Lecture 25: Overview of Research Methodology

Question 1

Primary Research Question

Answer 1

– The one the investigators are most interested in answering
– The question on which the sample size of the study is based
– The outcome that must be emphasized in the reporting of results

Question 2

Secondary Research Question

Answer 2

– Related to the primary question but are “less important”
• Explore a different outcome than the primary question
• Explore a different patient subgroup

Is drug effective (primary) and safe (secondary)

Question 3

what research do clincians encounter most?

Answer 3

phase 3 or 4

typically most helpful for clinical decision making.

Question 4

describe pre-clinical research

Answer 4

In vitro or animal studies

molecules to be tested to determine efficacy and safety

15-20 year process

Question 5

describe Phase 1

Answer 5

Human pharmacology studies: drug tolerance, metabolism, interactions, pharmacokinetics, pharmacodynamics, dose finding

tests how we move from tube to pts, how body tolerates with healthy volunteers

Question 6

describe Phase 2

Answer 6

Therapeutic exploratory studies: effects of various doses, surrogate (biomarker) outcomes

research for group of small patients, surrogate endopoint trials come into play, effect of a med on biomarkers or lab tests

Question 7

describe Phase 3

Answer 7

Therapeutic confirmatory studies: demonstrate clinical use & establish safety profile.
– “Prospective studies comparing the effects and value of interventions() against a control
in human beings.”

prove drug is beneficial, safe, efficacious for a large pop

Question 8

describe Phase 4

Answer 8

Therapeutic use studies: examine drug in broad or special populations, seek to identify uncommon adverse events.
– ”Long term studies or studies conducted after regulatory agency approval of the drug or device”

on market, look at special poplations (Chronic kidney disease), uncommon AE

Question 9

what is the 1st q to ask to decide what type of study should be used?

Answer 9

descriptive (PO) vs analytic (PICO)

Q1: was the aim to describe a population (PO) or quantify the relationship b/w factors (PICO)
Quantify relationship b/.w exposure and outcome (drug and effect) = analytical type of research

Question 10

what is the 2nd q to ask to decide what type of study should be used?

Answer 10

analytic - experimental vs observational analytic

Was the intervention allocated randomly?
- Randomized to active treatment and control, cross over studies
- Observational research: if not being controlled by research and not randomly assigned
○ Cohort vs cross sectional and case control studies

Question 11

what is the 3rd q to ask to decide what type of study should be used?

Answer 11

cohort vs cross sectional vs case control study

Q3: when were the outcomes determined in relation to exposure we are trying to determine (after, same time, before exposure)

- Cohort study: AFTER the exposure
- Cross sectional (analytic): exposure and outcome AT THE SAME TIME 
- Case Control Study: looking at outcome and know it before the information about exposure is available; identifying cases who we know have outcome of interest and look back to see whether or not they've had exposure in the past

Question 12

look at Oxford levels of evidence

Answer 12

Benefits
Level 1: therapy related qs with systematic reviews or randomized systemic revies
Level 2: RCT
L3-4: Cohort study or control study
Level 5: mechanism based reasoning 

Harms
Similar RCTs, sometimes only have observational research, not ethical to expose someone

If asking about how common a problem is, we won’t do a RCT, but survey or census

Question 13

what are fundamentals to a study?

smoking cessation example

Answer 13

Exposure: early NRT nicotine replacement therapy
- Usually for course of 12 wks
Outcome: did the subject quit

Must include a comparison

Research q: In smokers, does NRT started 2 wks prior to the quit date improve cessation rates at 6 months

Quit rate is outcome

Revised research q: in smokers, does early NRT in comparison to NRT started on the quit date improve cessation rates at 6 months or 1 year

Question 14

define confounding variable

Answer 14

“A variable other than the risk factor & outcome variable under study which is related independently to each of the other two and can create an apparent association or mask a real one.”

smoking, coffee and cancer

Randomized experimental studies will control confounding variables

Question 15

observational vs experimental (randomized studies)

Answer 15

1. Observational Studies
   – No manipulation of study groups
   • Only observe patients and outcomes
   – Good for questions relating to harm (causation)
2. Experimental (Randomized) Studies
   – Comparable to Cohort studies EXCEPT the exposure is determined by
   the researchers
   • Follow the 2 groups to see who has outcome of interest
   – Good for questions of therapy/prevention

Question 16

Randomized Controlled Trials

goal

Answer 16

The goal of a randomized controlled trial is to make exposed and control similar in all respects other than the intervention at the start of the study and maintain that balance as the trial progresses.

defined pop gets new treatment or control/current treatment
- outcome with disease or no disease

Exposure is determined by the researchers
– Researchers expose one group to a therapy & not the other group
– Then follow the 2 groups to see who has outcome of interest

Question 17

Randomized Controlled Trials

strengths and weaknesses

Answer 17

• Gold standard to answer “therapy” or “prevention” questions
• Strengths
– Low susceptibility to bias vs. other designs
– Why? reduce confounders
• Weaknesses
– Expensive & time consuming
– Less generalizable (i.e., less applicability)
– May introduce “hidden bias”

Question 18

efficacy vs effectiveness research

which does RCT does?

Answer 18

efficacy: does treatment work under ideal conditions?
effectiveness: does treatment work under ordinary circumstances?

RCT gives efficacy rather than effectiveness

Question 19

Superiority RCTs

Answer 19

Superiority trial to show one intervention is better than another

– Most common RCT done
– Comparator most often is placebo
– Assesses whether the new intervention is better or worse than control
– Aim to rule out equality between treatments

Question 20

Equivalence or Non-inferiority RCTs

Answer 20

Equivalence: show tha 2 drugs are same in terms of effectiveness and efficacy

Non-inferiority: New drug is no worse than an existing gold standard

– Sometimes it is unethical to do a placebo controlled RCT
– Aim to rule out differences between two treatments

Question 21

“Quasi Experimental” Designs

Answer 21

– Definition: look like experimental design but lack true randomization
but there is some aspect of randomization

Question 22

Cohort Studies

design

Answer 22

group of pts

exposed or not exposed

do they develop disease or not?

Randomization is not the process of detemrining when ppl are exposed or not exposed

Ppl are exposed because a pt decides to take an otc or hcp recommended

Question 23

prospective vs retrospective study

Answer 23

Prospective study that happens forwardf in time, in the future
- Not always feasible

Prospective study that happens forwardf in time, in the future

• Not always feasible
• Retro uses data that is already collected like in a pt med record or alberta health services
• Define a cohort back in the past to see whether there are ppl exposed to a certain med and see if they got an outcome of interest

Question 24

Cohort Studies

When are they used?

Answer 24

• Used when it is not reasonable to expose people to something
• Can be used to answer questions about causation (therapy)
• Good for answering questions about prognosis
- harm questions, can be therapy tho not highest level of evidence

Inception cohort: group od people with same in disease, stage, early in disease
Follow them in time

Question 25

Cohort Studies

what are they

Answer 25

• Two or more groups of people are selected
• Basis for selection is EXPOSURE to a particular agent
– (e.g., Occupational exposure, environmental toxin)
• Groups are followed-up to see how many develop the outcome of interest

Key Points
• Hallmark is the comparison of EXPOSED to NON-EXPOSED
• No intervention – Only observe patients during course of study

Question 26

Case-Control Study

design

Answer 26

Associations b/w exposure and outcome rather than starting with exposure status

Outcome determined first; recall exposure

study group - identify cases or controls

determine if they were exposed or not exposed previously

Question 27

Case-Control Study

When are they used?

Answer 27

• Generally concerned with establishing the causes of disease
• Usually the only option for studying rare conditions

key pts
• People are selected on the basis of outcome/disease NOT exposure
• Cannot demonstrate causality, just associations

Question 28

Case-Control Study

what are they?

Answer 28

• Type of retrospective observational study
• Identify a group of people with a disease of interest (cases) and
compare them to a similar group of people without the disease
(controls)
• Data are then collected on past exposure to a possible causal agent
for the disease

Question 29

Cross - Sectional Survey

what are they?

Answer 29

– A representative sample of participants is recruited
– They are interviewed, examined or otherwise studied
– Defining feature: data collection at a single time point
• e.g. What do first year students think about PHARM 324?
• e.g. What is the prevalence of Peripheral Arterial Disease in adults over
the age of 50 in Alberta?1

Question 30

Cross - Sectional Survey

advantages, disadvantages

Answer 30

simple, cheap

no causation

Hopw prevalent is a disease
Sample survey: we get some people
Census survey: everyone in populaiton

Cannot look at causation

Question 31

Case Reports & Case Series

define

Answer 31

Case report – description of an individual patient
• Case series – descriptions of a series of patients
• No comparison group
• AKA descriptive studies
• Used to report rare/unusual occurrences

• Commonly reported in literature and can describe cases or unsual expeirence/scnearios
• Landmark future research
• Case series: multiple cases in a group of people
• Limited in use for practice

Question 32

name 3 systematic errors

Answer 32

selection bias, info bias, confounding

Question 33

Qualitative Research

when is it useful?

Answer 33

• Sometimes the goal is in-depth understanding of human behavior rather than numerical outcomes
• These types of questions are better suited to qualitative investigation
– E.g., Interviews, focus groups, etc.

Research Question:
• Why do continuing smokers not access Stop Smoking Services offered by clinicians?

Question 34

Biased RCT vs. Good Quality Cohort Study

“Nuanced” Hierarchy of Evidence - The GRADE Approach

what can decrease confidence in evidence (5)

see picture for more

Answer 34

RCTs have high confience evidence
Observational studies have low confience because of confounding and other facotrs

risk of bias: If a RCT is biased because of factors, this lowers confidence

Inconsistency: conflicting evidence, lower confidence

Indirectness: If evidence is not directly applicable to practice, lower confidence. If trial participant results are different that target population

Imprecision: Results not precise and large range of data, less confident

Publication bias: showing research that is shows benefit for a med

Observational studies with low confidence can be increased with factors

Question 35

how can we differentiate cohort, cross sectional, and case control studies?

Answer 35

looking at when the study outcomes were determined in relation to when the exposure of
interest occurred