Inspection Strategy for Clinical Trials

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Cover Letter

Health Products and Food Branch
Inspectorate
Holland Cross, Tower "A"
2^nd Floor, 11 Holland Avenue
Address Locator # 3002C
OTTAWA, Ontario
K1A 0K9

January 15, 2002

01-118529-18

To: Associations

Subject: Inspection Strategy for Clinical Trials

I am pleased to inform you that the approved version of the "Inspection Strategy for Clinical Trials" is now available on the Inspectorate Website at:

Compliance and Enforcement

This strategy was developed by the Health Products and Food Branch Inspectorate (HPFBI), in consultation with the Therapeutic Products Directorate (TPD) and the Biologics and Genetic Therapies Directorate (BGTD) of the Health Products and Food Branch (HPFB). Comments received from our stakeholders on the draft version published on August 31, 2001 were considered.

The implementation of the inspection component of this inspection strategy starts in January 2002. Activities related to investigations will be performed as needed.

Further communications with representatives of stakeholders will take place in the Fall 2002 to obtain further feedback and communicate expectations of this new inspection function.

Inquiries about this document can be addressed to Jean Saint-Pierre, Coordinator, Good Clinical Practices, National Coordination Centre, Health Products and Food Branch Inspectorate by telephone at (613) 952-8173, by fax at (613) 952-9805 or by e-mail at jean_saint_pierre@hc-sc.gc.ca.

Original signed by
Daniele Dionne (for)

Jean Lambert
Director General

Cover Page

OUR MANDATE:

To promote good nutrition and informed use of drugs, food, medical devices and natural health products, and to maximize the safety and efficacy of drugs, food, natural health products, medical devices, biologics and related biotechnology products in the Canadian marketplace and health system.

Health Products and Food Branch Inspectorate Policy Inspection Strategy for Clinical Trials

Supersedes
Draft issued August 31, 2001

Date issued
January 15, 2002

Date of implementation
January 15, 2002

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Contact Information and Complete Document for Printing

Table of Content:

1. Purpose
2. Background
3. Scope
4. Definitions
5. Compliance and Monitoring Activities
6. Response to Non-Compliance
7. Responsibilities
8. Procedures
9. Effective Date
10. References

1. Purpose

The purpose of this document is to inform all stakeholders involved in clinical trials including sponsors, the research community, patient groups, associations and others about the strategy Health Canada intends to adopt for the effective and uniform implementation of the new Regulations on Clinical Trials as detailed in Division 5 of the Regulations to the Food and Drugs Act.

2. Background

As part of the regulatory amendments to the Food and Drug Regulations on clinical trials, an inspection function for clinical trials was announced on January 21, 2000 by the Minister of Health. These new regulations, Drugs for Clinical Trials Involving Human Subjects, came into force on September 1, 2001. Regulatory activities to be conducted will include inspections and investigations to assess compliance with these Regulations.

Inspections and investigations will be conducted by Health Canada under the authority of section 23 of the Food and Drugs Act. These activities will be conducted by the Health Products and Food Branch Inspectorate (HPFBI). Collaboration with all stakeholders involved in clinical trials will be essential to ensure compliance with the new Regulations.

Investigations of clinical trials involving any stakeholders may be initiated. As of September 1, 2001, all clinical trials are subject to Division 5; investigations will be carried out in accordance with the new Division. However, in the case of clinical trials authorized prior to September 2001, the applicable Regulations, including Division 8, will be used.

3. Scope

This inspection strategy applies to all clinical trials as defined in Division 5 of the Food and Drug Regulations. Inspections will be performed according to these Regulations, which integrate the rules of conduct of Good Clinical Practices (GCP) as described in the International Conference on Harmonization Guidance document E6 and adopted by the Health Products and Food Branch. Inspections and investigations will be in accordance with Division 5 and will be conducted mainly at Qualified Investigator sites, Sponsors and Contract Research Organizations.

Inspections at Qualified Investigator sites, also referred to as clinical trial sites, will be performed to assess compliance with the Regulations and GCP, as adopted by Health Canada in 1997. These inspections will allow verification of source documents, including medical records, drug accountability and storage conditions. Direct and on-site access to those records should provide increased assurance that the confidentiality of the records will be maintained.

The main objectives for the inspection of clinical trials is to ensure that the generally accepted principles of good clinical practices are met, validate the quality of the data generated, and verify compliance to Division 5 of the Regulations.

4. Definitions

Clinical trial

Division 5 of the Food and Drug Regulations defines a Clinical Trial as, "an investigation in respect of a drug for use in humans that involves human subjects and that is intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events in respect of the drug, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug."

Good clinical practices

Division 5 defines Good Clinical Practices as, "generally accepted clinical practices that are designed to ensure the protection of the rights, safety and well-being of clinical trial subjects and other persons, and the good clinical practices referred to in section C.05.010."

Inspection

The International Conference on Harmonization defines "inspection" in topic E6 of the Guidelines for Good Clinical Practice as "The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor's and/or contract research organization's (CRO's) facilities, or at other establishments deemed appropriate by the regulatory authority(ies)".

Investigation

Specific response to known or suspected non-compliance. Investigations typically are undertaken when there are reasonable grounds to suspect that noncompliance has occurred and that enforcement measures may be necessary (e.g. product quality complaints, reports from other regulatory authorities, reports of adverse reactions).

For additional definitions, please consult the Food and Drug Regulations, Division 5.

5. Compliance and Monitoring Activities

The Health Products and Food Branch (HPFB) will provide information and encourage voluntary compliance to Canadian Regulations and standards. Compliance will be assessed through inspection and investigation.

5.1 Inspection

5.1.1 Two phases are planned for the implementation of inspections. First, there will be a one (1) year confidence building and voluntary phase starting January 1, 2002. During this period, inspections will be performed at the request of the Sponsor. These inspections will be limited in number.

Second, the final implementation phase will commence on January 1, 2003. From that date, the Inspectorate will become responsible for site selection. The selection will be made according to the following criteria:

• Number of clinical trials conducted at the site.
• Number of subjects enrolled in the specified clinical trial.
• Number of serious unexpected adverse drug reactions at the clinical trial site.
• Observations made during past inspections.

5.1.2 Inspection activity:

• Sponsors, Qualified Investigators, Contract Research Organizations and Site Management Organizations will be inspected.
• Up to 2% of all Canadian clinical trial sites will be inspected each year. This percentage is based on experience in other jurisdictions where audits / GCP inspections are conducted. This represents approximately 80 inspections per year and is based on information that there are approximately 4000 on-going clinical trials in Canada. The total number of inspections may vary depending on the time required for investigations.
• Two types of inspections will be performed:
  • inspection during clinical trials, and
  • inspection after the completion of clinical trials.
• The choice of inspection sites will be reviewed periodically in consultation with the Therapeutic Products Directorate (TPD) and the Biologics and Genetic Therapies Directorate (BGTD) of the HPFB and will take into consideration:
  • the level of risk to the enrolled subjects, and
  • the observations made during past inspections.
• Compliance will be assessed in accordance with Division 5 of the Food and Drug Regulations, Good Clinical Practices (GCP) and other pertinent guidelines.
• An average time of one week per inspection is envisaged. Most inspections will be conducted as announced inspections and will give sufficient preparation time to the concerned parties. Unannounced inspections may be conducted at the discretion of Health Canada.

5.1.3 Good Manufacturing Practices (GMP) Inspections of drugs used in clinical trials: GMP inspections will be conducted separately from the GCP inspections and will be in accordance with the regulations and policies pertaining to the manufacture and sale of drug products in Canada.

5.1.4 Rating and reporting:

• Two ratings will be used:
  • compliant, and
  • non-compliant
• Reports will be generated using the Inspection Reporting System of the HPFB Inspectorate and will be issued to Sponsors in a timely manner.
• Responses to the observations made in the Inspection Report will be required from the party being inspected.
• A formal appeal process will be instituted.
• The reports will be written in such a way as to protect the identity of subjects.
• Results of inspections may be accessible, according to the Access to Information Act.

5.2 Investigation

When a potential noncompliance or risk has been identified by Health Canada, an investigation will be conducted if deemed necessary. Problems or concerns related to the performance of clinical trials may originate from:

• External sources or referrals from other jurisdictions.
• Internal Branch and Departmental sources, such as TPD and BGTD.

6. Response to Noncompliance

Where non-conformity to Regulations is identified, the Sponsor will have the opportunity to correct identified deficiencies. The Inspectorate will consider actions where necessary in accordance with its Compliance and Enforcement Policy. In all cases, the results will be communicated to TPD or BGTD with the information required to make appropriate recommendations regarding:

• the suspension of authorization to proceed with the clinical trial, and
• the assessment of the validity of the data submitted.

7. Responsibilities

It is the responsibility of the Inspectorate and all stakeholders to collaborate and act in partnership in the application of this Inspection Strategy.

8. Procedures

Specific investigations and inspections activities will be documented and supported by detailed standard operating procedures.

9. Effective Date

The implementation date of investigation activities under the new Regulation is September 1, 2001. The confidence building and voluntary inspection phase will be initiated on January 1, 2002. It is expected that the second and final phase will start on January 1, 2003.

Communications with representatives of all stakeholders is scheduled to take place in the Fall 2002, once sufficient data has been collected for reporting on the outcome of the first phase of the confidence building and voluntary phase. The objective will be to share further the expectations from the inspection strategy, along with concerns, if any, from this new Regulatory initiative.

10. References