Phase 1 clinical trials Flashcards
What is the primary aim of phase 1 clinical studies
To describe the dose-concentration-response relationship usually in healthy volunteers
What are the pros of using healthy participants in a phase 1 clinical trial (4)
Easier, quicker, lower cost of recruitment
No confounding disease or medications
Data applicable to several indications
Wide choice of trial locations
High internal validity
What are the cons of using healthy participants in a phase 1 clinical trial
No or limited PD (pharmacodynamic) biomarkers
Limited relevance of target expression (may not be present or only at low concentrations)
On-target safety profile may not be relevant (off-target will be)
Low external validity
What are the pros of using patients in phase 1 clinical studies
PD biomarkers may only be available in patients
Target safety can be tested
Possibility of benefit
High external validity
(oncology setting)
What are the cons of using patients in phase 1 clinical studies
Recruitment and trial management can be difficult (higher costs)
Trial sites with access to patients have limited first in human experience
Concurrent diseases or medications confound safety data
Greater variability in safety data
Target safety data may not be relevant to other indications
Single or low doses may not be of therapeutic benefit to justify patient recruitment
Ethics of placebo use
What are the key objectives of phase 1 clinical studies
Tolerability
Pharmacokinetics
Pharmacodynamic activity
How is tolerability viewed and measured?
Side effects and safety
vital signs, ECG, LFTs, others guided by pre-clinical testing
What is meant by pharmacokinetics
what the body does to a drug
what are the 3 measurements taken when looking at pharmacokinetics
basic pharmacokinetics parameters of drug and metabolites (Max, Vd etc)
ADME
dose-concentration relationship over ascending single doses and multiple doses
what is meant by pharmacodynamics
what the dug does to the body
what are the 2 factors of pharmacodynamic activity and how are they measured
efficacy (biomarkers)
safety (TQT studies)
What are the substages of phase 1 clinical studies (3)
First in human (FIH)
Single ascending dose (SAD) study - TQT study
Multiple ascending dose (MAD) study - Food study
What are the key issues in first in human studies (3)
Dose selection
Dosing design
Dose escalation
How do you estimate the maximum safe starting dose (3)
Determine no observed effect level (mg/kg) in toxicity studies
Extrapolate to human equivalent dose (HED) - (mg/kg OR body surface area)
HED (from most appropriate species)/safety factor (typically 100) -> maximum recommended starting dose
Describe the steps involved in calculating the maximum recommended starting dose (MRSD) (3)
Identify target organ(s) toxicity
The no observed (non-toxic) effect level (NOEL) and no observed adverse effect level (NOAEL) (“therapeutic index”)
The toxicokinetics
What is a parallel dosing design
Subjects randomised to A (active treatment) OR P (placebo) throughout study
What are the pros of a parallel dosing design
Simple robust design
No doses omitted, so full dose-response established within individuals
What are the cons of a parallel dosing design
Inter subject variability is large
Difficult to maintain blinding
Subjects cannot serve as “own control” for intra-subject comparison
What is a cross-over dosing design
Subjects randomised to BOTH A (active treatment) AND P (placebo) throughout study
What are the pros of a cross-over dosing design
Maximum information from a small sample
Easier to maintain blinding
Less intrasubject variability
What are the cons of a cross-over dosing design
Incomplete dose range for each individual
Dose escalation may stop before each subject receives a placebo; so cross-over is incomplete
What are key considerations for dose escalation in phase 1 studies
Formal process led by trail safety review committee
Review:
- Safety data
- Pharmacokinetic data
- Pharmacodynamic data
Use pre defined stop/go criteria
Decision formally documented
