses of the people and the margins of the table, and we’ll go back to the graph in a moment to review these responses. In the case where we are interested in the interaction, we have to compare the responses in the cells instead of in the margins

Question 20

Large simple designs?

Answer 20

Many participants to find modest benefit

Question 21

Large simple designs- interactions?

Answer 21

Another premise to a large, simple design is that there are unlikely to be many treatment interactions. We aren’t likely to have a well-defined subgroup of people that respond well to therapy when others don’t. Given the assumption that it’s unlikely to have treatment interactions, it’s not that important to collect a lot of information about baseline characteristics and interim response variables because we are not expecting to want to look at the treatment effect in lots of different subgroups or examine the mechanism, because we aren’t expecting a group of people to respond very differently from another group of people.

Question 22

Large simple design-countering a eror

Answer 22

We’ll have less control over the training and standardization of administration of treatment and of outcome assessment, so we have to expect that there will be more error or increased variance in the estimation of the outcome measures. And we counter this increase in error with a large sample size.

Question 23

Requirements for large simple designs?

Answer 23

• easily administred product
• The treatment shouldn’t require any adjustments to the dose or the timing of the administration, and it also shouldn’t need any ongoing monitoring for adverse events.
• easily-ascertained outcome.
• no complex baseline measurements
• simple data are persuasive enough

Question 24

Why people use equvivaleny and noninferiority designs?

Answer 24

• These are designs that can be used to compare a new intervention to an established intervention. When we use one of these designs we might think that treatment A is as good as or the same as treatment B for treating or preventing a specific condition. But we believe that the use of treatment A might have some other kind of benefit such as less severe adverse events, or treatment A might be easier to administer than treatment B, or treatment A might be cheaper than treatment B.
• Another use of these designs is to do head-to-head comparisons to two or more established treatments for a specific condition. This uses has been discussed recently quite a bit with respect to comparative effectiveness research.

Question 25

objective of equivalance design?

Answer 25

the objective is to show that the intervention response falls sufficiently close to the control response. That is, we are trying to demonstrate the equivalence of the two treatments.

Question 26

Do we need a large or small sample for equivalance desihn?

Answer 26

Large, couse we need to rule out large differencies and we need to have a high probability of detecting them.

Question 27

differences between superiority and equivalency designs?

Answer 27

where for superiority design we are used to saying that the null hypothesis is that there is no difference between the treatments. For an equivalence design, we say that the null hypothesis is that there is a difference between the two treatments. And our alternative hypothesis for the equivalence design is that there’s no difference between the two treatments

We are also essentially flipping our Type I and Type II errors. So that for an equivalence design, the Type I error is to show no difference when there is one. And the Type II error is to show a difference when there isn’t one.

Question 28

What is non inferiority design?

Answer 28

the objective is to determine whether a new treatment is at least as good as an established treatment.

Question 29

null hypothesis in non- inferiority studies?

Answer 29

So our null hypothesis is that the new treatment is worse than the established treatment, and to reject this hypothesis, we need evidence to show that the new treatment is at least as good as the established treatment.

Question 30

difference between non-inferiority and equivalance design?

Answer 30

for the non-inferiority trial, the hypothesis is one-sided, whereas with the equivalence design, the hypothesis is two-sided. A one-sided test does not require as much evidence to reject the null, as a two-sided test at the same error level. Which means that a non-inferiority design does not require as large a sample size as the corresponding equivalence design.
level ov evidence is low

Question 31

What is point estimate?

Answer 31

A point estimate is a single value that estimates some population parameter based on our sample data.

Question 32

Interval estimate?

Answer 32

An interval estimate specifies a range within which the population parameter is estimated to lie based on the sample.

Question 33

confidence level and 95% confidence level?

Answer 33

How likely the interval is to contain the parameter is determined by the confidence level. And that’s usually expressed as a percentage. The most commonly used confidence interval is the 95% confidence interval. For a 95% confidence interval, one can expect that if you sample repeatedly from the same population, 95% of the confidence intervals of the sample mean will contain the population mean of interest.

Question 34

non inferiority margin?

Answer 34

If the confidence interval crosses or falls to the right of the non-inferiority margin, then we cannot reject the null that the experimental is worse than the control.

Question 35

when usually people use non inferiority?

Answer 35

Trials are sometimes designed with nested non-inferiority and superiority hypotheses. Investigators might design the trial so that if non-inferiority is established when the study is finished, then they can go on and test for superiority.

The more common situation is when investigators fail to show superiority, but they might then test if they can show non-inferiority. So they can’t say that the experimental treatment is better than the control, but they can say that it’s at least not inferior by some small amount.

Question 36

What are adaptive designs?

Answer 36

some trials are designed to change depending on what’s observed in the trial. And these are called adaptive designs.

Question 37

fixed designs?

Answer 37

for fixed designs the design characteristics and features such as the sample size, and the hypotheses of interest, the outcomes, and the treatment groups, those are all established before the trial starts.

Question 38

Advantages of adaptive designs?

Answer 38

by adapting to what’s happening in a trial they have the potential to be more efficient and more likely to demonstrate an effect of a drug if there is one.

Question 39

FDA document foradaptive designs?

Answer 39

To respond to this interest, the FDA has begun drafting a guidance document for industry on the use of adaptive trials. The FDA has started drafting a guidance document for industry on the use of adaptive trials in the drug development process so that the adaptive trials can be used as part of the new drug application for submission to the FDA. In the draft of the guidance from February of 2010, the FDA defines an adaptive trial as a study that includes prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on the analysis of data, usually interim data, from subjects in the study.

Question 40

Possible adaptations in adaptive designs?

Answer 40

• randomization probabilities
• sample size
• visit schedule
• hypothesis tested (non infer- to superiority and vice versa, eligibility crietria, outcomes, analytical methods)

Question 41

IRB with adaptive designs?

Answer 41

In most trials with a fixed design, investigators have to submit amendments to the IRB in order to make design changes like the ones that we’ve talked about in the past two slides. However, in an adaptive design the IRB submission and approval includes the planned adaptations. So amendments are not required for adaptations that occur as planned.

Question 42

More advantages of adaptive?

Answer 42

the advantage of an adaptive design is that it’s more flexible than a fixed design insomuch as that design allows for changes within the specified list of possible adaptations.

• may be more efficiet
• may show effect if one exist

Question 43

limitations of adaptive?

Answer 43

• can be difficult to explain design and interpret results
• rely on a interim results to change trials
• may provide interim information on efficacy and safety to investigator and sponsors
• may be hard to implement (need quick access of data, extensive documentation)