ich gcp history
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Principles & Practice of ICHPrinciples & Practice of ICH--GCP:GCP:An Investigator's GuideAn Investigator's Guide
Dr Rod OwenDr Rod Owen
Manager, Clinical Trials UnitManager, Clinical Trials UnitArrowe Park HospitalArrowe Park Hospital
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ICH-GCP: An InvestigatorAn Investigator’’s Guide ...s Guide ...
Principles Principles & Practice& Practice
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ICH: What does it mean?
International Conference on Harmonisation(of technical requirements for registrationof pharmaceutical products for human use)
“Tripartite Agreement” between European Union, United States and Japan (1 May 1996)
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ICH-GCP: ‘EU’ Countries
‘New’ EU = Bulgaria, Cyprus, Czech Republic, Estonia, Hungary, Latvia, Lithuania, Malta, Poland, Rumania, Slovakia & Slovenia; EEA = Iceland, Norway, Switzerland & Liechtenstein. Note: Canada & WHO are also now ICH signatories
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GCP: Good Clinical Practice
Ethical and scientific quality standards for:
Design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials … and to ensure the rights, integrity and confidentiality of trial subjects are protected
ICH-GCP: 1.24
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1. Extent of Population Exposure
2. Clinical Safety Data Management
3. Structure and Content of Clinical Trial Reports
4. Dose-Response Data
5. Ethnicity in Clinical Trials
6. Part 6 “Good Clinical Practice” Guidelines7. Evaluation of Drugs for Use in Geriatric Populations
8. General Considerations
9. Statistics
10. Period Reviews of Safety Data for Marketed Products
11. Evaluation of Drugs for Use in Paediatric Populations
ICH-GCP: Components
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ICH-GCP: Part 6 GCP Guidelines
Provide public assurance that:
the rights, safety and well-being of trial subjects are protected by the principles of the “Declaration of Helsinki”
ICH-GCP 2.1, 2.3
the trial data are credible, and thus acceptable for mutual acceptance by the regulatory authorities (in those countries for which the Guidelines were developed)
ICH-GCP 2.10
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Declaration of Helsinki♣
Adopted June, 1964
Amended Tokyo, 1975
Amended Venice, 1983
Amended Hong Kong, 1989
Amended South Africa, 1996
Amended Scotland, 2000
“Ethical Principles for Medical ResearchInvolving Human Subjects”
♣World Medical Association (WMA)
Amendment expected October 2008
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Declaration of Helsinki(Amended Scotland, 2000)
Significant new Principles:
Protocol to be made public
Results to be made public
Comparator product preferred to placebo
Best treatment identified by study to be given to all study participants after completion of study
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“ The WMA hereby reaffirms its position that it is necessary during the study planning process to identify post-trial access by study participants to prophylactic, diagnostic and therapeutic procedures identified as beneficial in the study, or other appropriate care.
Post-trial access arrangements or other care must be described in the study protocol so the ethical review committee may consider such arrangements during its review ”
Declaration of Helsinki(Tokyo Statement, 2004)
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Belmont Report
“Ethical Principles and Guidelines for the Protection of Human Subjects of Research”
Three Principles:
Respect of Persons
Beneficence
Justice
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Ethical Principles (1):
Respect of Persons
Treat each subject as autonomous agent
Those with diminished autonomy must be protected
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Beneficence
Subjects must not be exposed to harm
Researchers must maximise any possible benefits while minimizing possible risks
Ethical Principles (2):
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Justice
Neither wealth nor poverty should be reasons for the inclusion or exclusion of subjects who are likely to be beneficiaries of the research
Subjects must not be selected solely by their easy availability, compromised position, manipulability or reasons other than those directly related to the research
Ethical Principles (3):
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GCP: EU & UK Legislation
2005/28/EC The “GCP” Directive
2001/20/EC The “Clinical Trials” Directive
Medicines for Human Use (Clinical Trials)Regulations 2004 [SI 1031]Medicines for Human Use (Clinical Trials)Amendment Regulations 2006 [SI 1928]
Medicines for Human Use (Clinical Trials)No 2 Amendment Regulations 2006 [SI 2984]
Medicines for Human Use (Clinical Trials)No 3 Amendment Regulations 2008 [SI xxxx]
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ICH-GCP: An InvestigatorAn Investigator’’s Guide ...s Guide ...
Principles &Principles & PracticePractice
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Source Documents
Definition: Original documents, data and records (eg hospital notes, clinical charts, laboratory results, pharmacy dispensing records, X-Rays etc).
Source documents may be originals or may be copies, microfiches, photographic negatives once certified as being accurate copies of the original document
ICH-GCP 1.51, 1.52
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Case Report Form (CRF)
A printed, optical or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject
ICH-GCP 1.11
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CRF: Investigator responsibility
Ensure the accuracy, completeness, legibility and timeliness of the data in the CRF and all reports
ICH-GCP 4.9.1, 4.9.2
Initial, date (and explain) CRF changes - do not obliterate the original entry
ICH-GCP 4.9.3
37.4
RO28/09/2007
34.7
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Safety Reporting
Adverse Drug Reaction (ADR)Any untoward and unintended medical response to an investigational medicinal product, and related to any dose of the product.
ICH-GCP 1.1Article 2 (n)
Adverse Event (AE)Any untoward medical occurrence, including laboratory abnormalities, whether or not considered related to the product, and no matter how minor
ICH-GCP 1.2*Article 2 (m)
*EU Directives: 2001/20/EC & 2005/28/EC
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Serious Adverse Event (SAE)Any untoward medical occurrence that:
results in death
is life threatening (as perceived at the time)
results in persistent disability or incapacity
requires (or prolongs) hospitalisation
is a congenital defectICH-GCP 1.50
Article 2 (o)
Safety Reporting
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Suspected Unexpected Serious Adverse Reaction(SUSAR)
An adverse reaction, the nature and severity of which is not consistent with the applicable product information( eg Investigator's Brochure if unlicensed; SmPC if licensed)
ICH-GCP 1.60Article 2 (p)
Safety Reporting
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Causal Relationship
Unrelated …
Unlikely to be related …
Possibly related …
Probably related …
Definitely related …
… to product, device or procedure
“Don’t know”
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A patient gave consent and was entered into a trial yesterday. This morning the patient took the first dose of study medication and felt “severely nauseated” shortly afterwards. The patient said she was “violently sick” about an hour later.
AE, SAE, NEITHER?
Question 1
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2 AEs (nausea, vomiting)
Serious adverse events are not necessarily severe;“severe” adverse events are not necessarily serious
Answer 1
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A female patient, who gave consent and agreed to practice adequate contraception in accordance with the study protocol, began treatment with the trial drug three months ago. Last week, the patient reported that she had become pregnant.
AE, SAE or NEITHER?
Question 2
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SAE or AE … or Neither
ALL pregnancies are usually recorded as SAEs or AEs. This is the convention. However, unless the Investigator believes there may be a drug-drug interaction with a contraceptive drug, it should not be reported as an AE for licensing.
NOTE: A Report of In Utero Drug Exposure (RIUDE)* mustbe completed for all pregnancies and sent to the MHRA. The Sponsor must follow each pregnancy to term, and report outcome to MHRA (even if birth & baby “normal”).
*Clinical Trial Pregnancy Reporting Form
Answer 2
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A patient entered a 6-week study comparing nicotine patch and nicotine patch plus weekly counselling for ‘initial-phase’ smoking cessation. One week after consenting to take part in the trial, the patient underwent elective repair of a hernia. The operation was planned to take place in eight weeks time (ie after the study) but a cancellation created the opportunity for earlier surgery, which the patient gratefully accepted.
AE, SAE, NEITHER?
Question 3
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NEITHER
The surgical repair of the patient’s hernia was a planned, elective procedure; the altered date makes no difference
(The patient’s case notes should show that diagnosis and schedule for surgery pre-dated trial entry)
Answer 3
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A patient with advanced malignancy consents to take part in pilot study of a new, patient-operated device for delivering pain relief medication, and continues to receive all other medications as per the Trust’s “standard practice” in Palliative Care. During the planned 3-week study, the patient dies from disease progression.
AE, SAE, NEITHER?
Question 4
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SAE
Although death may well be considered inevitable for a patient with advanced cancer, and who is receiving palliative care, death is ALWAYS an SAE
NB: If stated in Protocol, SAEs need not be reported using the “expedited” procedure – provided MHRA & REC have agreed
Answer 4
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Adverse Event Reporting
Adverse Event
Non Serious
Expected
Trial report or periodicsafety update
Serious
Unexpected
Fatal orLife threatening
7 days
Other
15 days
As per Protocol:including deathfrom progressivedisease if MHRAand REC approve