2021 Clinical drug
research
Master: Klinisch wetenschappelijk
onderzoek
Hanne De wael
,Open vragen + MCQ
Je kan ICH-GCP certificaat krijgen om clinical work in master thesis uit te voeren. “Example of examination
questions” les 1 zijn alle examinatievragen die ze stellen op de test voor het certificaat. (was echt super easy)
Inhoud
Les 1: ICH-GCP ................................................................................................................................................................... 7
Part 1: Introduction to ICH-GCP .................................................................................................................................... 7
Voorbeeld examenvragen ......................................................................................................................................... 7
Part 2: Legislation for clinical research ....................................................................................................................... 10
Part 3: Terminology on Pharmacovigilance ................................................................................................................ 10
Part 4: Definition of Clinical research ......................................................................................................................... 11
Part 5: 13 principles of ICH-GCP.................................................................................................................................. 13
Part 6: Role of IRB’s and IEC’s ..................................................................................................................................... 14
Part 7: How to obtain an informed consent ............................................................................................................... 15
Part 8: Quality management of clinical research ........................................................................................................ 15
Part 9: Translation of ICH-GCP principles into documents related to clinical research ............................................. 16
Part 10: Study protocol ............................................................................................................................................... 17
Part 11: Log forms ....................................................................................................................................................... 18
Part 12: Case report forms CRF ................................................................................................................................... 20
Part 13: investigator brochure .................................................................................................................................... 22
Part 14: Other relevant documents ............................................................................................................................ 22
Responsibilities ........................................................................................................................................................... 23
Part 15: Responsibilities of sponsor ............................................................................................................................ 23
Part 16: Responsibilities of CRO = contract research organization ............................................................................ 23
Part 17: Responsibilities of CRA: clinical research associate/ CTA: clinical trial administrator .................................. 23
Part 18: Responsibilities of clinical data management (sponsor) ............................................................................... 24
Part 19: Responsibilities of principal investigator....................................................................................................... 24
Part 20: Involvement of study coordinator and/or study nurse = investigator team ................................................ 24
Part 21: Mutual responsibilities between sponsor and investigator team ................................................................ 25
Part 22: Skills involved in clinical research.................................................................................................................. 25
Part 23: Essential documents within TMF trial master file and ISF investigator site file ............................................ 26
Part 24: Clinical investigation of medical devices for human subjects ....................................................................... 28
Les 2: Patrick Cras: Ethics committee => examen = general knowledge, enkel grote lijnen in MCQ ............................. 30
What is an ethics committee ...................................................................................................................................... 30
Why ethics committees .............................................................................................................................................. 30
Ethical review .............................................................................................................................................................. 30
Clinical ethics versus research ethics .......................................................................................................................... 30
Protection of subject................................................................................................................................................... 31
Basic texts on ethics in clinical research ..................................................................................................................... 31
Nuremberg Code ......................................................................................................................................................... 31
, The declaration of Helsinki (2013) .............................................................................................................................. 31
Additional guidelines .................................................................................................................................................. 31
Clinical trial regulation ................................................................................................................................................ 32
Functie ethics committee: ICH guidelines................................................................................................................... 33
Written policies and procedures................................................................................................................................. 33
Participation in clinical trials ....................................................................................................................................... 34
Negative advice ........................................................................................................................................................... 34
Faq’s ............................................................................................................................................................................ 34
Financial aspects of clinical trials ................................................................................................................................ 35
Follow-up .................................................................................................................................................................... 35
Ethics of EC/IRB ........................................................................................................................................................... 35
Potential conflict of interest ....................................................................................................................................... 36
Dealing with conflicts of interest ................................................................................................................................ 36
Quality of ethical review ............................................................................................................................................. 36
Quality assurance metrics ........................................................................................................................................... 36
Quality of decision making .......................................................................................................................................... 37
Current status of CTR clinical trial regulation ............................................................................................................. 37
Low intervention clinical trial...................................................................................................................................... 37
Research challenged by GDPR?................................................................................................................................... 38
Data storage and handling .......................................................................................................................................... 38
Difficulty in identifying (secondary) research purposes in the future in advance ...................................................... 38
Conclusions ................................................................................................................................................................. 38
Les 2.1 Statistics in clinical trials: Does sample size really matter for a clinical trial? .................................................... 40
1. Circle of research ................................................................................................................................................ 40
2. What is hypothesis testing? ................................................................................................................................ 40
3. Statistical methods.............................................................................................................................................. 40
4. What is a sample size? ........................................................................................................................................ 41
5. How large should the sample be? ....................................................................................................................... 41
6. Significance level α and power (1 − β) ................................................................................................................ 41
7. Fundamental points ............................................................................................................................................ 42
8. Treatment A or B? ............................................................................................................................................... 42
9. How to get sample size – rough idea .................................................................................................................. 43
10. What is needed for sample size calculation? .................................................................................................. 43
11. Sample size calculation ................................................................................................................................... 43
12. Simple formula for difference in proportions ................................................................................................. 44
13. Exercise ........................................................................................................................................................... 44
14. Effect size ↔ sample size per group .............................................................................................................. 44
15. Some further topics ........................................................................................................................................ 45
16. Summary ......................................................................................................................................................... 45
,Les 3: Start up and conduct of a clinical trial (open and general questions), Role, tasks, responsibilities of CRO,
CRA, monitor, sponsor, investigator.......................................................................................................................... 46
Definitions ................................................................................................................................................................... 46
Medical device development timeline........................................................................................................................ 47
Main players................................................................................................................................................................ 48
Set-up and conduct of a clinical trial:.......................................................................................................................... 49
Material requirements – sponsor and investigator .................................................................................................... 49
Clinical trials start-up and conduct ............................................................................................................................. 52
Safety reporting .......................................................................................................................................................... 56
Les 4: Study design => multiple choice questions, geen details, geen historische details, de belangrijke concepten
goed kennen ................................................................................................................................................................... 59
Introduction: towards the gold standard.................................................................................................................... 59
Historical examples ................................................................................................................................................. 59
Why clinical trials? ...................................................................................................................................................... 59
Choosing the right timing............................................................................................................................................ 59
Study protocol ............................................................................................................................................................. 59
RCT = golden standard for clinical trials = randomized controlled trials .................................................................... 60
Randomised double-blind placebo-controlled clinical trial = golden standard ..................................................... 61
Posing the right question ............................................................................................................................................ 62
Choosing the right population .................................................................................................................................... 63
Defining the treatment schedule ................................................................................................................................ 64
Special designs ............................................................................................................................................................ 65
Les 4.2 Data management (geen slides van, wel document van wat te kennen) .......................................................... 65
Les 4.3 Data analysis ....................................................................................................................................................... 68
Clinical trial Reporting ................................................................................................................................................. 68
Les 4.4 Placebo................................................................................................................................................................ 69
History ......................................................................................................................................................................... 69
Placebo-RCT-Double blind .......................................................................................................................................... 69
From decoy to powerfull to powerless ....................................................................................................................... 70
Hoe lang werkt placebo? ............................................................................................................................................ 70
What results are most important?.............................................................................................................................. 70
Natural history ............................................................................................................................................................ 71
Regression to the mean .............................................................................................................................................. 71
Conditioning ................................................................................................................................................................ 71
Hawthorne effect ........................................................................................................................................................ 71
Chirurgische placebo ................................................................................................................................................... 71
Special placebo’s ......................................................................................................................................................... 71
Nocebo in clinical trials ............................................................................................................................................... 71
Pharmacology van placebo effecten ........................................................................................................................... 72
Vooroordeel in interpretatie van klinische trials ........................................................................................................ 72
, Verband tussen Compliance en mortaliteit ................................................................................................................ 72
Placebo in RCT ............................................................................................................................................................. 72
Placebo in de real world ............................................................................................................................................. 73
Betekenis van placebo voor interpretaties ................................................................................................................. 73
Conclusion ................................................................................................................................................................... 73
Les 5: Quality in clinical research .................................................................................................................................... 74
Aims............................................................................................................................................................................. 74
Quotes ......................................................................................................................................................................... 74
Module 1: Drug/device development process & quality ............................................................................................ 74
Aims......................................................................................................................................................................... 74
1) Drug development .............................................................................................................................................. 74
2) Clinical trial for drugs .......................................................................................................................................... 75
3) Definitie Investigational product ........................................................................................................................ 75
4) Medical device development .............................................................................................................................. 75
5) Clinical investigation in medical devices ............................................................................................................. 76
6) Definitie Medical device ..................................................................................................................................... 76
7) Vergelijking ......................................................................................................................................................... 77
8) Clinical trial.......................................................................................................................................................... 77
Cost, sponsor, duration ........................................................................................................................................... 78
Quality in clinical trials ............................................................................................................................................ 79
Module 2: Clinical trial ethics and regulations & quality ............................................................................................ 79
Aims......................................................................................................................................................................... 79
Ethics and human subject protection ..................................................................................................................... 80
Ethical tension: clinical equipoise ........................................................................................................................... 81
Guidelines, guidance documents and regulations .................................................................................................. 81
International conference of harmonization ICH ..................................................................................................... 82
Module 3: Quality management in clinical trials ........................................................................................................ 84
Aims......................................................................................................................................................................... 84
Sponsor ................................................................................................................................................................... 84
QA components – strategic roles ............................................................................................................................ 85
Monitoring .............................................................................................................................................................. 86
What can go wrong? ............................................................................................................................................... 87
Les 6: Medical devices and device studies ...................................................................................................................... 88
How to bring a product to the market ........................................................................................................................ 88
2 guidelines for medical device manufacturer’s QMS ................................................................................................ 88
Verschil competent authority vs notified body .......................................................................................................... 88
What is a medical device: definition ........................................................................................................................... 89
Special types of medical devices ............................................................................................................................. 89
Medical device development life cycle ....................................................................................................................... 89
, Market approval in EU => CE-marking ........................................................................................................................ 89
4 Risk-based medical device classes in EU .................................................................................................................. 90
3 types of medical devices concerning CE-marking .................................................................................................... 90
Directives vs regulations ............................................................................................................................................. 91
Speed vs quality ...................................................................................................................................................... 92
Document control ....................................................................................................................................................... 92
Example procedure: design control (linked to process of design & engineering) .................................................. 93
Risk management: ISO 14971 ..................................................................................................................................... 93
FMEA = failure mode & effect analysis ....................................................................................................................... 93
Verification .................................................................................................................................................................. 94
Validation: clinical evaluation for medical devices: ISO14155 ................................................................................... 94
Post-market surveillance ............................................................................................................................................ 94
Clinical trial approval cycle.......................................................................................................................................... 95
Difference medical device & medicinal product ......................................................................................................... 95
Main documents needed for a non-CE labelled medical device ................................................................................ 96
Key rules for running medical device trials (aka clinical investigations) ..................................................................... 97
Example 1: Colli-pee: a first void urine collection device ........................................................................................... 98
Example 2: Vax-ID: an intradermal injection device ................................................................................................... 98
Example 3: COVID-19 shortage of mouth masks ........................................................................................................ 98
Les 7 Medicines for children & paediatric drug development........................................................................................ 99
Background ................................................................................................................................................................. 99
A system of obligations and rewards for developers ................................................................................................. 99
What is PIP .................................................................................................................................................................. 99
What the PIP does not deal with ................................................................................................................................ 99
Waiver (afstandsverklaring) ...................................................................................................................................... 100
Examples of achievements based on PIPs ................................................................................................................ 100
More information on pediatric medicines ................................................................................................................ 100
Off-patent products .................................................................................................................................................. 100
Research in neonates ................................................................................................................................................ 100
Regulators supporting pediatric development ......................................................................................................... 101
Non-clinical studies for safe pediatric research ........................................................................................................ 101
Facilitation and collaboration ................................................................................................................................... 101
Conclusion impact of pediatric regulation ................................................................................................................ 101
Lessons learned in the process ................................................................................................................................. 102
Main challenges and needs: summary...................................................................................................................... 103
Study on economic impact of the pediatric regulation, including its rewards and incentives ................................. 104
How to fulfil the pediatric requirements in EU => in guidelines of European commission ...................................... 104
Ethical considerations ............................................................................................................................................... 105
Guideline on pharmaceutical development of medicines for pediatric use ............................................................ 105
, The extrapolation concept ........................................................................................................................................ 106
Pharmacovigilance .................................................................................................................................................... 106
Emprema network .................................................................................................................................................... 106
Les 8: European and federal regulatory agencies Part 1: Accelerated Development: How COVID-19 Vaccines are Being
Developed Safely in Record Time ................................................................................................................................. 108
Vaccine development: Benefit/risk evaluation......................................................................................................... 108
Role of national authorities in vaccine approval ...................................................................................................... 108
COVID-19 vaccine development: how was it so fast?............................................................................................... 108
Conclusions for a controlled human infection model (CHIM) for COVID-19 ............................................................ 110
Les 8: European and federal regulatory agencies Part 2: vaccine development and regulatory aspects .................... 111
The regulatory paradox............................................................................................................................................. 111
Vaccines, vaccination & regulatory affairs ................................................................................................................ 115
Les 9: pharma.be, Janssen, GSK .................................................................................................................................... 119
Pharma.be ................................................................................................................................................................. 119
Johnsson & Johnsson ................................................................................................................................................ 120
GSK ............................................................................................................................................................................ 120
,Les 1: ICH-GCP
Part 1: Introduction to ICH-GCP
Voorbeeld examenvragen
Efficacy guidelines
ICH GCP E6 = chapter 6 of efficacy guidelines
4e optie = juist
GCP wordt officieel geaccepteerd in USA, EU, Japan, Canada en Zwitserland
3e optie = juist => hogere exposure to risk
Als je GCP guidelines niet volgt, dan stel je je participanten bloot aan een verhoogd risico
ICH = international Council for Harmonisation of technical requirements for pharmaceuticals for human use => the
guideline is written specifically for the development of new pharmaceuticals for human use
• The regulatory authorities and pharmaceutical industry came together to discuss scientific and technical
aspects that are needed for drug registration
GCP = good clinical practice
,Why do you need to harmonize guidelines for GCP?
• Als je kijkt naar de output van clinical research, zoek je naar papers
die door experten gepubliceerd zijn => deze zijn allemaal van hoge
kwaliteit en goed gepresenteerd => vergeleken met een huis lijkt het op
een mooie villa met zwembad en welness
• Als je iets dieper graaft, kom je in een soort kelder waar alle
supplementaire data (die niet per se gepresenteerd worden in de
paper) op een logische manier gestructureerd zijn => het is niet nice-
looking, maar er zit wel structuur in
• Als je kelder slecht aangelegd is, ontstaan er lekken en krijg je
ongedierte => net zoals de paper, als je iets fout hebt gedaan in de
gestructureerde data kan je dit terugvinden in de ruwe data
Het is belangrijk dat nieuwe medicamenten op een onafhankelijke manier geëvalueerd worden vooraleer ze
op de markt komen. Tragedies zoals elixir sulfanilamide en softenon hebben tot deze realisatie geleid.
Elixir sulfanilamide: ze gebruikten solvent DEG (diethylene glycol) dat toxisch was. Het was al wel geweten dat
het toxisch was, maar de libraries waren niet goed beschikbaar waardoor de chief pharmacist van het bedrijf niet
doorhad dat DEG toxisch was => vele mensen stierven. Daarbovenop, alhoewel het al veel voorkwam om
proefdieren te gebruiken, gebruikte dit specifieke bedrijf geen proefdieren waardoor toxiciteit niet opgemerkt
werd.
• Stricter safety procedures
• Stricter pharmacovigilance
• Check by authorities before allowing commercializing!!
• Introduce more animal testing!!
• Boete (enkel omdat ze het woord ‘elixir’ ongewettigd gebruikten lol)
• Tijdens het onderzoek beweert het bedrijf dat ze dit niet hadden kunnen voorzien, en heeft de chief
pharmacist zelfmoord gepleegd
• Uit deze tragedie ontstond de 1938 Food, Drug and Cosmetic Act die zegt dat bedrijven animal-
safety tests moeten uitvoeren en rapporteren aan de FDA vooraleer hun drug op de markt gebracht
mag worden
Nuremberg trials:
• Doctor’s trial tegen 23 dokters uit de sterilisatie kampen
• De meesten kregen geen straf omdat experimenten voor de WW2 er ook zo aan toe gingen, en dat er niet
echt een wet was om legale en illegale experimenten te onderscheiden
• Er kwamen 10 ethische principes = Nuremburg code:
Vrijwillige toelating van participant om mee te doen aan clinical trial
, Er moet voordeel zijn for the good of society. Je mag dus niet zomaar een experiment doen zonder
fruitful results.
Design van de clinical trial moet gebaseerd zijn op animal experiments en op natural history van de
ziekte
Alles eraan doen om onnodig fysisch en mentaal lijden en letsel van de participanten te voorkomen
Trial niet uitvoeren als je weet dat het dodelijk kan zijn of letsels kan veroorzaken bij de participant,
“except in those experiments where experimental physicians also serve as subjects”.
Geen te hoge risico’s: het risico mag nooit hoger zijn dan wat het probleem zelf van risico’s geeft
(een kankerbehandeling mag niet dodelijker zijn dan de kanker zelf)
De vrijwilligers moeten beschermd worden tegen elke soort injury, disability or death
Enkel wetenschappelijk gekwalificeerde personen kunnen een trial uitvoeren
Vrijwilligers mogen op elk moment stoppen
Je moet voorbereid zijn als wetenschapper om de trial te stoppen als het gevaarlijk blijkt
Thalidomide scandal
• 10jaar na deze 10 ethische principes
• Thalidomide = immunomodulatory drug
• Werd voorgeschreven als kalmeringsmiddel of slaapmiddel, maar het bleek dat het ook goed werkte tegen
angst, insomnia, gastritis, misselijkheid en gespannenheid => het werd een over-the-counter drug => ook
zwangere vrouwen gebruikten het tegen ochtendmisselijkheid
• 5000-7000 kinderen vertoonden afwijkingen in de lidmaten
• => Introduce more elaborate reproduction toxicity testing studies
• => External regular inspections of the development processes
• => Animal testing in more than 1 species
• Declaration of Helsinki
▪ Algemene ethische principes
▪ Risico’s, burdens en voordelen
▪ Kwetsbare groepen
▪ Wetenschappelijke benodigdheden en research protocols
▪ Ethics committees zijn nodig vooraleer je clinical trials kan doen
▪ Privacy en confidentiality van data
▪ Informed consent
▪ Placebo gebruik, wanneer wordt het toegelaten en wanneer niet
▪ Post-trial provisions: hoe moeten de resultaten gepubliceerd worden
In de ICH-GCP staat:
• Wat de verantwoordelijkheden zijn van de stakeholders in het uitvoeren van de clinical trial
• Hoe je clinical trials moet monitoren en hoe je de resultaten moet rapporteren en archiveren
• Wat de essentiële documenten zijn voor een clinical trial => update voor elektronische records
• Beschrijving van de improved en meest efficiënte aanpak om een clinical trial uit te voeren waarbij de
vrijwilligers optimaal beschermd worden
Motivatie voor harmonisatie in GCP guidelines
• Hogere kosten voor healthcare als je patiënten niet behandelt
• R&D kosten moet zo laag mogelijk blijven zo
• Zo snel mogelijk een veilig en efficiënt medicijn hebben
Waarom moet clinical research gereguleerd worden?
• Minder fraude
• Zodat al je data geloofwaardig en eerlijk is
• Zodat studies gebaseerd zijn op goede wetenschappelijke principes
• Zodat de vrijwilligers ten volste beschermd zijn.
