health canada guidance: clinical trial applications

Change in the specifications for the drug substance involving: a. deletion or replacement of a test, relaxation of an acceptance criterion or addition of a test for a new impurity, b. addition of a test (other than a test for new impurity) or tightening of an acceptance criterion, 4. If there have not been any deficiencies identified and the CTA or CTA-A is deemed acceptable, a No Objection Letter (NOL) will be issued within the review period. For further information refer to the Health Canada / ICH Guidance Documents E6: Guideline for Good Clinical Practice and E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. 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. parameters, values, ranges or limits for indication(s) and clinical use(s), patient study population(s) and routes of administration. A list of preliminary questions to be addressed by the Directorate during the meeting; and. Where a sponsor wishes to make changes to the CTA under review, the sponsor should withdraw the active CTA and submit a new CTA. industry, academic, contract research organization] seeking authorization to sell or import a drug for the purpose of a clinical trial in Canada. Sponsors must provide the information requested by Clarifax within 2 calendar days [C.05.009]. Description of the impact on the proposed or ongoing trials 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 the discontinued sites has been stopped; and. 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. Health Canada targets to review applications to conduct comparative bioavailability trials and Phase I trials in healthy adult volunteers within 7 days (for both CTA and CTA-As), with the exception of Phase I trials using somatic cell therapies, xenografts, gene therapies, prophylactic vaccines or reproductive and genetic technologies. Sponsors must file a CTA-A to a previously approved application when changes that may affect the quality or safety of the clinical trial drug supplies are proposed. The additional pages listing multiple clinical trial sites are attached to Parts 1 and 2, and the complete document should be paginated (e.g., 1 of 5, 2 of 5, etc.). The forms may be faxed or mailed to the addresses identified in Section 5.2 prior to the commencement of the trial at that site. 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. MICYRN will be offering a regulatory submission service to Health Canada for investigator-initiated clinical trials in either the form of a Clinical Trial Application (CTA) for drug trials or an Investigational Testing Authorization (ITA) for medical device trials. controlled clinical trials to be used in support of food health claims and to verify bioactive efficacy. Clinical trial sponsors must conduct clinical trials according to generally accepted principles of good clinical practice that ensure the protection of the rights, safety and well-being of clinical trial subjects and other persons. Protocol Synopsis (PSEAT-CTA) a Protocol Synopsis in the format of the Protocol Safety and Efficacy Assessment Template - Clinical Trial Application (PSEAT-CTA)4 [see Appendix 4 for further guidance]. 24 January 2017 Updated contact information for fee section. 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. 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. Pharmacokinetic endpoint analysis, as applicable. (ii) Extension - if the approved shelf life is more than 18 months, 6. Health Canada Guidance for Records Related to â¦ This information will be reviewed and added to the file. This module contains Quality (Chemistry and Manufacturing) Information only. Notifications, as described below, must be provided for changes to CTAs and CTA-As. 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. Only the final page of the QIU would contain the QI's signature. 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. Change in radiolytic protective agent or antioxidant, 2. a tabular listing of completed nonclinical and clinical studies. Change in requirements for electronic specifications. If the application is deemed acceptable, a No Objection Letter (NOL) (Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications, section 2.5) is issued by Health Canada. A listing of the contents of Modules 2 and 3, if applicable; Applicable updated Quality Summary. Change in diluent, involving replacement or addition of a diluent for a lyophilized powder or concentrated solution by a diluent which is commercially available in Canada, is water for injection (WFI) or a salt solution, and after reconstitution, there is no change in the drug product specifications outside of the approved ranges. Post-Authorization Requirements. The Interim Order introduces efficiencies to help further facilitate the conduct of COVID-19 clinical trials â¦ For all clinical trial site information which becomes available after the time of application, a completed Clinical Trial Site Information Form must be provided to the appropriate Directorate. A copy of Appendix 1 should be included with the shipment along with the NOL. The cover letter to the application should include a rationale for the study; The current labelling or PM/Prescribing Information for the reference product in lieu of the IB; and. Health Canada Regulations and Guidances. CTAs for comparative bioavailability studies should be filed directly to the Therapeutic Products Directorate, addressed to the attention of the Director. These restrictions do not apply to co-investigators. A corresponding CTA-A 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 after the date of implementation of the amendment [C.05.008(4)]. For those types of studies please refer to section 2.3.2 for filing requirements and section 2.5 for review process and timelines. If the sponsor is required to immediately make one or more of the amendments referred to in subsection (2) of C.05.008 because the clinical trial or the use of the drug for the purposes of the clinical trial endangers the health of a clinical trial subject or other person, the sponsor may immediately make the amendment without prior review by Health Canada. a medical device and drug combination that is classified as a drug; Module 1 - contains administrative and clinical information about the proposed trial; Module 2 - contains Quality (Chemistry and Manufacturing) summaries about the drug product(s) to be used in the proposed trial; and. Where a sponsor wishes to make changes to the CTA under review, the sponsor should withdraw the active CTA and submit the amendment as a new CTA. Revive Therapeutics Ltd (OTCMKTS:RVVTF), announced Tuesday that it held a Pre-Clinical Trial Application meeting with Health Canada to evaluate the potential of a clinical study of Bucillamine to treat patients with mild-to-moderate COVID-19.. Under section C.05.015(2) of the Regulations, the sponsor may resume the trial in its entirety or at a site that was previously discontinued if the sponsor submits the following information: The above information may be submitted as a CTA-Notification if there are no changes to the study protocol or to the Chemistry and Manufacturing, and the trial may resume accordingly. The information provided in this Guidance document is for clinical trials involving drugs (pharmaceuticals and/or biologics and radiopharmaceuticals) in human subjects. If the application is considered complete, an acknowledgement letter will be issued to indicate that the 30-day default period commenced on the date of receipt in Health Canada. Change in the storage conditions for the drug product. The pre-CTA consultation meeting provides an opportunity for the sponsor to present relevant data, discuss concerns and issues regarding drug development. Health Details: Clinical Trial Regulations In most cases, Health Canada is not involved in conducting clinical trial research, but only in the regulation of the sale (distribution) and importation of non-approved drugs for use in human clinical trials. For joint reviews, refer to section 2.3.1.1. The sponsor is responsible for resolving issues identified by Health Canada during the review process. 3. However, the trial would not be considered to still be ongoing if all subjects enrolled globally have ceased study-related therapies, tests, and procedures, and have completed the "end of study" visit, including any follow-up for safety. Health Canada invites sponsors to request a pre-CTA consultation meeting. As required in Part C, Division 5 of the Food and Drug Regulations [C.05.012]: 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. Production of an immediate release drug product (tablet, capsule, liquids, semi-solids) within the same Manufacturer, b. Follow-up reports of fatal or life-threatening reactions. 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. For Biologicals and Radiopharmaceuticals: Additional information and any changes that have been incorporated in the updated Investigator's Brochure should be highlighted for ease of review and evaluation. As a reminder, Health Canada is advising sponsors of the new electronic adverse drug reactions (ADR) reporting that is currently in pilot with some sponsors. a listing of quality control procedures and specifications, a summary of product characteristics, and. Health Canada recommends a Pre-technical meeting for companies using eCTD for the first time. Change in the shelf life for the drug product, involving: 9. changes in drug substance and/or final product strength. Notifications should be submitted in accordance with current electronic specifications (see Appendix 2). This information will be added to the file. With an aim to make anonymized clinical information in drug submissions and medical devices applications publicly accessible, Health Canada released a guidance document named as Health Canada's Public Release of Clinical Information (PRCI). Enumeration of conditions determining participation in the proposed clinical trial. The additional pages listing multiple clinical trial sites should be attached to Parts 1 and 2, and the complete document should be paginated (e.g., 1 of 5, 2 of 5, etc.). The following documents may be useful in the preparation of the application: This HTML document is not a form. Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications. During a clinical trial the sponsor is required to inform Health Canada of any serious, unexpected adverse drug reaction that has occurred inside or outside Canada: Each ADR which is subject to expedited reporting should be reported individually in accordance with the data element(s) specified in the Health Canada / ICH Guidance Document E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. Guidance for Clinical Trial Sponsors: Clinical Trial Application. P.5 CONTROL OF DRUG PRODUCT where a test is removed from the specification and/or the test methods or limits are relaxed. Qualified Investigators must complete the Qualified Investigator Undertaking (QIU) or develop similar documentation that meets the requirements of the Regulations [C.05.012(3)(f)]. Clinical Trial Applications Health Canada Guidance Document 2 Revised Date: 2011/11/07; Effective Date: 2013/05/29 1.3 Scope and Application The information provided in this Guidance document is for clinical trials involving drugs (pharmaceuticals and/or biologics and radiopharmaceuticals) in â¦ The Guidance was revised based on stakeholder consultation processes and as part of Health Canada's statutory review of Part C, Division 5 of the Food and Drug Regulations (Drugs for Clinical Trials Involving Human Subjects). On August 13, 2020, the Minister of Health approved an order to temporarily extend the default period to review clinical trial applications and amendments.This Ministerial Order (MO) will give Health Canada an additional 15 days to review all clinical trial applications and amendments submitted under Division 5 of the Food and Drug Regulations. Total study duration (anticipated starting/ finishing dates). The outer label should be clearly identified with "Clinical Trial Application". Refer to Table 1 below for guidance on submission content, and to Appendix 2 (where applicable) for Guidance documents that may be useful in the preparation of the application. The "end of study visit" is the final visit for study-related tests and procedures, including the capture of any final potential study-related adverse events, and usually occurs some time after the subject has completed/discontinued study drug administration. Such consultations may be particularly useful for new active substances or applications that will include complex issues that may be new to Health Canada. 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. 1024) Clinical Trial Framework, Health Canada / ICH Guidance Documents E6: Guideline for Good Clinical Practice: Consolidated Guideline and E8: General Considerations for Clinical Trials. The sponsor is requested to notify the relevant Directorate(s) (via CTA-Notification) when a clinical trial is completed or a clinical trial site is closed. These trials are referred to as Phase IV clinical trials. Please refer to section 2.3.2 CTA Format for guidance in completing filing requirements for Clinical CTA-As; subsection 1.4.1 is not applicable. 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. 10. 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. Description of the process of clinical validation for participation in the clinical trial, including methodology / schedule of events. Although the scope of ICH's CTD does not include applications at the clinical research stage of development, the modular format of the CTD is being extended to CTAs that are filed with Health Canada. Health Canada must review the application and notify the sponsor within 30 days if the application is found to be deficient [C.05.006(1)]. Sponsors will be issued a letter itemizing each deficiency. Change in the source of drug substance (e.g., from a fermentation process to transgenic milk); Change in the host cells used to express the same coding sequence; Change in the strain of virus used in manufacturing a vaccine; Change in the strain of oncolytic virus used in cancer treatment; Change in the animal source of an immune globulin (e.g., from rabbit to sheep); Change in the source of a radionuclide (e.g., from nuclear reactor to cyclotron or linear accelerator) for labelling kits; Change in the source of the parent radionuclide (e.g., from nuclear reactor to cyclotron or linear accelerator) used in a generator; Change in the design, structure and operation of a radionuclidic generator. Items marked with an asterisk (*) should be submitted in hard copy and in electronic format accepted by Health Canada (e.g., CD-ROM). Sponsors may invite the qualified investigator(s) who will be involved in the proposed trial(s) in Canada to attend the meeting. Efficacy analysis methods and results of efficacy end-point analysis. The CTA is composed of three parts (modules) in accordance with the CTD format: The CTA 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. This restriction does not apply to sub-investigators. Health Canada completed a review of the clinical trials regulatory framework through 2006-2008. The approval and the views of the REB have been documented in writing, Lot numbers of materials being used during the trial and any Batch Identification Numbers that are assigned to lots received from elsewhere [that is (i.e.) This acknowledgement letter will also advise sponsors that if the CTA is authorized, and involves a trial in patients (phase I, II, or III), Health Canada will publish the following information about the clinical trial in Health Canada's publicly accessible database soon after an NOL is issued: All CTAs and CTA-As will be screened for completeness and if deficiencies are identified at screening, these will be addressed by a Request for Clarification or a Screening Rejection Letter. If a REB uses its own letter, it should explain how the REB complies with the membership requirements for REBs defined in the RegulationsFootnote 7 and must attest to the following 2 points: The REB letter does not need to include all the elements contained in PART 1, PART 2 and PART 3 of the Health Canada REB Attestation Form. Sponsors may only resume a trial when a No Objection letter (NOL) has been issued from the appropriate Directorate within 30 days of the submission of information. [It is recognized that this plan is subject to change as new information becomes available.]. 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)]. Health Canada acknowledges that protocol â¦ Sponsors should, however, refer to the control number of the prior application. service will be offered using a subsidized fee for service model where MICYRN will cover 50% of the cost. Similar to CTAs, CTA-As should be organized and numbered as per the CTD format. Expedited reporting is also inappropriate for serious events from clinical investigations that are considered unrelated to the study product, whether or not the event is expected. 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. This Guidance document applies to all sponsors (e.g., industry, academic, contract research organization, etc.) CTA-As must be approved by Health Canada prior to implementation of the changes [C.05.008]. Name of Authorized Signing Official: Signature: Date (YYYY/MM/DD): Title: Telephone: Fax: Name of Company to which the Authorized Signing Official Belongs: Date Received (YYYY/MM/DD): Name of Signing Official: Title: DSTS Control Number: Telephone: Fax: Signature: Date Sent (YYYY/MM/DD): Before commencement of a trial, the sponsor must ensure that Health Canada and the Research Ethics Board have raised no objections to the Clinical Trial Application. The Food and Drugs Act and the Food and Drug Regulations (herein referred to as the Regulations) govern the sale and importation of drugs for use in human clinical trials in Canada. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate justification. The lead Directorate / Bureau will be responsible for communicating the regulatory decision to the sponsor. 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. changes to the protocol that do not affect the safety of the trial participants and which would not be considered an amendment under section 6; information on site closure or completion of the Clinical Trial; 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); and. S.2 MANUFACTURE (Drug Substance), where new ingredients are used, including ingredients which do not appear in the final drug substance; S.3.2 IMPURITIES, where a new impurity or degradation product has been identified; S.4 CONTROL OF DRUG SUBSTANCE, where a test is removed from the specification and/or the test methods or limits are relaxed; P.3 MANUFACTURE (Drug Product), where new ingredients are used, including ingredients which do not appear in the final product; P.3.3 DESCRIPTION OF MANUFACTURING PROCESS AND PROCESS CONTROLS, for sterile products only where the sterilization process is changed; and. Applications that involve the use of a medical device with a drug must be submitted to the lead Bureau / Directorate6 in duplicate. If an Investigator's Brochure is updated more frequently, it should be submitted as required. For investigational prophylatic vaccines lot release for use in an authorized CTA, the BGTD will require the submission of testing protocols and/or Certificates of Analysis before its use in the trial. Health Canada's administrative seven (7) day review target applies to applications involving comparative bioavailability studies for pharmaceuticals only where: This section does not apply to biologics, radiopharmaceuticals and cellular therapies, which includes Phase I trials using somatic cell therapies, xenografts, gene therapies, prophylactic vaccines or reproductive and genetic technologies. 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 cover letter. Change in the composition of a dosage form, 3. In any other case, records must be provided within 7 days of a request [C.05.013]. Note: Notification of a premature discontinuation of a Clinical Trial outside Canada, for which there are ongoing trials in Canada, should also be submitted to the appropriate Directorate. Applicants should consult the Health Canada website for CTD/ eCTD update Notices for guidance on the filing of electronic review documents. 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.) extend the duration of the clinical trial. Cross-referencing is not acceptable. If the sponsor wishes to resubmit the information and material at a future time, it will be processed as new information and material, and will be assigned a new control number as per the Management of Drug Submissions Guidance5. Aspects of the conduct of the study that may increase the risk to the health of clinical trial subjects. CTAs or CTA-As must be submitted to the appropriate lead Directorate / Bureau when they involve the use of: Authorization for the sale and importation of all investigational products to be used within a CTA or CTA-A must be obtained prior to the initiation of the clinical trial or implementation of the protocol amendment. 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. Criteria, tests or procedures required to select or dismiss a clinical trial subject. A Rejection Letter will be issued if a timely response to a Clarifax has not been provided. Single copy is acceptable provided the application is submitted in accordance with current electronic specifications. Guidance documents â applications and submissions â drug products [Internet]. Following regulatory approval of a CTA or CTA-A, information regarding refusals by other regulatory authorities or Research Ethics Board(s), should be submitted as a notification. Prior to commencement of the Clinical Trial or implementation of a Clinical Trial Amendment, sponsors are required to complete and submit a Clinical Trial Site Information Form. In the Regulations a clinical trial is an investigation in respect of a drug 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. Description of other supportive measures and dose modifications for specific adverse events (anticipated toxicities), as applicable. Prior to initiating a clinical trial or implementing an amendment to a clinical trial at a site, the proposed trial protocol and informed consent must be reviewed and approved by a Research Ethics Board (REB) as defined in the Regulations. for each clinical trial site, an attestation, signed and dated by the REB for that clinical trial site, stating that it has reviewed and approved the protocol and ICF and that the board carries out its functions in a manner consistent with GCPs. 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. As required in Part C, Division 5 of the Food and Drug Regulations [C.05.012]: Records must be made available to the relevant Directorate within 2 days of a request 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. The Notification should include information such as that specified under 2.8.1 a), b), and c) above. The sponsor should prepare and send to the appropriate Directorate a written record of the discussions and conclusions of the consultation meeting within 14 days of the consultation date. the principal mandate of which is to approve the initiation of, and conduct periodic reviews of, biomedical research involving human subjects in order to ensure the protection of their rights, safety and well-being; and, that has at least five members, that has a majority of members who are Canadian citizens or permanent residents under the. The outer label should be clearly labelled with "Clinical Trial Application - Amendment". Clinical Trial Applications. Food and Drug Regulations, Division 5. Phase I trials also include trials in which new drugs are used as research tools to explore biological phenomena or disease processes.