Clinical Studies Flashcards
Requirements for research question
Feasable, interesting, novel, ethical, relevant (FINER)
Variables
Predictor (independent) variable Outcome (dependent) variable Confounding variables (other predictors of outcome that could be related and confuse the interpretation of findings, eg age/gender)
Types of study design
Observational study
(Cohort, Cross-sectional, Case-control)
Clinical trial
Observational study
Investigator is passive and observes the effects taking place in study subjects
Cohort study
Observation made in group of subjects followed over time.
Prospective (begin in present) or retrospective (info has been collected in past)
Cross-sectional study
A group examined at one point in time
Case-control study
Investigator compares a treatment group with control group
Clinical trial
Investigator applies an intervention and examines the effects (demonstrates causality!)
Which type of study has highest / lowest evidence level
Randomised controlled trial
Expert opinion
Clinical studies in industry vs academia
Industry: approval for new drugs, market access
Academia: new/optimized/off-label therapies for rare diseases or children etc
Criteria for good clinical trial
Reasonable/useful clearly defined objectives
Adherence to study protocol > systematic approach
Randomization of participants
Evenly matched control group
Blinding
Clinically relevant endpoints
Appropriate study design
Adequate and unbiased data analysis and publication of all results
Sufficiently large number of participants
Preferentially multi-centered
Randomized controlled trials
Participants chosen by inclusion/exclusion criterea. Random assignment to tratment and control group.
Types of blinding
None (open-label)
Single.
Double.
No blinding
Investigators + participants know who receives treatment and who control/placebo.
> Placebo affect only in treatment group
> observer bias
Single-blinding
Investigators know who receives treatment. Participants not.
> placebo effect in both groups (cancels out)
> observer bias possible
Double-blinding
Investigators and participants dont know who received treatment.
Placebo effect in both groups.
No observer bias.
Clinical Endpoints
Quantitative measurements from individual participants > determine outcome.
Primary: fit study aims, most relevant to patients.
Secondary: related to primary or secondary aims
Tertiary: exploratory, provide suggestions for future studies
if not possible > surrogate
Surrogate endpoints
If not possible to assess for clinical benefit (clinical endpoints).
May not reflect drug effectiveness/safety.
Eg blood pressure, LDL, haemoglobin in case of antidiabetic drug.
(clinical would be: mortality, stroke, amputation etc)
Study designs
Parallel group design (2 treatments, one for each group > simple) Crossover design (Both treatments subsequently given to each group in different orders > greater power, carry-over effects possible, difficulty pinpointing adverse effects) Factorial design (Two treatments, one for each group and one group with both simultaneously > good for studying adverse effects)
Triple-blinding
Data analysts do not know hich participants received treatment either.
Drop-out participant inclusion in analysis
Included > more reliable data
Excluded > attrition bias possible
Reporting bias
If only selected or only positive results are published
Declaration of Helsinki
Developed originally in 1964.
Standards for participant safety, study quality, benefits vs risks.
ICH-GCP
Standards for participent/patient safety, validity of methods, reliabiility of data.
Eu directives demand legal implementation of GCP standards.
Responsibility: sponsor.
Phases in drug development
Preclinical: Phase 1 IND Clinical trials: Phase I, II, III NDA Review by regulatory authority Postmarketing surveillance: Phase IV
Phase 0
“Prior to man”: in vitro studies and animal models.
To ensure safety of participants, determine optimal starting dose.
Investigational new drug application
IND
Application for authorization to commence clinical phase.
Phase I
“First in man” study in several dozen healthy male volunteers.
Assessment of safety, dosage increase, pharmacokinetics.
(open label, no control group)
Phase II
“First in patients” in several hundred selected patients with good prognosis and no concomitant disease.
Assessment of initial efficacy, optimal dosage, drug interactions, adverse effects.
Treatment and control group, randomised, blind
Phase III
“Decision making” in several thousand typical patients.
Assessment of efficacy evidence, safety evidence, profitability.
New drug application (NDA)
After Phase III for approval.
Results from animal and clinical studies. Safety, efficacy, labeling, manufacturing etc
Phase IV
Post-approval surveillance in dozens of thousand ordinary patients.
Long-term effectiveness, rare adverse effects, stability, advantage over comparotor
