GOOD CLINICAL PRACTICE
Drug research unit Ghent .....................................................................................................................2
Quality management system.............................................................................................................2
Expertise ..........................................................................................................................................4
Structure .........................................................................................................................................5
Principles of regulations and legislation ................................................................................................6
Introduction to the (inter)national legal framework for clinical research ...............................................6
European medicines agency ............................................................................................................... 12
Role of the EMA .............................................................................................................................. 13
Regulations of clinical trials ............................................................................................................ 13
Marketing authorisation .................................................................................................................. 16
Pharmacovigilance ......................................................................................................................... 18
Clinical trial designs ........................................................................................................................... 19
Observational studies ..................................................................................................................... 19
Experimental studies ...................................................................................................................... 22
Randomized controlled trial (RCT) ................................................................................................... 26
Systematic review .......................................................................................................................... 27
Level of evidence ............................................................................................................................ 28
Clinical studies .................................................................................................................................. 29
Phase I studies: 3+3 design ............................................................................................................. 29
Alternative phase I trials.................................................................................................................. 35
Statistical analysis ......................................................................................................................... 37
Biobanking ........................................................................................................................................ 43
cycle.............................................................................................................................................. 43
Importance .................................................................................................................................... 46
1
,DRUG RESEARCH UNIT GHENT = DRUG
= early phase clinical drug research unit at the Ghent University Hospital
! focus on phase I and early phase II clinical trials for healthy volunteers and oncology patients
• Contribute to the development of drugs/drug formulation by conducting clinical trials
• Offer trial access at national and international level
• Comply with international and national quality standards, legislation, GCP-ICH
• Harmonize trial conduct timelines
• Improve efficiency and optimize costs of trial conduct
QUALITY MANAGEMENT SYSTEM = QMS
= conform GCP – international legislation – protocol – validity of results
STRUCTURE
− Quality manual
• Introduction and purpose
• Organisation and organisational structure
• Staff: roles and qualifications
• Independency and confidentiality
• Quality system
• Equipment: calibration and maintenance
• Supplies and services
• Subjects (healthy volunteers and patients)
• Performing and control of activities
• Samples and measurements
• Archiving
− Procedures
• SOP = standard operating procedure: patient can decide for ICF
• STP = standard technical procedures: technical/analytical procedures
− Forms: who received what – how much time – return to sponsor = what goes in and out
− Documents: internal and external audits
CONTROL AND IMPROV EMENT
− Quality control: check if everything is according to quality requirements
• Approval: day-to-day verification
• Internal audits: 5 auditors within the unit
− Quality assurance: systematic actions foreseen to check if everything is according to legislation
• Independent higher-level oversight: 1 third party audit/2 years = GCP audit
− Second-party audits: conducted by sponsors to verify site compliance
− Regulatory inspections: FDA and FAGG ispections
2
, − Improvement: PDCA = plan-do-check-act = quality circle of Deming
• Plan: identify an issue or area for improvement and plan a charge
• Do: implement the change (on a small scale)
• Check: evaluate whether the change led to improvement
Each completed PDCA
• Act: if successful – implement broadly, if not – revise the plan
cycle results in a higher
level of quality and so
on over time
TRAINING AND RESOURCES
! ensure all staff are continuously and adequately trained
− Training employees
• SOP trainings (+/- 5 per year)
• Training + test in GCP and (inter)national legislation
• BLS/AED = basic life support/automatic external defibrillator
! important for healthy volunteers and patients
• IATA = international airport transport association: transport of biological samples
• Study-specific trainings: new protocols
• Individual trainings in SOP’s and STP’s
• In the framework of patient trials: training in oncology topics, training by psychologists, …
− Document management system
• Version control: only current approved version of each document is in use
• Approval: documents must be formally approved before use
• Readily available: to all relevant staff at all times
− Infrastructure
• Apparatus + storage areas: temperature management and control
• Calibrated + documented devices
EVALUATION
− Client satisfaction: monitoring is important for two factors
• Sponsors
o Involvement of management
o Involvement of team
• Subjects
− Complaint registration: formal recording and follow-up
− Evaluation of suppliers
− Inspections
• FDA inspection
• FAGG inspections
• Second party audits
3
, EXPERTISE
! whole organisation is involved: management – coordinators – team – …
− Healthy volunteer trials
• Early phase trials in healthy subjects
o First in human = FIH: single dose and multiple dose = SD/MD
- Assessment of safety and pharmacokinetics
- Pharmacodynamics and biomarkers
- Complex sample handling
o Food and drug-drug interaction trials = DDI
o Bio-equivalence trials: comparing two formulations of the same drug
o QT studies: assessing cardiac safety
• Types of investigational medicinal products = IMP
o Small molecules – peptides – biological – vaccines – …
• Study population
o Healthy subjects: male and female – 18-65 years
o Special groups: elderly – overweight – hypertensive – …
− Oncology trials
• Early phase oncology trials
o First in human: dose escalation
o Expansion cohorts – biomarker cohorts
o DDI and food cohorts
• Types of investigational medicinal products = IMP
o Small molecules
o Checkpoint inhibitors – immune agonists – bispecific T-cell engagers – ADC
o Cancer vaccines – oncolytic viruses – CAR-T
• Study population
o All tumour types and niche populations are included
o Pre-screening programmes are available
− Other patient trials: non-oncology
• Support for other UZ Ghent investigators
• Organ specialist = PI
o Intensive PK sampling
o Safety monitoring
- CRS = cytokine release syndrome
- ICANS = immunological shock reaction requiring rescue medication
- IRR = infusion related reactions
− Paediatric trials: specialised unit linked with Department of Paediatrics
• Trials: phase I – IV and observational studies
• Types of investigational medicinal products = IMP
o Small molecules – biologicals – vaccines – ATMPS
• Study population: healthy infants and paediatric patients – including rare disease population
! recruitment in ultra rare disease: in 50% of open studies
4
Drug research unit Ghent .....................................................................................................................2
Quality management system.............................................................................................................2
Expertise ..........................................................................................................................................4
Structure .........................................................................................................................................5
Principles of regulations and legislation ................................................................................................6
Introduction to the (inter)national legal framework for clinical research ...............................................6
European medicines agency ............................................................................................................... 12
Role of the EMA .............................................................................................................................. 13
Regulations of clinical trials ............................................................................................................ 13
Marketing authorisation .................................................................................................................. 16
Pharmacovigilance ......................................................................................................................... 18
Clinical trial designs ........................................................................................................................... 19
Observational studies ..................................................................................................................... 19
Experimental studies ...................................................................................................................... 22
Randomized controlled trial (RCT) ................................................................................................... 26
Systematic review .......................................................................................................................... 27
Level of evidence ............................................................................................................................ 28
Clinical studies .................................................................................................................................. 29
Phase I studies: 3+3 design ............................................................................................................. 29
Alternative phase I trials.................................................................................................................. 35
Statistical analysis ......................................................................................................................... 37
Biobanking ........................................................................................................................................ 43
cycle.............................................................................................................................................. 43
Importance .................................................................................................................................... 46
1
,DRUG RESEARCH UNIT GHENT = DRUG
= early phase clinical drug research unit at the Ghent University Hospital
! focus on phase I and early phase II clinical trials for healthy volunteers and oncology patients
• Contribute to the development of drugs/drug formulation by conducting clinical trials
• Offer trial access at national and international level
• Comply with international and national quality standards, legislation, GCP-ICH
• Harmonize trial conduct timelines
• Improve efficiency and optimize costs of trial conduct
QUALITY MANAGEMENT SYSTEM = QMS
= conform GCP – international legislation – protocol – validity of results
STRUCTURE
− Quality manual
• Introduction and purpose
• Organisation and organisational structure
• Staff: roles and qualifications
• Independency and confidentiality
• Quality system
• Equipment: calibration and maintenance
• Supplies and services
• Subjects (healthy volunteers and patients)
• Performing and control of activities
• Samples and measurements
• Archiving
− Procedures
• SOP = standard operating procedure: patient can decide for ICF
• STP = standard technical procedures: technical/analytical procedures
− Forms: who received what – how much time – return to sponsor = what goes in and out
− Documents: internal and external audits
CONTROL AND IMPROV EMENT
− Quality control: check if everything is according to quality requirements
• Approval: day-to-day verification
• Internal audits: 5 auditors within the unit
− Quality assurance: systematic actions foreseen to check if everything is according to legislation
• Independent higher-level oversight: 1 third party audit/2 years = GCP audit
− Second-party audits: conducted by sponsors to verify site compliance
− Regulatory inspections: FDA and FAGG ispections
2
, − Improvement: PDCA = plan-do-check-act = quality circle of Deming
• Plan: identify an issue or area for improvement and plan a charge
• Do: implement the change (on a small scale)
• Check: evaluate whether the change led to improvement
Each completed PDCA
• Act: if successful – implement broadly, if not – revise the plan
cycle results in a higher
level of quality and so
on over time
TRAINING AND RESOURCES
! ensure all staff are continuously and adequately trained
− Training employees
• SOP trainings (+/- 5 per year)
• Training + test in GCP and (inter)national legislation
• BLS/AED = basic life support/automatic external defibrillator
! important for healthy volunteers and patients
• IATA = international airport transport association: transport of biological samples
• Study-specific trainings: new protocols
• Individual trainings in SOP’s and STP’s
• In the framework of patient trials: training in oncology topics, training by psychologists, …
− Document management system
• Version control: only current approved version of each document is in use
• Approval: documents must be formally approved before use
• Readily available: to all relevant staff at all times
− Infrastructure
• Apparatus + storage areas: temperature management and control
• Calibrated + documented devices
EVALUATION
− Client satisfaction: monitoring is important for two factors
• Sponsors
o Involvement of management
o Involvement of team
• Subjects
− Complaint registration: formal recording and follow-up
− Evaluation of suppliers
− Inspections
• FDA inspection
• FAGG inspections
• Second party audits
3
, EXPERTISE
! whole organisation is involved: management – coordinators – team – …
− Healthy volunteer trials
• Early phase trials in healthy subjects
o First in human = FIH: single dose and multiple dose = SD/MD
- Assessment of safety and pharmacokinetics
- Pharmacodynamics and biomarkers
- Complex sample handling
o Food and drug-drug interaction trials = DDI
o Bio-equivalence trials: comparing two formulations of the same drug
o QT studies: assessing cardiac safety
• Types of investigational medicinal products = IMP
o Small molecules – peptides – biological – vaccines – …
• Study population
o Healthy subjects: male and female – 18-65 years
o Special groups: elderly – overweight – hypertensive – …
− Oncology trials
• Early phase oncology trials
o First in human: dose escalation
o Expansion cohorts – biomarker cohorts
o DDI and food cohorts
• Types of investigational medicinal products = IMP
o Small molecules
o Checkpoint inhibitors – immune agonists – bispecific T-cell engagers – ADC
o Cancer vaccines – oncolytic viruses – CAR-T
• Study population
o All tumour types and niche populations are included
o Pre-screening programmes are available
− Other patient trials: non-oncology
• Support for other UZ Ghent investigators
• Organ specialist = PI
o Intensive PK sampling
o Safety monitoring
- CRS = cytokine release syndrome
- ICANS = immunological shock reaction requiring rescue medication
- IRR = infusion related reactions
− Paediatric trials: specialised unit linked with Department of Paediatrics
• Trials: phase I – IV and observational studies
• Types of investigational medicinal products = IMP
o Small molecules – biologicals – vaccines – ATMPS
• Study population: healthy infants and paediatric patients – including rare disease population
! recruitment in ultra rare disease: in 50% of open studies
4
