Ich Gcp History

Principles & Practice of ICH-GCP: An Investigator's Guide

Dr Rod Owen Manager, Clinical Trials Unit Arrowe Park Hospital

1

ICH-GCP: An Investigator’s Guide ...

Principles & Practice

2

ICH: What does it mean? International Conference on Harmonisation (of technical requirements for registration of pharmaceutical products for human use) “Tripartite Agreement” between European Union, United States and Japan (1 May 1996)

3

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 4

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 5

ICH-GCP: Components 1. 2. 3. 4. 5.

Extent of Population Exposure Clinical Safety Data Management Structure and Content of Clinical Trial Reports Dose-Response Data Ethnicity in Clinical Trials

6. Part 6 “Good Clinical Practice” Guidelines 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 7.

6

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

7

Declaration of Helsinki♣ “Ethical Principles for Medical Research Involving Human Subjects” Adopted Amended Amended Amended Amended Amended

June, 1964 Tokyo, 1975 Venice, 1983 Hong Kong, 1989 South Africa, 1996 Scotland, 2000

Amendment expected October 2008 ♣World Medical Association (WMA)

8

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

9

Declaration of Helsinki (Tokyo Statement, 2004)

“ 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 ”

10

Belmont Report “Ethical Principles and Guidelines for the Protection of Human Subjects of Research”

Three Principles: Respect of Persons Beneficence Justice 11

Ethical Principles (1): Respect of Persons Treat each subject as autonomous agent Those with diminished autonomy must be protected 12

Ethical Principles (2): Beneficence Subjects must not be exposed to harm Researchers must maximise any possible benefits while minimizing possible risks

13

Ethical Principles (3): 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 14

GCP: EU & UK Legislation 2001/20/EC

The “Clinical Trials” Directive

2005/28/EC

The “GCP” 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]

15

ICH-GCP: An Investigator’s Guide ...

Principles & Practice

16

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 17

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

18

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 34.7

RO 28/09/2007 19

CRFs: Typical data entry errors

Can you spot the error or errors on this page?

20

21

CRFs: Typical data entry errors

How about this one?

22

23

Valid or fake data?

24

Safety Reporting 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)

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 1.1 Article 2 (n) *EU Directives: 2001/20/EC & 2005/28/EC

25

Safety Reporting

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 defect ICH-GCP 1.50 Article 2 (o) 26

Safety Reporting

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 1.60 Article 2 (p)

27

Causal Relationship

Unrelated … Unlikely to be related … Possibly related …

“Don’t know”

Probably related … Definitely related … … to product, device or procedure 28

‘Severity’ of Adverse Events

29

Adverse Events: Summary Unrelated

Related to IMP

AE

ADR

SAE SUSAR

30

Is it a SUSAR?

31

Is it a SUSAR? … SmPC … 4.8

32

Question 1 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? 33

Answer 1

2 AEs (nausea, vomiting)

Serious adverse events are not necessarily severe; “severe” adverse events are not necessarily serious

34

Question 2 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?

35

Answer 2 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)* must be 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

36

Question 3 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?

37

Answer 3

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) 38

Question 4

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? 39

Answer 4 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 40

Adverse Event Reporting Adverse Event Non Serious

Serious Unexpected Fatal or Other Life threatening 7 days

15 days

Expected As per Protocol: including death from progressive disease if MHRA and REC approve

Trial report or periodic safety update

41

And finally ...

Call R&D: Extn 2520 (APH) or 4917 (CCO) 42