health canada guidance: clinical trial applications
4. Should the sponsor be unable to provide the requested information within the specified time frame, the submission may be withdrawn and resubmitted without prejudice. Note: Notification of a premature discontinuation of a clinical trial or clinical trial site outside Canada, for which there are ongoing trials with the drug in Canada, should also be submitted to the appropriate Directorate if such discontinuation was carried out for safety reasons. for each clinical trial site, an attestation, signed and dated by the Research Ethics Board for that clinical trial site, stating that it has reviewed and approved the protocol and informed consent form and that the board carries out its functions in a manner consistent with good clinical practices. CTA-As should be submitted on electronic media, accompanied by a hard copy cover letter, and be organized in accordance with the current electronic specifications; Guidance Document: Preparation of Drug Regulatory Activities in the "Non-eCTD Electronic-Only" Format. Sponsors will be issued a letter itemizing each deficiency. Sponsors should also refer to the applicable Health Canada Quality guidances for additional information. If such changes are submitted as CTA-As they will be subject to reclassification as a CTA. Enumeration and description of all dis-/allowed drug/ medications, in addition to the study drugs. Prior to commencement of the clinical trial or implementation of a CTA-A, sponsors are required to complete and submit a Clinical Trial Site Information (CTSI) form for each clinical trial site [C.05.006(1)(d)/C.05.008(1)(c)]. a major safety finding from a newly completed animal study. Rationale and calculation for sample size requirement, anticipated drop-out rate etc. For an "expected" serious ADR, an increase in the rate of occurrence which is judged clinically important; A significant hazard to the patient population, such as lack of efficacy with a drug used in treating a life-threatening disease; and. It should be noted that for Biologicals and Radiopharmaceuticals, certain changes relating to the production of a given drug may be considered beyond the scope of an approved CTA. The version number of the protocol should also be provided. Where a sponsor wishes to make changes to the CTA under review, the sponsor should withdraw the active CTA and submit a new CTA. 7 Refer to related Quality guidances for drug submissions in the CTD format for additional, specific information on the other available options under Module 2.3. all other aspects of the clinical trial that are necessary for that person to make the decision to participate in the clinical trial. an outline of the observed adverse events and a discussion of potential safety problems; a proposed global clinical plan for the current stage of drug development including regulatory status in other countries; details of the proposed clinical trials to be conducted in Canada, within the scope of the intended CTA, including: parameters, values, ranges or limits for indication(s) and clinical use(s), patient study population(s) and routes of administration. The lead Directorate will be responsible for communicating the regulatory decision to the sponsor. In any other case, records must be provided within 7 days of a request [C.05.013]. the sponsor shall maintain complete and accurate records in respect of the use of a drug in a clinical trial, including: a copy of all versions of the Investigator's Brochure for the drug; records respecting each change made to the Investigator's Brochure, including the rationale for each change and documentation that supports each change; records respecting all adverse events in respect of the drug that have occurred inside or outside Canada, including information that specifies the indication for use and the dosage form of the drug at the time of the adverse event; records respecting the enrolment of clinical trial subjects, including information sufficient to enable all clinical trial subjects to be identified and contacted in the event that the sale of the drug may endanger the health of the clinical trial subjects or other persons; records respecting the shipment, receipt, disposition, return and destruction of the drug; for each clinical trial site, an undertaking from the qualified investigator that is signed and dated by the qualified investigator prior to the commencement of his or her responsibilities in respect of the clinical trial, that states that: the qualified investigator will conduct the clinical trial in accordance with good clinical practices, and. 6 The lead Bureau / Directorate is that defined as the Bureau / Directorate responsible for the review of the product filed by the sponsor of the CTA or CTA-A. Safety analysis methods and results of safety end-point analysis. The rationale for each proposed change should be submitted and the revised information should be clearly identified. Medical Device Regulations, Part 3. Health Canada invites sponsors to request a pre-CTA consultation meeting. It should be noted, however, that there may be certain scenarios [e.g., gene therapies, drugs with very long half-lives (i.e., several months)] where a study may be considered to be ongoing well beyond the period of study treatment, i.e., where long-term safety monitoring and reporting would be required in accordance with Division 5. This will be faxed back to the sponsor/manufacturer within 48 hours, providing the CTA has received prior BGTD authorization. Brief description of the study drug(s) and formulation to be used in the clinical trial. This is a guidance document for the administration of the Food and Drug Regulations Amendment (Schedule No. For enquiries, contact us. Health Canada recognizes that all information requested in the CTSI form (e.g., dates for Boxes 35 and 47) may not be available at the time of submission. Description of other supportive measures and dose modifications for specific adverse events (anticipated toxicities), as applicable. This document does not constitute part of the Regulations and in the event of any inconsistency or conflict, the Regulations take precedence over this guidance document. In the situation where a change made to the commercial product has not yet been approved and is affecting the clinical material, a CTA-A or a CTA-N must be submitted according to the tables below. Together, they define parameters for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials. Applications and Submissions - Drug Products, Guidance Documents – Applications and submissions – Drug products, 5.4 Comparative Bioavailability Trial Application Requirements, 7.3 Filing of Trial Commencement Information, Clinical Trials Involving Investigational Medical Devices and A Drug (pharmaceutical or Biological / Radiopharmaceutical), Clinical Trials Involving A Pharmaceutical and A Biological / Radiopharmaceutical Drug, 12.2 Premature Discontinuation of a Trial, Appendix 4: Guidance Notes for Protocol Synopsis (, Biologics and Genetic Therapies Directorate, International Conference on Harmonization, National Council on Ethics in Human Research, Reflecting necessary changes from finalization of the protocol safety and efficacy assessment template - clinical trial application (, Information on Prior-related Applications, Canadian Research Ethics Board(s) Refusals, Common Technical Document Table of Contents, the risks and anticipated benefits to his or her health arising from participation in the clinical trial; and. An acknowledgement letter will be issued to indicate the start of the review period and to indicate that the Minister is in receipt of a complete application. Sponsors must provide the information requested by Clarifax within 2 calendar days [C.05.009]. 1.4.1 Protocol Safety and Efficacy Assessment Template - Clinical Trial Application (PSEAT-CTA), 1.7.3 Canadian Research Ethics Board (REB) Refusals, 1.7.4 Information on Prior-related Applications. proposed procedures and/or criteria for patient monitoring, clinical efficacy and safety assessments, alternative treatments, premature patient discontinuation and other considerations, as appropriate; a summary of significant Quality (Chemistry and Manufacturing) aspects of the drug, if applicable; a summary of the method of manufacture for both drug substance and dosage form. Phase I trials are designed mainly to determine the pharmacological actions of the drug and the side effects associated with increasing doses. A table of comments from industry stakeholders in response to the draft CTA Guidance is available upon request. Affect the selection, assessment, or dismissal of a clinical trial subject; Affect the evaluation of the clinical efficacy of the drug; Alter the risk to the health of a clinical trial subject; Affect the safety evaluation of the drug; or. Notification changes include the following changes to CTAs and CTA-As: Updated information regarding the change should be submitted in the form of a cover letter and any supporting documentation. Sponsors of trials which qualify for the expedited review process can only proceed if: 5 Management of Drug Submissions Guidance 2003/04/04 is located on the Health Canada website. Change in the batch size for the drug substance (no impact on quality). changes to Quality (Chemistry and Manufacturing) information that do not affect the quality or safety of the drug, for example: for Pharmaceuticals: production scale-ups with no changes in the process. Guidance documents also provide assistance to staff on how Health Canada mandates and objectives should be implemented in a manner that is fair, consistent and effective. Concomitantly, adverse reactions that are considered to be unrelated to the study drug by both the investigator and the sponsor should not be reported. Change in the manufacturing process for the drug substance intermediate, involving: a. the fermentation process [for example (e.g. 7. Clinical Protocol Number (must be assigned) Clinical Trial Protocol Title. These CTD-related guidances may undergo further changes based upon practical experience gained through the use of the CTD and with efforts to further harmonise internationally. The sponsor must file a CTA prior to the initiation of the trial [C.05. With the exception of Phase IV studies, clinical trial sponsors must submit a clinical trial application (CTA) to Health Canada for authorization to sell or import a drug for the purpose of a clinical trial. Guidance for Clinical Trial Sponsors: Clinical Trial Application. The extent of available supporting information may vary depending upon the stage of drug development (e.g., Phase I-III studies). Further definitions and standards for expedited reporting of adverse drug reactions are described in the Health Canada / ICH Guidance Document E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. 2. disease/ stage/ indication/ conditions/ treatment etc.) Amendments submitted with a CTA or when the CTA is under review will not be accepted. Sponsors must file applications to conduct clinical trials in Phases I through III of drug development and comparative bioavailability trials. The revised guidance includes application requirements for comparative bioavailability trials and filing requirements for the importation of clinical trial supplies. Prior to filing a Clinical Trial regulatory transaction in eCTD format, each company must file a sample transaction to Health Canada in accordance with the eCTD guidance document. The regulatory requirements for CTAs outlined in Part C, Division 5 of the Food and Drug Regulations also apply to institution / investigator-initiated clinical trials. A completed "Fax-Back" form, including the required certification, should be sent to the BGTD. Confirmation that reasonable measures to ensure the return of all unused quantities of the drug will be taken. Both a copy of the signed form as well as the NOL (and Appendix 1 of the HC/SC 3011 form, if applicable) should be included with the shipment to facilitate processing at the Port of Entry. Receipt of the Clinical Trial Site Information Form will not be subject to an acknowledgment letter. All stakeholder comments were considered in the finalization of this guidance document. one member who is from the community or is a representative of an organization interested in the areas of research to be approved and who is not affiliated with the sponsor or the site where the clinical trial is to be conducted. In all cases, the updated IB should be accompanied by a list of changes that clearly describes the sections that have changed, including a rationale for each change. A copy of the amended or working protocol and a clear description of the changes that are being proposed (i.e., original wording vs. revised wording); This should include a copy of the most recently approved protocol and a rationale for each proposed change. On September 1, 2001, the regulatory amendments to Part C, Division 5 of the Food and Drug Regulations (Drugs for Clinical Trials Involving Human Subjects) came into force to strengthen protections for clinical trial subjects in Canada. The changes may be implemented immediately, but Health Canada must be informed in writing, within 15 calendar days of the day of the change [C.05.007]. For a CTA, this module reflects Quality (Chemistry and Manufacturing) Information only. For a product commercially available and used in clinical trials for which a quality change has been made according to the Post-NOC Changes Guidance document, supporting data are not required in support of the same change affecting the clinical product. Clinical Trial Regulations - Canada.ca. This section explains in detail the process of preparation of an application, its submission, screening, evaluation, authorization/rejection, submission of amendments and post-authorization requirements. a listing of quality control procedures and specifications, a summary of product characteristics, and. Sponsors are required by the Regulations to obtain REB approval for each clinical trial site prior to commencing the trial at that site [C.05.006(1)(c)]. If the Quality information was previously submitted to, and authorized by Health Canada and has not changed, re-submission of the applicable Quality Summary may not be required. A REB may use its own letter of attestation in lieu of the form provided by Health Canada. In general, the CTA filing requirements (section 2.3.2) also apply to the comparative bioavailability studies that meet the criteria provided above, with some exceptions as follows: CTA-A and CTA-Notification (CTA-N) filing requirements (refer to sections 2.4 and 2.6, respectively) also apply to comparative bioavailability studies. Note: A cover letter, indicating the original CTA(s) with file number and control number(s), should be included. If you wish to use the form, you must use the alternate format below. Most of the definitions listed below were taken from the Food and Drug Regulations Amendment (Schedule No. Name of the drug product as stated on the marketed label: Name of the country where the product is sourced: Name of the company as stated on the marketed label: Common name of the active ingredient: Dosage form: Strength: This table may be replicated as many times as necessary to cover all additional medicinal products to be imported. Requests for a pre-CTA consultation meeting should be submitted in writing by the sponsor to the appropriate Directorate (refer to Appendix 1). 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: This information should be submitted where applicable to either: Office of Clinical Trials, Therapeutic Products Directorate Pharmaceuticals Fax: 613-954-4474. The lead Bureau / Directorate will be responsible for communicating the regulatory decision to the sponsor. Sponsors must conduct all clinical trials, including Phase IV trials, in accordance with the principles of Good Clinical Practices [C.05.010]. All CTAs and CTA-As are subject to a 30-day default review period from the date of receipt in Health Canada. Adding or removing a concomitant medication, which may impact on the analysis of efficacy or increase the risk to clinical trial subjects; Criteria for expedited reporting of serious, unexpected adverse drug reactions; Increases in blood volume, changes in procedures, enrolling additional subjects in PK studies or confirmatory testing in PK studies that were not specified in the original CTA protocol; and/or. Pharmacokinetic endpoint analysis, as applicable. This information will be reviewed and added to the file. description of the impact on the proposed or ongoing trials, in respect of the drug, conducted in Canada; 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; confirmation that the sale or importation of the drug to all sites involved has been stopped; and. In such cases, a new CTA is required. In other studies, alternate Health Canada is pleased to announce the release of the finalized Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications which provides guidance to all sponsors [for example (e.g.) Health Canada Investigational Testing Application (ITA) This guidance document provides assistance to manufacturers and importers in organizing and submit- ting an investigational testing application (ITA) to perform a clinical trial in Canada ⦠), those that could be used in support of a marketing application], safety endpoints, sample size estimation, or addition of interim analyses that will affect the analysis and interpretation of the study results; Dose level, dosage schedule, or treatment duration; Changes to the post-treatment follow-up period that may affect the safety evaluation of the drug. Questions or comments regarding this initiative should be directed to: Office of Clinical Trials Therapeutic Products Directorate Health Canada 1600 Scott Street Holland Cross, Tower B 5th Floor, Address Locator 3105A Ottawa, Ontario K1A 0K9, Facsimile: 613-954-4474 E-mail: OCT_BEC_Enquiries@hc-sc.gc.ca, Published by authority of the Minister of Health, Date Adopted: 2003/06/25 Revised Date: 2011/11/07 Effective Date: 2013/05/29 Revised Date: 2016/03/17. Submit the name of the REB that approved the trial or trial amendment prior to the commencement of the trial or trial amendment at that site (see Clinical Trial Site Information Form); Retain as records a REB Attestation, signed by the REB Chair that approved the protocol or protocol amendment at each site in a manner consistent with GCPs. Criteria, tests or procedures required to select or dismiss a clinical trial subject. CTA-As should be filed directly to the appropriate Directorate (Appendix 1). Health Canada's Clinical Trials Database Certain clinical trials involving drugs, medical devices or natural health products may require an application for regulatory approval be filed with Health Canada prior to the recruitment of the first study subject.