Clinical Studies

Question 1

Requirements for research question

Answer 1

Feasable, interesting, novel, ethical, relevant (FINER)

Question 2

Variables

Answer 2

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)

Question 3

Types of study design

Answer 3

Observational study
(Cohort, Cross-sectional, Case-control)
Clinical trial

Question 4

Observational study

Answer 4

Investigator is passive and observes the effects taking place in study subjects

Question 5

Cohort study

Answer 5

Observation made in group of subjects followed over time.

Prospective (begin in present) or retrospective (info has been collected in past)

Question 6

Cross-sectional study

Answer 6

A group examined at one point in time

Question 7

Case-control study

Answer 7

Investigator compares a treatment group with control group

Question 8

Clinical trial

Answer 8

Investigator applies an intervention and examines the effects (demonstrates causality!)

Question 9

Which type of study has highest / lowest evidence level

Answer 9

Randomised controlled trial

Expert opinion

Question 10

Clinical studies in industry vs academia

Answer 10

Industry: approval for new drugs, market access
Academia: new/optimized/off-label therapies for rare diseases or children etc

Question 11

Criteria for good clinical trial

Answer 11

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

Question 12

Randomized controlled trials

Answer 12

Participants chosen by inclusion/exclusion criterea. Random assignment to tratment and control group.

Question 13

Types of blinding

Answer 13

None (open-label)
Single.
Double.

Question 14

No blinding

Answer 14

Investigators + participants know who receives treatment and who control/placebo.
> Placebo affect only in treatment group
> observer bias

Question 15

Single-blinding

Answer 15

Investigators know who receives treatment. Participants not.
> placebo effect in both groups (cancels out)
> observer bias possible

Question 16

Double-blinding

Answer 16

Investigators and participants dont know who received treatment.
Placebo effect in both groups.
No observer bias.

Question 17

Clinical Endpoints

Answer 17

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

Question 18

Surrogate endpoints

Answer 18

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)

Question 19

Study designs

Answer 19

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)

Question 20

Triple-blinding

Answer 20

Data analysts do not know hich participants received treatment either.

Question 21

Drop-out participant inclusion in analysis

Answer 21

Included > more reliable data

Excluded > attrition bias possible

Question 22

Reporting bias

Answer 22

If only selected or only positive results are published

Question 23

Declaration of Helsinki

Answer 23

Developed originally in 1964.

Standards for participant safety, study quality, benefits vs risks.

Question 24

ICH-GCP

Answer 24

Standards for participent/patient safety, validity of methods, reliabiility of data.
Eu directives demand legal implementation of GCP standards.
Responsibility: sponsor.

Question 25

Phases in drug development

Answer 25

Preclinical: Phase 1
IND
Clinical trials: Phase I, II, III
NDA
Review by regulatory authority
Postmarketing surveillance: Phase IV

Question 26

Phase 0

Answer 26

“Prior to man”: in vitro studies and animal models.

To ensure safety of participants, determine optimal starting dose.

Question 27

Investigational new drug application

IND

Answer 27

Application for authorization to commence clinical phase.

Question 28

Phase I

Answer 28

“First in man” study in several dozen healthy male volunteers.
Assessment of safety, dosage increase, pharmacokinetics.
(open label, no control group)

Question 29

Phase II

Answer 29

“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

Question 30

Phase III

Answer 30

“Decision making” in several thousand typical patients.

Assessment of efficacy evidence, safety evidence, profitability.

Question 31

New drug application (NDA)

Answer 31

After Phase III for approval.

Results from animal and clinical studies. Safety, efficacy, labeling, manufacturing etc

Question 32

Phase IV

Answer 32

Post-approval surveillance in dozens of thousand ordinary patients.
Long-term effectiveness, rare adverse effects, stability, advantage over comparotor