CLINICAL TRIAL MANAGEMENT
, 1. INTRODUCTION TO CLINICAL RESEARCH 1
1. How Are Medicinal Products Developed? 1
2. What Is Clinical Research? 1
3. What Are the Di erent Types of Clinical Trials? 2
4. Synopsises 4
2. GOOD CLINICAL PRACTICE (I) 5
1. Medical Research History 5
2. Declaration of Helsinki 5
3. ICH (E6 Guideline) GCP 6
4. 11 Principals of ICH-GCP 7
5. Annex 1 7
3. GOOD CLINICAL PRACTICE II 9
1. The Sponsor 9
2. Data Governance - Investigator & Sponsor 9
3. Appendices 9
4. CLINICAL TRIAL LEGISLATION 13
1. EU Clinical Trial Legislation 13
2. Belgian Clinical Trial Legislation 15
3. US Clinical Trial Legislation 16
4. Clinical Trial Databases 16
5. IMPLICATIONS GCP & REGULATIONS – AUDITS & INSPECTIONS 17
1. Audits & Inspections 17
2. Quality Assurance in Pharma R&D 17
3. Audit / Inspection Process 19
4. Audit Outcome 19
6. STUDY PARTICIPANT MANAGEMENT - ICF 23
1. Study Participant Recruitment 23
2. Informed Consent 24
7. DRUG SAFETY/PHARMACOVIGILANCE IN CLINICAL TRIALS 29
1. Legal Basis 29
2. De nition of Terms 29
3. Reporting & Databases 31
4. The Process 32
5. Post Marketing – Good Pharmacovigilance Practices (GVP) 33
8. CLINICAL RESEARCH METHODOLOGY (I) 35
1. Design and Set-Up Phase 35
2. Active Phase 38
9. CLINICAL RESEARCH METHODOLOGY (II) 41
1. Project Management Fundamentals 41
2. Project Phases 43
10. PROCESSING OF CLINICAL TRIAL RESULTS 47
1. Data Management - De nitions 47
2. Data Management Principles 47
3. Data Management Processes 48
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, 1. INTRODUCTION TO CLINICAL RESEARCH
1. HOW ARE MEDICINAL PRODUCTS DEVELOPED?
How does a drug come to the market?
1. Discovery: screen compounds that may become a future drug
2. Preclinical studies
3. Clinical studies
4. Apply for marketing authorisation
→ expensive, takes a long time (10 -12 years)
R&D = Research & Development
→ research = discovering the compound
→ once the compound is de ned = development stage → proof safety & e cacy
→ discovery of a new product / improvement of an existing product
Medicinal products:
- a pharmaceutical product
- an immunological product (vaccine)
- a metabolical product
- a biological compound
- a diagnostic product
- to prevent, to treat, to diagnose or to relieve (symptoms of) a disease.
- a medical device = di erent from a medicinal product (pacemaker, app for glucose,…)
→ laws about studies to prove safety
Proof safety & e cacy: work with a controlled study: compare with placebo or an existing
compound (later on in the study) → must be better than existing products
2. WHAT IS CLINICAL RESEARCH?
- Clinical trials = experiments or observations done in clinical research = prospective
(= start collecting data in the future) biomedical or behavioural research studies on human
participants → designed to answer speci c questions about biomedical or behavioural
interventions, incl new treatments (novel vaccines, drugs, dietary choices, dietary supplements,
and medical devices) & known interventions that warrant further study & comparison
→ Clinical trials generate data on safety & e cacy
- Di erence w/ normal clinical practice: highly monitored, possible risk for the patient,…
- Hypothesis testing = used to determine whether an observed treatment e ect is real or due to
chance.
- Null hypothesis (H₀) assumes no e ect
- Alternative hypothesis (H₁) assumes a di erence or treatment e ect.
- Results are evaluated using a p-value a a prede ned signi cance level (α, usually 0.05)
→ if p ≤ α, H₀ is rejected
- Con dence intervals show the size and precision of the e ect, and statistical signi cance
must always be interpreted alongside clinical relevance
- A regulatory authority will grant o cial permission to use medicinal products in a general
population, only if there is evidence about safety & e cacy
- Registration: the approval to market the new medicinal product
- Pre-registration clinical research to investigate
- a new treatment,
- or a new indication,
- or a new population
1
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, - Post-registration clinical research → it doesn’t stop after approval
- to compare with competitors
- to evaluate the therapeutic value
- to observe safety in large population, to detect signals not picked up before
→ pharmacovigilance: needed because before approval your testing population still isn’t as
big as the real-world setting
3. WHAT ARE THE DIFFERENT TYPES OF CLINICAL TRIALS?
- Phase 0: Human Microdosing trial (mainly for oncology)
- Phase I: Human pharmacology trial
- Phase II: Therapeutic exploratory trial
- Phase III: Therapeutic con rmatory trial
- Phase IV: Therapeutic use trial
Administer the product in humans for the very rst time = phase I
Intermediate step = phase 0: single dose with very few voluntary patients (healthy) to have a quick
idea about the PK of the products = minimalistic, quick step → to decide the dose in the phase I
- Phase 0:
- Designed to speed up the development of promising drugs or imaging agents by establishing
very early on whether the drug or agent behaves in human subjects as was expected from
preclinical studies.
- Distinctive features of Phase 0 trials include the administration of single subtherapeutic
doses of the study drug to a small number of subjects to gather preliminary data on the
agent's pharmacokinetics
- No safety nor e cacy data obtained
- First-In-Human trial
- Limited number of subjects (≈10-12)
- Very limited drug exposure
- Low, supposedly non-toxic doses
- Limited duration of dosing (≈ ≤7 days)
- 1 course
- No therapeutic (or diagnostic) intent
- Conducted prior to traditional Phase 1 dose escalation, safety, and tolerance studies that
ordinarily initiate a clinical drug development program
- Can be initiated with a less extensive pre-clinical data than traditional Phase 1 trials
- Also referred to as:
- Pre-phase 1 trial
- Pilot study
- Exploratory Investigational New Drug (IND) study
- Generate data to:
- Inform subsequent development of the agent
- Enhance e ciency of subsequent development of the agent
- Increase chance of success of subsequent development of the agent
- Phase I:
- Healthy volunteers → exception: oncology (patients w/ no treatment options anymore)
- Purpose = look at safety + tolerance
- Pharmacokinetics
- Pharmacodynamics
- Duration & dose of Activity = essential info for later studies
- Phase I: 1st administration in man, biological e ect & safety evaluation in healthy man
→ most cases: in man (risk form female reproductive system)
2
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, 1. INTRODUCTION TO CLINICAL RESEARCH 1
1. How Are Medicinal Products Developed? 1
2. What Is Clinical Research? 1
3. What Are the Di erent Types of Clinical Trials? 2
4. Synopsises 4
2. GOOD CLINICAL PRACTICE (I) 5
1. Medical Research History 5
2. Declaration of Helsinki 5
3. ICH (E6 Guideline) GCP 6
4. 11 Principals of ICH-GCP 7
5. Annex 1 7
3. GOOD CLINICAL PRACTICE II 9
1. The Sponsor 9
2. Data Governance - Investigator & Sponsor 9
3. Appendices 9
4. CLINICAL TRIAL LEGISLATION 13
1. EU Clinical Trial Legislation 13
2. Belgian Clinical Trial Legislation 15
3. US Clinical Trial Legislation 16
4. Clinical Trial Databases 16
5. IMPLICATIONS GCP & REGULATIONS – AUDITS & INSPECTIONS 17
1. Audits & Inspections 17
2. Quality Assurance in Pharma R&D 17
3. Audit / Inspection Process 19
4. Audit Outcome 19
6. STUDY PARTICIPANT MANAGEMENT - ICF 23
1. Study Participant Recruitment 23
2. Informed Consent 24
7. DRUG SAFETY/PHARMACOVIGILANCE IN CLINICAL TRIALS 29
1. Legal Basis 29
2. De nition of Terms 29
3. Reporting & Databases 31
4. The Process 32
5. Post Marketing – Good Pharmacovigilance Practices (GVP) 33
8. CLINICAL RESEARCH METHODOLOGY (I) 35
1. Design and Set-Up Phase 35
2. Active Phase 38
9. CLINICAL RESEARCH METHODOLOGY (II) 41
1. Project Management Fundamentals 41
2. Project Phases 43
10. PROCESSING OF CLINICAL TRIAL RESULTS 47
1. Data Management - De nitions 47
2. Data Management Principles 47
3. Data Management Processes 48
fi ff fi
, 1. INTRODUCTION TO CLINICAL RESEARCH
1. HOW ARE MEDICINAL PRODUCTS DEVELOPED?
How does a drug come to the market?
1. Discovery: screen compounds that may become a future drug
2. Preclinical studies
3. Clinical studies
4. Apply for marketing authorisation
→ expensive, takes a long time (10 -12 years)
R&D = Research & Development
→ research = discovering the compound
→ once the compound is de ned = development stage → proof safety & e cacy
→ discovery of a new product / improvement of an existing product
Medicinal products:
- a pharmaceutical product
- an immunological product (vaccine)
- a metabolical product
- a biological compound
- a diagnostic product
- to prevent, to treat, to diagnose or to relieve (symptoms of) a disease.
- a medical device = di erent from a medicinal product (pacemaker, app for glucose,…)
→ laws about studies to prove safety
Proof safety & e cacy: work with a controlled study: compare with placebo or an existing
compound (later on in the study) → must be better than existing products
2. WHAT IS CLINICAL RESEARCH?
- Clinical trials = experiments or observations done in clinical research = prospective
(= start collecting data in the future) biomedical or behavioural research studies on human
participants → designed to answer speci c questions about biomedical or behavioural
interventions, incl new treatments (novel vaccines, drugs, dietary choices, dietary supplements,
and medical devices) & known interventions that warrant further study & comparison
→ Clinical trials generate data on safety & e cacy
- Di erence w/ normal clinical practice: highly monitored, possible risk for the patient,…
- Hypothesis testing = used to determine whether an observed treatment e ect is real or due to
chance.
- Null hypothesis (H₀) assumes no e ect
- Alternative hypothesis (H₁) assumes a di erence or treatment e ect.
- Results are evaluated using a p-value a a prede ned signi cance level (α, usually 0.05)
→ if p ≤ α, H₀ is rejected
- Con dence intervals show the size and precision of the e ect, and statistical signi cance
must always be interpreted alongside clinical relevance
- A regulatory authority will grant o cial permission to use medicinal products in a general
population, only if there is evidence about safety & e cacy
- Registration: the approval to market the new medicinal product
- Pre-registration clinical research to investigate
- a new treatment,
- or a new indication,
- or a new population
1
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, - Post-registration clinical research → it doesn’t stop after approval
- to compare with competitors
- to evaluate the therapeutic value
- to observe safety in large population, to detect signals not picked up before
→ pharmacovigilance: needed because before approval your testing population still isn’t as
big as the real-world setting
3. WHAT ARE THE DIFFERENT TYPES OF CLINICAL TRIALS?
- Phase 0: Human Microdosing trial (mainly for oncology)
- Phase I: Human pharmacology trial
- Phase II: Therapeutic exploratory trial
- Phase III: Therapeutic con rmatory trial
- Phase IV: Therapeutic use trial
Administer the product in humans for the very rst time = phase I
Intermediate step = phase 0: single dose with very few voluntary patients (healthy) to have a quick
idea about the PK of the products = minimalistic, quick step → to decide the dose in the phase I
- Phase 0:
- Designed to speed up the development of promising drugs or imaging agents by establishing
very early on whether the drug or agent behaves in human subjects as was expected from
preclinical studies.
- Distinctive features of Phase 0 trials include the administration of single subtherapeutic
doses of the study drug to a small number of subjects to gather preliminary data on the
agent's pharmacokinetics
- No safety nor e cacy data obtained
- First-In-Human trial
- Limited number of subjects (≈10-12)
- Very limited drug exposure
- Low, supposedly non-toxic doses
- Limited duration of dosing (≈ ≤7 days)
- 1 course
- No therapeutic (or diagnostic) intent
- Conducted prior to traditional Phase 1 dose escalation, safety, and tolerance studies that
ordinarily initiate a clinical drug development program
- Can be initiated with a less extensive pre-clinical data than traditional Phase 1 trials
- Also referred to as:
- Pre-phase 1 trial
- Pilot study
- Exploratory Investigational New Drug (IND) study
- Generate data to:
- Inform subsequent development of the agent
- Enhance e ciency of subsequent development of the agent
- Increase chance of success of subsequent development of the agent
- Phase I:
- Healthy volunteers → exception: oncology (patients w/ no treatment options anymore)
- Purpose = look at safety + tolerance
- Pharmacokinetics
- Pharmacodynamics
- Duration & dose of Activity = essential info for later studies
- Phase I: 1st administration in man, biological e ect & safety evaluation in healthy man
→ most cases: in man (risk form female reproductive system)
2
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