Compliance Updates from Health Canada’s Inspectorate · ASKA Research - Precision Competence Quality 3 Contact Information Suite 410 -1385 West 8 th Avenue Vancouver, BC Canada

A Division of Valerie Willetts & Associates, Inc.A Division of Valerie Willetts & Associates, Inc.

Compliance Updates from Health Canada’s InspectorateBy Valerie Willetts, RN, BScN, CCRA, CCRT

Research Coordinators Network at St. Paul’s HospitalJune 3rd, 2008

ASKA Research - Precision Competence Quality 2

We facilitate growth in our clinical research community with extraordinary serviceWe facilitate growth in our clinical research community with extraordinary service


Contact Information

Suite 410 - 1385 West 8th Avenue

Vancouver, BC Canada V6H 3V9

Phone : (604) 736-3166

Fax : (604) 736-1936

Email : [email protected]

Website: www.askaresearch.com

Contact Information

Suite 410 - 1385 West 8th Avenue

Vancouver, BC Canada V6H 3V9

Phone : (604) 736-3166

Fax : (604) 736-1936

Email : [email protected]

Website: www.askaresearch.com

CompanyCompany

BackgroundBackground


What is GCP?

�Good Clinical Practice (GCP) is a standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurances that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial Subjects are protected. Health Canada : Good Clinical Practices Consolidated Guideline, 1997 p. 5

Guidance and Principles of ICH GCP


Quality References

We associate the word ‘quality’ with words like

�Accuracy

�Consistency

�Reliability

�Safety

�Effectiveness

�Durability


Quality References

Examples of 99.9% reliability

�Two unsafe landings at O’Hare each day

�16,000 lost pieces of mail per hour

�20,000 wrong drug prescriptions each year

�22,000 cheques deducted from the wrong chequing account each hour

�50 babies dropped at birth each day


Quality References

Glossary

Quality Assurance (QA) all those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice and the applicable regulatory requirement(s)


Quality References

Glossary

Quality Control (QC) the operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled


Quality References – ICH

The Principles of ICH GCP

2.13 Systems with procedures that assure the quality of every aspect of the trial should be implemented.


Quality Reference – ICH

Sponsor

5.1.1 The Sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).



5.1.3 Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.



5.2.1 A Sponsor may transfer any or all of the Sponsor’s trial-related duties and functions to a Contract Research Organization (CRO), but the ultimate responsibility for the quality and integrity of the trial data always resides with the Sponsor. The CRO should implement quality assurance and quality control.


Quality Reference – ICH5.19 If or when Sponsors perform audits, as part of

implementing quality assurance, they should consider the purpose of a Sponsor's audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.


must include explanations of

� consequences of Subject decision to withdraw

� procedures for orderly termination of participation

must include explanations of

� probability of random assignment

� Subject responsibilities

� anticipated prorated payments (if any)

only Subject/legal representative must sign except when short form ICF presented orally

Subject/legal representative and person who administered must sign ICF

does not state that it has to be a signed copy

Subject receives signed & dated copy of IC

Informed Consent Form (ICF)

FDAICH

Global Comparison – ICH and FDA


Sponsor must provide IB to Investigator but some Sponsors require documentation of receipt from PI IRB

Investigator must provide a copy of IB to REB

REB/IRB

does not require Sponsors to obtain statement

Sponsor must obtain statement that REB is organized according to GCP

does not specifyrecommends Principal Investigator informs Subject’s physician with Subject permission

Notification to primary care Physician

FDAICH



does not specify – most PIs request and obtain from Sponsor

Sponsor provided insurance/indemnify PI against claims

Indemnification

does not specify - most Sponsor’s have internal procedures

Sponsor and PI sign the protocol

Signed protocols

does not mandate direct access

PI make ALL records available for direct access by CRA/Monitor, auditor, REB or regulatory agency

Financial records

FDAICH



does not specifyInvestigator documents and explains

documentation of protocol violations

does not require documentation of authorization to CRF changes

Monitor ensures the changes are made, dated, explained (if necessary) and initialed by PI or designee (authorization documented on signature sheet)

CRF changes

FDAICH

Global Comparison - ICH and FDA


does not specify – most Sponsors have internal procedures

prohibits shipping IP until required documentation received from REB

requires return of unused supplies; does not specify responsibility for reconciliation

PI maintains records & reconcile IP received from Sponsor

Investigational Product (IP)

FDAICH



does not require CVs for SI typically a Sponsor requirement

require CVs for PI and Sub-Investigator (SI)

CV

does not require documentation of PI/staff signatures

require signatures & initials of all persons authorized to make entries and/or corrections on CRFs

signature sheet

FDAICH



PI responsible for the accuracy and completeness

CRA responsible to ensure all study documents on file at site

Study documentation

CRA must confirm all necessary documents on site prior to study closure

does not require Sponsor to document review of MR

Sponsor must document management review of MR

Monitoring Reports (MR)

not requiredCRA report must be kept on site in Investigator file

Site Initiation Report

FDAICH



� TPD can audit both Sponsor and site.

� TPD can audit both Sponsor and site.

� FDA can audit both Sponsor and site.

� FDA can audit both Sponsor and site.

Sponsor can audit site

Global Comparison - Audits


Definitions

Audit – independent assessment to determine overall compliance and adherence to a given standard.


DefinitionsInspection – the act by a regulatory authority of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority to be related to the clinical trial and that may be located at the site of the trial, at the Sponsor’s and/or CRO facilities, or at other establishments deemed appropriate by the regulatory authority.

Reference: http://www.hc-sc.gc.ca/dhp-mps/compli-conform/clini-pract-prat/docs/insp_strat_e.html#def


GCP Compliance: Canada GCP Compliance: Canada


Health Canada Inspections

�primary focus on Subject safety

�objectives of inspections

�ensure that the generally accepted principles of Good Clinical Practices are met

�validate the quality of the data generated

�verify compliance to Division 5 and ICH GCP


GCP Compliance: CanadaGCP Compliance: Canada

Inspection of Clinical Trial Sites: Context

� Approx. 4000 sites in Canada� Up to 2% of total sites are inspected each year� 5 Regions: Atlantic, Quebec, Ontario, Central,

Western� Coordination Center: Ottawa� 10 days for regular inspection (5 days onsite)� 2 days for partial inspection� 1 or 2 Inspectors / inspection

Health Canada’s Food and Drug Regulations, Six Year Review of Clinical Trials Inspections in Canada by Asma Syed

Inspection of Clinical Trial Sites: Context

� Approx. 4000 sites in Canada� Up to 2% of total sites are inspected each year� 5 Regions: Atlantic, Quebec, Ontario, Central,

Western� Coordination Center: Ottawa� 10 days for regular inspection (5 days onsite)� 2 days for partial inspection� 1 or 2 Inspectors / inspection


27


Six Year Review of Inspections

The number of clinical trial

sites and REBs inspected

during the past six fiscal

years of the inspection

program.


Six Year Review of Inspections

The number of clinical trial

sites and REBs inspected

during the past six fiscal

years of the inspection

program.


21

0

45

5

22

2

58

11

40

1015

5

0

10

20

30

40

50

60

2002\ 03 2004\ 05 2006\ 07

Fiscal year CT Sites REBs

21

0

45

5

22

2

58

11

40

1015

5

0

10

20

30

40

50

60

2002\ 03 2004\ 05 2006\ 07

Fiscal year CT Sites REBs



Prohibition

Notification

Authorization

ADR

Modification

Application for Authorization

Labelling

Records

Good Clinical Practices

Deviations Observed at Investigator Sites

59.1%

18.6%

13.0%

2.9%

0.8%

0.6%

0.5%

0.4%

0.2%

0.2%

0% 20% 40% 60% 80%

C.05.007

C.05.003

C.05.006

C.05.014

C.05.005

C.05.008

C.05.011

C.05.001

C.05.012

C.05.010




Details of deviations from section C.05.010 of the Regulations for the

past six years

# of QI per site

Protocol

REB Approval

Medical Decision

Qualification

GMP

Protocol Deviations

Informed Consent

Systems & Procedures

# of QI per site

Protocol

REB Approval

Medical Decision

Qualification

GMP

Protocol Deviations

Informed Consent

Systems & Procedures

41.2%

16.1%

16.1%

9.7%

8.4%

4.2%

1.1%

0.9%

2.3%

0% 10% 20% 30% 40% 50%

C.05.010(c)

C.05.010(h)

C.05.010(b)

C.05.010(j)

C.05.010(g)

C.05.010(f)

C.05.010(d)

C.05.010(a)

C.05.010(e)

41.2%

16.1%

16.1%

9.7%

8.4%

4.2%

1.1%

0.9%

2.3%

0% 10% 20% 30% 40% 50%

C.05.010(c)

C.05.010(h)

C.05.010(b)

C.05.010(j)

C.05.010(g)

C.05.010(f)

C.05.010(d)

C.05.010(a)

C.05.010(e)




Observations Recorded Under Section C.05.010 from the Past Two

Years

0 (-)1 (0.5%)# of QI per siteC.05.010(e)

3 (2.5%)6 (2.9%)GeneralC.05.010

0 (-)1 (0.5%)ProtocolC.05.010(a)

2 (.7%)1 (0.5%)REB ApprovalC.05.010(d)

10 (8.4%)12 (5.9%)Medical DecisionsC.05.010(f)

15 (12.6%)12 (5.9%)QualificationsC.05.010(g)

3 (2.5%)20 (9.8%)GMPC.05.010(j)

10 (8.4%)27 (13.2%)Informed ConsentC.05.010(h)

26 (21.8%)42 (20.5%)ProtocolC.05.010(b)

50 (42%)80 (39%)System & ProceduresC.05.010(c)

2007/20082006/2007

DescriptionSubsection




� Our number one priority relates to the protection of Subjects enrolled in clinical trials, our focus for inspections will remain linked to the review of every element in the conduct of trials that has an impact on the risk to the health of the Subject.

Jean Saint-Pierre,

HPFB Inspectorate

The Global GCP Compliance Report 2006: US, EU and Japan, Barnett Educational Services, 2005, p. 223-224

� Our number one priority relates to the protection of Subjects enrolled in clinical trials, our focus for inspections will remain linked to the review of every element in the conduct of trials that has an impact on the risk to the health of the Subject.

Jean Saint-Pierre,

HPFB Inspectorate

The Global GCP Compliance Report 2006: US, EU and Japan, Barnett Educational Services, 2005, p. 223-224



Examples of Deficiencies Observed

� C.05.010(c) Systems and procedures that assure the quality of every aspect of the clinical trial are implemented;

� “There was no on-site monitoring at this site by the Sponsor, before, during and after the conduct of the clinical trial… (now a closed trial at this site).”


� C.05.010(c) Systems and procedures that assure the quality of every aspect of the clinical trial are implemented;

� “There was no on-site monitoring at this site by the Sponsor, before, during and after the conduct of the clinical trial… (now a closed trial at this site).”




� C.05.010(h) Informed consent

� “…the informed consent for… stated that there would be a total of six visits in the first fiscal year. This differed from the protocol and from the actual practice at the clinical trial site… only 3 visits…”


� C.05.010(h) Informed consent

� “…the informed consent for… stated that there would be a total of six visits in the first fiscal year. This differed from the protocol and from the actual practice at the clinical trial site… only 3 visits…”




� C.05.010(b) the clinical trial is conducted, and the drug is used, in accordance with the protocol and this Division;

� “The baseline blood chemistry tests for subject y did not include bilirubin as required by the protocol.”


� C.05.010(b) the clinical trial is conducted, and the drug is used, in accordance with the protocol and this Division;

� “The baseline blood chemistry tests for subject y did not include bilirubin as required by the protocol.”


GCP Compliance: USAGCP Compliance: USA

Food and

Drug Administration

Centre for

Drug Evaluation

and Research

CDER

Centre for

Devices and

Radiological Health

CDRH

Centre for

Biologics

Evaluation

and Research

CBER



The Global GCP Compliance Report 2006, p. 82The Global GCP Compliance Report 2006, p. 82

31%enrollment of ineligible Subjects

31%inadequate/inaccurate case histories

48%failure to follow the protocol

CBER Clinical Investigators Deficiencies, 2003-2005



“These are the issues that clinical trial sites are struggling with…but number one on my list is the lack of GCP knowledge and

training”

M. Rashti, FDA field monitoring specialist

The Global GCP Compliance Report 2006, p. 61

“These are the issues that clinical trial sites are struggling with…but number one on my list is the lack of GCP knowledge and

training”

M. Rashti, FDA field monitoring specialist

The Global GCP Compliance Report 2006, p. 61


The more things change, the more they stay the same.

~Hugh Prather

The more things change, the more they stay the same.

~Hugh Prather

Documents

Compliance Updates from Health Canada’s Inspectorate · ASKA Research - Precision Competence Quality 3 Contact Information Suite 410 -1385 West 8 th Avenue Vancouver, BC Canada