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Clinical Trials - UTHealth > MidtermReview > Flashcards

MidtermReview Flashcards

1
Q

What is a clinical trial?

A

A prospective study comparing the effects and value of intervention(s) against a control in human beings.

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2
Q

What is a case-control study?

A

Study that compares patients who have a disease or outcome of interest (cases) with patients who do not( controls, and looks back retrospectively to compare how frequently the exposure to a risk factor is present in each group to determine the relationship between the risk factor and the disease.

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3
Q

Information Bias

A

Misclassification of information/data collected

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4
Q

Confounding

A

the association between the predictor and outcome is distorted by extraneous factors (confounders)

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5
Q

Publication Bias

A

Studies with significant results are more likely to be published than studies without significant results

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6
Q

How do you decrease bias?

A

Rigorous study design, appropriate study population, comparison group , appropriate trial and appropriate analytic methods.

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7
Q

Rank types of study and evidence of Cause and Effect

A

1) Clinical Trial 2) Cohort Study 3) Case-control study 4) Cross-sectional study 5) case series

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8
Q

Rank strength of evidence as evidence of cause and effect

A

1) Temporality 2) strength of effect 3) Reversibility 4) Dose-response 5) consistency of response 6) biologic plausibility 6) Analogy

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9
Q

What are the advantages of a case-control study?

A

Advantages:

  • Good for studying rare conditions or diseases
  • less time needed to conduct the study b/c the condition/disease has already occurred
  • useful as initial studies to establish an association
  • useful when it is not ethical to randomize participants
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10
Q

What are the disadvantages of a case-control study?

A

Disadvantages:

  • Retrospective studies have more problems with data quality b/c they rely on memory and people with a condition may be more motivated to recall risk factors (recall bias)
  • Finding a suitable control group can be challenging (to avoid confounding)
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11
Q

What is a Cohort study?

A

Study where one or more samples (cohorts) are followed up prospectively and subsequent status evaluations with respect to a disease or outcome are conducted. In this type of study participants are identified based on their exposure characteristics (risk factors) associated with the disease or outcome of interest.

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12
Q

What are the advantages of a cohort study?

A

Advantages:

  • Subjects can be matched (to reduce influence of confounding variables)
  • Standardization of criteria/outcome is possible
  • Easier and cheaper than a RCT
  • (Not mentioned in slides, but sometimes we cannot ethically randomize people to an exposure of interest)
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13
Q

What are the disadvantages of a cohort?

A

Disadvantages:

  • May be hard to identify cohorts due to confounding variables
  • No randomization (potential for imbalances in unmeasured patient characteristics)
  • Blinding/masking is difficult
  • Outcome of interest could take a long time to occur
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14
Q

Describe a Phase I (Clinical Pharmacology and Toxicity) clinical trial.

A

Primary Concern: Safety
Participants: Healthy volunteers or patients who have already tried and failed to improve on existing standard therapies.
Goal: Estimate tolerability and characterize pharmacokinetics and pharmacodynamics. (Max. Tolerable Dose etc)
n is typically 15-30 participants
Clinical Considerations: Route, schedule and starting dose, Plan for escalation, patient selection, extent of toxicity
Statistical Considerations: Number of patients per dose, Well-defined escalation theme, stopping rule, decision rule for recommended dose

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15
Q

Describe a Phase II (Initial Assessment of Efficacy) clinical Trial.

A

Primary Concern: Efficacy (how does the drug work in controlled setting) and refine the toxicity profile in small-scale investigation.
Goal:
-screen out ineffective drugs
-send promising drugs to phase III trials
- precise estimate of response probability
N is usually 30-100 patients
Other Information:
-single arm or multi arm
Issues:
- which patients to enroll? (most likely to respond?)
- Which endpoint to use? (survival, biomarker, tumor shrinkage)
Notes: Specify a single primary outcome, or composite/global outcome. Bayesian methods could formally look at multiple outcomes.

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16
Q

Describe a Phase III (Full-scale evaluation of Treatment) clinical trial.

A

Goals:
-define the “best” treatment which has implication of changing current practice
N is typically hundreds or thousands of patients

Types:
Comparative Trial (New/treatment is different than standard/placebo)
Equivalence Trial (new treatment may not be better, but is cheaper/less side-effects)

Therapeutic trial(disease is present and being treated)
Prevention Trial (prevention of progression, perhaps second malignancies in cancer trials)
Individual-based trial
Community/population based trials

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17
Q

Phase IV (Postmarketing Serveillance) Trial

A

Goals: Monitor adverse effects, long-term morbidity and mortality after treatment is applied to large number of patients and follow up for a long period of time

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18
Q

What is the relationship between the Target population, the study population and eligibility criteria?

A

The target population is the population which we want to generalize our results to.

The study population is the population from which we select our participants.

Eligibility criteria are the rules we follow to determine if a specific individual can be included in the study or not (to determine if they are part of our study population or not).

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19
Q

List 3 reasons it is important to be clear in defining inclusion/exclusion criteria.

A

1) Interventions usually work best in certain target groups.
2) Homogenous environment reduces variability (thus reducing required sample size)
3) Replicable results.
(Okay one more)
4) Subject protection

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20
Q

What is an advantage of setting broad eligibility criteria?

A

Heterogenous groups let us study the mechanism in action

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21
Q

What is an advantage of setting restrictive criteria?

A

Homogenous groups, smaller variance, smaller n

disadvantage - we don’t know if it works in other subpopulations

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22
Q

What are goals of setting eligibility criteria?

A
  • setting certain eligibility criteria can increase the likelihood of detecting an effect
  • minimizing the possibility of adverse effects (exclude pregnant women, exclude people without adequate liver/renal function)
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23
Q

What are some impacts of generalizability of a study from both eligibility criteria and the recruitment of participants?

A
  • Many studies are performed in academic medical centers which may not be representative of general population
  • underrepresentation of minorities
  • underrepresentation of women
  • participants may be different from non-participants in many significant ways (health, disease, racial or sex, etc)
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24
Q

What is a primary objective?

A

The statement of what you hope to achieve.

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25
Q

What is an outcome of a clinical trial?

A

The measurement used in assessing the primary objective (often defined in the “specific aim or aims”

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26
Q

What is the Hypothesis of a study/trial?

A

This is often a specific aim redefined in terms of a formal hypothesis, typically written as the alternative hypothesis of a statistical test.

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27
Q

What role to secondary questions/objectives have in a clinical trial?

A

these are secondary to the primary objective

  • may identify subgroups of the population that are also of interest
  • must be relevant scientifically, medically and for public health
28
Q

What is an ancillary Question?

A

these are questions that may not be directly related to the primary and secondary objectives but are of general interest in the study population

29
Q

Describe ideal characteristics of an outcome.

A
  • valid and reliable
  • easy to observe
  • free of measurement error and other bias
  • ideally complete observation in all subjects
  • capable of being observed independent of treatment assignment
  • clinically relevant
30
Q

List types of outcomes.

A
  • continuous
  • categorical (attractive for descriptive purposes, but we lose power and can lose information, difficult to generalize as we saw in the studies we read on COVID treatments)
  • dichotomous
  • count, ordinal
  • nominal
  • time to event
  • composite or global
31
Q

Define a surrogate outcome.

A

A biomarker that is intended to substitute for a clinical endpoint; expected to PREDICT the effect of an intervention on the clinical outcome.

32
Q

What are the advantages of a surrogate outcome?

A
  • Measured earlier
  • easier and more convenient to measure
  • observed more frequently
  • less affected by other factors than the “true” endpoint
  • less costly
33
Q

What is the distinction between a surrogate and prognostic variable?

A

Prognostic variable - predicts clinical outcome
(these are our x’s, and are associated with our outcome)
Prognostic Example: Covid-19 study
Outcome is Death, studying remdisivir
Capture Age as well, which is prognostic of death

Surrogate variable - predicts the effect of an intervention on the clinical outcome

34
Q

What makes a good surrogate outcome?

A
  • strongly associated with definitive outcome
  • part of the causal pathway
  • yields the same inference as the definitive outcome
  • responsive to the treatment
  • short latency

Prentice Criteria:

  • proposed outcome predictive of true (clinical) outcome
  • proposed surrogate must fully capture effect of intervention on (clinical) outcome
35
Q

Provide an example of surrogate/outcome pairs.

A

1) Treatment of hypertension:
- Clinical outcome - Myocardial Infarction
- Surrogate - Change in blood pressure
2) Treatment of MS
- clinical outcome - relapse lesions
- surrogate - MRI changes

36
Q

What are limitations of Surrogates?

A
  • requires validation, correlation is not proof of adequate surrogate. (analogy: check and cash - check can still bounce)
  • possibly not in causal pathway
  • possibly better for disease prevention than studies of treatment, why?
37
Q

When is it appropriate to use a global test?

A
  • when no one outcome is sufficient or desirable

- outcome is difficult to measure and combination of correlated outcomes is useful

38
Q

Identify 4 different types of control groups.

A

Placebo - same look and delivery method as treatment, but lacks an active ingredient.

No Treatment - control group has no treatment

Standard of care - control group receives the standard of care that is currently in practice.

Another treatment - not necessarily considered “standard of care”

Historical Control (new treatment is used and compared to historical outcomes from database)

Prospective registries as controls

39
Q

What is the importance of a control group?

A

In the absence of a control group, the natural improvement cannot be distinguished from the effect of a treatment.

40
Q

When is a placebo control not appropriate?

A
  • Equivalence trials: We are trying to determine if two treatments are equivalent.
  • noninferiority trial: we are trying to see if a new treatment works as well as an existing treatment

In both cases we must compare to an active control

41
Q

What is meant by randomization in the context of a clinical trial?

A

The randomization of participants to control and intervention groups.

42
Q

What are the advantages of the use of randomization?

A

-The characteristics at the point of randomization (baseline) should be balanced between intervention and control groups.
-Removes bias (conscious or unconscious)
- validity of results is guaranteed (iid, exchangeability)
-

43
Q

Describe a cross-over design study.

A

Participants randomized to group, then washout time period, then change to other group.

Advantage - every person receives both treatments and is their own control

Assumption - no carry over effect, no drug interaction, no time effect, no treatment-period interaction

44
Q

Describe Factorial Design.

A

Compare two interventions in single experiment and observe interaction

-advantage: efficient, quantify interaction, pairwise comparisons

disadvantages- lose power with interaction, possible increase of toxicity

45
Q

Define a cluster randomized trial

A

Group/cluster allocation

clusters are randomized rather than individuals
Useful when easier to randomize group (school, classroom etc)

Disadvantage is loss of power so increased sample size

46
Q

Stepped wedge Design

A

Variation of cross over in which clusters start sequentially, risk of temporal trend.

When intra-cluster correlation is low, parallel studies have better performance.

ICC larger or clusters are large this is more powerful than parallel design.

47
Q

Adaptive design

A

Make adjustments depending on specific criteria

48
Q

Define fixed allocation randomization.

A

Assignment of treatment intervention to participances is performed with a fixed, pre-specified probability in either equal allocations (most efficient design) or unequal allocation (typically more participants in the treatment group expected to have the best outcome).

49
Q

Define Simple randomization and its advantages/disadvantages.

A
  • flipping coin
  • Advantage - easy to implement
  • Disadvantage - in small studies can lead to imbalance
    NOTE: Alternating assignment is not random
50
Q

Define blocked randomization

A
  • specify blocks of particular size and number of allocations within each block and within the block assign different permutations of assignment according to some random generation of ranking. Then randomly assign the blocks.

Example: A A B B are in our block, Randomly generate 4 numbers from uniform distribution(0,1) and first number is assigned to A, second to A, third to B fourth to B. Rank the assigned numbers in order small to big 1-4. The order of the block is according to the rank numbers.

Disadvantage: With known block sizes the remaining assignments are known. Solution is to have random block sizes.

Advantage: balance can be maintained even when trial is terminated early.

51
Q

Define Stratified Randomization

A

-stratify by risk factor and achieve balance allocation within subgroup
-stratify by center for multicenter studies
Disadvantage - Must be careful to not have too many strata that are each sparse

Advantage - Covariate effect can be prospectively dealt with to increase power and reduce risk of confounding

52
Q

Define Adaptive Randomization

A

Allocation probability is not fixed and continues to change throughout study

Goal: more balanced allocation of treatment, and more ethical.

Types:

  • adjust/adopt allocation prob. according to imbalance of participants or in baseline chars between two groups
  • adjust allocation probabilities according to response to intervention
53
Q

Discuss how to implement randomization

A
  • independent central unit should be responsible for developing randomization process (biostatistician for single center or data coordinating center for multicenter)
  • Best if investigators are blind to randomization
  • Sequenced and sealed envelopes that have assignment
  • randomization list kept in pharmacy for double-blind drug studies
  • web-based randomization - capture basic eligibility data, gives randomization assignment
54
Q

What is meant by a “single blinded” trial?

A
  • A trial in which the participant is unaware of which treatment group they have been assigned, but the investigator is aware of the assignment.

Advantage: design is similar to unblinded, simple to carry out

Disadvantage - investigators van add bias b/c they are aware of treatment assignment. Investigator may intentionally or unintentionally un-blind the participants.

55
Q

What is meant by a “double blinded” trial?

A
  • A trial in which neither the participant nor the investigators following the participants know the identity of intervention assignment.

Advantages:

  • reduce risk of bias
  • account for placebo effect

Disadvantage:

  • must manufacture placebo to match treatment
  • periodic sampling drug content
  • lab test such as checking serum level may be helpful but must be confidential
56
Q

What is a triple-blinded trial?

A
  • patients, investigators and data monitoring committee are all blinded
  • disadvantage: DMC’s ability to monitor safety and efficacy can be hampered and this can be counterproductive
  • improvement: DMC is blinded at first but code can be broken upon request.
57
Q

What is the most efficient allocation?

A
  • For two sample it is balanced study (see homework)

- Why? Variance is minimized with equal sample size in the two groups.

58
Q

What is the risk of not considering the clustering effect in sample size estimation for cluster randomized trials?

A

If cluster effect is not accounted for, then variance is underestimated, standard error looks smaller than it actually is and the likelihood of committing a type 1 error increases.

59
Q

What is the effect of unbalanced designs on sample size?

A

Increased variance, increased required sample size to achieve the same power

(Or if sample size is constant-> increased variance and decreased power)

60
Q

Assume we have calculated a sample size of N for our study for our specified power and desired effect detection. Assume a 15% loss to follow up that is assumed to be at random, explain how to calculate N*.

A

N*=N/(1-.15)

61
Q

Assume we have calculated a sample size of N for our study for our specified power and desired effect detection. Assume a 15% loss to follow up that is assumed to be NOT at random and thus additional sensitivity analyses may be required, explain how to calculate N*.

A

N*=N/((1-.15)^2)

62
Q

Identify issues with incorporating baseline measures of the outcome into change from baseline.

A
  • if the baseline is related with the outcome can induce spurious correlation
  • percent changes is dependent on what the baseline value is (we can have the same percent increase, but magnitude of change is very different)
63
Q

Define Power.

A

The probability of rejecting the null hypothesis given the alternative hypothesis is true.

64
Q

Define Type I error.

A

The probability of rejecting the null hypothesis given the null hypothesis is true.

65
Q

Define p-value.

A

The probability of observing the observed statistic or one more “extreme” towards the alternative hypothesis under the assumption that the null hypothesis is true.

(Consider Normal distribution, look at bell curve with mean set at the null hypothesis mean. Place a mark at the observed x-bar. p-value in this case is the probability of observing x-bar or an x-bar further away from the bell curve mean. If one sided hypothesis we only look at one side, if two-sided we also consider the “mirror” values on the other side of the bell curve.)

66
Q

Describe Cohen’s effect size.

A
  • based on behavioral science data
  • essentially the same as a z-score for two sample test with s-pooled as SE
  • D=(mu1-mu2)/s-pooled
    General Rules:
    0.2<=D<0.5 (Small Effect)
    0.5<=D<0.8 (Medium Effect)
    D>=0.8(Large Effect)

Clinical Trials - UTHealth (5 decks)

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