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DRAFT Guidance Document for Industry - Preparation and Submission of Summary Reports for Marketed Health Products Annual Summary Reports and Issue-Related Summary Reports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: [email protected] 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

Guidance Document for Industry - Preparation and Submission of Summary Reports for Marketed Health Products i

Forward 1

2 Guidance documents are meant to provide assistance on how to comply with governing statutes and regulations. 3 Guidance documents also provide assistance to staff on how Health Canada mandates and objectives should be 4 implemented in a manner that is fair, consistent and effective. 5 6 Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in 7 approach. Alternate approaches to the principles and practices described in this document may be acceptable 8 provided they are supported by adequate justification. Alternate approaches should be discussed in advance with the 9 relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not 10 been met. 11 12 As a corollary to the above, it is equally important to note that Health Canada reserves the right to request 13 information or material, or define conditions not specifically described in this document, in order to allow the 14 Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed 15 to ensuring that such requests are justifiable and that decisions are clearly documented. 16 17 This document should be read in conjunction with relevant sections of other applicable guidance documents. 18 19

Guidance Document for Industry - Preparation and Submission of Summary Reports for Marketed Health Products iii

Table of Contents 20

1 Introduction ........................................................................................................................................................ 1 21

1.1 Objectives ...................................................................................................................................................... 1 22 1.2 Scope and Application ................................................................................................................................... 1 23 1.3 Guiding Principles ......................................................................................................................................... 1 24 1.4 Background .................................................................................................................................................... 2 25

2 Annual Summary Reports ................................................................................................................................. 3 26

2.1 Preparing and Maintaining Annual Summary Reports .................................................................................. 3 27 2.2 Acceptable Annual Summary Report Format ................................................................................................ 4 28

2.2.1 Periodic Benefit-Risk Evaluation Report (PBRER) .................................................................................... 4 29 2.2.2 Periodic Safety Update Report (PSUR) ....................................................................................................... 4 30 2.2.3 Annual Summary Report Alternative Format .............................................................................................. 4 31

2.3 Canadian-Specific Sections ........................................................................................................................... 5 32 2.4 Notifying Health Canada of a Change in the Risks and Benefits of a Health Product .................................. 6 33 2.5 Use of Foreign Reviews ................................................................................................................................ 6 34

3 Issue-Related Summary Reports ....................................................................................................................... 7 35

3.1 Acceptable Issue-Related Summary Report Format ...................................................................................... 7 36

4 Submission Procedures for Annual Summary Reports and Issue-Related Summary Reports ................... 9 37

4.1 General Considerations .................................................................................................................................. 9 38 4.2 When to Submit an Annual Summary Report or Issue-Related Summary Report to Health Canada ............ 9 39 4.3 Instructions for Submitting Annual Summary Reports and Issue-Related Summary Reports for Drugs ...... 9 40

4.3.1 eCTD Format Requirements ...................................................................................................................... 10 41 4.3.2 Non-eCTD Format Requirements .............................................................................................................. 10 42

4.4 Cover Letter ................................................................................................................................................. 10 43 4.5 Health Canada’s Review of Annual Summary Report and Issue-Related Summary Report Submissions .. 10 44 4.6 Status Requests ............................................................................................................................................ 11 45

Appendix 1: Requirements for Lower Risk Health Products (e.g., certain over-the-counter (OTC) 46 drugs and natural health products) ......................................................................................................................... 13 47

Appendix 2: Regulations Pertaining to Annual Summary Reports and Issue-Related Summary Reports ....... 15 48

Appendix 3: Glossary ................................................................................................................................................ 19 49

Appendix 4: Contact Information ............................................................................................................................ 23 50

Appendix 5: List of Relevant Guidance Documents ............................................................................................... 27 51

52

Guidance Document for Industry - Preparation and Submission of Summary Reports for Marketed Health Products 1

1 Introduction 53

1.1 Objectives 54

This guidance document is intended to: 55 56

• define Health Canada’s expectations for post-approval regulatory requirements for health products, and; 57 • provide an overview of the procedures for submitting annual summary reports and issue-related summary 58

reports to Health Canada. 59 60 An annual summary report is a comprehensive assessment of all known safety information for a marketed health 61 product. It is prepared by the market authorization holder (MAH) to provide an update on the worldwide safety 62 profile of a health product at defined intervals post-authorization, and submitted to Health Canada upon request. 63 An issue-related summary report is a concise, critical analysis of a specific safety or effectiveness issue that may be 64 related to a health product. It is prepared by the MAH at the request of Health Canada. 65 66

1.2 Scope and Application 67

This guidance document provides MAHs with information on how to comply with the Food and Drugs Act, the 68 Food and Drug Regulations, and the Natural Health Products Regulations with respect to the preparation and 69 submission of annual summary reports and issue-related summary reports for marketed health products. 70 71 The principles and practices outlined in this document apply to the following health products for human use: 72 73

• pharmaceutical drugs (prescription and non-prescription drugs, including generics); 74 • biologics; 75 • biotechnology products; 76 • radiopharmaceuticals; 77 • preventative vaccines; 78 • therapeutic vaccines; 79 • natural health products; and, 80 • medical devices (when part of a combination product submission). 81

82 This guidance document does not apply to annual summary reports provided to pre-market Directorates as part of a 83 submission. 84 85 While these principles can be applied across all product lines, please see Appendix 1 for certain products that are 86 within the scope of lower risk health products (e.g., certain over-the-counter (OTC) drugs and natural health 87 products). 88 89

1.3 Guiding Principles 90

Health Canada uses a “lifecycle approach” to continually promote high standards of health product vigilance, to 91 protect the health and safety of Canadians, and to facilitate access to health products which are important to health 92 and well-being. 93

Guidance Document for Industry - 2 Preparation and Submission of Summary Reports for Marketed Health Products

94 In addition to Canadian legislative and regulatory requirements, Health Canada aligns health product vigilance with 95 international best practices wherever possible. Health Canada, as an official member to the International Conference 96 on Harmonisation (ICH) is committed to the adoption and implementation of ICH guidances. 97 98

1.4 Background 99

According to the World Health Organization (WHO), pharmacovigilance is defined as the science and activities 100 relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related 101 problem. As the scope of health products regulated in Canada is broader than drugs, Health Canada uses the term 102 “health product vigilance” in relation to the WHO definition. 103 104 Health Canada encourages and monitors good vigilance practices (GVPs) by industry, reflecting the fact that 105 industry is responsible for the safety and efficacy of their health products. MAHs have primary responsibility for the 106 safety of any health products they sell, manufacture, import or distribute to the Canadian public, and must comply 107 with all Canadian legislative and regulatory requirements. Health Canada has a shared responsibility to enforce 108 Canadian legislative and regulatory requirements and monitor risks associated with marketed health products. 109 110 In 1996, ICH endorsed the ICH E2C guidance on Clinical Safety Data Management: Periodic Safety Update Reports 111 (PSURs) for Marketed Drugs, which provided guidance on the format and content of safety updates. The ICH 112 E2C(R1) harmonized periodic safety reporting requirements for MAHs and provided a common international 113 format. On April 1, 2010, Health Canada adopted ICH E2C(R1) and implemented a two year risk-prioritized PSUR 114 Regulatory Review Pilot. Since that time, the science of pharmacovigilance has evolved globally, prompting 115 reassessment of the role of the PSUR in the spectrum of safety documents submitted to regulatory authorities. 116 117 In December 2012, ICH finalized the ICH E2C(R2): Periodic Benefit-Risk Evaluation Report (PBRER) guidance. 118 On March 1, 2013, Health Canada announced to stakeholders that it has adopted the ICH E2C(R2). This guidance is 119 intended to ensure that worldwide safety experience is provided to authorities at defined times after marketing, with 120 maximum efficiency and avoiding duplication of effort. The PBRER format will allow MAHs to prepare a 121 comprehensive, concise, and critical analysis of new or emerging information on the risks and benefits of their 122 health products and to enable an evaluation of the product’s overall benefit-risk profile. 123


2 Annual Summary Reports 124

In accordance with the Food and Drug Regulations1, the MAH must, on an annual basis and whenever requested by 125 the Minister of Health, conduct a concise, critical analysis of the adverse reactions and serious adverse reactions for 126 a health product and prepare a summary report with respect to the reports received during the previous twelve 127 months. When preparing the report, the MAH must determine whether or not there has been a significant change in 128 the benefit-risk profile of the health product. The current interpretation of benefit-risk profile for a health product is 129 a reflection of the overall balance of the product's potential benefits with its identified risks as revealed through 130 safety and efficacy evidence, and through consideration of how that evidence contextualizes with normal conditions 131 of use on the market.2 If the MAH concludes that there has been a significant change in the benefit-risk profile, they 132 must notify the Minister immediately. 133 134 If Health Canada determines that an examination of the safety and/or effectiveness of a health product are 135 warranted, a request may be made to the MAH to submit an annual summary report, and/or the case reports of all 136 adverse reactions that are known to the MAH. 137 138 In accordance with the Natural Health Products Regulations3, the MAH must, on an annual basis, prepare and 139 maintain a summary report that contains a concise and critical analysis of all domestic adverse reactions to a natural 140 health product, and all foreign serious unexpected adverse reactions to a natural health product taken at the 141 recommended dose, reported during the previous twelve months. If the Minister has reasonable grounds to believe 142 that the natural health product may no longer be safe when used under the recommended conditions of use, the 143 Minister may request any summary reports, interim summary reports and all adverse reactions for which a case 144 report is required, to be submitted to Health Canada within 30 days after the day on which the request is received by 145 the MAH. 146 147

2.1 Preparing and Maintaining Annual Summary Reports 148

The MAH must ensure that all regulatory requirements of the Food and Drug Regulations, and the Natural Health 149 Products Regulations are met and any relevant Health Canada guidance documents are applied. There may be 150 instances when the MAH choses to engage in a contractual agreement with another party whereby they carry out 151 certain regulatory responsibilities on behalf of the MAH (e.g., maintaining records related to adverse reaction (AR) 152 data and preparing annual summary reports). In these cases, it remains the responsibility of the MAH to ensure that 153 any documents requested by Health Canada are sent accordingly. For further guidance on GVPs with respect to drug 154 post-approval reporting requirement responsibilities of the MAH and the importer, refer to Health Canada’s Good 155 Pharmacovigilance Practices (GVP) Guidelines (GUI-0102). 156 157 The MAH is required to prepare and maintain annual summary reports for all of their licensed health products. The 158 requirement to prepare annual summary reports begins on the date that the MAH receives Canadian market 159 authorization for the health product. These reports need to be submitted to Health Canada only in certain 160 circumstances (see Section 4.2). However, all annual summary reports must be maintained by the MAH on site or be 161 easily accessible and, when requested, be submitted to Health Canada within 30 calendar days unless otherwise 162 specified. 163 164 The selected 12-month period for the annual summary report is specified by the MAH. It is the preference of Health 165 Canada that annual summary reports be prepared with harmonized Data Lock Points (DLPs) based on the 166


International Birth Date4 (IBD) of the active substance. If the MAH is unable to identify the IBD, they should refer 167 to the EU reference dates (EURD) list5. For natural health products, the date of first licensing in Canada should be 168 used. 169 170

2.2 Acceptable Annual Summary Report Format 171

MAHs may prepare summary reports in the Periodic Benefit-Risk Evaluation Report (PBRER) format in accordance 172 with the standards defined in the ICH E2C(R2)6 guidance, or the Periodic Safety Update Report (PSUR) format in 173 accordance with the standards defined in the ICH E2C(R1)7 guidance. Health Canada has been accepting annual 174 summary reports in either PSUR or PBRER format since the ICH E2C(R2) guidance was adopted. The vast majority 175 of MAHs have made the transition to PBRER reporting, and as of January 2015 Health Canada’s preference is that 176 MAHs prepare annual summary reports in PBRER format. 177 178

2.2.1 Periodic Benefit-Risk Evaluation Report (PBRER) 179 PBRERs should be prepared annually using the time interval for submission outlined in the ICH E2C(R2) 180 guidance. For further guidance on the format and content of a PBRER please refer to the ICH E2C(R2) 181 guidance document8. Line listings are not required if MAHs prepare annual summary reports in the PBRER 182 format. 183 184 2.2.2 Periodic Safety Update Report (PSUR) 185 The PSUR format is also acceptable to Health Canada. Unless otherwise specified by Health Canada, PSURs 186 should be prepared annually using the time interval for submission outlined in the ICH E2C(R1) guidance, 187 which is available upon request to Health Canada. 188 189 2.2.3 Annual Summary Report Alternative Format 190 An annual summary report needs to take into account not only adverse reaction reports but also consumer 191 complaints and other publicly available information that might be necessary for the analysis. MAHs should 192 supplement their collection and analysis of AR and complaint reportsa relating to patient symptoms, with 193 external information searches regarding emergent safety issues (e.g. Canada Vigilance, foreign regulatory 194 websites, scientific literature, etc.). The appropriate timing, frequency and nature of environmental scanning 195 depend on such factors as the risk profile of the product, any specific emergent issues, the scheduling of the 196 summary report, etc. 197 198 The preparation of annual summary reports should result in increasing cumulative knowledge of real-world use 199 that can be compared against referenced safety information (e.g. product monographs, core company data 200 sheets, core company safety information, etc.) 201 202 If an MAH is not able to prepare an annual summary report in either PBRER or PSUR format or if these 203 formats are not optimal or appropriate, a simpler or alternate format may be used. Health Canada expects that 204 such a report would contain the following sectionsb: 205

• Introduction 206 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.


• Summary of changes (if any) to what is known about the product’s safety, based on information 207 collected during the reporting period 208

• Significant domestic or foreign regulatory actions (if any) bearing on safety during the reporting 209 period 210

• Patient exposure (e.g. estimated from sales figures) 211 • A critical analysis to determine if there has been, since the last reporting period: 212

• Any significant change in the characteristics of expected adverse reactions and/or the overall 213 safety profile of the health product (e.g., severity, outcome, target population, changes in 214 effectiveness, use patterns) 215

• Serious unexpected reactions, placing into perspective the cumulative reports since marketing 216 • Non-serious unexpected reactions in vulnerable sub-populations 217 • An increased reporting frequency of expected reactions, including comments on whether it is 218

believed the data reflect a meaningful change in AR occurrence 219 • Significant changes in reporting rates, including consideration of patient exposure 220 • Any new safety issues identified for the following: 221

o drug interactions 222 o experience with overdose, deliberate or accidental, and its treatment 223 o drug abuse, misuse, or off-label use 224 o positive or negative experiences during pregnancy or lactation 225 o experience in special patient groups (e.g., children, elderly, organ impaired) 226 o effects of long-term exposure 227

• Other information needed for the analysis 228 • Conclusion as to whether there has been a significant change in what is known about the risks and 229

benefits of the health product during the period covered by the report 230 • Adverse reactions line listing(s) and summary tabulations 231

232 The information included in the annual summary report will vary depending on the adverse reaction cases 233 reported to the MAH. A lack of significant new information should be mentioned for each section. 234

235

2.3 Canadian-Specific Sections 236

Although standardized periodic summary reports (i.e. PBRERs and PSURs) are used globally, regional differences 237 may exist and should be accounted for. Below are examples of special considerations related to medical practice or 238 populations in Canada that should be considered when preparing an annual summary report: 239 240

• Include information such as the epidemiology of the medical condition(s) or risk factors that reflect the 241 authorized indication(s) in Canada in cases where it varies from the authorized indication(s) in other 242 jurisdictions; 243

• Reference the latest available version of the Terms of Market Authorization [e.g., Canadian Product 244 Monograph (PM)]; 245

• Include information related to Canadian patient exposure (when relevant); 246 • Provide post-marketing experience in the Canadian context; 247 • Discuss pharmacovigilance activities within the Canadian context; this could involve monitoring of 248

domestic adverse events known to the MAH, and reconciliation of such reaction(s) with Health Canada’s 249 Canada Vigilance Database; and 250


• Include information that is applicable to the Canadian context, in relation to risk minimization strategies 251 and evaluation of effectiveness of risk minimization activities. 252

253 Canadian-specific section(s) can be provided in the form of a Canadian-specific summary report or as an appendix 254 or annex to an already prepared summary report. 255 256

2.4 Notifying Health Canada of a Change in the Risks and Benefits of a Health 257 Product 258

In accordance with the Food and Drug Regulations1, in preparing the annual summary report, the MAH must 259 determine whether there has been a significant change in what is known about the risks and benefits of the drug. If 260 the MAH concludes from the annual summary report that there has been a significant change, they must inform 261 Health Canada immediately in a letter sent to the Office of Submissions and Intellectual Property (OSIP). The 262 notification should include the most recent completed annual summary report, and a cover letter indicating that the 263 information is being sent pursuant to the reporting requirements detailed in C.01.018(4) of the Food and Drug 264 Regulations. The Marketed Health Products Directorate (MHPD) may request additional information as a follow-up 265 to such a notification. 266 267 For natural health products, in addition to complying with regulatory requirements to report safety and efficacy 268 information, Health Canada expects that MAHs will inform MHPD if the MAH concludes from the annual summary 269 report that there is a significant change in what is known about the risks and benefits of a natural health product. 270 271 Examples of a significant change in what is known about the risks and benefits of a health product include a 272 significant change in the frequency or severity of a known risk (e.g., a sudden increase in reporting of QT 273 prolongation and torsades de pointes), or the identification of a previously unknown serious risk (e.g., a new risk of 274 liver failure). 275 276

2.5 Use of Foreign Reviews 277

Reviews completed by regulatory authorities in the United States (US Food and Drug Administration) and the 278 European Union’s centralized procedure (European Medicines Agency) should be provided if available. The use of 279 reviews from other foreign regulatory authorities may also be considered (e.g., Switzerland’s Swissmedic; 280 Australia’s Therapeutic Goods Administration; and Singapore’s Health Sciences Authority). 281 282


3 Issue-Related Summary Reports 283

Health Canada may request at any time that the MAH perform a further analysis of a specific safety issue by 284 requesting that an issue-related summary report be submitted for the specific safety issue. For example, an issue-285 related summary report may be requested as a follow-up to a PSUR or PBRER review. 286 287 Pursuant to section C.01.019 1 of the Food and Drug Regulations, Health Canada may, for the purposes of assessing 288 the safety and effectiveness of a drug, request in writing that the MAH submit an issue-related summary report 289 which contains a concise, critical analysis of the adverse drug reactions and serious adverse drug reactions to a drug. 290 Typically, a 30 day period is requested for the submission of the report; however, the period may be shorter than 30 291 days if the information is required on an expedited basis in order to determine whether the drug poses a serious and 292 imminent risk to human health. 293 294 There are no provisions in the Natural Health Products Regulations for issue-related summary reports. However, for 295 the purposes of assessing the safety and effectiveness of natural health products, Health Canada may on occasion 296 request in writing that the MAH submit an issue-related summary report which contains a concise, critical analysis 297 of the adverse reactions and serious adverse reactions to a natural health product. 298 299

3.1 Acceptable Issue-Related Summary Report Format 300

The information requested in an issue-related summary report should contain, but is not limited to, the following: 301 • Definition used for the adverse event of interest; 302 • Description of the search strategy to retrieve the cases; 303 • Detailed summary analysis of the cases. Information should include, but not be limited to: tabulation of all 304

events; MAH comments on the cases; summary analysis of the temporal relationship between health 305 product administration and the occurrence of the event; and summary analysis of possible risk factors and 306 confounding variables; 307

• Canadian and international patient exposure data using both patient-years and total number of patients 308 exposed; 309

• A conclusion as to the safety and/or the effectiveness of the health product with regards to the occurrence 310 of these events and if applicable, any planned risk mitigating actions or change to the Risk Management 311 Plan, Product Monograph, or labelling; 312

• Copy of all the Council for International Organizations of Medical Sciences (CIOMS) reports for the 313 adverse event of interest reported with the use of the product since its international birth date. 314

315


4 Submission Procedures for Annual Summary Reports and Issue-Related 316 Summary Reports 317

4.1 General Considerations 318

MAHs are strongly encouraged to consider the following when preparing annual summary reports and issue-related 319 summary reports: 320 321

• Include the most recent data available unless otherwise indicated; 322 • Incorporate Canadian-specific data and information when possible (refer to section 2.3 for more detail); 323 • Provide a foreign review report (when available); 324 • The submission should be provided in either English or French. 325

326

4.2 When to Submit an Annual Summary Report or Issue-Related Summary 327 Report to Health Canada 328

Annual summary reports and issue-related summary reports should be submitted in, but are not limited to, the 329 following circumstances: 330 331

• If a summary report is requested by Health Canada; 332 • To fulfill commitments for market authorization [e.g., Notice of Compliance with Conditions (NOC/c)]; or 333 • If the MAH concludes that there has been a significant change in what is known about the risks and 334

benefits of the health product (e.g., a serious safety issue which may significantly affect the benefit-risk 335 profile of the health product). In this case, Health Canada must be notified in writing immediately (see 336 Health Canada contact information provided in Appendix 4). 337

338 Annual summary reports and issue-related summary reports may be requested at any time by Health Canada as part 339 of an ongoing safety review. Under the current regulatory framework, Health Canada may request additional 340 information on a case-by-case basis or in follow-up to an annual summary report or issue-related summary report 341 review. 342 343 Annual summary reports and issue-related summary reports, when requested, are to be submitted to Health Canada 344 within 30 calendar days or unless otherwise specified. 345 346

4.3 Instructions for Submitting Annual Summary Reports and Issue-Related 347 Summary Reports for Drugs 348

All annual summary reports and issue-related summary reports should be provided (when necessary) to Health 349 Canada in electronic format. No paper copies should be provided, with the exception of the cover letter (refer to 350 section 4.4 for more detail). 351 352 Electronic documents should be submitted as Portable Document Format (PDF) files. PDF versions of documents 353 should be generated from electronic source documents and not from scanned material, except where access to the 354 source electronic file is unavailable or where a signature is required. 355 356


4.3.1 eCTD Format Requirements 357 Health Canada strongly recommends that electronic documents be provided in electronic common technical 358 document (eCTD) format. Annual summary reports and issue-related reports provided in eCTD format should 359 be prepared using applicable sections of the Guidance Document: Preparation of Drug Regulatory Activities in 360 Electronic Common Technical Document (eCTD) Format published on the Health Canada Website. 361

362 4.3.2 Non-eCTD Format Requirements 363 Alternatively, Health Canada will also accept electronic documents in “non-eCTD electronic-only” format. 364 Annual summary reports and issue-related reports provided in “non-eCTD electronic-only” format should be 365 prepared using applicable sections of the document: Health Canada’s requirements for filing regulatory 366 activities in “non-eCTD electronic-only” format published on the Health Canada Website. 367

368 The annual summary report should be filed in the section "5.3.6 Reports of Postmarketing Experience" and the 369 issue-related summary report should be filed in the section "1.3.8.4 Other Pharmacovigilance Information" 370 using the structured template recommended in "Appendix D: Common Technical Document (CTD) Format" of 371 the guidance document Preparation of Drug Regulatory Activities in the Common Technical Document (CTD) 372 Format. 373

374

4.4 Cover Letter 375

All submissions should be accompanied by both an electronic and a paper cover letter. MAHs should address the 376 cover letter to OSIP. The cover letter should indicate the submission type as well as the reason for filing: 377 378

• To inform Health Canada of a significant change in what is known about the risks and benefits of the health 379 product; 380

• REQUESTED PERIODIC PSUR/PBRER - requested by Health Canada (for example Risk Management 381 Plan (RMP) follow-up or post-authorization commitment); 382

• REQUESTED AD HOC PSUR/PBRER - submitted as a one-time request made by either the premarket 383 review directorate (reviewing the associated regulatory submission) or by MHPD (the requestor should be 384 specified in the cover letter). 385

• ISSUE-RELATED SUMMARY REPORT- submitted as a one-time request made by MHPD (the requestor 386 should be specified in the cover letter). 387

388

4.5 Health Canada’s Review of Annual Summary Report and Issue-Related 389 Summary Report Submissions 390

Reviews of annual summary reports and issue-related summary reports are conducted by the MHPD. Reviews of 391 annual summary reports related to a submission (e.g., PSUR-c / PBRER-c), are conducted by the respective 392 premarket review Directorate (e.g., TPD, BGTD, NNHPD). 393 394 Possible outcomes of Health Canada’s reviews of annual summary reports and issue-related summary reports 395 reviews may include, but are not limited to, the following: 396 397

• continuous surveillance / monitoring; 398 • additional assessments or safety reviews; 399


• a request that the MAH submit future annual summary report(s) or an issue-related summary report; or, 400 • a request that the MAH submit clarification on information provided in the submission. 401

402 During the review of an annual summary report or an issue-related summary report, Health Canada may 403 communicate in writing with the MAH to clarify information. If deficiencies have been identified, timelines for a 404 response by the MAH will be included in a letter sent by Health Canada. The timelines may vary depending on the 405 safety issue being managed and the type and amount of information being sought. The MAH is generally provided 406 with a minimum of 30 days to respond. 407 408

4.6 Status Requests 409

For drugs, MAHs are able to access information about their own submissions via the Drug Submission Tracking 410 System - Industry Access (DSTS-IA). 411 412 MAHs with questions about the status or progress of their submission may contact the relevant bureau (see 413 Appendix 4 for contact information). Information will be provided to MAHs in keeping with the confidentiality of 414 the process and without pre-empting the final decision of Health Canada on the disposition of the submission. 415 416


Appendix 1: Requirements for Lower Risk Health Products (e.g., certain over-the-417 counter (OTC) drugs and natural health products) 418

Annual summary reports summarize and integrate new cumulative safety knowledge gained from experience during 419 the reporting period. For products that have already been shown - with a high degree of certainty - to be inherently 420 safe when used in the real world such reports will not likely yield significant new knowledge; as long as significant 421 new knowledge is considered and (if necessary) reported, summary reporting requirements may be kept to a 422 reasonable minimum. Hard-surface disinfectants and products at the cosmetic-drug interface (i.e. cosmetic-like 423 drugs), for example, are likely to fall into this category. 424 425 Health Canada expects that the annual summary report for these products should contain the following sections: 426 427

• Summary of changes, if any, to what is known about the product’s safety, based on information collected 428 during the reporting period 429

• Significant regulatory actions, if any, bearing on safety (domestic and foreign) during the reporting period 430 • A critical analysis to determine if there has been, since the last reporting period: 431

o Any significant change in the overall safety profile of the product 432 o Significant changes in reporting rates 433 o Any new safety issues identified 434

• Other information needed for the analysis 435 • Conclusion, if any, as to whether there has been a significant change in what is known about the risks and 436

benefits of the health product during the period covered by the report 437 • Adverse reactions line listing(s), if any, and summary tabulations 438

439 Annual summary reports and issue-related summary reports should be submitted in, but are not limited to, the 440 following circumstances: 441 442

• If a summary report is requested by Health Canada; 443 • If the MAH concludes that there has been a significant change in what is known about the risks and 444

benefits of the health product (e.g., a serious safety issue which may significantly affect the benefit-risk 445 profile of the health product). In this case, Health Canada must be notified in writing without delay (see 446 Health Canada contact information provided in Appendix 4). 447


Appendix 2: Regulations Pertaining to Annual Summary Reports and Issue-448 Related Summary Reports 449

The sections of the applicable regulations that set out the summary reporting requirements are listed below. 450 451

Food and Drug Regulations 452 453

Prohibition and Serious Adverse Drug Reaction Reporting (C.01.016, C.01.017) 454 455 Prohibition 456 457 C.01.016. No manufacturer shall sell a drug unless the manufacturer complies with the conditions set out 458 in sections C.01.017 to C.01.019. 459

460 Serious Adverse Drug Reaction Reporting 461 462 C.01.017. The manufacturer shall submit to the Minister a report of all information relating to the following 463 serious adverse drug reactions within 15 days after receiving or becoming aware of the information, 464 whichever occurs first: 465 466

(a) any serious adverse drug reaction that has occurred in Canada with respect to the drug; and 467 468 (b) any serious unexpected adverse drug reaction that has occurred outside Canada with respect to 469 the drug. 470

471 Annual Summary Report and Case Reports (C.01.018) 472 473 C.01.018. (1) The manufacturer shall prepare an annual summary report of all information relating to 474 adverse drug reactions and serious adverse drug reactions to the drug that it received or became aware of 475 during the previous 12 months. 476 477 (2) The annual summary report shall contain a concise, critical analysis of the adverse drug reactions and 478 serious adverse drug reactions to the drug. 479 480 (3) In preparing the annual summary report, the manufacturer shall determine, on the basis of the analysis 481 referred to in subsection (2), whether there has been a significant change in what is known about the risks 482 and benefits of the drug during the period covered by the report and shall include its conclusions in this 483 regard in the summary report. 484 485 (4) If, in preparing the annual summary report, the manufacturer concludes that there has been a significant 486 change, it shall notify the Minister without delay, in writing, unless this has already been done. 487 488 (5) The Minister may, for the purposes of assessing the safety and effectiveness of the drug, request in 489 writing that the manufacturer submit to the Minister one or both of the following: 490 (a) the annual summary reports; 491


492 (b) the case reports relating to the adverse drug reactions and serious adverse drug 493

reactions to the drug that are known to the manufacturer. 494 495 (6) The Minister shall, after giving the manufacturer an opportunity to be heard, specify a period for the 496 submission of the annual summary reports or case reports, or both, that is reasonable in the circumstances, 497 and the manufacturer shall submit the reports within that period. 498 499 Issue-related Summary Reports (C.01.019) 500 501 C.01.019. (1) The Minister may, for the purposes of assessing the safety and effectiveness of the drug, 502 request in writing that the manufacturer submit to the Minister an issue-related summary report. 503 504 (2) The report shall contain a concise, critical analysis of the adverse drug reactions and serious adverse 505 drug reactions to the drug, as well as case reports of all or specified adverse drug reactions and serious 506 adverse drug reactions to the drug that are known to the manufacturer in respect of the issue that the 507 Minister directs the manufacturer to analyze in the report. 508 509 (3) The Minister shall, after giving the manufacturer an opportunity to be heard, specify a period for the 510 submission of the report that is reasonable in the circumstances. The Minister may specify a period that is 511 shorter than 30 days if the Minister needs the information in the report to determine whether the drug poses 512 a serious and imminent risk to human health. 513 514 (4) The manufacturer shall submit the report within the specified period. 515 516 Maintenance of Records (C.01.020) 517 518 C.01.020. (1) The manufacturer shall maintain records of the reports and case reports referred to in sections 519 C.01.017 to C.01.019. 520 521 (2) The manufacturer shall retain the records for 25 years after the day on which they were created. 522 523 New Drugs (C.08.007, C.08.008) 524 525 C.08.007. (1) Where a manufacturer has received a notice of compliance issued in respect of a new drug 526 submission, an extraordinary use new drug submission, an abbreviated new drug submission, an 527 abbreviated extraordinary use new drug submission or a supplement to any of those submissions, the 528 manufacturer shall establish and maintain records, in a manner that enables an audit to be made, 529 respecting… 530 531 (g) any failure of one or more distributed lots of the new drug to meet the specifications established for that 532 new drug in the submission or supplement; and 533 534 (h) any unusual failure in efficacy of that new drug. 535 536


C.08.008. No manufacturer shall sell a new drug unless the manufacturer has, with respect to all the 537 manufacturer's previous sales of that new drug, furnished to the Minister... 538 539 (c) a summary of a record respecting any information referred to in paragraph C.08.007(g) or (h), within 540 15 days of the day on which the manufacturer established the record. 541 542 Natural Health Products Regulations (Section 24) 543 544 Section 24 545 546 24.(1) A licensee shall provide the Minister with 547 548

(a) a case report for each serious adverse reaction to the natural health product that occurs inside 549 Canada, within 15 days after the day on which the licensee becomes aware of the reaction; and 550

551 (b) a case report for each serious unexpected adverse reaction to the natural health product that occurs 552 inside or outside Canada, within 15 days after the day on which the licensee becomes aware of the 553 reaction. 554

555 (2) A licensee who sells a natural health product shall annually prepare and maintain a summary report that 556 contains a concise and critical analysis of 557 558

(a) all adverse reactions to the natural health product that have occurred inside Canada; and 559 560

(b) all reactions for which a case report is required to be provided under subsection (1), that have 561 occurred 562

563 (i) during the previous 12 months, and 564 565 (ii) at a dose used or tested for the diagnosis, treatment or prevention of a disease or for modifying 566 organic functions in humans. 567

568 (3) If after reviewing a case report provided under subsection (1) or after reviewing any other safety data 569 relating to the natural health product, the Minister has reasonable grounds to believe that the natural health 570 product may no longer be safe when used under the recommended conditions of use, the Minister may 571 request that, within 30 days after the day on which the request is received, the licensee 572 573

(a) provide to the Minister a copy of any summary report prepared under subsection (2); or 574 575

(b) prepare and provide to the Minister an interim summary report containing a concise and critical 576 analysis of 577

578 (i) all adverse reactions to the natural health product that have occurred inside Canada, and 579

580 (ii) all reactions for which a case report is required to be provided under subsection (1), that 581

have occurred 582


583 (A) since the date of the most recent summary report prepared under subsection (2), and 584

585 (A) at a dose used or tested for the diagnosis, treatment or prevention of a disease or 586

for modifying organic functions in humans. 587


Appendix 3: Glossary 588

Adverse reaction (AR) 589 For the purpose of this guidance document, adverse reaction means a noxious and unintended response to a 590 marketed health product covered by this document, and includes "adverse drug reaction" as defined in the Food and 591 Drug Regulations 1 and "adverse reaction" as defined in the Natural Health Products Regulations9. 592 593 Drug 594 According to the Food and Drugs Act1, a drug includes any substance or mixture of substances manufactured, sold 595 or represented for use in: 596

a. the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its 597 symptoms, in human beings or animals, 598

b. restoring, correcting or modifying organic functions in human beings or animals, or 599 c. disinfection in premises in which food is manufactured, prepared or kept. 600

601 European Union Reference Date (EURD) 602 The European Union reference date corresponds to the date of the first marketing authorisation of a medicine 603 containing that active substance or that combination of active substances in the EU, or alternatively the earliest of 604 the known dates of the marketing authorisations for a medicine containing that active substance or that combination 605 of active substances. 606 607 Foreign reviews (also referred to as foreign review reports) 608 Scientific safety, efficacy, and quality reports prepared by foreign regulatory authorities, upon which foreign 609 regulatory decisions on health products are based. Includes initial scientific assessments, regulatory correspondence 610 with the sponsor/applicant, follow-up assessments, and the final decision (e.g., positive, negative, conditional). 611 Includes, where applicable, risk management plans and on-site evaluation reports (or equivalent). Does not include 612 the data package filed with the foreign regulatory authority. 613 614 Health product 615 For the purpose of this guidance document includes products regulated under the Food and Drug Regulations 616 ("drugs") and the Natural Health Products Regulations ("natural health products"). Drugs include both prescription 617 and non-prescription pharmaceuticals; biotechnology products and biologically-derived products such as vaccines, 618 serums, and blood -derived products; disinfectants; and radiopharmaceuticals. Note however, as set out in Section 619 1.2, that only some of these health products fall within the scope of this guidance document. 620 621 International Birth Date (IBD) 622 The date of the first marketing authorisation for any product containing the active substance granted to any company 623 in any country in the world. 624 625 International Conference on Harmonisation (ICH) 626 The International Conference on Harmonisation is a joint regulatory-industry initiative pertaining to the international 627 harmonisation of regulatory requirements for drug products. This is carried out via the development and 628 implementation of harmonised technical guidelines and standards for the development, registration and surveillance 629 of pharmaceutical products. Health Canada is committed to the adoption and implementation of ICH guidances. 630 631 632


Market authorization holder (MAH) 633 For the purpose of this guidance document, market authorization holder (MAH) means the entity that holds the 634 Notice of Compliance, the Drug Identification Number (DIN), the Natural Product Number (NPN), the 635 Homeopathic Medicine Number (DIN-HM), or the product licence. 636 637 Natural health product (NHP) 638 A substance set out in Schedule 1 of the Natural Health Products Regulations9 or a combination of substances in 639 which all the medicinal ingredients are substances set out in Schedule 1 of the Natural Health Products Regulations, 640 a homeopathic medicine or a traditional medicine that is manufactured, sold or represented for use in 641 642

a. the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state or its 643 symptoms in humans; 644

b. restoring or correcting organic functions in humans; or 645 c. modifying organic functions in humans, such as modifying those functions in a manner that maintains or 646

promotes health. 647 648

However, a natural health product does not include a substance set out in Schedule 2 of the Natural Health Products 649 Regulations, any combination of substances that includes a substance set out in Schedule 2 of the Natural Health 650 Products Regulations or a homeopathic medicine or a traditional medicine that is or includes a substance set out in 651 Schedule 2 of the Natural Health Products Regulations. 652 653 Periodic Benefit Risk Evaluation Report (PBRER) 654 The PBRER is a pharmacovigilance document intended to provide a comprehensive, concise, and critical analysis of 655 new or emerging information on the risks of the health product, and on its benefit in approved indications, to enable 656 an appraisal of the product’s overall benefit-risk profile. The updated ICH E2C(R2) guidance ensures that annual 657 summary reports for marketed health products have the role of being periodic benefit-risk evaluation reports by 658 covering: Safety evaluation, evaluation of all relevant available information accessible to MAHs and benefit-risk 659 evaluation. 660 661 Pharmacovigilance 662 Defined by the World Health Organization (WHO) as the science and activities relating to the detection, assessment, 663 understanding and prevention of adverse effects or any other drug-related problems. 664 665 Periodic Safety Update Report (PSUR) 666 The PSUR is a practical and achievable mechanism for summarizing interval safety data, and for conducting an 667 overall safety evaluation. It is a tool for MAHs to conduct systematic analyses of safety data on a regular basis. In 668 addition to covering ongoing safety issues, the PSUR should also include updates on emerging and/or urgent safety 669 issues, and major signal detection and evaluation that are addressed in other documents. 670 671 Serious adverse reaction 672 For the purpose of this guidance document, serious adverse reaction means a noxious and unintended response to a 673 marketed health product covered by this document that occurs at any dose and that requires in-patient hospitalization 674 or prolongation of existing hospitalization, that causes congenital malformation, results in persistent or significant 675 disability or incapacity, is a medically important event or reaction, is life-threatening or results in death and includes 676 "serious adverse drug reaction" as defined in the Food and Drug Regulations1 and "serious adverse reaction" as 677 defined in the Natural Health Products Regulations9. 678


679 Terms of Market Authorization (TMA) 680 The Terms of Market Authorization (TMA) are comprised of all labelling information (e.g., PM, prescribing 681 information, inserts, etc.) that accompanies the Notice of Compliance (NOC) and/or in the document that assigns a 682 DIN, and any related labelling material for health products. This information is derived from the review of 683 information on the health product that is submitted for regulatory review and authorization, as required by the Food 684 and Drug Act, and respective Regulations, (and as interpreted by guidance documents and policies). 685 686 For natural health products, the TMA is all labelling information (e.g., risk information) that accompanies the 687 product licence and/or document that assigns an NPN or DIN-HM, and any related material for labelling of the 688 health product. 689


Appendix 4: Contact Information 690

Submissions Address- Drugs 691 Annual summary reports and issue-related summary reports for drugs must be submitted to the OSIP within the 692 period for submission specified by the Minister. MAHs are requested to send their information and material to the 693 following address: 694 695

Office of Submissions and Intellectual Property (OSIP) 696 Health Products and Food Branch, Therapeutic Products Directorate 697 Health Canada 698 101 Tunney's Pasture Driveway 699 Address Locator 0201A1 700 Ottawa, ON K1A 0K9 701

702 For inquiries related to electronic format, please contact Health Canada using the following e-mail address: 703 E-mail: [email protected] 704 705 Submissions Address- Natural Health Products 706 Annual summary reports and issue-related summary reports for natural health products must be submitted to the 707 Marketed Biologicals, Biotechnology and Natural Health Products Bureau within the MHPD within 30 calendar 708 days. MAHs are requested to send their information and material to the following address: 709 710

Marketed Biologicals, Biotechnology and Natural Health Products Bureau 711 Marketed Health Products Directorate 712 Health Canada 713 200 Tunney’s Pasture Driveway 714 Address Locator 0701A 715 Ottawa, ON K1A 0K9 716

717 Review Bureau Contact Information 718 719

The Marketed Health Products Directorate: 720 721 Marketed Pharmaceuticals and Medical Devices Bureau 722 Regulatory Project Management Section, servicing MPMDB 723 Health Protection Building 724 200 Tunney’s Pasture Driveway, Address Locator 0702L 725 Ottawa, ON K1A 0K9 726 E-mail: [email protected] 727 Fax: (613) 960-9754 728 729 Marketed Biologicals, Biotechnology and Natural Health Products Bureau 730 Regulatory Project Management Section, servicing MBBNHPB 731 Health Protection Building 732 200 Tunney’s Pasture Driveway, Address Locator 0701A 733 Ottawa, ON K1A 0K9 734

mailto:[email protected]


E-mail: [email protected] 735 Facsimile: 613-954-2354 736

737 738

For submissions or inquiries related to premarket submissions or an NOC/c: 739 740

A. For all biologics and radiopharmaceuticals - Office of Regulatory Affairs (ORA) 741 742 The Biologics and Genetic Therapies Directorate 743 200 Tunney's Pasture Driveway, 744 Tunney's Pasture, Address Locator 0701A 745 Ottawa, ON K1A 0K9 746 E-mail: [email protected] 747 Telephone: 613-957-1722 748 Facsimile: 613-946-9520 749 Teletypewriter: 1-800-267-1245 (Health Canada) 750

751 B. For prescription pharmaceutical products – Therapeutic Products Directorate 752 753 The Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS) 754 Regulatory Project Management Division, servicing BMORS 755 Finance Building #2 756 Tunney’s Pasture Driveway, Address Locator 0202D2 757 Ottawa, ON K1A 1B9 758 Fax: (613) 941-1365 759 760 The Bureau of Gastroenterology, Infection and Viral Diseases (BGIVD) 761 Regulatory Project Management Division, servicing BGIVD 762 Finance Building #2 763 Tunney’s Pasture Driveway, Address Locator 0202B1 764 Ottawa, ON K1A 1B9 765 Fax: (613) 941-1183 766 767 The Bureau of Cardiology, Allergy and Neurological Sciences (BCANS) 768 Regulatory Project Management Division, servicing BCANS 769 Finance Building #2 770 Tunney’s Pasture Driveway, Address Locator 0202A1 771 Ottawa, ON K1A 1B9 772 Fax: (613) 941-1668 773 774 The Bureau of Pharmaceutical Sciences (BPS) 775 Regulatory Project Management Division, servicing BPS 776 Finance Building #2 777 Tunney’s Pasture Driveway, Address Locator 0201D 778 Ottawa, ON K1A 1B9 779 Fax: (613) 957-3989 780


781 C. For non-prescription pharmaceutical products and natural health products – Natural and Non-782

prescription Health Products Directorate (NNHPD) 783 784 Bureau of Licensing and Services Systems 785 Submission Management Division 786 2nd floor, Qualicum, Tower A 787 2936 Baseline Rd, AL 3302B 788 Ottawa, Ontario K1A 0K9, Couriers: K2H 1B3 789

790 General Inquires 791 If you have any questions or comments about the above messaging, please do not hesitate to contact MHPD for 792 clarification. All inquiries pertaining to this Guidance should include the phrase: "Preparation and Submission of 793 Summary Reports for Marketed Health Products Guidance", in the subject line. 794 795 Email: [email protected] 796 797 For inquiries related to electronic format, please contact Health Canada using the following e-mail address: E-mail: 798 [email protected] 799

mailto:[email protected]?subject=PBRER%20Notice-%20ORMS

mailto:[email protected]


Appendix 5: List of Relevant Guidance Documents 800

MAHs should refer to the most up-to-date versions of the following Guidance documents. This list is provided as a 801 starting point to help manufacturers, and is not exhaustive. 802 803 Health Canada Guidance Documents and Notices 804 805

• Management of Drug Submissions 806 • Draft Guidance Document: Preparation of Drug Regulatory Activities in Electronic Common Technical 807

Document (eCTD) 808 • Preparation of Drug Regulatory Activities in the Common Technical Document (CTD) Format 809 • Guidance Document: Creation of the Canadian Module 1 Backbone 810 • Canadian Module 1 Schema Version 2.2 811 • Notice: Adoption of the International Conference on Harmonisation (ICH) Guidance on Periodic Benefit 812

Risk Evaluation Report - ICH Topic E2C(R2), as of March 1, 2013 813 • Reporting Adverse Reactions to Marketed Health Products 814 • Good Pharmacovigilance Practices (GVP) Guidelines (GUI-0102) 815

816 International Conference on Harmonization (ICH) Guidance Documents 817 818

• ICH E2C(R2): Periodic Benefit-Risk Evaluation Reports (PBRERs) 819 • ICH E2C(R1): Periodic Safety Update Reports (PSURs) 820


End Notes 821

1. Food and Drug Regulations, Part C, Division 1, C.R.C., c. 870. 822 2. Benefit-Risk Profile; http://www.hc-sc.gc.ca/dhp-mps/homologation-licensing/gloss/index-eng.php#b 823 3. Natural Health Products Regulations, Section 24, Reaction Reporting, C.R.C., SOR/2003-196. 824 4. The date of the first marketing authorisation for any product containing the active substance granted to any 825

company in any country in the world. 826 5. European Medicines Agency, European Union reference dates and submission of periodic safety update 827

reports: 828 http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_00036829 1.jsp&mid=WC0b01ac058066f910 830

6. International Conference on Harmonisation, Periodic Benefit-Risk Evaluation Report (PBRER) (ICH 831 E2C(R2)) (2012). 832

7. International Conference on Harmonisation, Clinical Safety Data Management: Periodic Safety Update 833 Reports for Marketed Drugs (ICH E2C(R1)) (2005). 834

8. Guidance Document - Periodic Benefit-Risk Evaluation Report (PBRER) International Conference on 835 Harmonisation (ICH) Topic E2C(R2); http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-836 ld/ich/efficac/e2c%28r2%29_step4_etape4-eng.php 837

9. Natural Health Products Regulations, Interpretation, C.R.C., SOR/2003-196 838