CLINICAL DRUG RESEARCH
INHOUDSOPGAVE
Introduction ................................................................................................................................. 4
Good Clinical Practice .................................................................................................................. 4
Introduction to ICH-GCP ..................................................................................................................4
Legislation for clinical research ...................................................................................................... 10
Terminology on pharmacovigilance ................................................................................................. 11
Definition of clinical research ......................................................................................................... 13
Eleven principles of ICH-GCP E6(R6)............................................................................................... 15
The role of IRB’s and IEC’s .............................................................................................................. 21
How to obtain an informed consent? ............................................................................................... 23
Quality management of clinical research ........................................................................................ 24
Translation of ICH-GCP principles into documents related to clinical research ................................. 25
Study protocol ............................................................................................................................... 25
Log forms ...................................................................................................................................... 27
Case report forms (CRF) ................................................................................................................. 30
Investigator’s brochure .................................................................................................................. 30
Other relevant documents.............................................................................................................. 31
Responsibilities of the sponsor ....................................................................................................... 32
Responsibilities of the CRO ............................................................................................................ 33
Responsibilities of CRA/CTA ........................................................................................................... 33
Responsibilities of Clinical Data Management (Sponsor) .................................................................. 34
Responsibilities of the (principal) investigator .................................................................................. 36
Involvement of study coordinator and/or study nurse team (investigator team) .................................. 37
Mutual responsibilities between sponsor and investigator ................................................................ 38
Skills involved in clinical research ................................................................................................... 39
Essential documents within trial master file (TMF) and investigator site file (ISF) ................................ 41
ISO 14155 – clinical investigation of medical devices for human subjects .......................................... 43
GDPR & clinical research ............................................................................................................... 46
Ethics committees ......................................................................................................................48
General principles ......................................................................................................................... 48
What? ........................................................................................................................................... 49
1
, Why? ............................................................................................................................................ 51
ICH-GCP guidelines ....................................................................................................................... 53
Belgian legislation .......................................................................................................................... 54
European regulation of clinical trials ............................................................................................... 56
Take away messages ..................................................................................................................... 57
Start & conduct of a clinical trial ..................................................................................................58
Definitions ..................................................................................................................................... 58
Drug development ......................................................................................................................... 59
Main players .................................................................................................................................. 60
Required material .......................................................................................................................... 63
Set-up and conduct of a clinical trial ............................................................................................... 67
Clinical trial start-up .................................................................................................................. 67
Site visits .................................................................................................................................. 69
Non-compliance and safety reporting ............................................................................................. 72
Involved parties: roles and responsibilities ...................................................................................... 79
Career in clinical research.............................................................................................................. 81
Study design & protocol ...............................................................................................................82
Introduction / background .............................................................................................................. 82
Study design .................................................................................................................................. 82
Study protocol ............................................................................................................................... 87
History pharmaceutical industry ..................................................................................................... 92
Study execution ............................................................................................................................. 94
Data analysis, report and publication .............................................................................................. 99
Conclusion.................................................................................................................................. 103
Device studies & application procedures .................................................................................... 105
Quality in clinical research ........................................................................................................ 115
Introduction ................................................................................................................................ 115
Regulatory ................................................................................................................................... 116
QA/QC ........................................................................................................................................ 118
How can regulations help? ........................................................................................................... 121
Examples .................................................................................................................................... 122
Vaccine trials ............................................................................................................................ 124
Preclinical development .............................................................................................................. 125
Clinical trials ............................................................................................................................... 128
2
, Controlled human infection models (CHIM) .................................................................................. 131
Vulnerable populations ................................................................................................................ 136
Health economics ..................................................................................................................... 146
Health production & health care expenditures ............................................................................... 146
Economic evaluation ................................................................................................................... 149
Policy .......................................................................................................................................... 155
The placebo effect ..................................................................................................................... 163
Statistics in clinical trials........................................................................................................... 175
Regulatory agencies ..................................................................................................................... 175
Scope ..................................................................................................................................... 175
Legislation making organisations .............................................................................................. 177
EU ...................................................................................................................................... 177
National .............................................................................................................................. 180
Regulatory agencies ................................................................................................................ 181
European Medicines Agency (EMA) ....................................................................................... 181
Federal Agency of Medicines and Health Products (FAMHP) .................................................. 185
Heads of Medicine Agencies (HMA) ...................................................................................... 190
Role of agencies in regulatory procedure .................................................................................. 190
Shortly situating EDQM ............................................................................................................ 204
Statistics ..................................................................................................................................... 205
Examenvragen 2025-2026........................................................................................................... 215
3
,INTRODUCTION
• Exam
o Written
o Open & MCQ
• Optional: GCP certificate
o Obtain an ICH-GCP E6(R3) certificate (valid for 3 years), which is needed
to work in a clinical environment (e.g. master thesis)
o For interested students: mail to &
→ deadline: 27/03/202
GOOD CLINICAL PRACTICE
INTRODUCTION TO ICH-GCP
• GCP certificaat
o Every 3 years
o Minimally 80%
• Obligated to apply
• Example exam questions
o The ICH-GCP Good Clinical Practice Guideline of the internatural Counci
Harmonisation of technical requirements for pharmaceuticals for human
use can be retrieved within the
▪ Efficacy guidelines
▪ Multidisciplinary guidelines
▪ Quality guidelines
▪ Safety guidelines
o The purpose of the ICH-GCP Good Clinical Practice ICH-GCP E6R3
guideline is to provide a unified standard for
▪ All member countries of the World Health Organization (WHO)
▪ Countries within the United States of America (USA) and the
European Union (EU)
▪ Japan and the countries within the United States of America (USA)
and the European Union (EU)
▪ Brazil, Canada, China, Chinese Taipei, Japan, Singapore,
Switzerland, the United Kingdom (UK) and the countries within
the United States of America (USA) and the European Union
(EU)
4
, o One of the consequences of NOT respecting the ICH-GCP E6R3 guideline
can be...
▪ Validity of data processing
▪ Reliability of data collection
▪ Exposure to an increased risk for participants of a clinical trial
▪ Respecting of the rights of participants of a clinical trial
• Introduction
o ICH = International Council for Harmonisation of technical requirements
for pharmaceuticals for human use
▪ Regulatory authorities
▪ Pharmaceutical Industry
▪ Discuss scientific and technical aspects of drug registration
o GCP = Good Clinical Practice
o Extrapolation
▪ Application of ICH-GCP guideline is possible to other clinical
investigations that may have an impact on the safety and (physical
and mental) well-being of human subjects
• Objective of ICH-GHP Goof Clinical Practice
o Unified standards for EU, Japan, USA, Switzerland, Canada
o Facilitate mutual acceptance of clinical (experimental) data by the
regulatory authorities in these jurisdictions
o ICH-GCP E6 (R3) approved on Monday January 6th, 2025
▪ (Consultation: Brazil, EU, USA, Singapore, Canada, Japan, UK,
China, Switzerland, Chinese Taipei)
• Need for harmonization
o It is important to have an independent evaluation of medicinal products
before they are allowed on the market
o Realisation at different times in different regions throughout the world
(however, mostly tragedy-driven)
• Elixir sulfanilamide tragedy
o 1937: S.E. Massengill Company created a preparation of sulfanilamide
using diethylene glycol (DEG) as a solvent and called it “Elixir
Sulfanilamide”
▪ First case of fatality from DEG occurred in 1930 and studies were
published in medical journals stating DEG could cause kidney
damage/failure, resulting in death
▪ DEG toxicity, however, was not widely known and as a result
Harold Watkins (chief pharmacist/ chemist of S.E. Massengill
Company) was not aware of the DEG toxicity described, and added
raspberry flavor to the sulfanilamide drug dissolved in DEG
5
, ▪ Animal testing, although routine in most drug company operations,
was not performed at S.E. Massengill Company (no regulations
requiring premarket safety testing of new drugs)
o September 1937: commercialisation of Elixir sulfanilamide
o October 11th, 1937: the American Medical Association received a report
of several deaths
o Food and Drug Administration (FDA) was notified, and an extensive search
was conducted to recover the distributed medicine, while investigations
had learned that DEG was responsible for the fatal adverse effects (over
100 deaths)
o Letter of a woman to president Theodore Roosevelt describing the death
of her daughter
o Only laws at this time
▪ Pure Food and Drug Act (you can market medicine if it’s correctly
described)
Firm got a fine because “there is no alcohol in the drug”, but
DEG is an alcohol so wrongly described
Diethyleenglycol is now used as anti-freeze, but was used
to make a syrup of the powder/pill
Elixir could only be used for products containing ethylene
glycol (drinking alcohol) so FDA could only give a fine based
on this regulation, otherwise they could just continue and
more people could die
▪ Harrison Narcotics Taks Act
• Nuremberg trial
o August 20th, 1947: Verdict of the judges in the “Doctor’s trial” against Karl
Brandt and 22 others:
▪ These trials trials focused on doctors involved in human
experiments in concentration camps
▪ Suspects were involved in over 3,500,000 sterilisations
▪ Trials had begun on December 9th, 1946 in Nuremberg (Germany)
and were led exclusively by the United States
▪ Most of the suspects escaped punishment for their crimes
▪ Several of the accussed argued that their experiments differed
little from pre-war experiments and that there was no law that
differentiated between legal and illegal experiments
o 10 ethical principles for scientific research (Nuremberg code)
▪ 1. Voluntary consent of the human subject is absolutely essential
▪ 2. Experiment should be such as to yield fruitful results for the
good of society
6
, ▪ 3. The experiments should be so designed and based on the results
of animal experimentation and a knowledge of the natural history
of the disease or other problem under study that the anticipated
results will justify the performance of the experiment
▪ 4. The experiment should be so conducted as to avoid all
unnecessary physical and mental suffering and injury
▪ 5. Experiment should not be conducted where there is a prior
reason to believe that death or disabling injury will occur; except
in those experiments where experimental physicians also serve as
subjects (so you can if you’re willing to participate yourself)
▪ 6. The degree of risk to be taken should never exceed that
determined by the humanitarian importance of the problem to be
solved by the experiment
▪ 7. Proper preparations should be made and adequate facilities
provided to protect the experimental subject against even
remote possibilities of injury, disability, or death
▪ 8. The experiment should be conducted only by scientifically
qualified persons
▪ 9. During the course of the experiment the human subject should
be at liberty to bring the experiment to an end if he has reached
the physical or mental state where continuation of the experiment
seems to him to be impossible
▪ 10. During the course of the experiment the scientist in charge
must be prepared to terminate the experiment at any stage
• Thalidomide scandal
o Thalidomide is an immunomodulatory drug and the prototype of the
thalidomide class of drugs
▪ First marketed in 1957 in West Germany, developed and sold by
the German drug company Chemie Grünenthal (Contergan)
▪ Primarily prescribed as a sedative or hypnotic, thalidomide also
claimed to cure anxiety, insomnia, gastritis and tension
▪ Afterwards, it was used against nausea and to alleviate morning
sickness in pregnant women and it became an over-the-counter
drug in Germany on October 1st, 1957
Over-the-counter = you can get it without prescription
▪ Shortly after the drug was sold in Germany, between 5,000 and
7,000 infants were born with phocomelia (malformation of limbs):
only 40 % of these children survived
▪ Only tested for effects on mom, not on possible child effects
o After this only prescription for the right indications, only for indications for
which the drug has been approved
7
, o In the USA they didn’t approve the drug because of signs of nerve damage
after long-term thalidomide use
o In some regions thalidomide is still used in pregnant women, especially
South-America, because they don’t have GCP and are not obligated to
check results from other countries
o The negative effects of thalidomide have led to the development of more
structured drug regulations and control over drugs use and development
▪ Throughout the world, about 10,000 cases were reported of
thalidomide-induced phocomelia, of which only approximately
50% survived (estimation of 17 cases in the USA from use of
Thalidomide in clinical trials before FDA disapproved the use of
Thalidomide)
▪ Today, thalidomide is still being marketed by Celgene, mainly as
treatment of:
Certain cancers (multiple myeloma)
Complications of leprosy
• Declaration of Helsinki
o Adopted by the 18th World Medical Association (WMA) General Assembly
(Helsinki, June 1964) and amended several times since (@ October 2024)
o Statement of ethical principles for medical research involving human
subjects, including research on identifiable human material and data
o Addressed primarily to physicians but encouraged to be adopted by
others involved in medical research involving human subjects
o General ethical principles
o Risks, burdens and benefits
o Vulnerable groups and individuals
o Scientific requirements and research protocols
o Research ethics committees
o Privacy and confidentiality
o Informed consent
o Use of placebo
o Post-trial provisions
o Research registration, publication and dissemination of results
o Unproven interventions in clinical practice
• History of ICP-GCP
o 1937 Sulfanilamide Elvir tragedy
o 1938 USA Food, Drug and Cosmetic Act
o 1940-1947 Experiments WWII and Nuremberg Trial
o 1947 Nuremberg Code
o 1957-1961 Thalidomide-induced phocomelia scandal
o 1964 Declaration of Helsinki
8
, o 1996 ICH-GCP E6 (R1) Guideline
▪ Description of responsibilities and expectations of all stakeholders
in the conduct of clinical trials
▪ ICH-GCP covers aspects of monitoring, reporting and archiving of
clinical trials
▪ Addenda for essential documents and investigator brochures
o 1997-2001 International legislation regarding ICH-GCP
o 2016 ICH-GCP E6 (R2) Guideline
▪ Addendum to encourage implementation of improved and more
efficient approaches, while continuing to ensure human subject
protections
▪ Updated standars for electronic records
o 2025 ICH-GCP E6 (R3) Guideline (approved)
▪ To develop a responsive ICH-GCP Guideline
▪ Provide flexibility
Acknowledge the diversity of trial designs, data sources,
and the different contexts in which clinical trials can be
conducted
Highlight that ICH-GCP principles can be satisfied in a
variety of ways
▪ Alignment with ICH E8 (R1) chapter
▪ Annexes
Annex 1 on interventional clinical trials
Annex 2 on non-traditional interventional clinical trials
• Motivation for harmonization
o Concerns over rising costs of healthcare
o Escalation of costs for research and development (R&D)
o Need to meet public expectation that there should be a minimum delay in
making safe and efficacious new treatments available to patients in need
• Why clinical research needs to be regulated?
o To ensure
▪ Proper protection of study subjects
▪ Studies to be based on good scientific principles including a well-
designed study protocol and proper statistical analysis of data
▪ Study procedures to be properly undertaken and documented
o Legal framework
▪ Nuremberg Code (1947): First international standard to protect
patients
▪ Declaration of Helsinki (1964, last revision 2024): Ethical standard
▪ ICH-GCP Guideline (1996, addenda 2016 & 2025): Worldwide
harmonization
9
, ▪ Local initiatives to implement ICH-GCP within national legislation
(1997-2001) within USA, Europe and Japan
o Survey results (2012) (The Netherlands)
▪ Organiser survery: Medisch Contact Magazine for Dutch MD’s
▪ 800 participants (general practicioners, medical specialists)
o Claims of experiences
▪ 15 % scientific results were made up
▪ 22 % scientific results were enhanced statistically (significance)
▪ 36 % co-authors are added without any contribution
• ICH-GCP Good Clinical Practice
o A standard for all aspects of clinical trials (design, conduct, performance,
monitoring, auditing, recording, analyses, reporting) that provides
assurance that the:
▪ Data and reported results are credible and accurate
▪ Rights, integrity and confidentiality of clinical trial subjects are
protected
o Origin of ICH-GCP Good Clinical Practice dates back to 1996 → clinical
trials have evolved substantially, with increases in globalisation, study
complexity, and technological capabilities
o ICH-GCP should be modernised to enable implementation of innovative
approaches to clinical trial design, management, oversight, conduct,
documentation, and reporting that will better ensure human subject
protection and data quality
o Facilitation of broad and consistent international implementation of new
methodologies
LEGISLATION FOR CLINICAL RESEARCH
• European legislation for clinical research
o Based on the principles of the Declaration of Helsinki (1964)
o Clinical Trials Regulation EU 536/2014 on clinical trials on medicinal
products for human use (published in May 2014)
➜ Regulation (EU) 2022/641 amending Regulation EU 536/2014
(published in April 2022)
o Commission Directive 2005/28/EC laying down principles and detailed
guidelines for good clinical practice as regards investigational medicinal
products for human use, as well as the requirements for authorization of
the manufacturing or importation of such products
o Commission Directive 2003/94/EC laying down the principles and
guidelines for good manufacturing practice in respect of medicinal
products for human use and investigational medicinal products for
human use
10
INHOUDSOPGAVE
Introduction ................................................................................................................................. 4
Good Clinical Practice .................................................................................................................. 4
Introduction to ICH-GCP ..................................................................................................................4
Legislation for clinical research ...................................................................................................... 10
Terminology on pharmacovigilance ................................................................................................. 11
Definition of clinical research ......................................................................................................... 13
Eleven principles of ICH-GCP E6(R6)............................................................................................... 15
The role of IRB’s and IEC’s .............................................................................................................. 21
How to obtain an informed consent? ............................................................................................... 23
Quality management of clinical research ........................................................................................ 24
Translation of ICH-GCP principles into documents related to clinical research ................................. 25
Study protocol ............................................................................................................................... 25
Log forms ...................................................................................................................................... 27
Case report forms (CRF) ................................................................................................................. 30
Investigator’s brochure .................................................................................................................. 30
Other relevant documents.............................................................................................................. 31
Responsibilities of the sponsor ....................................................................................................... 32
Responsibilities of the CRO ............................................................................................................ 33
Responsibilities of CRA/CTA ........................................................................................................... 33
Responsibilities of Clinical Data Management (Sponsor) .................................................................. 34
Responsibilities of the (principal) investigator .................................................................................. 36
Involvement of study coordinator and/or study nurse team (investigator team) .................................. 37
Mutual responsibilities between sponsor and investigator ................................................................ 38
Skills involved in clinical research ................................................................................................... 39
Essential documents within trial master file (TMF) and investigator site file (ISF) ................................ 41
ISO 14155 – clinical investigation of medical devices for human subjects .......................................... 43
GDPR & clinical research ............................................................................................................... 46
Ethics committees ......................................................................................................................48
General principles ......................................................................................................................... 48
What? ........................................................................................................................................... 49
1
, Why? ............................................................................................................................................ 51
ICH-GCP guidelines ....................................................................................................................... 53
Belgian legislation .......................................................................................................................... 54
European regulation of clinical trials ............................................................................................... 56
Take away messages ..................................................................................................................... 57
Start & conduct of a clinical trial ..................................................................................................58
Definitions ..................................................................................................................................... 58
Drug development ......................................................................................................................... 59
Main players .................................................................................................................................. 60
Required material .......................................................................................................................... 63
Set-up and conduct of a clinical trial ............................................................................................... 67
Clinical trial start-up .................................................................................................................. 67
Site visits .................................................................................................................................. 69
Non-compliance and safety reporting ............................................................................................. 72
Involved parties: roles and responsibilities ...................................................................................... 79
Career in clinical research.............................................................................................................. 81
Study design & protocol ...............................................................................................................82
Introduction / background .............................................................................................................. 82
Study design .................................................................................................................................. 82
Study protocol ............................................................................................................................... 87
History pharmaceutical industry ..................................................................................................... 92
Study execution ............................................................................................................................. 94
Data analysis, report and publication .............................................................................................. 99
Conclusion.................................................................................................................................. 103
Device studies & application procedures .................................................................................... 105
Quality in clinical research ........................................................................................................ 115
Introduction ................................................................................................................................ 115
Regulatory ................................................................................................................................... 116
QA/QC ........................................................................................................................................ 118
How can regulations help? ........................................................................................................... 121
Examples .................................................................................................................................... 122
Vaccine trials ............................................................................................................................ 124
Preclinical development .............................................................................................................. 125
Clinical trials ............................................................................................................................... 128
2
, Controlled human infection models (CHIM) .................................................................................. 131
Vulnerable populations ................................................................................................................ 136
Health economics ..................................................................................................................... 146
Health production & health care expenditures ............................................................................... 146
Economic evaluation ................................................................................................................... 149
Policy .......................................................................................................................................... 155
The placebo effect ..................................................................................................................... 163
Statistics in clinical trials........................................................................................................... 175
Regulatory agencies ..................................................................................................................... 175
Scope ..................................................................................................................................... 175
Legislation making organisations .............................................................................................. 177
EU ...................................................................................................................................... 177
National .............................................................................................................................. 180
Regulatory agencies ................................................................................................................ 181
European Medicines Agency (EMA) ....................................................................................... 181
Federal Agency of Medicines and Health Products (FAMHP) .................................................. 185
Heads of Medicine Agencies (HMA) ...................................................................................... 190
Role of agencies in regulatory procedure .................................................................................. 190
Shortly situating EDQM ............................................................................................................ 204
Statistics ..................................................................................................................................... 205
Examenvragen 2025-2026........................................................................................................... 215
3
,INTRODUCTION
• Exam
o Written
o Open & MCQ
• Optional: GCP certificate
o Obtain an ICH-GCP E6(R3) certificate (valid for 3 years), which is needed
to work in a clinical environment (e.g. master thesis)
o For interested students: mail to &
→ deadline: 27/03/202
GOOD CLINICAL PRACTICE
INTRODUCTION TO ICH-GCP
• GCP certificaat
o Every 3 years
o Minimally 80%
• Obligated to apply
• Example exam questions
o The ICH-GCP Good Clinical Practice Guideline of the internatural Counci
Harmonisation of technical requirements for pharmaceuticals for human
use can be retrieved within the
▪ Efficacy guidelines
▪ Multidisciplinary guidelines
▪ Quality guidelines
▪ Safety guidelines
o The purpose of the ICH-GCP Good Clinical Practice ICH-GCP E6R3
guideline is to provide a unified standard for
▪ All member countries of the World Health Organization (WHO)
▪ Countries within the United States of America (USA) and the
European Union (EU)
▪ Japan and the countries within the United States of America (USA)
and the European Union (EU)
▪ Brazil, Canada, China, Chinese Taipei, Japan, Singapore,
Switzerland, the United Kingdom (UK) and the countries within
the United States of America (USA) and the European Union
(EU)
4
, o One of the consequences of NOT respecting the ICH-GCP E6R3 guideline
can be...
▪ Validity of data processing
▪ Reliability of data collection
▪ Exposure to an increased risk for participants of a clinical trial
▪ Respecting of the rights of participants of a clinical trial
• Introduction
o ICH = International Council for Harmonisation of technical requirements
for pharmaceuticals for human use
▪ Regulatory authorities
▪ Pharmaceutical Industry
▪ Discuss scientific and technical aspects of drug registration
o GCP = Good Clinical Practice
o Extrapolation
▪ Application of ICH-GCP guideline is possible to other clinical
investigations that may have an impact on the safety and (physical
and mental) well-being of human subjects
• Objective of ICH-GHP Goof Clinical Practice
o Unified standards for EU, Japan, USA, Switzerland, Canada
o Facilitate mutual acceptance of clinical (experimental) data by the
regulatory authorities in these jurisdictions
o ICH-GCP E6 (R3) approved on Monday January 6th, 2025
▪ (Consultation: Brazil, EU, USA, Singapore, Canada, Japan, UK,
China, Switzerland, Chinese Taipei)
• Need for harmonization
o It is important to have an independent evaluation of medicinal products
before they are allowed on the market
o Realisation at different times in different regions throughout the world
(however, mostly tragedy-driven)
• Elixir sulfanilamide tragedy
o 1937: S.E. Massengill Company created a preparation of sulfanilamide
using diethylene glycol (DEG) as a solvent and called it “Elixir
Sulfanilamide”
▪ First case of fatality from DEG occurred in 1930 and studies were
published in medical journals stating DEG could cause kidney
damage/failure, resulting in death
▪ DEG toxicity, however, was not widely known and as a result
Harold Watkins (chief pharmacist/ chemist of S.E. Massengill
Company) was not aware of the DEG toxicity described, and added
raspberry flavor to the sulfanilamide drug dissolved in DEG
5
, ▪ Animal testing, although routine in most drug company operations,
was not performed at S.E. Massengill Company (no regulations
requiring premarket safety testing of new drugs)
o September 1937: commercialisation of Elixir sulfanilamide
o October 11th, 1937: the American Medical Association received a report
of several deaths
o Food and Drug Administration (FDA) was notified, and an extensive search
was conducted to recover the distributed medicine, while investigations
had learned that DEG was responsible for the fatal adverse effects (over
100 deaths)
o Letter of a woman to president Theodore Roosevelt describing the death
of her daughter
o Only laws at this time
▪ Pure Food and Drug Act (you can market medicine if it’s correctly
described)
Firm got a fine because “there is no alcohol in the drug”, but
DEG is an alcohol so wrongly described
Diethyleenglycol is now used as anti-freeze, but was used
to make a syrup of the powder/pill
Elixir could only be used for products containing ethylene
glycol (drinking alcohol) so FDA could only give a fine based
on this regulation, otherwise they could just continue and
more people could die
▪ Harrison Narcotics Taks Act
• Nuremberg trial
o August 20th, 1947: Verdict of the judges in the “Doctor’s trial” against Karl
Brandt and 22 others:
▪ These trials trials focused on doctors involved in human
experiments in concentration camps
▪ Suspects were involved in over 3,500,000 sterilisations
▪ Trials had begun on December 9th, 1946 in Nuremberg (Germany)
and were led exclusively by the United States
▪ Most of the suspects escaped punishment for their crimes
▪ Several of the accussed argued that their experiments differed
little from pre-war experiments and that there was no law that
differentiated between legal and illegal experiments
o 10 ethical principles for scientific research (Nuremberg code)
▪ 1. Voluntary consent of the human subject is absolutely essential
▪ 2. Experiment should be such as to yield fruitful results for the
good of society
6
, ▪ 3. The experiments should be so designed and based on the results
of animal experimentation and a knowledge of the natural history
of the disease or other problem under study that the anticipated
results will justify the performance of the experiment
▪ 4. The experiment should be so conducted as to avoid all
unnecessary physical and mental suffering and injury
▪ 5. Experiment should not be conducted where there is a prior
reason to believe that death or disabling injury will occur; except
in those experiments where experimental physicians also serve as
subjects (so you can if you’re willing to participate yourself)
▪ 6. The degree of risk to be taken should never exceed that
determined by the humanitarian importance of the problem to be
solved by the experiment
▪ 7. Proper preparations should be made and adequate facilities
provided to protect the experimental subject against even
remote possibilities of injury, disability, or death
▪ 8. The experiment should be conducted only by scientifically
qualified persons
▪ 9. During the course of the experiment the human subject should
be at liberty to bring the experiment to an end if he has reached
the physical or mental state where continuation of the experiment
seems to him to be impossible
▪ 10. During the course of the experiment the scientist in charge
must be prepared to terminate the experiment at any stage
• Thalidomide scandal
o Thalidomide is an immunomodulatory drug and the prototype of the
thalidomide class of drugs
▪ First marketed in 1957 in West Germany, developed and sold by
the German drug company Chemie Grünenthal (Contergan)
▪ Primarily prescribed as a sedative or hypnotic, thalidomide also
claimed to cure anxiety, insomnia, gastritis and tension
▪ Afterwards, it was used against nausea and to alleviate morning
sickness in pregnant women and it became an over-the-counter
drug in Germany on October 1st, 1957
Over-the-counter = you can get it without prescription
▪ Shortly after the drug was sold in Germany, between 5,000 and
7,000 infants were born with phocomelia (malformation of limbs):
only 40 % of these children survived
▪ Only tested for effects on mom, not on possible child effects
o After this only prescription for the right indications, only for indications for
which the drug has been approved
7
, o In the USA they didn’t approve the drug because of signs of nerve damage
after long-term thalidomide use
o In some regions thalidomide is still used in pregnant women, especially
South-America, because they don’t have GCP and are not obligated to
check results from other countries
o The negative effects of thalidomide have led to the development of more
structured drug regulations and control over drugs use and development
▪ Throughout the world, about 10,000 cases were reported of
thalidomide-induced phocomelia, of which only approximately
50% survived (estimation of 17 cases in the USA from use of
Thalidomide in clinical trials before FDA disapproved the use of
Thalidomide)
▪ Today, thalidomide is still being marketed by Celgene, mainly as
treatment of:
Certain cancers (multiple myeloma)
Complications of leprosy
• Declaration of Helsinki
o Adopted by the 18th World Medical Association (WMA) General Assembly
(Helsinki, June 1964) and amended several times since (@ October 2024)
o Statement of ethical principles for medical research involving human
subjects, including research on identifiable human material and data
o Addressed primarily to physicians but encouraged to be adopted by
others involved in medical research involving human subjects
o General ethical principles
o Risks, burdens and benefits
o Vulnerable groups and individuals
o Scientific requirements and research protocols
o Research ethics committees
o Privacy and confidentiality
o Informed consent
o Use of placebo
o Post-trial provisions
o Research registration, publication and dissemination of results
o Unproven interventions in clinical practice
• History of ICP-GCP
o 1937 Sulfanilamide Elvir tragedy
o 1938 USA Food, Drug and Cosmetic Act
o 1940-1947 Experiments WWII and Nuremberg Trial
o 1947 Nuremberg Code
o 1957-1961 Thalidomide-induced phocomelia scandal
o 1964 Declaration of Helsinki
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, o 1996 ICH-GCP E6 (R1) Guideline
▪ Description of responsibilities and expectations of all stakeholders
in the conduct of clinical trials
▪ ICH-GCP covers aspects of monitoring, reporting and archiving of
clinical trials
▪ Addenda for essential documents and investigator brochures
o 1997-2001 International legislation regarding ICH-GCP
o 2016 ICH-GCP E6 (R2) Guideline
▪ Addendum to encourage implementation of improved and more
efficient approaches, while continuing to ensure human subject
protections
▪ Updated standars for electronic records
o 2025 ICH-GCP E6 (R3) Guideline (approved)
▪ To develop a responsive ICH-GCP Guideline
▪ Provide flexibility
Acknowledge the diversity of trial designs, data sources,
and the different contexts in which clinical trials can be
conducted
Highlight that ICH-GCP principles can be satisfied in a
variety of ways
▪ Alignment with ICH E8 (R1) chapter
▪ Annexes
Annex 1 on interventional clinical trials
Annex 2 on non-traditional interventional clinical trials
• Motivation for harmonization
o Concerns over rising costs of healthcare
o Escalation of costs for research and development (R&D)
o Need to meet public expectation that there should be a minimum delay in
making safe and efficacious new treatments available to patients in need
• Why clinical research needs to be regulated?
o To ensure
▪ Proper protection of study subjects
▪ Studies to be based on good scientific principles including a well-
designed study protocol and proper statistical analysis of data
▪ Study procedures to be properly undertaken and documented
o Legal framework
▪ Nuremberg Code (1947): First international standard to protect
patients
▪ Declaration of Helsinki (1964, last revision 2024): Ethical standard
▪ ICH-GCP Guideline (1996, addenda 2016 & 2025): Worldwide
harmonization
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, ▪ Local initiatives to implement ICH-GCP within national legislation
(1997-2001) within USA, Europe and Japan
o Survey results (2012) (The Netherlands)
▪ Organiser survery: Medisch Contact Magazine for Dutch MD’s
▪ 800 participants (general practicioners, medical specialists)
o Claims of experiences
▪ 15 % scientific results were made up
▪ 22 % scientific results were enhanced statistically (significance)
▪ 36 % co-authors are added without any contribution
• ICH-GCP Good Clinical Practice
o A standard for all aspects of clinical trials (design, conduct, performance,
monitoring, auditing, recording, analyses, reporting) that provides
assurance that the:
▪ Data and reported results are credible and accurate
▪ Rights, integrity and confidentiality of clinical trial subjects are
protected
o Origin of ICH-GCP Good Clinical Practice dates back to 1996 → clinical
trials have evolved substantially, with increases in globalisation, study
complexity, and technological capabilities
o ICH-GCP should be modernised to enable implementation of innovative
approaches to clinical trial design, management, oversight, conduct,
documentation, and reporting that will better ensure human subject
protection and data quality
o Facilitation of broad and consistent international implementation of new
methodologies
LEGISLATION FOR CLINICAL RESEARCH
• European legislation for clinical research
o Based on the principles of the Declaration of Helsinki (1964)
o Clinical Trials Regulation EU 536/2014 on clinical trials on medicinal
products for human use (published in May 2014)
➜ Regulation (EU) 2022/641 amending Regulation EU 536/2014
(published in April 2022)
o Commission Directive 2005/28/EC laying down principles and detailed
guidelines for good clinical practice as regards investigational medicinal
products for human use, as well as the requirements for authorization of
the manufacturing or importation of such products
o Commission Directive 2003/94/EC laying down the principles and
guidelines for good manufacturing practice in respect of medicinal
products for human use and investigational medicinal products for
human use
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