DRAFT Preparation and Submission of Summary Reports for Marketed Health Products Annual Summary Reports and Issue-Related Summary Reports (effective date: Month dd, yyyy)
Health Canada is the federal department responsible for helping the people of Canada maintain and improve their health. We assess the safety of drugs and many consumer products, help improve the safety of food, and provide information to Canadians to help them make healthy decisions. We provide health services to First Nations people and to Inuit communities. We work with the provinces to ensure our health care system serves the needs of Canadians. Également disponible en français sous le titre : XXXXXXXXXXXXXXXXXXXXXXXX To obtain additional information, please contact: Health Canada Address Locator 0900C2 Ottawa, ON K1A 0K9 Tel.: 613-957-2991 Toll free: 1-866-225-0709 Fax: 613-941-5366 TTY: 1-800-465-7735 E-mail: publications@hc-sc.gc.ca This publication can be made available in alternative formats upon request. Her Majesty the Queen in Right of Canada, as represented by the Minister of Health, 2015 Publication date: Month 2015 This publication may be reproduced for personal or internal use only without permission provided the source is fully acknowledged. Cat.: XXXXXXX ISBN: XXXXXXX Pub.: XXXXXXX
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Forward Guidance documents are meant to provide assistance on how to comply with governing statutes and regulations. 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. 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 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 document, 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 relevant sections of other applicable guidance documents. Preparation and Submission of Summary Reports for Marketed Health Products i
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Table of Contents 1 Introduction... 1 1.1 Objectives... 1 1.2 Scope and Application... 1 1.3 Guiding Principles... 1 1.4 Background... 2 2 Annual Summary Reports... 3 2.1 Preparing and Maintaining Annual Summary Reports... 3 2.2 Acceptable Annual Summary Report Format... 4 2.2.1 Periodic Benefit-Risk Evaluation Report (PBRER)... 4 2.2.2 Periodic Safety Update Report (PSUR)... 4 2.2.3 Annual Summary Report Alternative Format... 4 2.3 Canadian-Specific Sections... 5 2.4 Notifying Health Canada of a Change in the Risks and Benefits of a Health Product... 6 2.5 Use of Foreign Reviews... 6 3 Issue-Related Summary Reports... 7 3.1 Acceptable Issue-Related Summary Report Format... 7 4 Submission Procedures for Annual Summary Reports and Issue-Related Summary Reports... 9 4.1 General Considerations... 9 4.2 When to Submit an Annual Summary Report or Issue-Related Summary Report to Health Canada... 9 4.3 Instructions for Submitting Annual Summary Reports and Issue-Related Summary Reports for Drugs... 9 4.3.1 ectd Format Requirements... 10 4.3.2 Non-eCTD Format Requirements... 10 4.4 Cover Letter... 10 4.5 Health Canada s Review of Annual Summary Report and Issue-Related Summary Report Submissions.. 10 4.6 Status Requests... 11 Appendix 1: Requirements for Lower Risk Health Products (e.g., certain over-the-counter (OTC) drugs and natural health products)... 13 Appendix 2: Regulations Pertaining to Annual Summary Reports and Issue-Related Summary Reports... 15 Appendix 3: Glossary... 19 Appendix 4: Contact Information... 23 Appendix 5: List of Relevant Guidance Documents... 27 Preparation and Submission of Summary Reports for Marketed Health Products iii
53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 1 Introduction 1.1 Objectives This guidance document is intended to: define Health Canada s expectations for post-approval regulatory requirements for health products, and; provide an overview of the procedures for submitting annual summary reports and issue-related summary reports to Health Canada. An annual summary report is a comprehensive assessment of all known safety information for a marketed health product. It is prepared by the market authorization holder (MAH) to provide an update on the worldwide safety profile of a health product at defined intervals post-authorization, and submitted to Health Canada upon request. An issue-related summary report is a concise, critical analysis of a specific safety or effectiveness issue that may be related to a health product. It is prepared by the MAH at the request of Health Canada. 1.2 Scope and Application This guidance document provides MAHs with information on how to comply with the Food and Drugs Act, the Food and Drug Regulations, and the Natural Health Products Regulations with respect to the preparation and submission of annual summary reports and issue-related summary reports for marketed health products. The principles and practices outlined in this document apply to the following health products for human use: pharmaceutical drugs (prescription and non-prescription drugs, including generics); biologics; biotechnology products; radiopharmaceuticals; preventative vaccines; therapeutic vaccines; natural health products; and, medical devices (when part of a combination product submission). This guidance document does not apply to annual summary reports provided to pre-market Directorates as part of a submission. While these principles can be applied across all product lines, please see Appendix 1 for certain products that are within the scope of lower risk health products (e.g., certain over-the-counter (OTC) drugs and natural health products). 1.3 Guiding Principles Health Canada uses a lifecycle approach to continually promote high standards of health product vigilance, to protect the health and safety of Canadians, and to facilitate access to health products which are important to health and well-being. Preparation and Submission of Summary Reports for Marketed Health Products 1
94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 In addition to Canadian legislative and regulatory requirements, Health Canada aligns health product vigilance with international best practices wherever possible. Health Canada, as an official member to the International Conference on Harmonisation (ICH) is committed to the adoption and implementation of ICH guidances. 1.4 Background According to the World Health Organization (WHO), pharmacovigilance is defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. As the scope of health products regulated in Canada is broader than drugs, Health Canada uses the term health product vigilance in relation to the WHO definition. Health Canada encourages and monitors good vigilance practices (GVPs) by industry, reflecting the fact that industry is responsible for the safety and efficacy of their health products. MAHs have primary responsibility for the safety of any health products they sell, manufacture, import or distribute to the Canadian public, and must comply with all Canadian legislative and regulatory requirements. Health Canada has a shared responsibility to enforce Canadian legislative and regulatory requirements and monitor risks associated with marketed health products. In 1996, ICH endorsed the ICH E2C guidance on Clinical Safety Data Management: Periodic Safety Update Reports (PSURs) for Marketed Drugs, which provided guidance on the format and content of safety updates. The ICH E2C(R1) harmonized periodic safety reporting requirements for MAHs and provided a common international format. On April 1, 2010, Health Canada adopted ICH E2C(R1) and implemented a two year risk-prioritized PSUR Regulatory Review Pilot. Since that time, the science of pharmacovigilance has evolved globally, prompting reassessment of the role of the PSUR in the spectrum of safety documents submitted to regulatory authorities. In December 2012, ICH finalized the ICH E2C(R2): Periodic Benefit-Risk Evaluation Report (PBRER) guidance. On March 1, 2013, Health Canada announced to stakeholders that it has adopted the ICH E2C(R2). This guidance is intended to ensure that worldwide safety experience is provided to authorities at defined times after marketing, with maximum efficiency and avoiding duplication of effort. The PBRER format will allow MAHs to prepare a comprehensive, concise, and critical analysis of new or emerging information on the risks and benefits of their health products and to enable an evaluation of the product s overall benefit-risk profile. 2 Preparation and Submission of Summary Reports for Marketed Health Products
124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 2 Annual Summary Reports In accordance with the Food and Drug Regulations 1, the MAH must, on an annual basis and whenever requested by the Minister of Health, conduct a concise, critical analysis of the adverse reactions and serious adverse reactions for a health product and prepare a summary report with respect to the reports received during the previous twelve months. When preparing the report, the MAH must determine whether or not there has been a significant change in the benefit-risk profile of the health product. The current interpretation of benefit-risk profile for a health product is a reflection of the overall balance of the product's potential benefits with its identified risks as revealed through safety and efficacy evidence, and through consideration of how that evidence contextualizes with normal conditions of use on the market. 2 If the MAH concludes that there has been a significant change in the benefit-risk profile, they must notify the Minister immediately. If Health Canada determines that an examination of the safety and/or effectiveness of a health product are warranted, a request may be made to the MAH to submit an annual summary report, and/or the case reports of all adverse reactions that are known to the MAH. In accordance with the Natural Health Products Regulations 3, the MAH must, on an annual basis, prepare and maintain a summary report that contains a concise and critical analysis of all domestic adverse reactions to a natural health product, and all foreign serious unexpected adverse reactions to a natural health product taken at the recommended dose, reported during the previous twelve months. If the Minister has reasonable grounds to believe that the natural health product may no longer be safe when used under the recommended conditions of use, the Minister may request any summary reports, interim summary reports and all adverse reactions for which a case report is required, to be submitted to Health Canada within 30 days after the day on which the request is received by the MAH. 2.1 Preparing and Maintaining Annual Summary Reports The MAH must ensure that all regulatory requirements of the Food and Drug Regulations, and the Natural Health Products Regulations are met and any relevant Health Canada guidance documents are applied. There may be instances when the MAH choses to engage in a contractual agreement with another party whereby they carry out certain regulatory responsibilities on behalf of the MAH (e.g., maintaining records related to adverse reaction (AR) data and preparing annual summary reports). In these cases, it remains the responsibility of the MAH to ensure that any documents requested by Health Canada are sent accordingly. For further guidance on GVPs with respect to drug post-approval reporting requirement responsibilities of the MAH and the importer, refer to Health Canada s Good Pharmacovigilance Practices (GVP) Guidelines (GUI-0102). The MAH is required to prepare and maintain annual summary reports for all of their licensed health products. The requirement to prepare annual summary reports begins on the date that the MAH receives Canadian market authorization for the health product. These reports need to be submitted to Health Canada only in certain circumstances (see Section 4.2). However, all annual summary reports must be maintained by the MAH on site or be easily accessible and, when requested, be submitted to Health Canada within 30 calendar days unless otherwise specified. The selected 12-month period for the annual summary report is specified by the MAH. It is the preference of Health Canada that annual summary reports be prepared with harmonized Data Lock Points (DLPs) based on the Preparation and Submission of Summary Reports for Marketed Health Products 3
167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 International Birth Date 4 (IBD) of the active substance. If the MAH is unable to identify the IBD, they should refer to the EU reference dates (EURD) list 5. For natural health products, the date of first licensing in Canada should be used. 2.2 Acceptable Annual Summary Report Format MAHs may prepare summary reports in the Periodic Benefit-Risk Evaluation Report (PBRER) format in accordance with the standards defined in the ICH E2C(R2) 6 guidance, or the Periodic Safety Update Report (PSUR) format in accordance with the standards defined in the ICH E2C(R1) 7 guidance. Health Canada has been accepting annual summary reports in either PSUR or PBRER format since the ICH E2C(R2) guidance was adopted. The vast majority of MAHs have made the transition to PBRER reporting, and as of January 2015 Health Canada s preference is that MAHs prepare annual summary reports in PBRER format. 2.2.1 Periodic Benefit-Risk Evaluation Report (PBRER) PBRERs should be prepared annually using the time interval for submission outlined in the ICH E2C(R2) guidance. For further guidance on the format and content of a PBRER please refer to the ICH E2C(R2) guidance document 8. Line listings are not required if MAHs prepare annual summary reports in the PBRER format. 2.2.2 Periodic Safety Update Report (PSUR) The PSUR format is also acceptable to Health Canada. Unless otherwise specified by Health Canada, PSURs should be prepared annually using the time interval for submission outlined in the ICH E2C(R1) guidance, which is available upon request to Health Canada. 2.2.3 Annual Summary Report Alternative Format An annual summary report needs to take into account not only adverse reaction reports but also consumer complaints and other publicly available information that might be necessary for the analysis. MAHs should supplement their collection and analysis of AR and complaint reports a relating to patient symptoms, with external information searches regarding emergent safety issues (e.g. Canada Vigilance, foreign regulatory websites, scientific literature, etc.). The appropriate timing, frequency and nature of environmental scanning depend on such factors as the risk profile of the product, any specific emergent issues, the scheduling of the summary report, etc. The preparation of annual summary reports should result in increasing cumulative knowledge of real-world use that can be compared against referenced safety information (e.g. product monographs, core company data sheets, core company safety information, etc.) If an MAH is not able to prepare an annual summary report in either PBRER or PSUR format or if these formats are not optimal or appropriate, a simpler or alternate format may be used. Health Canada expects that such a report would contain the following sections b : Introduction a It is desirable tor records of symptomatic product complaints to include the four basic vigilance elements: product name, unique patient identifier (e.g. initials, age), the nature of the reaction/symptoms, and reporter contact information. b See Appendix 1 for a format for certain consumer health products. 4 Preparation and Submission of Summary Reports for Marketed Health Products
207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 Summary of changes (if any) to what is known about the product s safety, based on information collected during the reporting period Significant domestic or foreign regulatory actions (if any) bearing on safety during the reporting period Patient exposure (e.g. estimated from sales figures) A critical analysis to determine if there has been, since the last reporting period: Any significant change in the characteristics of expected adverse reactions and/or the overall safety profile of the health product (e.g., severity, outcome, target population, changes in effectiveness, use patterns) Serious unexpected reactions, placing into perspective the cumulative reports since marketing Non-serious unexpected reactions in vulnerable sub-populations An increased reporting frequency of expected reactions, including comments on whether it is believed the data reflect a meaningful change in AR occurrence Significant changes in reporting rates, including consideration of patient exposure Any new safety issues identified for the following: o drug interactions o experience with overdose, deliberate or accidental, and its treatment o drug abuse, misuse, or off-label use o positive or negative experiences during pregnancy or lactation o experience in special patient groups (e.g., children, elderly, organ impaired) o effects of long-term exposure Other information needed for the analysis Conclusion as to whether there has been a significant change in what is known about the risks and benefits of the health product during the period covered by the report Adverse reactions line listing(s) and summary tabulations The information included in the annual summary report will vary depending on the adverse reaction cases reported to the MAH. A lack of significant new information should be mentioned for each section. 2.3 Canadian-Specific Sections Although standardized periodic summary reports (i.e. PBRERs and PSURs) are used globally, regional differences may exist and should be accounted for. Below are examples of special considerations related to medical practice or populations in Canada that should be considered when preparing an annual summary report: Include information such as the epidemiology of the medical condition(s) or risk factors that reflect the authorized indication(s) in Canada in cases where it varies from the authorized indication(s) in other jurisdictions; Reference the latest available version of the Terms of Market Authorization [e.g., Canadian Product Monograph (PM)]; Include information related to Canadian patient exposure (when relevant); Provide post-marketing experience in the Canadian context; Discuss pharmacovigilance activities within the Canadian context; this could involve monitoring of domestic adverse events known to the MAH, and reconciliation of such reaction(s) with Health Canada s Canada Vigilance Database; and Preparation and Submission of Summary Reports for Marketed Health Products 5
251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 Include information that is applicable to the Canadian context, in relation to risk minimization strategies and evaluation of effectiveness of risk minimization activities. Canadian-specific section(s) can be provided in the form of a Canadian-specific summary report or as an appendix or annex to an already prepared summary report. 2.4 Notifying Health Canada of a Change in the Risks and Benefits of a Health Product In accordance with the Food and Drug Regulations 1, in preparing the annual summary report, the MAH must determine whether there has been a significant change in what is known about the risks and benefits of the drug. If the MAH concludes from the annual summary report that there has been a significant change, they must inform Health Canada immediately in a letter sent to the Office of Submissions and Intellectual Property (OSIP). The notification should include the most recent completed annual summary report, and a cover letter indicating that the information is being sent pursuant to the reporting requirements detailed in C.01.018(4) of the Food and Drug Regulations. The Marketed Health Products Directorate (MHPD) may request additional information as a follow-up to such a notification. For natural health products, in addition to complying with regulatory requirements to report safety and efficacy information, Health Canada expects that MAHs will inform MHPD if the MAH concludes from the annual summary report that there is a significant change in what is known about the risks and benefits of a natural health product. Examples of a significant change in what is known about the risks and benefits of a health product include a significant change in the frequency or severity of a known risk (e.g., a sudden increase in reporting of QT prolongation and torsades de pointes), or the identification of a previously unknown serious risk (e.g., a new risk of liver failure). 2.5 Use of Foreign Reviews Reviews completed by regulatory authorities in the United States (US Food and Drug Administration) and the European Union s centralized procedure (European Medicines Agency) should be provided if available. The use of reviews from other foreign regulatory authorities may also be considered (e.g., Switzerland s Swissmedic; Australia s Therapeutic Goods Administration; and Singapore s Health Sciences Authority). 6 Preparation and Submission of Summary Reports for Marketed Health Products
283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 3 Issue-Related Summary Reports Health Canada may request at any time that the MAH perform a further analysis of a specific safety issue by requesting that an issue-related summary report be submitted for the specific safety issue. For example, an issuerelated summary report may be requested as a follow-up to a PSUR or PBRER review. Pursuant to section C.01.019 1 of the Food and Drug Regulations, Health Canada may, for the purposes of assessing the safety and effectiveness of a drug, request in writing that the MAH submit an issue-related summary report which contains a concise, critical analysis of the adverse drug reactions and serious adverse drug reactions to a drug. Typically, a 30 day period is requested for the submission of the report; however, the period may be shorter than 30 days if the information is required on an expedited basis in order to determine whether the drug poses a serious and imminent risk to human health. There are no provisions in the Natural Health Products Regulations for issue-related summary reports. However, for the purposes of assessing the safety and effectiveness of natural health products, Health Canada may on occasion request in writing that the MAH submit an issue-related summary report which contains a concise, critical analysis of the adverse reactions and serious adverse reactions to a natural health product. 3.1 Acceptable Issue-Related Summary Report Format The information requested in an issue-related summary report should contain, but is not limited to, the following: Definition used for the adverse event of interest; Description of the search strategy to retrieve the cases; Detailed summary analysis of the cases. Information should include, but not be limited to: tabulation of all events; MAH comments on the cases; summary analysis of the temporal relationship between health product administration and the occurrence of the event; and summary analysis of possible risk factors and confounding variables; Canadian and international patient exposure data using both patient-years and total number of patients exposed; A conclusion as to the safety and/or the effectiveness of the health product with regards to the occurrence of these events and if applicable, any planned risk mitigating actions or change to the Risk Management Plan, Product Monograph, or labelling; Copy of all the Council for International Organizations of Medical Sciences (CIOMS) reports for the adverse event of interest reported with the use of the product since its international birth date. Preparation and Submission of Summary Reports for Marketed Health Products 7
316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 4 Submission Procedures for Annual Summary Reports and Issue-Related Summary Reports 4.1 General Considerations MAHs are strongly encouraged to consider the following when preparing annual summary reports and issue-related summary reports: Include the most recent data available unless otherwise indicated; Incorporate Canadian-specific data and information when possible (refer to section 2.3 for more detail); Provide a foreign review report (when available); The submission should be provided in either English or French. 4.2 When to Submit an Annual Summary Report or Issue-Related Summary Report to Health Canada Annual summary reports and issue-related summary reports should be submitted in, but are not limited to, the following circumstances: If a summary report is requested by Health Canada; To fulfill commitments for market authorization [e.g., Notice of Compliance with Conditions (NOC/c)]; or If the MAH concludes that there has been a significant change in what is known about the risks and benefits of the health product (e.g., a serious safety issue which may significantly affect the benefit-risk profile of the health product). In this case, Health Canada must be notified in writing immediately (see Health Canada contact information provided in Appendix 4). Annual summary reports and issue-related summary reports may be requested at any time by Health Canada as part of an ongoing safety review. Under the current regulatory framework, Health Canada may request additional information on a case-by-case basis or in follow-up to an annual summary report or issue-related summary report review. Annual summary reports and issue-related summary reports, when requested, are to be submitted to Health Canada within 30 calendar days or unless otherwise specified. 4.3 Instructions for Submitting Annual Summary Reports and Issue-Related Summary Reports for Drugs All annual summary reports and issue-related summary reports should be provided (when necessary) to Health Canada in electronic format. No paper copies should be provided, with the exception of the cover letter (refer to section 4.4 for more detail). Electronic documents should be submitted as Portable Document Format (PDF) files. PDF versions of documents should be generated from electronic source documents and not from scanned material, except where access to the source electronic file is unavailable or where a signature is required. Preparation and Submission of Summary Reports for Marketed Health Products 9
357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 4.3.1 ectd Format Requirements Health Canada strongly recommends that electronic documents be provided in electronic common technical document (ectd) format. Annual summary reports and issue-related reports provided in ectd format should be prepared using applicable sections of the Guidance Document: Preparation of Drug Regulatory Activities in Electronic Common Technical Document (ectd) Format published on the Health Canada Website. 4.3.2 Non-eCTD Format Requirements Alternatively, Health Canada will also accept electronic documents in non-ectd electronic-only format. Annual summary reports and issue-related reports provided in non-ectd electronic-only format should be prepared using applicable sections of the document: Health Canada s requirements for filing regulatory activities in non-ectd electronic-only format published on the Health Canada Website. The annual summary report should be filed in the section "5.3.6 Reports of Postmarketing Experience" and the issue-related summary report should be filed in the section "1.3.8.4 Other Pharmacovigilance Information" using the structured template recommended in "Appendix D: Common Technical Document (CTD) Format" of the guidance document Preparation of Drug Regulatory Activities in the Common Technical Document (CTD) Format. 4.4 Cover Letter All submissions should be accompanied by both an electronic and a paper cover letter. MAHs should address the cover letter to OSIP. The cover letter should indicate the submission type as well as the reason for filing: To inform Health Canada of a significant change in what is known about the risks and benefits of the health product; REQUESTED PERIODIC PSUR/PBRER - requested by Health Canada (for example Risk Management Plan (RMP) follow-up or post-authorization commitment); REQUESTED AD HOC PSUR/PBRER - submitted as a one-time request made by either the premarket review directorate (reviewing the associated regulatory submission) or by MHPD (the requestor should be specified in the cover letter). ISSUE-RELATED SUMMARY REPORT- submitted as a one-time request made by MHPD (the requestor should be specified in the cover letter). 4.5 Health Canada s Review of Annual Summary Report and Issue-Related Summary Report Submissions Reviews of annual summary reports and issue-related summary reports are conducted by the MHPD. Reviews of annual summary reports related to a submission (e.g., PSUR-c / PBRER-c), are conducted by the respective premarket review Directorate (e.g., TPD, BGTD, NNHPD). Possible outcomes of Health Canada s reviews of annual summary reports and issue-related summary reports reviews may include, but are not limited to, the following: continuous surveillance / monitoring; additional assessments or safety reviews; 10 Preparation and Submission of Summary Reports for Marketed Health Products
400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 a request that the MAH submit future annual summary report(s) or an issue-related summary report; or, a request that the MAH submit clarification on information provided in the submission. During the review of an annual summary report or an issue-related summary report, Health Canada may communicate in writing with the MAH to clarify information. If deficiencies have been identified, timelines for a response by the MAH will be included in a letter sent by Health Canada. The timelines may vary depending on the safety issue being managed and the type and amount of information being sought. The MAH is generally provided with a minimum of 30 days to respond. 4.6 Status Requests For drugs, MAHs are able to access information about their own submissions via the Drug Submission Tracking System - Industry Access (DSTS-IA). MAHs with questions about the status or progress of their submission may contact the relevant bureau (see Appendix 4 for contact information). Information will be provided to MAHs in keeping with the confidentiality of the process and without pre-empting the final decision of Health Canada on the disposition of the submission. Preparation and Submission of Summary Reports for Marketed Health Products 11
417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 Appendix 1: Requirements for Lower Risk Health Products (e.g., certain over-thecounter (OTC) drugs and natural health products) Annual summary reports summarize and integrate new cumulative safety knowledge gained from experience during the reporting period. For products that have already been shown - with a high degree of certainty - to be inherently safe when used in the real world such reports will not likely yield significant new knowledge; as long as significant new knowledge is considered and (if necessary) reported, summary reporting requirements may be kept to a reasonable minimum. Hard-surface disinfectants and products at the cosmetic-drug interface (i.e. cosmetic-like drugs), for example, are likely to fall into this category. Health Canada expects that the annual summary report for these products should contain the following sections: Summary of changes, if any, to what is known about the product s safety, based on information collected during the reporting period Significant regulatory actions, if any, bearing on safety (domestic and foreign) during the reporting period A critical analysis to determine if there has been, since the last reporting period: o Any significant change in the overall safety profile of the product o Significant changes in reporting rates o Any new safety issues identified Other information needed for the analysis Conclusion, if any, as to whether there has been a significant change in what is known about the risks and benefits of the health product during the period covered by the report Adverse reactions line listing(s), if any, and summary tabulations Annual summary reports and issue-related summary reports should be submitted in, but are not limited to, the following circumstances: If a summary report is requested by Health Canada; If the MAH concludes that there has been a significant change in what is known about the risks and benefits of the health product (e.g., a serious safety issue which may significantly affect the benefit-risk profile of the health product). In this case, Health Canada must be notified in writing without delay (see Health Canada contact information provided in Appendix 4). Preparation and Submission of Summary Reports for Marketed Health Products 13
448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 Appendix 2: Regulations Pertaining to Annual Summary Reports and Issue- Related Summary Reports The sections of the applicable regulations that set out the summary reporting requirements are listed below. Food and Drug Regulations Prohibition and Serious Adverse Drug Reaction Reporting (C.01.016, C.01.017) Prohibition C.01.016. No manufacturer shall sell a drug unless the manufacturer complies with the conditions set out in sections C.01.017 to C.01.019. Serious Adverse Drug Reaction Reporting C.01.017. The manufacturer shall submit to the Minister a report of all information relating to the following serious adverse drug reactions within 15 days after receiving or becoming aware of the information, whichever occurs first: (a) any serious adverse drug reaction that has occurred in Canada with respect to the drug; and (b) any serious unexpected adverse drug reaction that has occurred outside Canada with respect to the drug. Annual Summary Report and Case Reports (C.01.018) C.01.018. (1) The manufacturer shall prepare an annual summary report of all information relating to adverse drug reactions and serious adverse drug reactions to the drug that it received or became aware of during the previous 12 months. (2) The annual summary report shall contain a concise, critical analysis of the adverse drug reactions and serious adverse drug reactions to the drug. (3) In preparing the annual summary report, the manufacturer shall determine, on the basis of the analysis referred to in subsection (2), whether there has been a significant change in what is known about the risks and benefits of the drug during the period covered by the report and shall include its conclusions in this regard in the summary report. (4) If, in preparing the annual summary report, the manufacturer concludes that there has been a significant change, it shall notify the Minister without delay, in writing, unless this has already been done. (5) The Minister may, for the purposes of assessing the safety and effectiveness of the drug, request in writing that the manufacturer submit to the Minister one or both of the following: (a) the annual summary reports; Preparation and Submission of Summary Reports for Marketed Health Products 15
492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 (b) the case reports relating to the adverse drug reactions and serious adverse drug reactions to the drug that are known to the manufacturer. (6) The Minister shall, after giving the manufacturer an opportunity to be heard, specify a period for the submission of the annual summary reports or case reports, or both, that is reasonable in the circumstances, and the manufacturer shall submit the reports within that period. Issue-related Summary Reports (C.01.019) C.01.019. (1) The Minister may, for the purposes of assessing the safety and effectiveness of the drug, request in writing that the manufacturer submit to the Minister an issue-related summary report. (2) The report shall contain a concise, critical analysis of the adverse drug reactions and serious adverse drug reactions to the drug, as well as case reports of all or specified adverse drug reactions and serious adverse drug reactions to the drug that are known to the manufacturer in respect of the issue that the Minister directs the manufacturer to analyze in the report. (3) The Minister shall, after giving the manufacturer an opportunity to be heard, specify a period for the submission of the report that is reasonable in the circumstances. The Minister may specify a period that is shorter than 30 days if the Minister needs the information in the report to determine whether the drug poses a serious and imminent risk to human health. (4) The manufacturer shall submit the report within the specified period. Maintenance of Records (C.01.020) C.01.020. (1) The manufacturer shall maintain records of the reports and case reports referred to in sections C.01.017 to C.01.019. (2) The manufacturer shall retain the records for 25 years after the day on which they were created. New Drugs (C.08.007, C.08.008) C.08.007. (1) Where a manufacturer has received a notice of compliance issued in respect of a new drug submission, an extraordinary use new drug submission, an abbreviated new drug submission, an abbreviated extraordinary use new drug submission or a supplement to any of those submissions, the manufacturer shall establish and maintain records, in a manner that enables an audit to be made, respecting (g) any failure of one or more distributed lots of the new drug to meet the specifications established for that new drug in the submission or supplement; and (h) any unusual failure in efficacy of that new drug. 16 Preparation and Submission of Summary Reports for Marketed Health Products
537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 C.08.008. No manufacturer shall sell a new drug unless the manufacturer has, with respect to all the manufacturer's previous sales of that new drug, furnished to the Minister... (c) a summary of a record respecting any information referred to in paragraph C.08.007(g) or (h), within 15 days of the day on which the manufacturer established the record. Natural Health Products Regulations (Section 24) Section 24 24.(1) A licensee shall provide the Minister with (a) a case report for each serious adverse reaction to the natural health product that occurs inside Canada, within 15 days after the day on which the licensee becomes aware of the reaction; and (b) a case report for each serious unexpected adverse reaction to the natural health product that occurs inside or outside Canada, within 15 days after the day on which the licensee becomes aware of the reaction. (2) A licensee who sells a natural health product shall annually prepare and maintain a summary report that contains a concise and critical analysis of (a) all adverse reactions to the natural health product that have occurred inside Canada; and (b) all reactions for which a case report is required to be provided under subsection (1), that have occurred (i) during the previous 12 months, and (ii) at a dose used or tested for the diagnosis, treatment or prevention of a disease or for modifying organic functions in humans. (3) If after reviewing a case report provided under subsection (1) or after reviewing any other safety data relating to the natural health product, the Minister has reasonable grounds to believe that the natural health product may no longer be safe when used under the recommended conditions of use, the Minister may request that, within 30 days after the day on which the request is received, the licensee (a) provide to the Minister a copy of any summary report prepared under subsection (2); or (b) prepare and provide to the Minister an interim summary report containing a concise and critical analysis of (i) all adverse reactions to the natural health product that have occurred inside Canada, and (ii) all reactions for which a case report is required to be provided under subsection (1), that have occurred Preparation and Submission of Summary Reports for Marketed Health Products 17
583 584 585 586 587 (A) since the date of the most recent summary report prepared under subsection (2), and (A) at a dose used or tested for the diagnosis, treatment or prevention of a disease or for modifying organic functions in humans. 18 Preparation and Submission of Summary Reports for Marketed Health Products
588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 Appendix 3: Glossary Adverse reaction (AR) For the purpose of this guidance document, adverse reaction means a noxious and unintended response to a marketed health product covered by this document, and includes "adverse drug reaction" as defined in the Food and Drug Regulations 1 and "adverse reaction" as defined in the Natural Health Products Regulations 9. Drug According to the Food and Drugs Act 1, a drug includes any substance or mixture of substances manufactured, sold or represented for use in: a. the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms, in human beings or animals, b. restoring, correcting or modifying organic functions in human beings or animals, or c. disinfection in premises in which food is manufactured, prepared or kept. European Union Reference Date (EURD) The European Union reference date corresponds to the date of the first marketing authorisation of a medicine containing that active substance or that combination of active substances in the EU, or alternatively the earliest of the known dates of the marketing authorisations for a medicine containing that active substance or that combination of active substances. Foreign reviews (also referred to as foreign review reports) Scientific safety, efficacy, and quality reports prepared by foreign regulatory authorities, upon which foreign regulatory decisions on health products are based. Includes initial scientific assessments, regulatory correspondence with the sponsor/applicant, follow-up assessments, and the final decision (e.g., positive, negative, conditional). Includes, where applicable, risk management plans and on-site evaluation reports (or equivalent). Does not include the data package filed with the foreign regulatory authority. Health product For the purpose of this guidance document includes products regulated under the Food and Drug Regulations ("drugs") and the Natural Health Products Regulations ("natural health products"). Drugs include both prescription and non-prescription pharmaceuticals; biotechnology products and biologically-derived products such as vaccines, serums, and blood -derived products; disinfectants; and radiopharmaceuticals. Note however, as set out in Section 1.2, that only some of these health products fall within the scope of this guidance document. International Birth Date (IBD) The date of the first marketing authorisation for any product containing the active substance granted to any company in any country in the world. International Conference on Harmonisation (ICH) The International Conference on Harmonisation is a joint regulatory-industry initiative pertaining to the international harmonisation of regulatory requirements for drug products. This is carried out via the development and implementation of harmonised technical guidelines and standards for the development, registration and surveillance of pharmaceutical products. Health Canada is committed to the adoption and implementation of ICH guidances. Preparation and Submission of Summary Reports for Marketed Health Products 19
633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 Market authorization holder (MAH) For the purpose of this guidance document, market authorization holder (MAH) means the entity that holds the Notice of Compliance, the Drug Identification Number (DIN), the Natural Product Number (NPN), the Homeopathic Medicine Number (DIN-HM), or the product licence. Natural health product (NHP) A substance set out in Schedule 1 of the Natural Health Products Regulations 9 or a combination of substances in which all the medicinal ingredients are substances set out in Schedule 1 of the Natural Health Products Regulations, a homeopathic medicine or a traditional medicine that is manufactured, sold or represented for use in a. the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state or its symptoms in humans; b. restoring or correcting organic functions in humans; or c. modifying organic functions in humans, such as modifying those functions in a manner that maintains or promotes health. However, a natural health product does not include a substance set out in Schedule 2 of the Natural Health Products Regulations, any combination of substances that includes a substance set out in Schedule 2 of the Natural Health Products Regulations or a homeopathic medicine or a traditional medicine that is or includes a substance set out in Schedule 2 of the Natural Health Products Regulations. Periodic Benefit Risk Evaluation Report (PBRER) The PBRER is a pharmacovigilance document intended to provide a comprehensive, concise, and critical analysis of new or emerging information on the risks of the health product, and on its benefit in approved indications, to enable an appraisal of the product s overall benefit-risk profile. The updated ICH E2C(R2) guidance ensures that annual summary reports for marketed health products have the role of being periodic benefit-risk evaluation reports by covering: Safety evaluation, evaluation of all relevant available information accessible to MAHs and benefit-risk evaluation. Pharmacovigilance Defined by the World Health Organization (WHO) as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems. Periodic Safety Update Report (PSUR) The PSUR is a practical and achievable mechanism for summarizing interval safety data, and for conducting an overall safety evaluation. It is a tool for MAHs to conduct systematic analyses of safety data on a regular basis. In addition to covering ongoing safety issues, the PSUR should also include updates on emerging and/or urgent safety issues, and major signal detection and evaluation that are addressed in other documents. Serious adverse reaction For the purpose of this guidance document, serious adverse reaction means a noxious and unintended response to a marketed health product covered by this document that occurs at any dose and that requires in-patient hospitalization or prolongation of existing hospitalization, that causes congenital malformation, results in persistent or significant disability or incapacity, is a medically important event or reaction, is life-threatening or results in death and includes "serious adverse drug reaction" as defined in the Food and Drug Regulations 1 and "serious adverse reaction" as defined in the Natural Health Products Regulations 9. 20 Preparation and Submission of Summary Reports for Marketed Health Products
679 680 681 682 683 684 685 686 687 688 689 Terms of Market Authorization (TMA) The Terms of Market Authorization (TMA) are comprised of all labelling information (e.g., PM, prescribing information, inserts, etc.) that accompanies the Notice of Compliance (NOC) and/or in the document that assigns a DIN, and any related labelling material for health products. This information is derived from the review of information on the health product that is submitted for regulatory review and authorization, as required by the Food and Drug Act, and respective Regulations, (and as interpreted by guidance documents and policies). For natural health products, the TMA is all labelling information (e.g., risk information) that accompanies the product licence and/or document that assigns an NPN or DIN-HM, and any related material for labelling of the health product. Preparation and Submission of Summary Reports for Marketed Health Products 21