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Clinical Trial Applications for Comparative Bioavailability Studies for Pharmaceuticals

2001-10-09
01-114186-294

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Contact: Bureau of Pharmaceutical Sciences (BPS) Enquiries

Therapeutic Products
Directorate
Holland Cross, Tower "B"
6th Floor, 1600 Scott Street
Address Locator # 3106B
Ottawa, Ontario
K1A 1B6

To: Associations

In light of the amendments to the Food and Drug Regulations (1024 - Clinical Trials), the Therapeutic Products Directorate (TPD) has taken the opportunity to develop a draft Guidance document and a Quality Overall Summary template for the purpose of clarifying the requirements for Clinical Trial Applications (CTAs) for comparative bioavailability studies for pharmaceuticals. This Guidance document and Quality Overall Summary template outline the specific requirements for filing comparative bioavailability studies and the process for the review and approval of these applications. The document will be available in French when translation is completed.

This and other Guidance documents and forms for Clinical Trial Applications (as outlined below) are available on the Therapeutic Products Directorate (TPD) Website).

  • CTA Guidance Document
  • CTAs for Comparative Bioavailability Studies
  • Quality Guidance for CTAs
  • Quality Overall Summary - Chemical Entities (CTAs) (QOS-CE (CTAs))
  • Quality Overall Summary - Bioavailability Studies (CTAs) (QOS-BS (CTA))
  • Revised Application Form HPB 3011
  • Clinical Trial Site Information Form C Qualified Investigator Undertaking
  • Research Ethics Board Attestation Form
  • ADR Expedited Reporting Summary Form
  • Electronic Clinical Trials Application

The forms should be used when filing Clinical Trial Applications. The existing HPB 3011(06-00) posted on the website under Forms should continue to be used for all submission types other than Clinical Trial Applications and Amendments.

Please note that the current acceptable electronic format for Clinical Trial Applications is WordPerfect. It is expected that as the project on the implementation of electronic-CTA (e-CTA) evolves, the requirements for electronic format will likely change.

The deadline to provide comments on the attached documents is November 30, 2001. Any comments regarding the documents may be forwarded to:

Dr. Siddika Mithani
Bureau of Pharmaceutical Assessment
A.L. 0202C1
Finance Building
Tunney's Pasture
Ottawa, Ontario
K1A 1B9
E-mail: siddika_mithani@hc-sc.gc.ca

These documents will be further revised as necessary, following comments received.

Yours sincerely,

Original signed by:

Robert G. Peterson, MD, PhD, MPH
Director General

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with the policies and governing statutes and regulations. They also serve to provide review and compliance guidance to staff, thereby ensuring that mandates are implemented in a fair, consistent and effective manner.

Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this guidance, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidances.

Document Change Log
Change Date Location (section, paragraph) Nature of and/or Reason for Change
2001/10/09   Draft Date
2008/02/27 Appendix 4 and
throughout document		 Reflecting necessary changes from finalization of the protocol safety and efficacy assessment template - clinical trial application (PSEAT-CTA).

Table of Contents


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1.0 Purpose

Sponsors must file a Clinical Trial Application (CTA) with the Health Products and Food Branch (HPFB) of Health Canada prior to conducting a clinical drug trial, including a comparative bioavailability study.

HPFB has published a number of guidance documents to assist sponsors in filing the necessary information. This guidance document defines the application requirements for sponsors wishing to conduct comparative bioavailability studies for pharmaceuticals where:

  1. the studies are performed on healthy adult volunteers;

  2. the reference drug product is marketed in Canada, US, EU, Australia, or Switzerland; and

  3. the study does not include a maximum single or total daily dose that exceeds that specified in the labelling of the reference drug product; or the simultaneous administration of a radioactive labelled and unlabelled drug product.

Note: Non-Canadian Reference Products may be acceptable for use in comparative bioavailability studies intended for submission to the HPFB in support of Abbreviated New Drug Submissions only if they meet the criteria defined in the HPFB guidance Canadian Reference Product (December 4, 1995).

This guidance document supersedes the HPFB policy Clinical Trials Review and Approval Policy (1997), as it related to this type of comparative bioavailability studies.

2.0 Regulatory Framework

The Food and Drug Regulations provide authority to the Health Products and Food Branch (HPFB) of Health Canada to regulate the sale of drugs for the purposes of use in human clinical trials. Division 5 of the Regulations define specific Clinical Trial Application (CTA) requirements and prescribe a 30- day default review period for these applications.

The Regulations are consistent with the principles, definitions and standards found in the Good Clinical Practice: Consolidated Guideline 1, General Considerations for Clinical Trials 2 and Clinical Safety Data Management: Definitions and Standards for Expedited Reporting 3. These guidelines, developed through the International Conference on Harmonization 4 (ICH) process have been adopted by the HPFB. Together, they define parameters for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials.

Sponsors 5 must file applications to conduct clinical trials in Phases I through III of drug development. This includes applications to conduct clinical trials involving marketed products where the proposed of the product is outside the parameters of the approved Notice of Compliance (NOC) or Drug Identification Number (DIN) application.

Applications to conduct Phase IV trials 6 do not need to be filed with the HPFB. The HPFB may authorize the sale of a drug for use in a clinical trial if the protocol is scientifically sound, meets the regulatory requirements, and the drug is considered not to pose an unacceptable risk to the trial subjects under the proposed conditions of use.

A CTA must be filed prior to the initiation of a clinical trial in Canada. HPFB must review the application and notify the sponsor within 30 days if the application is found to be deficient or else the sponsor may proceed.

HPFB targets to review applications to conduct comparative bioavailability trials and Phase I trials in healthy adult volunteers within seven days, with the exception of applications for Phase I trials using somatic cell therapies, xenografts, gene therapies, prophylactic vaccines or reproductive and genetic technologies. Trials which do qualify for the expedited review process cannot however proceed within the seven days unless a No Objection Letter (NOL) is received from the HPFB.

1 Therapeutic Products Directorate Guideline/ICH Harmonized Tripartite Guideline: Good Clinical Practice: Consolidated Guideline: Cat. No. H42-2/67-11-1997IN

2 Therapeutic Products Directorate Guideline/ICH Harmonized Tripartite Guideline: General Considerations for Clinical Trials: Cat. No. H42-2/67-12-1997IN

3 Therapeutic Products Directorate Guidelines/ICH Harmonized Tripartite Guideline: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting: Cat. No. H42-2/67-8-1995

4 For more information on the Next link will take you to another Web site International Conference on Harmonization, consult the ICH website.

5 Sponsor means an individual, corporate body, institution or organization that conducts a clinical trial.

6 Post-marketing trials that are proposed to be conducted within the parameters of the Notice of Compliance (NOC) or Drug Identification Number (DIN) approved for that product. For example: epidemiological trials, pharmacoeconomic evaluations, additional drug-drug interaction, dose-response and safety trials, etc.

3.0 Clinical Trial Applications (CTAs)

Applications must be filed by the sponsor prior to the initiation of the trial.

Sponsors must conduct all clinical trials, including Phase IV trials, in accordance with the principles of Good Clinical Practice.

Sponsors are not required to file a CTA for clinical trials involving marketed drugs where the investigation is to be conducted within the parameters of the approved NOC or DIN application. These trials are often referred to as Phase IV clinical trials and may include epidemiological studies, pharmaco-economic evaluations, mortality/ morbidity studies, additional drugdrug interaction, dose-response and safety studies, etc. The use of a marketed drug by a physician or dentist for individual patient treatment is not considered to be a clinical trial.

The requirements for filing a CTA are defined in Division 5 of the Food and Drug Regulations. This guidance document defines the requirements for filing CTAs for comparative bioavailability studies for pharmaceuticals that are conducted in healthy adult volunteers as described in 1.0.

3.1 CTA Requirements for Comparative Bioavailability Studies for Pharmaceuticals

CTAs should be filed directly to the Therapeutic Products Directorate, addressed to the attention of the Director. The outer label of the shipping carton should be clearly identified with "Clinical Trial Application for Bioavailability Studies." Items marked with an asterisk (*) should be submitted in hard copy and in electronic format approved by the HPFB.

Part 1: Master Volume

The Master Volume must include:

  1. a cover letter;

  2. a completed and signed Drug Submission Application Form (HPB 3011);

  3. a completed CTA Application/Attestation Form [Appendix 2 of the Drug Submission Application Form, HPB 3011], signed by the Senior Medical or Scientific Officer in Canada and the Senior Executive Officer;

  4. a Table of Contents, including a listing of the contents of Part 1 (Master Volume) and Part 2 (Quality or Chemistry and Manufacturing);

  5. * a submission rationale;

  6. a listing of prior applications relating to the drug in Canada;

  7. * a copy of the current labelling and Product Monograph/Prescribing Information for the reference product;

  8. * a copy of the final proposed protocol(s), including a protocol outline in the format of the Protocol Safety and Efficacy Assessment Template - Clinical Trial Application (PSEAT-CTA) [Appendix 4];

  9. copy of the Informed Consent document(s) to be used in conjunction with the clinical trial(s), including a statement regarding the risks and anticipated benefits to the clinical trial subjects as a result of their participation in the clinical trial(s);

    Informed Consent document(s) to be used in conjunction with the clinical trial(s) should be prepared in accordance with the HPFB guideline Good Clinical Practice: Consolidated Guideline.

  10. a list of proposed clinical trial sites, the proposed date of commencement at each site, the name of the qualified investigator responsible for each site, and the name of the REB that approved the protocol and informed consent form at each site (if known at the time of the application) [Clinical Trial Site Information Form]; If not available at the time of the application, the name, address, telephone number and, if applicable, fax number and e-mail address of the qualified investigator and REB must be submitted prior to commencement of the trial at each site. This information will be added to the file upon receipt; however, an acknowledgment letter will not be sent to the sponsor upon receipt of this information.

    The REB that approves the trial must be comprised of at least five members, the majority of whom are Canadian citizens or permanent residents. Board members must collectively possess the experience and expertise defined in section C.05.001 of the Regulations.

  11. information related to REB refusals to approve the protocol, if applicable, including the name, address, telephone number and, if applicable, the fax number of the REB, the reasons for the refusal and the date on which refusal was given;


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Part 2: Quality (Chemistry and Manufacturing)

This Part does not apply, if the test drug product to be used in the clinical trial has been assigned a Drug Identification Number and/or a Notice of Compliance. If the Quality (Chemistry and Manufacturing) information was previously submitted to the HPFB by the sponsor of this CTA and has not changed, re-submission of the applicable Quality Summary template is not required. Sponsors should however, refer to the Control Number of the prior application.

Please refer to the following documents:

  • Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications
  • Quality Overall Summary - Bioavailability Studies (CTAs)(QOS-BS(CTA))
  • Quality Overall Summary - Chemical Entities (CTAs) (QOS-CE(CTA))

If the reference lot used in the clinical trial is for a Reference Drug Product that is marketed in Canada, US, EU, Australia or Switzerland, sponsors should complete the QOS-BS (CTA) . Otherwise, the QOS-CE (CTA) should be completed.

Provide one hard copy in a separate volume and one electronic copy on a separate diskette of the completed Quality Summary in the HPFB approved electronic format (e.g., diskette or CDROM) as well as additional Quality (Chemistry and Manufacturing) information outlined in the Quality Summary;

Note: It is expected that the manufacturing and controls of the clinical trial material will be subjected to the GMP compliance.

4.0 CTA Amendments

CTA Amendments are applications in which a sponsor proposes information to support changes to a previously approved application. CTA-Amendments may involve changes to clinical trial supplies, e.g., the manufacturing process for the drug has changed, changes to a proposed protocol, or both.

CTA Amendments must be approved by the HPFB prior to implementation of the changes. Amendments submitted with a CTA or when the CTA is under review will not be accepted. Where a sponsor wishes to make significant changes to the CTA under review, the sponsor must withdraw the active CTA and submit a new Clinical Trial Application.

To eliminate an immediate hazard to clinical trial subjects however, the sponsor may amend the protocol without prior review by the HPFB. A corresponding CTA-Amendment which provides the information required below, and which clearly identifies the change and the rationale for immediate implementation of the change must be filed within 15 days of the change.

4.1 Clinical Amendments

Sponsors must file a Clinical Amendment when the proposed changes:

  1. affect the selection, the criteria for selection, monitoring, or dismissal of subjects in the clinical trial;

  2. affect the evaluation of the clinical efficacy of the drug;

  3. alter the risk to health of a clinical trial subject;

  4. affect the safety evaluation of the drug; or,

  5. extend of the duration of the clinical trial.

4.1.1 Filing a Clinical Amendment

A single copy of the application should be filed directly to the Therapeutic Products Directorate, addressed to the Director. The outer label should be clearly labelled with "Clinical Trial Application - Amendment" Items marked with an asterisk (*) should be submitted in both hard copy and electronic formats as approved by the HPFB.

All Clinical Amendments should consist of a Master Volume containing the following:

  1. a cover letter

    This should be cross-referenced to the original CTA(s) and should include any Control number(s) or submission tracking number(s) previously assigned;

  2. a completed and signed Drug Submission Application Form (HPB 3011);

  3. a completed Clinical Trial Application/Attestation Form [Appendix 2 of the Drug Submission Application Form, HPB 3011], signed by the Senior Medical or Scientific Officer in Canada and the Senior Executive Officer;

  4. * a complete copy of the amended protocol that clearly indicates what changes are being proposed;

    This should include a copy of the original protocol and a rationale for each proposed change.

  5. revised statements, regarding the protocol amendments being made, to be included in the Informed Consent document;

  6. the proposed date of implementation of the amended protocol at each site;

  7. the name of the REB that approved the amended protocol and Informed Consent document at each site [Clinical Trial Site Information Form];

  8. the name(s) of the qualified investigator(s) at each site, if changed from the original application [Clinical Trial Site Information Form];

  9. the name, address, telephone number and, if applicable, fax number and e-mail address of the qualified investigator(s) and REB [Clinical Trial Site Information Form];

    If not available at the time of filing of the application, information outlined in (g), (h) and (i) above must be submitted prior to the implementation of the change at each site [Clinical Trial Site Information Form].

  10. information related to REB refusals to approve the amended protocol, if applicable, including the name, address, telephone number and if applicable, the fax number and e-mail address of the REB, the reasons for the refusal and the date on which the refusal was given.

4.2 Quality Amendments

Sponsors must file a Quality Amendment to a previously approved application when changes that may affect the quality or safety of the clinical trial supplies are proposed. Changes to the quality summary subsections listed below, but not limited to, warrant the filing of a Quality Amendment:

  1. S 3 Control of the Drug Substance, where a new impurity or degradation product has been identified or where a test is removed from the specification and/or the test methods or limits are relaxed;

  2. P 1 Description and Composition of the Drug Product, where new ingredients are used, including ingredients which do not appear in the final product;

  3. P 3 Control of the Drug Product, where a new impurity or degradation product has been identified or where a test is removed from the specification and/or the test methods or limits are relaxed.

4.2.1 Filing a Quality Amendment

Submit one (1) copy of the following information to the Therapeutic Products Directorate, addressed to the Director. Clearly identify the submission on the outer label with "Clinical Trial Application - Amendment"

All Quality Amendments should contain the following:

  1. a cover letter highlighting all proposed changes together with an attestation thatthere are not any other changes other than those highlighted, the submission tracking number(s) for the original CTA(s) should also be included;

  2. completed and signed Drug Submission Application Form (HPB 3011) and

  3. a completed Clinical Trial Application/Attestation Form [Appendix 2 of the Drug Submission Application Form, HPB 3011], signed by the Senior Medical or Scientific Officer in Canada and the Senior Executive Officer, and

  4. one hard copy in a separate volume and one electronic copy on a separate diskette of the applicable updated quality summary [QOS-BS (CTA)] in the HPFB approved electronic format, e.g., diskette or CD-ROM, as well as supporting quality (chemistry and manufacturing) information.


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5.0 CTA and CTA-Amendment Review Process

All CTAs and CTA-Amendments are subject to a 30-day default review period from the date of receipt in the HPFB. Nevertheless, HPFB targets to review applications to conduct comparative bioavailability trials and Phase I trials in healthy adult volunteers within seven (7) days, with the exception of Phase I trials using somatic cell therapies, xenografts, gene therapies, prophylactic vaccines or reproductive and genetic technologies.

5.1 Screening

All CTAs and CTA Amendments will be screened for acceptability and deficiencies identified at screening will be addressed by either:

a) a Request for Clarification (Clarifax), or
b) a Screening Deficiency/Rejection;

5.1.1 Request for Clarification

Requests for clarification that are issued during screening should be responded to within two (2) calendar days. A Screening Deficiency/Rejection will be issued if a response to the clarification request has not been provided.

5.1.2 Screening Deficiency Notice

Screening Deficiency Notices will be issued when significant information requirements have not been included in the CTA or CTA Amendment. Sponsors will be sent a letter itemizing all the information required to complete their application and will be notified when the completed CTA has been received.

5.2 Review

The sponsor is responsible for resolving issues identified during HPFB review. Sponsors must respond to and provide the information requested by Clarifax within two (2) calendar days.

A Not Satisfactory Notice (NSN) will be issued if significant deficiencies are identified during the review of the application, or if a timely response to a Clarifax issued has not been provided.

If there have not been any deficiencies identified and the trial is deemed acceptable, a No Objection Letter (NOL) will be issued within the review period. Sponsors of trials which qualify for the expedited seven day target review process cannot proceed within the shortened time frame until a No Objection Letter (NOL) is received.

In the case where a sponsor provides an attestation that certain Quality (Chemistry and Manufacturing) data will be provided prior to the commencement of the study (e.g., a certificate of analysis for the drug product used in the bioavailability studies), a No Objection Letter will be issued including conditions that the data must be provided prior to the commencement of the study within an agreed upon time frame (e.g., seven calendar prior to the study). The sponsor may proceed with the study unless notified by the Directorate. If the data is not provided by the sponsor within the time frame, the study should not proceed.

5.3 Filing of Trial Commencement Information

Following receipt of a No Objection Letter (NOL), and prior to commencement, sponsors are required to complete and submit, by fax or e-mail, to the Therapeutic Products Directorate, site and start date information for each clinical trial site [Clinical Trial Site Information Form]. This information will be added to the file but will not be subject to an acknowledgement letter.

6.0 Notification

Sponsors must notify the HPFB of the following changes, within 15 calendar days of the day of the change:

  1. changes to the protocol that do not affect the safety of the trial participants;

  2. when the clinical trial has been discontinued in its entirety or at any clinical trial site for reasons not related to the safety of clinical trial participants (e.g. for administrative purposes, lack of recruitment, etc);

  3. changes to Quality (Chemistry and Manufacturing) information that do not affect the quality or safety of the drug, for example:

    1. production scale-ups with no changes in the process;
    2. tightening of existing test specifications;
    3. changes in contract testing laboratories;
    4. changes in packaging material;
    5. extension of expiry dating periods based on the satisfactory stability data, and
    6. changes not listed under Section 4.2;

Updated information regarding the change should be submitted. The change may then be implemented immediately.

7.0 Labelling Requirements

Labelling of clinical trial supplies must include the following information in both official languages:

  1. the statements "Investigational Drug" and "To be used by Qualified Investigator Only" and the French equivalents "Drogue de recherche" and "Reservee uniquement a l'usage de chercheurs competents."

  2. the name, number, or identifying mark of the drug;

  3. expiry date;

  4. the recommended storage conditions

  5. the lot number;

  6. the name and address of the sponsor;

  7. the protocol code or identification.

8.0 Continuous Assessment


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8.1 Premature Discontinuation of a Trial

In the event of the premature discontinuation of a trial in its entirety or at a clinical trial site for which a Clinical Trial Application has been filed in Canada, the responsible Directorate must be notified as soon as possible but no later than 15 calendar days from the date of discontinuance.

This notification should include the following information:

  1. a detailed rationale for this action, particularly if the trial is discontinued for issues relating to the safety of clinical trial subjects;

  2. a description of the impact on the proposed or ongoing trials in Canada;

  3. confirmation that the sale or importation of the drug to all sites involved has been stopped;

  4. confirmation that reasonable measures to ensure the return of all unused quantities of the drug will be taken, and

  5. confirmation that all qualified investigators have been notified of the discontinuation and the reasons for the discontinuance and have been advised in writing of any potential risks to the health of clinical trial subjects or other persons.

The sponsor may resume the trial in its entirety or at a site that was previously discontinued if the sponsor submits the following information:

  1. the name of the qualified investigator for each site and the REB that approved reinitiation of the trial at each site;

  2. information related to REB refusals to resume the trial, if applicable, and

  3. the proposed date of re-initiation at each site.

This information will be subject to review, and should be submitted as a CTA Amendment (see Section 4.0), in conjunction with the information submitted at the time of notification of trial suspension. Sponsors may only resume a trial in the absence of written communication from the appropriate Directorate within 30 days of the submission of the information.

8.2 Adverse Drug Reactions (ADRs)

An adverse drug reaction is a response to a drug which is noxious and unintended.

Only adverse drug reactions that are both serious and unexpected are subject to expedited reporting to the HPFB. Expedited reporting of reactions which are serious but expected is not required and expedited reporting is also inappropriate for serious events from clinical investigations that are considered unrelated to the study product, whether the event is expected or not.

During a clinical trial the sponsor is required to inform the HPFB of any serious, unexpected adverse drug reaction that has occurred inside or outside Canada:

  1. where it is neither fatal nor life-threatening, within 15 days after becoming aware of the information;

  2. where it is fatal or life-threatening, immediately where possible and, in any event, within seven days after becoming aware of the information, and

  3. within eight days after having informed the HPFB of the ADR, submit a complete report which includes an assessment of the importance and implication of any findings made.

Each ADR which is subject to expedited reporting should be reported individually in accordance with the data element(s) specified in the HPFB guideline Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, (1995).

A completed ADR Expedited Reporting Summary Form should be attached to the front of the report and reports should be submitted, by fax, directly to the appropriate review Directorate. Hard copies of ADR reports should not be submitted.

Further definitions and standards for expedited reporting adverse drug reactions are described in the HPFB guideline Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, (1995). In situations when causality assessment and determination of expectedness is not straightforward, the report should be submitted in the expedited manner and the relevant issues addressed in a covering letter.

Final reports of fatal or life-threatening reactions must include an assessment of the importance and implication of the findings, including relevant previous experience with the same or similar drugs.

There are situations in addition to the above that may necessitate rapid communication to HPFB, and appropriate scientific and medical judgment should be applied to each situation. For example, information that might influence the risk-benefit assessment of a drug or that would be sufficient to consider changes in drug administration or in the overall conduct of a clinical trial represent such situations, including:

  1. for an "expected" serious ADR, an increase in the rate of occurrence which is judged clinically important;

  2. a significant hazard to the patient population, such as lack of efficacy with a drug treating a life-threatening disease, and

  3. a major safety finding from a newly completed animal study.

Adverse reactions reported to the HPFB in an expedited manner, as described in Section 8.2, should be simultaneously conveyed to investigators and their REBs.

9.0 Records

Sponsors must maintain the following information as records for a period of 25 years.

  1. all versions of the Investigator's Brochure, including records of each change with the rationale for the change and documentation to support the change;

  2. all adverse events for the drug, irrespective of country of reporting, indication(s) being investigated, or dosage form including:

    1. tabular summaries of:
      • the most serious adverse event (AE);
      • the most frequent AE (>3%);
      • drop-outs due to AE;
      • the remaining AE (<3%); and
      • list of subjects who died during the investigation, organized by cause of death [this information should be organized by indication];

    2. line listing of all expedited safety reports submitted (sponsor's case identificationnumber, study identifiers, reaction reported, outcome);

  3. enrollment records for clinical trial subjects including the number of subjects/patients initially planned for inclusion in the trial, number enrolled in the trial to-date, number treated to-date, number of those who completed the trial, number of those who dropped out of trial for any reason, and number of those who dropped out of trial due to any adverse event, whether or not thought to be drug related;

  4. documentation on shipment, receipt, disposition, return and destruction of the drug;

  5. undertakings signed by qualified investigators, stating that he or she will conduct the trial according to Good Clinical Practices and that he or she will inform both the clinical trial subjects and the REB at the site if the trial is discontinued. If the trial is discontinued for safety reasons, the investigator must advise these parties in writing of any potential risks to health [Qualified Investigator Undertaking Form].

  6. copies of the protocol, informed consent form and any amendment to the protocol or informed consent form that have been approved by the REB for each site

  7. attestations signed by the REB that approved the protocol at each site that it carries out its functions in a manner consistent with Good Clinical Practices [Research Ethics Board Attestation Form].

Sponsors should also maintain the following information as records:

  1. a brief summary of significant foreign marketing developments with the drug during the past year, such as approval of marketing in any country, or withdrawal, or suspension from marketing in any country, or any safety related regulatory action taken by foreign authorities;

  2. self-auditing of an institution must be kept on file and made available upon request.

Records must be made available to the relevant Directorate within 2 days if there is a concern regarding the use of the drug for the purposes of a clinical trial and a risk to health of the subjects involved in that trial. In any other case, records must be provided within 7 days of a request.

10.0 Research Ethics Board Review

Prior to initiating a clinical trial at a site, the proposed trial protocol and informed consent must be reviewed and approved by a Canadian Research Ethics Board (REB). REB members must collectively possess the expertise defined in the Regulations.

As described previously, the sponsor must:

  1. submit the name of the REB that approved the trial prior to the commencement of the trial at that site;

  2. retain as records, an attestation signed by the REB that approved the protocol at each site that it carries out its functions in a manner consistent with Good Clinical Practices, and

  3. submit information pertaining to the refusal of the protocol for any reason by a REB.

Further information on standards relevant to REB review of clinical trials are available in the Good Clinical Practice: Consolidated Guideline and Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans7

7 Medical Research Council of Canada, Natural Sciences and Engineering Research Council of Canada, Social Sciences and Humanities Research Council of Canada: Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, August 1998


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11.0 Qualified Investigators

Under the Food and Drug Regulations, a qualified investigator must be a licensed physician or dentist. There must be no more than one qualified investigator at each site. The investigator is responsible for the medical decisions and care provided to clinical trial subjects.

As described previously, the sponsor must:

  1. submit the name of the qualified investigator for each site prior to the commencement of the trial at that site; and

  2. retain as records, an undertaking signed by the qualified investigator stating that he or she will conduct the trial according to Good Clinical Practices and that he or she will inform both the clinical trial subjects and the REB at the site if the trial is discontinued. If the trial is discontinued for safety reasons, the investigator must advise these parties in writing of any potential risks to health.

12.0 Index of Appendices

Appendix 1: List of Abbreviations

ADR
Adverse Drug Reaction
AE
Adverse Event
CTA
Clinical Trial Application
GCP
Good Clinical Practice: Consolidated Guideline
HC
Health Canada
HPFB
Health Products and Food Branch
ICH
International Conference on Harmonization
NOC
Notice of Compliance
NOL
No Objection Letter
NSN
Not Satisfactory Notice
PSEAT-CTA
Protocol Safety and Efficacy Assessment Template - Clinical Trial Application
QOS-BS (CTA)
Quality Overall Summary - Bioavailability Studies (CTA)
REB
Research Ethics Board

Appendix 2: Pertinent Internet Website Addresses

Appendix 3: Reference Documents

The HPFB guideline on Good Clinical Practice: Consolidated Guideline supersedes the existing guidelines Preparation of Investigational New Drug Submissions (1991) and Conduct of Clinical Investigations (1989). Sponsors are reminded that additional HPFB guidance documents regarding the nature of clinical studies and the target population studied should be followed. These guidelines include, but are not limited to, the following

Reference Document Access
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (1995) CGPC Order Form
Dose-Response Information to Support Drug Registration (1994) CGPC Order Form
Extent of Population Exposure to Assess Clinical Safety, The (1995) CGPC Order Form
Inclusion of Paediatric Subjects in Clinical Trials (draft, 1997) TPD Website
Inclusion of Women in Clinical Trials (1997) TPD Website
Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals  
Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications TPD Website
Structure and Content of Clinical Safety Reports (1997) TPD Website
Studies in Support of Special Populations: Geriatrics (1994) CGPC Order Form
Timing of Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals. TPD Website
Toxicological Evaluation CGPC Order Form
Tri-Council Policy Statement Next link will take you to another Web site Ethical Conduct for Research Involving Humans (1998)

The following templates required for Clinical Trial Applications are available on the TPD website:

Protocol Safety and Efficacy Assessment Template - Clinical Trial Application (PSEAT-CTA)

Quality Overall Summary - Bioavailability Studies (CTA) (QOS-BS (CTA))

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Appendix 4: Guidance Notes for Protocol Synopsis (PSEAT-CTA)

Guidance Notes: "Protocol Synopsis"

Trial Title and Protocol Number/Code

Provide the title and protocol number/code of the trial. The version number of the protocol should also be provided.

Background and Rationale

A brief, concise introduction into the clinical problem and previous treatments and developments, i.e., pertinent data from previous preclinical/clinical pharmacology studies and therapeutic exploratory studies taking into account relevant scientific literature (citations by consecutive numbering, with list at end of this section; important or not readily available references may be included with the paper submission, if appropriate). This section should also contain information on the new drug.

Rationale: Reasoning and justification for the proposed new approach/ therapy.

Trial Objectives

Statement of the precise goal(s) of the trial (may be subdivided into primary and secondary objectives) which may including testing of the null hypothesis (Ho), i.e., testing a new drug population/ indication etc., as applicable.

Study Design and Duration

  1. The statement of study design should include the method of randomization, blinding and the comparative agent, if applicable.
  2. A "Brief outline of the study conduct" should be included, if applicable.
  3. The design of the study should be able to support any claims related to the proposed study.
  4. Total study duration (anticipated starting/ finishing dates).
  5. Duration for each subject including post treatment period etc.

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Total Number of Sites and Number of Canadian Sites

Total number of trial sites with list of countries/geographical areas and number of sites in Canada.

List of Investigators

Qualified Investigator at each Canadian site.

Sample Size

Rationale and calculation for sample size requirement, anticipated drop-out rate etc. The sample determination may include Ho testing and desired power of the study.

Patient Population

Description of specific characteristics of the trial participants (e.g. disease/ stage/ indication/ conditions/ treatment etc.) as applicable and of diagnostic criteria and assessment.

Inclusion Criteria

Enumeration of conditions determining participation in the proposed clinical trial.

Exclusion Criteria

Enumeration of conditions determining participation in the proposed clinical trial.

Drug Formulation

Brief description of the study drug(s) and formulation to be used in the clinical trial. The relationship to the formulations used in the preclinical and/or other clinical trials should be delineated, as applicable. This may also include disclosure of the formulation intended to be marketed and/or any bridging studies which may be necessary, planned, initiated and/or already performed if different formulations have been used during clinical development.

Instructions for safe handling.

Dosage Regimen

Rationale for dose selection.

Description of the schedule(s) for using the study drug(s) including escalations/ maintenance / reductions / discontinuation, as applicable.
Description of other supportive measures and dose modifications for specific adverse events (anticipated toxicities), as applicable.

Washout Period

Description for pre-, during- and post-trial, as applicable.

Pre-study Screening and Baseline Evaluation

Description of the process of clinical validation for participation in the clinical trial, including methodology / schedule of events.

Treatment / Assessment Visits

Schedule of all events / visits / procedures during the clinical trial.

Concomitant Medication

Enumeration and description of all dis-/allowed drug/ medications, in addition to the study drugs.

Rescue Medication and Risk Management

Description of available supportive measures/ antidotes/ medications/ dosages / procedures (including follow-up) used to help reverse untoward effects or lack of efficacy resulting from any applications of drug(s)/ procedures in connection with the clinical trial.

This section should include any risks, for example, dose dumping from slow release formulations or immunogenicity.

Premature Withdrawal / Discontinuation Criteria

Enumeration of all conditions / criteria and management for drug/ patient's withdrawal or (premature) discontinuation, including voluntary withdrawal by subject without prejudice to future treatment by the physician.

Early stopping rules for the trial.

Efficacy Variables and Analysis

Description and validation of primary endpoint(s), ie. responses/changes from baseline over time in relation to clinical trial events. Description and validation of related secondary changes (secondary endpoints) following from clinical trial events.

Safety Variables and Analysis

Monitoring/ assessing adverse drug reactions/ adverse events/ toxicities/ clinical laboratory parameters etc. in relation to clinical trial events.

Statistical Analysis

(The following points are presented for consideration while completing this section)

  1. Analysis of trial parameters (primary/ secondary endpoints), population, demographics, as applicable.
  2. Efficacy analysis methods and results of efficacy end-point analysis.
  3. Safety analysis methods and results of safety end-point analysis.
  4. Exploratory end-point analysis: evaluation effect(s) (or lack of effects) of relevant biochemical/ pharmacological etc parameters, as applicable.
  5. Pharmacokinetic endpoint analysis, as applicable.
    Interim analysis and role of Data Safety Monitoring Board, as applicable.
Date Modified: 2009-09-23

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