Research Studies and Evidence Flashcards
BHIVA adopts the Grade system for it’s recommendations. What are the grades of recommendations? What do they mean?
Grade 1) is a strong recommendation to do (or not do) something, where the
benefits clearly outweigh the risks (or vice versa) for most if not all people living with HIV. “We recommend”
Grade 2) weaker or conditional recommendation, where the risks and
benefits are more closely balanced or are more uncertain. “We suggest”
In BHIVA guidelines the quality of evidence is graded A-D. What does is grade mean?
A) high-quality evidence from consistent results from well-performed randomised
controlled trials, or overwhelming evidence of some other sort (such as well-executed observational studies with consistent strong effects and a low likelihood of uncorrected bias).
B) moderate-quality evidence from randomised trials that suffer from serious flaws in conduct, inconsistency, indirectness, imprecise estimates, reporting bias, or some combination of
these limitations, or from other study designs with special strengths such as observational studies with consistent effects and exclusion of most potential sources of bias.
C) low-quality evidence from controlled trials with several very serious limitations or observational studies with limited evidence on effects and exclusion of most potential sources of bias.
D) case studies, expert judgement or observational studies with inconsistent effects and a potential for substantial bias.
What are the different phases of clinical research? What is the focus of each phase? How many patients?
I) the safety and proper dose [20-100]
II) effectiveness and side effects [100-300]
III) compare new treatment to existing treatment [300-3000]
IV) approved and available. Long term effects observed [1000’s]
What is meant by non-inferiority in a trial?
What are the benefits and draw backs?
Intended to show that the effect of a new treatment is not worse than that of anestablished or licenced treatment by more than a specified margin.
Benefits: not always possible to have a placebo trial for ethical reasons
Draw back- difficulty in defining the non-inferiority margin
Discontinuations from the trial can obscure a true treatment effect
May still be difficult to justify change to a treatment in a non-inferiority if it is more expensive
What is the benefit of double blinding in a trial?
Reduces Performance bias (systematic differences
in the care provided apart from the
intervention being evaluated)
Describe a case control study
Observational study that compares individuals with a condition or outcome to those who do not have a condition
Useful for pros and cons
Cons
Not randomised intervention so risk of selection bias
Pros
Efficient for rare disease
Used existing data
Requires fewer participants than a cohort
What is a cohort study
Observational study where a group of individuals sharing a common characteristic are followed over time to observe outcomes
may be prospective or retrospective
Pros: Longitudinal data
A retrospective cohort study can be completed fast and is relatively inexpensive compared with a prospective cohort study
Follow-up of the study participants is very important in a cohort study and losses are an important source of bias in these types of studies.
Describe some recent trials relating to rabies vaccination strategies
Incomplete
Intradermal vs IM administration
Auerswald et al (Cambodia). PEP of 2 x ID Vs 3x doses, induced same response (t and B cell)
NOTE Green book says JCVI have not recommended intradermal, off label use
Schedule changes: Overduin et al (Netherlands, Lancet): Showed single visit IM injections induced non-inferior to 2 visit IM pre-exposure
Note that the UK schedule is 3 doses (pre-exposure, 0,7,28)
Describe the AURORA trial
(design, participants and outcome)
Phase III non-inferiority of maribavir vs valgan for CMV pre-emptive disease
-HCT patients with first infection
-clearance at 8 weeks
-Maribavir did not meet non-inferiority
-one reason was the developement of resistance
What is an intention to treat analysis
Inclusion of all participants randomised, regardless of whether they were lost or removed from trial
(the opposite would be a completer analysis, however this reduces the effect that randomisation is supposed to have)
Benefits: Reduces bias
yields an unbiased estimate of the efficacy of the intervention on the primary study outcome at the level of adherence observed in the trial.
ITT analysis represents real-world practice where patients may or may not take their medications as advised and drop out if they feel that they are not improving or if they do not like the side effects of the drug
What is a per protocol analysis
Per-protocol analysis is a special type of completer analysis. Data are analyzed only for those
patients who completely adhere to the treatment protocol. This means that the patients not only reach the study endpoint without dropping out but also complete all key assessments at all study
visits, show good treatment adherence
Something on Kaplan meier curves
Labels: X axis time (bottom), Y axis survival probability
Survival analysis time-to-event data
used for comparing survival curves between groups
Cox regression
AKA proportional hazards regression
- allows for the inclusion of covariates to assess impact on survival
Based on estimating hazrds ratios
Used for examining the effects of multiple covariates on survival time
Indications:
Survival analysis
Takes in to account multiple predictors
Cohort studies
Benefits of blinding in trials
Reduces of physician associated bias
Reduces placebo effect
Describe MELODY trial
Phase 3 trial
1490 infants randomised to nirsevumab vs placebo, born at at least 35 weeks,
End point: 1ry medically attended RSV associated infections
2ry: Hospitilsation for RSV
Outcome: Reduced hospital presentations in nirevumab group
(note mainly well babies, not extreme prem, predominantly well)
The 2–3 MEDLEY trial: saefty trial for those who can have palivuzimab
