2023 - 2024
CLINICAL DRUG RESEARCH
Biomedische wetenschappen
Anke Clerbout
0
,Inhoudsopgave
Chapter 1: ICH – GCP E6(R3) Good Clinical Prac<ce.......................................................................................... 1
1. History of GCP ........................................................................................................................................... 1
2. Legisla5on ................................................................................................................................................. 4
3. Pharmacovigilance .................................................................................................................................... 4
4. Clinical research ........................................................................................................................................ 5
5. GCP principles ........................................................................................................................................... 6
6. Ethics commiAee ..................................................................................................................................... 11
7. Informed consent .................................................................................................................................... 11
8. Quality..................................................................................................................................................... 12
9. Study protocol ......................................................................................................................................... 13
10. Study documents ................................................................................................................................ 13
11. Roles ................................................................................................................................................... 15
12. ISO/CD 14155 ..................................................................................................................................... 16
13. Exam ques5ons................................................................................................................................... 17
Chapter 2: The role of the Ethics CommiCee................................................................................................. 23
1. General principles ................................................................................................................................... 23
2. What is an ethics commiAee? ................................................................................................................. 23
3. Why ethics commiAees? ......................................................................................................................... 24
4. ICH-GCP Guidelines ................................................................................................................................. 26
5. Belgian Legisla5on .................................................................................................................................. 27
6. European Regula5on on clinical studies .................................................................................................. 28
7. Summary ................................................................................................................................................. 29
8. Examples of exam ques5ons ................................................................................................................... 30
Chapter 3: The Placebo-effect in clinical trials ............................................................................................... 31
1. Defini5ons ............................................................................................................................................... 31
2. Placebo – RCT – Double Blind .................................................................................................................. 32
3. From decoy to powerful to powerless ..................................................................................................... 32
4. How long does a placebo work? Placebo and OA ................................................................................... 33
5. Placebo: different components ............................................................................................................... 33
6. Special Placebo’s ..................................................................................................................................... 34
7. Nocebo (vaccines) ................................................................................................................................... 34
8. How does it work? The pharmacology of the placebo effect .................................................................. 34
9. How do you improve/enhance a placebo ................................................................................................ 35
10. Compliance to Placebo and ….. mortality ........................................................................................... 35
11. Ethics: placebo in the RCT!? Placebo in the “real world”? .................................................................. 35
1
, 12. Placebo its proper5es and the interpreta5on of the RCT ................................................................... 36
13. Effect of placebo on drop-out rate in RCT ........................................................................................... 36
14. Conclusion & why does it work? ......................................................................................................... 36
Chapter 4: Role, tasks, and responsibili<es of the main players ..................................................................... 37
1. Clinical research – Defini5ons ................................................................................................................. 37
2. Clinical research – Main players.............................................................................................................. 38
3. Set-up and conduct of a clinical trial – material requirements sponsor and inves5gator. ...................... 40
4. Set-up and conduct of a clinical trial. ...................................................................................................... 41
5. Clinical trial start-up ................................................................................................................................ 41
6. Monitoring visit ....................................................................................................................................... 43
7. Clinical trial closure ................................................................................................................................. 44
8. Safety repor5ng. ..................................................................................................................................... 45
9. Persons involved in a clinical trial and responsibili5es. ........................................................................... 46
Chapter 5: Quality in clinical research ........................................................................................................... 49
1. A few defini5ons ................................................................................................................................. 49
2. Clinical trial ethics, regula5ons, and quality ........................................................................................... 51
3. Avoid unethical behaviors ....................................................................................................................... 52
4. Quality management in clinical trials in detail ........................................................................................ 55
5. How can regula5ons help? ...................................................................................................................... 59
6. In prac5ce ............................................................................................................................................... 59
Chapter 6: European and federal regulatory agencies.................................................................................... 61
1. Scope ....................................................................................................................................................... 61
2. Legisla5on making organiza5ons – EU ................................................................................................... 62
3. Legisla5on making organiza5ons – Belgium........................................................................................... 63
4. Regulatory agencies – European Medicines Agency ............................................................................... 63
5. Regulatory agencies – Federal agency of medicines and health products .............................................. 64
6. Regulatory agencies – Heads of medicine agencies ................................................................................ 65
7. Role of agencies in regulatory procedures .............................................................................................. 65
8. Shortly situa5ng EDQM ........................................................................................................................... 72
Chapter 7: Medical device studies and applica<ons procedures .................................................................... 73
1. How place qualita5ve devices onto the market ...................................................................................... 73
2. Two primary guidelines for medical device manufacturer’s QMS ........................................................... 74
3. ISO 13485 versus ISO 9001 ...................................................................................................................... 75
4. Risk management – What is risk? ........................................................................................................... 75
5. What is a medical device? ....................................................................................................................... 75
6. Special types of medical devices ............................................................................................................. 76
7. MDD/MDD-IVD à MDR/MDR-IVDR ....................................................................................................... 76
2
, 8. 3 types of medical devices....................................................................................................................... 77
9. Competent authority vs no5fied body. .................................................................................................... 77
10. EU CE mark process vs US FDA approval process ............................................................................... 78
11. Medical device classes in EU – 4 classes based on 22 rules. ............................................................... 78
12. Medical device development life cycle ............................................................................................... 79
13. Design control .................................................................................................................................... 79
14. Traceability ......................................................................................................................................... 79
15. Market approval in EU – CE marking.................................................................................................. 80
16. Post-market surveillance .................................................................................................................... 80
17. ISO 14155 for medical devices vs ICH-GCP for medicinal products..................................................... 80
18. Medical device (MDD) or Medicinal Product (MPD)? ......................................................................... 81
19. Main documents needed for a non-CE labelled medical device. ........................................................ 82
20. Key rules for running medical device trials. ........................................................................................ 82
Chapter 8: Study data from protocol to report .............................................................................................. 85
1. Study design: types of clinical trials ........................................................................................................ 85
2. Study design: the study protocol ............................................................................................................. 88
3. Study execu5on ....................................................................................................................................... 91
4. Study data ............................................................................................................................................... 93
Chapter 9: Vaccine trials – Controlled human infec<on models ..................................................................... 97
1. Defini5on and purpose ............................................................................................................................ 97
2. History and evolu5on .............................................................................................................................. 98
3. Safety of CHIM and ethical considera5ons.............................................................................................. 99
4. Steps towards a vaccine CHIM trial ....................................................................................................... 100
5. Place of CHIM in clinical development .................................................................................................. 101
6. Specialized facili5es............................................................................................................................... 102
7. Conclusions ........................................................................................................................................... 102
Chapter 10: Exam Ques<ons Clinical Drug Research 2023-3024 ................................................................... 105
3
,Chapter 1: ICH – GCP E6(R3) Good Clinical Prac<ce
The abbreviation ICH stands for International Council for Harmonization of technical
requirements for pharmaceuticals for human use. This council is unique in bringing together
the regulatory authorities and pharmaceutical industry to discuss scientific and technical
aspects of drug registration.
The abbreviation GCP stands for Good Clinical Practice.
Extrapolation of ICH-GCP: The application of ICH-GCP guideline is possible to other clinical
investigations that may have an impact on the rights, safety and (physical and mental) well-
being of human subjects.
Good Clinical Practice (CGP) is an international, ethical, scientific, and quality standard for the
conduct of trials that involve human participants. Clinical trials conducted in accordance
with this standard will help to assure that the rights, safety, and well-being of trial
participants are protected, that the conduct is consistent with the principles that have their
origin in the Declaration of Helsinki, and that the clinical trial results are reliable. The term
“trial conduct” includes processes from planning to reporting, including planning, initiating,
performing, recording, oversight, evaluation, analysis, and reporting activities as appropriate.
The objective of the ICH GCP Guideline is to provide a unified standard to facilitate the mutual
acceptance of clinical trial data for ICH member countries and regions by applicable
regulatory authorities.
The GCP guideline builds on key concepts outlined in ICH E8(R1) General Consideration for
Clinical Studies. This includes fostering a quality culture and proactively designing quality into
clinical trials and drug development planning, identifying factors critical to trial quality, and
engaging stakeholders, as appropriate, using a proportionate risk-based approach. Clinical
trials vary widely in scale, complexity, and cost. Careful evaluation of the priorities involved
in each trial and the risks associated with the priorities will help ensure efficiency by focusing
on activities critical to achieving the trial objectives.
1. History of GCP
There was a need to have an independent evaluaLon of medicinal products before they are
allowed on the market. The realizaKon of this happened at different Kmes in different regions
throughout the world (mostly tragedy-driven).
An example of such a tragedy is the Elixir Sulfanilamide tragedy of 1937. S.E. Massengill
Company created a preparaKon of sulfanilamide using diethylene glycol (DEG) as a solvent
and called it “Elixir Sulfanilamide”. The first case of fatality from DEG already occurred in 1930
and studies were published in medical journals staKng DEG could cause kidney
damage/failure, resulKng in death. DEG toxicity, however, was not widely known and the chief
pharmacist/chemist of the company was not aware of the DEG toxicity as described and added
raspberry flavor to the sulfanilamide drug dissolved in DEG. Animal tesLng, although rouKne
in most drug company operaKons, was not performed at S.E. Massengill Company (no
1
, regulaLon requiring premarket safety tesKng of new drugs). This resulted in the
commercializaLon of the product. A month later, the American Medical AssociaKon received
a report of several deaths. Food and Drug administraKon (FDA) was noKfied, and an extensive
search was conducted to recover the distributed medicine, while invesKgaKons had learned
that DEG was responsible for the fatal adverse effects. The company paid a minimum fine.
At that Kme, there only was the Federal regulatory control ensuring the safety of new drugs
(USA). Pure Food and Drug Act: “An act for prevenKng the manufacture, sale, or transportaKon
of adulterated or misbranded or poisonous or deleterious foods, drugs, medicines, and
liquors, and for regulaKng traffic therein, and for other purposes.” Harrison NarcoLcs Tax Act:
“An act to provide for the registraKon of, with collectors of internal revenue, and to impose a
special tax on all persons who produce, import, manufacture, compound, deal in, dispense,
sell, distribute, or give away opium or coca leaves, their salts, derivaKves, or preparaKons,
and for other purposes.”
The congress responded to this Elixir Sulfanilamide tragedy by passing the 1938 Food, Drug
and CosmeLc Act by which companies will need to perform and report animal safety tests to
the FDA before being allowed to market their products.
Another example is the Nuremberg trial of 1946 that focused on doctors who were involved
in human experiments in the concentraKon camps. Most of the suspects escaped punishment
for their crimes. Several of the accused argued that their experiments differed liWle form pre-
war experiments and that there was no law that differenKated between legal and illegal
experiments. This resulted in the Nuremberg Code (1947), lisKng 10 ethical principles.
1) Voluntary consent of the human subject is essenKal.
2) Experiment should be such as to yield fruiXul results for the good of society.
3) The experiments should be so designed and based on the results of animal
experimentaLon and a knowledge of the natural history of the disease or other
problem under study that the anLcipated results will jusLfy the performance of the
experiment.
4) The experiment should be so conducted as to avoid all unnecessary physical and
mental suffering and injury.
5) Experiments 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.
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 preparaLons should be made, and adequate faciliLes provided to protect the
experimental subject against even remote possibiliKes of injury, disability, or death.
8) The experiment should be conducted only by scienLfically qualified persons.
9) During 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 conKnuaKon of the
experiment seems to him to be impossible.
10) During the experiment the scienLst in charge must be prepared to terminate the
experiment at any stage.
Even while following the Nuremberg Code, the Thalidomide scandal happened. Thalidomide
is an immunomodulatory drug and the prototype of the thalidomide class of drugs. It was first
marketed in 1957 and primarily prescribed as a sedaLve or hypnoLc, thalidomide also claimed
2
CLINICAL DRUG RESEARCH
Biomedische wetenschappen
Anke Clerbout
0
,Inhoudsopgave
Chapter 1: ICH – GCP E6(R3) Good Clinical Prac<ce.......................................................................................... 1
1. History of GCP ........................................................................................................................................... 1
2. Legisla5on ................................................................................................................................................. 4
3. Pharmacovigilance .................................................................................................................................... 4
4. Clinical research ........................................................................................................................................ 5
5. GCP principles ........................................................................................................................................... 6
6. Ethics commiAee ..................................................................................................................................... 11
7. Informed consent .................................................................................................................................... 11
8. Quality..................................................................................................................................................... 12
9. Study protocol ......................................................................................................................................... 13
10. Study documents ................................................................................................................................ 13
11. Roles ................................................................................................................................................... 15
12. ISO/CD 14155 ..................................................................................................................................... 16
13. Exam ques5ons................................................................................................................................... 17
Chapter 2: The role of the Ethics CommiCee................................................................................................. 23
1. General principles ................................................................................................................................... 23
2. What is an ethics commiAee? ................................................................................................................. 23
3. Why ethics commiAees? ......................................................................................................................... 24
4. ICH-GCP Guidelines ................................................................................................................................. 26
5. Belgian Legisla5on .................................................................................................................................. 27
6. European Regula5on on clinical studies .................................................................................................. 28
7. Summary ................................................................................................................................................. 29
8. Examples of exam ques5ons ................................................................................................................... 30
Chapter 3: The Placebo-effect in clinical trials ............................................................................................... 31
1. Defini5ons ............................................................................................................................................... 31
2. Placebo – RCT – Double Blind .................................................................................................................. 32
3. From decoy to powerful to powerless ..................................................................................................... 32
4. How long does a placebo work? Placebo and OA ................................................................................... 33
5. Placebo: different components ............................................................................................................... 33
6. Special Placebo’s ..................................................................................................................................... 34
7. Nocebo (vaccines) ................................................................................................................................... 34
8. How does it work? The pharmacology of the placebo effect .................................................................. 34
9. How do you improve/enhance a placebo ................................................................................................ 35
10. Compliance to Placebo and ….. mortality ........................................................................................... 35
11. Ethics: placebo in the RCT!? Placebo in the “real world”? .................................................................. 35
1
, 12. Placebo its proper5es and the interpreta5on of the RCT ................................................................... 36
13. Effect of placebo on drop-out rate in RCT ........................................................................................... 36
14. Conclusion & why does it work? ......................................................................................................... 36
Chapter 4: Role, tasks, and responsibili<es of the main players ..................................................................... 37
1. Clinical research – Defini5ons ................................................................................................................. 37
2. Clinical research – Main players.............................................................................................................. 38
3. Set-up and conduct of a clinical trial – material requirements sponsor and inves5gator. ...................... 40
4. Set-up and conduct of a clinical trial. ...................................................................................................... 41
5. Clinical trial start-up ................................................................................................................................ 41
6. Monitoring visit ....................................................................................................................................... 43
7. Clinical trial closure ................................................................................................................................. 44
8. Safety repor5ng. ..................................................................................................................................... 45
9. Persons involved in a clinical trial and responsibili5es. ........................................................................... 46
Chapter 5: Quality in clinical research ........................................................................................................... 49
1. A few defini5ons ................................................................................................................................. 49
2. Clinical trial ethics, regula5ons, and quality ........................................................................................... 51
3. Avoid unethical behaviors ....................................................................................................................... 52
4. Quality management in clinical trials in detail ........................................................................................ 55
5. How can regula5ons help? ...................................................................................................................... 59
6. In prac5ce ............................................................................................................................................... 59
Chapter 6: European and federal regulatory agencies.................................................................................... 61
1. Scope ....................................................................................................................................................... 61
2. Legisla5on making organiza5ons – EU ................................................................................................... 62
3. Legisla5on making organiza5ons – Belgium........................................................................................... 63
4. Regulatory agencies – European Medicines Agency ............................................................................... 63
5. Regulatory agencies – Federal agency of medicines and health products .............................................. 64
6. Regulatory agencies – Heads of medicine agencies ................................................................................ 65
7. Role of agencies in regulatory procedures .............................................................................................. 65
8. Shortly situa5ng EDQM ........................................................................................................................... 72
Chapter 7: Medical device studies and applica<ons procedures .................................................................... 73
1. How place qualita5ve devices onto the market ...................................................................................... 73
2. Two primary guidelines for medical device manufacturer’s QMS ........................................................... 74
3. ISO 13485 versus ISO 9001 ...................................................................................................................... 75
4. Risk management – What is risk? ........................................................................................................... 75
5. What is a medical device? ....................................................................................................................... 75
6. Special types of medical devices ............................................................................................................. 76
7. MDD/MDD-IVD à MDR/MDR-IVDR ....................................................................................................... 76
2
, 8. 3 types of medical devices....................................................................................................................... 77
9. Competent authority vs no5fied body. .................................................................................................... 77
10. EU CE mark process vs US FDA approval process ............................................................................... 78
11. Medical device classes in EU – 4 classes based on 22 rules. ............................................................... 78
12. Medical device development life cycle ............................................................................................... 79
13. Design control .................................................................................................................................... 79
14. Traceability ......................................................................................................................................... 79
15. Market approval in EU – CE marking.................................................................................................. 80
16. Post-market surveillance .................................................................................................................... 80
17. ISO 14155 for medical devices vs ICH-GCP for medicinal products..................................................... 80
18. Medical device (MDD) or Medicinal Product (MPD)? ......................................................................... 81
19. Main documents needed for a non-CE labelled medical device. ........................................................ 82
20. Key rules for running medical device trials. ........................................................................................ 82
Chapter 8: Study data from protocol to report .............................................................................................. 85
1. Study design: types of clinical trials ........................................................................................................ 85
2. Study design: the study protocol ............................................................................................................. 88
3. Study execu5on ....................................................................................................................................... 91
4. Study data ............................................................................................................................................... 93
Chapter 9: Vaccine trials – Controlled human infec<on models ..................................................................... 97
1. Defini5on and purpose ............................................................................................................................ 97
2. History and evolu5on .............................................................................................................................. 98
3. Safety of CHIM and ethical considera5ons.............................................................................................. 99
4. Steps towards a vaccine CHIM trial ....................................................................................................... 100
5. Place of CHIM in clinical development .................................................................................................. 101
6. Specialized facili5es............................................................................................................................... 102
7. Conclusions ........................................................................................................................................... 102
Chapter 10: Exam Ques<ons Clinical Drug Research 2023-3024 ................................................................... 105
3
,Chapter 1: ICH – GCP E6(R3) Good Clinical Prac<ce
The abbreviation ICH stands for International Council for Harmonization of technical
requirements for pharmaceuticals for human use. This council is unique in bringing together
the regulatory authorities and pharmaceutical industry to discuss scientific and technical
aspects of drug registration.
The abbreviation GCP stands for Good Clinical Practice.
Extrapolation of ICH-GCP: The application of ICH-GCP guideline is possible to other clinical
investigations that may have an impact on the rights, safety and (physical and mental) well-
being of human subjects.
Good Clinical Practice (CGP) is an international, ethical, scientific, and quality standard for the
conduct of trials that involve human participants. Clinical trials conducted in accordance
with this standard will help to assure that the rights, safety, and well-being of trial
participants are protected, that the conduct is consistent with the principles that have their
origin in the Declaration of Helsinki, and that the clinical trial results are reliable. The term
“trial conduct” includes processes from planning to reporting, including planning, initiating,
performing, recording, oversight, evaluation, analysis, and reporting activities as appropriate.
The objective of the ICH GCP Guideline is to provide a unified standard to facilitate the mutual
acceptance of clinical trial data for ICH member countries and regions by applicable
regulatory authorities.
The GCP guideline builds on key concepts outlined in ICH E8(R1) General Consideration for
Clinical Studies. This includes fostering a quality culture and proactively designing quality into
clinical trials and drug development planning, identifying factors critical to trial quality, and
engaging stakeholders, as appropriate, using a proportionate risk-based approach. Clinical
trials vary widely in scale, complexity, and cost. Careful evaluation of the priorities involved
in each trial and the risks associated with the priorities will help ensure efficiency by focusing
on activities critical to achieving the trial objectives.
1. History of GCP
There was a need to have an independent evaluaLon of medicinal products before they are
allowed on the market. The realizaKon of this happened at different Kmes in different regions
throughout the world (mostly tragedy-driven).
An example of such a tragedy is the Elixir Sulfanilamide tragedy of 1937. S.E. Massengill
Company created a preparaKon of sulfanilamide using diethylene glycol (DEG) as a solvent
and called it “Elixir Sulfanilamide”. The first case of fatality from DEG already occurred in 1930
and studies were published in medical journals staKng DEG could cause kidney
damage/failure, resulKng in death. DEG toxicity, however, was not widely known and the chief
pharmacist/chemist of the company was not aware of the DEG toxicity as described and added
raspberry flavor to the sulfanilamide drug dissolved in DEG. Animal tesLng, although rouKne
in most drug company operaKons, was not performed at S.E. Massengill Company (no
1
, regulaLon requiring premarket safety tesKng of new drugs). This resulted in the
commercializaLon of the product. A month later, the American Medical AssociaKon received
a report of several deaths. Food and Drug administraKon (FDA) was noKfied, and an extensive
search was conducted to recover the distributed medicine, while invesKgaKons had learned
that DEG was responsible for the fatal adverse effects. The company paid a minimum fine.
At that Kme, there only was the Federal regulatory control ensuring the safety of new drugs
(USA). Pure Food and Drug Act: “An act for prevenKng the manufacture, sale, or transportaKon
of adulterated or misbranded or poisonous or deleterious foods, drugs, medicines, and
liquors, and for regulaKng traffic therein, and for other purposes.” Harrison NarcoLcs Tax Act:
“An act to provide for the registraKon of, with collectors of internal revenue, and to impose a
special tax on all persons who produce, import, manufacture, compound, deal in, dispense,
sell, distribute, or give away opium or coca leaves, their salts, derivaKves, or preparaKons,
and for other purposes.”
The congress responded to this Elixir Sulfanilamide tragedy by passing the 1938 Food, Drug
and CosmeLc Act by which companies will need to perform and report animal safety tests to
the FDA before being allowed to market their products.
Another example is the Nuremberg trial of 1946 that focused on doctors who were involved
in human experiments in the concentraKon camps. Most of the suspects escaped punishment
for their crimes. Several of the accused argued that their experiments differed liWle form pre-
war experiments and that there was no law that differenKated between legal and illegal
experiments. This resulted in the Nuremberg Code (1947), lisKng 10 ethical principles.
1) Voluntary consent of the human subject is essenKal.
2) Experiment should be such as to yield fruiXul results for the good of society.
3) The experiments should be so designed and based on the results of animal
experimentaLon and a knowledge of the natural history of the disease or other
problem under study that the anLcipated results will jusLfy the performance of the
experiment.
4) The experiment should be so conducted as to avoid all unnecessary physical and
mental suffering and injury.
5) Experiments 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.
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 preparaLons should be made, and adequate faciliLes provided to protect the
experimental subject against even remote possibiliKes of injury, disability, or death.
8) The experiment should be conducted only by scienLfically qualified persons.
9) During 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 conKnuaKon of the
experiment seems to him to be impossible.
10) During the experiment the scienLst in charge must be prepared to terminate the
experiment at any stage.
Even while following the Nuremberg Code, the Thalidomide scandal happened. Thalidomide
is an immunomodulatory drug and the prototype of the thalidomide class of drugs. It was first
marketed in 1957 and primarily prescribed as a sedaLve or hypnoLc, thalidomide also claimed
2
