EXAM 3 STUDY GUIDE QUESTIONS - r and m

Is the literature review for a systematic review exhaustive? If so, what does this mean?

The literature review for a systematic review is extremely extensive. You should search AT LEAST 3 databases to see the majority of papers.

Detail the goals of clinical trials.

-Assess the safety and efficacy of a new investigational drug, device or intervention -Establish the role of the new drug, device or intervention in clinical practice

How is the research question for a systematic review defined?

-Population/condition -Intervention -Comparator -Outcome -Type of study

What are the 3 types of systematic reviews published in Cochrane Reviews?

1. Intervention reviews 2. Diagnostic test accuracy reviews 3. Methodology reviews

What is the process of conducting a systematic review?

1. State the study objective 2. Develop the protocol 3. Develop a search strategy 4. Conduct the search 5. Retrieve relevant papers 6. Screen & select papers that meet established criteria 7. Evaluate methodologic quality of selected studies 8. Analyze & synthesize findings 9. Determine if statistical data are sufficient for further analysis 10. If NOT, Report results of systematic review

What is the relationship between a meta-analysis and a systematic review?

A meta-analysis uses the results found in systematic reviews and goes a step further to analyze the effect size estimates.

Who is Archibald Cochrane? What is he known for and why?

Archibald Cochrane was a Scottish Doctor noted for his book Effectiveness and Efficiency: Random Reflections on Health Sciences. Advocated for randomized controlled trials eventually led to the development of the Cochrane Library database of systematic reviews & Cochrane Collaboration. Cochrane Collaboration- promotes clinical trials evidence & development & dissemination of systematic reviews of healthcare interventions. Known as the father of Epidemiology and evidence-based medicine

Understand both potential benefits and risks of participation in clinical research.

Benefits: -Early access to investigation medicines & test -Obtain expert medical care at leading health care facilities during the trial -Free lab work and trial meds -Frequent monitoring of health status and early detection of complications -Play and active role in own health care Risks: -May be unpleasant side effects -Experimental treatment may not be effective for the participant -Protocol may require more of time and attention that a non-protocol treatments -Feeling of being a guinea pig -Lack of treatment flexibility -May limit future tx options

What are biodistribution studies?

Biodistribution studies confirm that the drug reaches the target tissue and does NOT accumulate in non-target sites of potential toxicity -Performed in animals and humans

What is the difference between efficacy and effectiveness?

Efficacy is the biological effect of a treatment, for example, did product demonstrate a health benefit when compared to a placebo or other intervention when tested in an ideal situation Effectiveness is the effect of a treatment when widely used in practice

Where does animal research occur relative to Clinical Trials? What is the importance of animal and cell culture-based experimental studies?

It occurs in the pre-clinical phase. It is the initial data which provides preliminary information regarding drugs' effects on physiological changes to blood counts, electrolytes, liver function, immune function & cholesterol levels. -May provide info on side effects -Toxicology studies include 1 small animal study, 1 large animal study & 1 nonhuman primate *Exception if no appropriate animal model (Alziemers- no nonhuman primate model) - Blood samples taken at designated time points -Upon completion, necropsy examines are performed on all study animals

What is an IND? Who does it get filed to and when does that happen? What must it contain?

IND is an application for permission to administer a new drug to humans. It happens before clinical research begins. It must contain: - Animal pharmacology and toxicology studies: preclinical data to permit an assessment as to whether the product is reasonably safe for testing in humans - Manufacturing information: information pertaining to the composition, manufacture, stability and controls used for manufacturing the drug substance & drug product - Clinical protocols & investigator information * Becomes effective if the FDA does not disapprove it within 30 days

What is the purpose of a systematic review?

Identify, appraise & synthesize all empirical evidence that meets pre-specified eligibility criteria to answer a given research question. Explicit methods used to minimize bias.

What is a meta-analysis? What are the two stages in a meta-analysis?

It's a method of statistically combining results from 2 or more separate studies to estimate an average or common effect. Improves the precision of the estimated treatment of the effect. 1st Stage- Evaluate Heterogeneity. The degree to which studies in a systematic review are similar. It may be due to random effect due to chance differences between studies. Study samples may be drawn from different populations. 2nd Stage- Apply statistical methods to calculate combined estimates of effects to provide more confidence in outcome. - Effect size: estimate of the magnitude of difference btw groups or the effect of intervention -Effect size index: created for the data in each study that allows comparison across studies. Weighting Effect Size- adjustments in the calculation of the effect size used to weight the contribution of each individual study. Based on sample size.

What databases are searched when conducting a systematic review?

MEDLINE, EMBASE, CINAHL, Web of Science, EBM Reviews

What are DLT and MTD? Describe.

MTD- Max tolerated dose. This is the highest dose of a drug that does not cause unacceptable side effects. DLT- Dose limiting toxicity. This is the dose of the drug that causes severe, life-threatening, fatal reactions.

How many people review the systematic review prior to its publication?

Minimum of 2 primary reviewers. When disagreement occurs, describe if resolved by consensus or by resolution from a 3rd part

What are pharmacokinetic studies?

PK- How does the drug concentration change as it moves through the different compartments of the body

Differentiate between the various phases of clinical research. Understand the objectives, outcomes/endpoints, inclusion/exclusion criteria, average time to complete, number of participants, success rate, and use of placebo.

Preclinical: Molecular, in vitro, in vivo, Process development, GMP production, Epidemiologic 10% success rate 3-6 years to complete Provides prelim info regarding drugs' effect on physio changes to blood counts, electrolytes, liver function, and cholesterol levels. Must include 1 Large animal study, 1 small animal & 1 nonhuman primate. On study completion, necropsy examinations are performed on all study animals. Phase 1: Objectives: asses a safe & tolerated dose, determine if pharmokinetics differ from animal to man, detect effects unrelated to expected action, detect any predictable toxicity. 64% success rate Takes 3-12 months 20-100 participants INCLUSION: Healthy, uniformity of subjects: age, sex, nutrition EXCLUSION: women of child bearing age, children Phase 2: Objectives: Determine activity of new tx in a patient population, examine actue toxicity, define optimal schedule and dosing, further establish pharmacokinetics & determine biological effectiveness 32% success rate Takes 6-24 months 100-500 participants EARLY PHASE: Pilot trial to evaluate efficacy & safety in population of patients w/ disease to be tx and dx LATE PHASE: Well controlled trials to evaluate efficacy in pts with disease to be tx or dx. Usually represent the most rigorous demonstration of medicine's efficacy Phase 3: Objective= effectiveness 60% success rate 5 years 1000-5000 participants * Most Phase 3 trials fail because researches unable to demonstrate efficacy FDA REVIEW: 80% success rate - 1 year Phase 4: ? Unknown how long Helps detect rare ADRs, drug interactions, new uses for drugs Objectives: compare a drug with other drugs in market, monitor a drugs long term effectiveness & impact on a pt's quality of life, determine the cost-effectiveness relative to other traditional and new therapies.

What is a PRISMA?

Preferred Reporting Items for Systematic Reviews and Meta-Analyses - It is a checklist for reporting of systematic reviews and meta-analyses

What are the rating scales used for a systematic review?

Rating Scales: Criteria used & resultant ratings must be described so readers can evaluate the validity of the reviewer's conclusions. NO gold standard - most scoring systems have no been validated. Jadad Scale: Instrument to measure the likelihood of bias. PEDro Scale: Physiotherapy evidence database scale. Used in rehabilitation & medical literature QUADAS Scale: Review studies of diagnostic test accuracy

What are the biases that can influence the outcome or quality of a systematic review?

Selection Bias- may distort treatment effects. Random allocation & concealment of allocation are essential. Confounding bias- systematic differences in factors related to intervention & outcome Allocation bias- systematic differences due to the way that treatment groups are assembled Performance bias- Differences in the provision of care to experimental and control groups in a study. Blind to those who receive and give care. Attrition bias- differential loss of subjects across comparison groups. Intention to treat analysis. Detection Bias- outcome differs across comparison groups. Quality assessment tools. Quality assessment may provide explanations for differences in study results. Reporting bias- Systematic differences between reported & unreported findings.

What are the differences between a systematic review and a narrative review?

Systematic Review: Identify, appraise and synthesize all the empirical evidence that meets pre-specified eligibility criteria to answer a given research question. Explicit methods used to minimize bias. Types of Systematic Review: - Effectiveness of interventions - Accuracy of diagnostics tools -Identification of prognostic factors -Methodological factors Narrative Review: Qualitative summary of evidence on a given topic. Informal and subjective methods to collect and interpret information. Written by "expert" in the field.

Are PICO questions used in systematic reviews?

Yes- PICO for systematic PICo for narractive

How do you read a Forest Plot? How is it constructed? What is its purpose?

You look at the summary effect value which will tell you the preferred treatment compared to the studies. Need to also look at the confidence interval of the studies as well. Constructed using a scatter plot, error bars, line marking summary effect value, and formulating a x-axis Purpose is to study the effect size and confidence intervals.