LES 1: ICH-GCP
INTRODUCTION
ICH= international council for harmonization of technical requirements for pharmaceuticals for human use.
- Regulatory authorities
- Pharmaceutical industry
- Discuss scientific and technical aspects of drug registration
GCP= good clinical practice
Extrapolation of ICH-GCP: 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.
DEFINITION
- Good Clinical Practice (GCP) 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.
OBJECTIVE
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.
LEGISLATION
- Based on the principles of the Declaration of Helsinki.
- Clinical Trials Regulation on clinical trials on medicinal products for human use.
- Commission Directive 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
- Commission Directive 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
- Commission Delegated Regulation supplementing EU 536/2014 by specifying principles and guidelines
for good manufacturing practice for investigational medicinal products for human use and
arrangements for inspections
- EU General Data Protection Regulation (GDPR)
- European Medicines Agency (EMA, Europe)
- Federal Agency for Medicines and Health Products (FAHMP, Belgium)
- Competent authority responsible for the quality, safety and efficacy of medicines and health products
(in the interest of public health)
1
,PHARMACOVIGILANCE
= the science and activities relating to the detection, assessment, understanding and prevention of adverse
reactions or any other medicine-related problems.
The goal is public health protection by receipt and report of adverse drug reactions → surveillance, risk
management and safety reporting.
ADVERSE EVENT (AE)
Any unfavourable medical occurence in a trial participant. The adverse event does not necessarily have a
causal relationship with the treatment.
ADVERSE DRUG REACTIO N (ADR)
In the pre-approval clinical experience with a new medicinal product or its new usages: unfavourable and
unintended responses, such as a sign (e.g. laboratory results), symptoms or disease-related to any dose of a
medicinal product where a causal relationship between a medicinal product and an adverse event is a
reasonable possibility. The level of certainty about the relatedness of the adverse drug reaction to an
investigational product will vary. If the ADR is suspected to be medicinal product-related with a high level of
certainty, it should be included in the reference safety information (RSI) and/or the Investigator’s Brochure (IB).
For marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at
doses normally used in humans for prophylaxis, diagnosis or therapy of diseases or for modification of
physiological function.
SERIOUS ADVERSE EVEN T (SAE)
Any unfavorable medical occurrence that is considered serious at any dose if it:
- results in death;
- is life-threatening;
- requires inpatient hospitalization or prolongation of existing hospitalization
- results in persistent or significant disability/incapacity;
- is a congenital anomaly/birth defect.
SUSPECTED UNEXPECTED SERIOUS ADVERSE REA CTION (SUSAR)
- Suspected: There is a reasonable possibility that the drug caused the adverse drug reaction
- Unexpected: An adverse reaction, the nature of severity of which is not consisent with the applicable
product information (e.g. the Reference Saftey Information, see glossary term contained within the
Investigator’s Brochure or alternative documents according to applicable regulatory requirements.
Refer to ICH E2F Development Safety Update Report for more information about RSI).
- Serious: see SAE
DEVELOPMENT SAFETY U PDATE REPORTS (DSUR)
Once a year, during the entire duration of the experiment, the sponsor should provide the Minister and the
Ethics Committee in Belgium and those of the Member States on whose territory the trial is conducted in the
case of multicenter trials a list of all suspected serious adverse events that have occurred during that period as
well as a report on the safety of the participants.
2
,CLINICAL RESEARCH
DEFINITIONS
Clinical trial= any interventional investigation in human participants intended to discover or verify the clinical,
pharmacological and/or other pharmacodynamic effects of an investigational product(s); and/or to identify
any adverse reactions to an investigational product(s); and/or to study absorption, distribution, metabolism,
and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.
Trial Participant= An individual who participates in a clinical trial, either as a recipient of the investigational
product(s) or as a control.
Trial Participant Identification Code= A unique identifier assigned to each trial participant to protect the
participant’s identity and used in lieu of the participant’s name when the investigator reports adverse events
and/or other trial-related data.
PRECLINICAL RESEARCH
= determination of chemical and biological characteristics, toxicity, influence on fertility, pharmacokinetics,
safety (incl. carcinogenicity) and efficacy.
CLINICAL RESEARCH
PHASE 1
Concerns first studies in healthy human volunteers (20-80) under close medical supervision with
determination of:
- Pharmacokinetics
- Pharmacodynamics
- Tolerability
- Toxicity (maximal dose)
- Pharmacological profile
- Dose finding
Under exceptional circumstances phase I studies can be performed on patients (e.g. trials in oncology in a
specific phase I setting)
PHASE 2
Concerns first studies in patients (100-300) with determination of:
- Efficacy
- Optimal dose (dose-response relation)
- Therapeutic profile
PHASE 3
Concerns studies in a large number of patients (1000-5000) in a clinical setting close to normal practice with
determination of:
- Efficacy
- Therapeutic profile
PHASE 4
Concerns surveillance in huge patient groups (5000-10000) after the registration and marketing of a new
product → to look for long term effects.
3
, RANDOMIZATION
= the process of deliberately including an element of chance when assigning participants to groups that
receive different treatments in order to reduce bias. → you introduce an element of chance
BLINDING/MASKING
= a procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s).
1. SINGLE-BLINDING usually refers to the participant(s)s being unware.
2. DOUBLE-BLINDING usually refers to the participant(s), investigator(s) or other trial staff, as
appropriate, being unaware of the treatment assignment(s).
3. TRIPLE-BLINDING: in some cases the data analyst(s) are also unaware of the treatment assignment(s).
COMPARATOR (PRODUCT)
= an investigational or authorised medicinal product (i.e., active control), placebo or standard of care used as a
reference in a clinical trial.
INVESTIGATIONAL PROD UCT
= a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial,
including a product with a marketing authorization when used or assembled (formulated or packaged) in a way
different from the approved form, or when used for an unapproved indication, or when used to gain further
information about an approved use.
GCP PRINCIPLES (YOU DON’T NEED TO REPRODUCE THESE!!!)
- Clinical trials are a fundamental part of clinical research that support the development of new
medicines or uses of existing medicines. Well-designed and conducted clinical trials help answer key
questions in healthcare and drug development. Their results are essential for evidence-based
healthcare decisions.
- Trials with inadequate design and/or poorly conducted trials may place participant safety at risk and
yield inadequate or unreliable evidence and are unethical. They waste resources and the efforts and
time of investigators and participants.
- The principles of GCP are designed to be flexible and applicable to a broad range of clinical trials. This
guideline encourages thoughtful consideration and planning to address specific and potentially
unique aspects of an individual clinical trial. This includes evaluation of trial characteristics, such as
the design elements, the investigational product being evaluated, the medical condition being
addressed, the characteristics of the participants, the setting in which the clinical trial is being
conducted, and the type of data being collected. Careful consideration of factors relevant to ensuring
trial quality is needed for each clinical trial.
- The principles are intended to support efficient approaches to trial design and conduct. For example,
innovative digital health technologies, such as wearables and sensors, may expand the possible
approaches to trial conduct. Such technologies can be incorporated into existing healthcare
infrastructures and enable the use of a variety of relevant data sources in clinical trials. This will aid in
keeping clinical trial conduct in line with advancing science and technological developments. The use
of technology in the conduct of clinical trials should be adapted to fit the participant characteristics
and the particular trial design. The GCP guideline is intended to be media neutral to enable the use of
different technologies for the purposes of documentation.
4
INTRODUCTION
ICH= international council for harmonization of technical requirements for pharmaceuticals for human use.
- Regulatory authorities
- Pharmaceutical industry
- Discuss scientific and technical aspects of drug registration
GCP= good clinical practice
Extrapolation of ICH-GCP: 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.
DEFINITION
- Good Clinical Practice (GCP) 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.
OBJECTIVE
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.
LEGISLATION
- Based on the principles of the Declaration of Helsinki.
- Clinical Trials Regulation on clinical trials on medicinal products for human use.
- Commission Directive 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
- Commission Directive 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
- Commission Delegated Regulation supplementing EU 536/2014 by specifying principles and guidelines
for good manufacturing practice for investigational medicinal products for human use and
arrangements for inspections
- EU General Data Protection Regulation (GDPR)
- European Medicines Agency (EMA, Europe)
- Federal Agency for Medicines and Health Products (FAHMP, Belgium)
- Competent authority responsible for the quality, safety and efficacy of medicines and health products
(in the interest of public health)
1
,PHARMACOVIGILANCE
= the science and activities relating to the detection, assessment, understanding and prevention of adverse
reactions or any other medicine-related problems.
The goal is public health protection by receipt and report of adverse drug reactions → surveillance, risk
management and safety reporting.
ADVERSE EVENT (AE)
Any unfavourable medical occurence in a trial participant. The adverse event does not necessarily have a
causal relationship with the treatment.
ADVERSE DRUG REACTIO N (ADR)
In the pre-approval clinical experience with a new medicinal product or its new usages: unfavourable and
unintended responses, such as a sign (e.g. laboratory results), symptoms or disease-related to any dose of a
medicinal product where a causal relationship between a medicinal product and an adverse event is a
reasonable possibility. The level of certainty about the relatedness of the adverse drug reaction to an
investigational product will vary. If the ADR is suspected to be medicinal product-related with a high level of
certainty, it should be included in the reference safety information (RSI) and/or the Investigator’s Brochure (IB).
For marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at
doses normally used in humans for prophylaxis, diagnosis or therapy of diseases or for modification of
physiological function.
SERIOUS ADVERSE EVEN T (SAE)
Any unfavorable medical occurrence that is considered serious at any dose if it:
- results in death;
- is life-threatening;
- requires inpatient hospitalization or prolongation of existing hospitalization
- results in persistent or significant disability/incapacity;
- is a congenital anomaly/birth defect.
SUSPECTED UNEXPECTED SERIOUS ADVERSE REA CTION (SUSAR)
- Suspected: There is a reasonable possibility that the drug caused the adverse drug reaction
- Unexpected: An adverse reaction, the nature of severity of which is not consisent with the applicable
product information (e.g. the Reference Saftey Information, see glossary term contained within the
Investigator’s Brochure or alternative documents according to applicable regulatory requirements.
Refer to ICH E2F Development Safety Update Report for more information about RSI).
- Serious: see SAE
DEVELOPMENT SAFETY U PDATE REPORTS (DSUR)
Once a year, during the entire duration of the experiment, the sponsor should provide the Minister and the
Ethics Committee in Belgium and those of the Member States on whose territory the trial is conducted in the
case of multicenter trials a list of all suspected serious adverse events that have occurred during that period as
well as a report on the safety of the participants.
2
,CLINICAL RESEARCH
DEFINITIONS
Clinical trial= any interventional investigation in human participants intended to discover or verify the clinical,
pharmacological and/or other pharmacodynamic effects of an investigational product(s); and/or to identify
any adverse reactions to an investigational product(s); and/or to study absorption, distribution, metabolism,
and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.
Trial Participant= An individual who participates in a clinical trial, either as a recipient of the investigational
product(s) or as a control.
Trial Participant Identification Code= A unique identifier assigned to each trial participant to protect the
participant’s identity and used in lieu of the participant’s name when the investigator reports adverse events
and/or other trial-related data.
PRECLINICAL RESEARCH
= determination of chemical and biological characteristics, toxicity, influence on fertility, pharmacokinetics,
safety (incl. carcinogenicity) and efficacy.
CLINICAL RESEARCH
PHASE 1
Concerns first studies in healthy human volunteers (20-80) under close medical supervision with
determination of:
- Pharmacokinetics
- Pharmacodynamics
- Tolerability
- Toxicity (maximal dose)
- Pharmacological profile
- Dose finding
Under exceptional circumstances phase I studies can be performed on patients (e.g. trials in oncology in a
specific phase I setting)
PHASE 2
Concerns first studies in patients (100-300) with determination of:
- Efficacy
- Optimal dose (dose-response relation)
- Therapeutic profile
PHASE 3
Concerns studies in a large number of patients (1000-5000) in a clinical setting close to normal practice with
determination of:
- Efficacy
- Therapeutic profile
PHASE 4
Concerns surveillance in huge patient groups (5000-10000) after the registration and marketing of a new
product → to look for long term effects.
3
, RANDOMIZATION
= the process of deliberately including an element of chance when assigning participants to groups that
receive different treatments in order to reduce bias. → you introduce an element of chance
BLINDING/MASKING
= a procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s).
1. SINGLE-BLINDING usually refers to the participant(s)s being unware.
2. DOUBLE-BLINDING usually refers to the participant(s), investigator(s) or other trial staff, as
appropriate, being unaware of the treatment assignment(s).
3. TRIPLE-BLINDING: in some cases the data analyst(s) are also unaware of the treatment assignment(s).
COMPARATOR (PRODUCT)
= an investigational or authorised medicinal product (i.e., active control), placebo or standard of care used as a
reference in a clinical trial.
INVESTIGATIONAL PROD UCT
= a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial,
including a product with a marketing authorization when used or assembled (formulated or packaged) in a way
different from the approved form, or when used for an unapproved indication, or when used to gain further
information about an approved use.
GCP PRINCIPLES (YOU DON’T NEED TO REPRODUCE THESE!!!)
- Clinical trials are a fundamental part of clinical research that support the development of new
medicines or uses of existing medicines. Well-designed and conducted clinical trials help answer key
questions in healthcare and drug development. Their results are essential for evidence-based
healthcare decisions.
- Trials with inadequate design and/or poorly conducted trials may place participant safety at risk and
yield inadequate or unreliable evidence and are unethical. They waste resources and the efforts and
time of investigators and participants.
- The principles of GCP are designed to be flexible and applicable to a broad range of clinical trials. This
guideline encourages thoughtful consideration and planning to address specific and potentially
unique aspects of an individual clinical trial. This includes evaluation of trial characteristics, such as
the design elements, the investigational product being evaluated, the medical condition being
addressed, the characteristics of the participants, the setting in which the clinical trial is being
conducted, and the type of data being collected. Careful consideration of factors relevant to ensuring
trial quality is needed for each clinical trial.
- The principles are intended to support efficient approaches to trial design and conduct. For example,
innovative digital health technologies, such as wearables and sensors, may expand the possible
approaches to trial conduct. Such technologies can be incorporated into existing healthcare
infrastructures and enable the use of a variety of relevant data sources in clinical trials. This will aid in
keeping clinical trial conduct in line with advancing science and technological developments. The use
of technology in the conduct of clinical trials should be adapted to fit the participant characteristics
and the particular trial design. The GCP guideline is intended to be media neutral to enable the use of
different technologies for the purposes of documentation.
4
