global vaccine safety blueprint 2.0 (gvsb2.0) · global vaccine safety blueprint (gvsb) 2.0...

Global Vaccine Safety Blueprint (GVSB) 2.0 Drafting Group

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Global Vaccine Safety Blueprint 2.0 (GVSB2.0) 3

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Registered participants in the Global Vaccine Safety Summit are 24

requested to submit questions and comments to 25

[email protected] 26

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Those will be prioritized by the Chairperson of the Global Vaccine 28

Safety Blueprint 2.0 hearing for 2-minutes interventions. Additional 29

information on the conduct of the Hearing is available on the portal 30 https://www.who.int/vaccine_safety/global-vaccine-safety-summit-hearing-meeting-day-1-2019/en/ 31

mailto:[email protected]

https://www.who.int/vaccine_safety/global-vaccine-safety-summit-hearing-meeting-day-1-2019/en/


Table of Contents 32

Table of Contents ............................................................................................................................ 2 33 Recognition ..................................................................................................................................... 3 34 Acronyms ........................................................................................................................................ 4 35 Introduction .................................................................................................................................... 5 36 Strategic area 1 - Governance and systems development ........................................................... 10 37

Introduction ........................................................................................................................... 10 38 Governance ............................................................................................................................... 10 39

Rationale ................................................................................................................................ 10 40 Objectives .............................................................................................................................. 11 41

System Funding and Financing .................................................................................................. 11 42

Rationale ................................................................................................................................ 11 43 Address injuries caused by vaccine reactions ........................................................................... 14 44

Strategic area 2 - Coordination of Safety Systems ....................................................................... 15 45 Introduction ........................................................................................................................... 15 46 Rationale ................................................................................................................................ 15 47 Objectives .............................................................................................................................. 15 48

Strategic area 3 - Regulatory framework ...................................................................................... 18 49 Introduction ........................................................................................................................... 18 50 Rationale ................................................................................................................................ 18 51 Objectives .............................................................................................................................. 19 52

Strategic area 4 – Surveillance of adverse events following immunisation (AEFI)....................... 22 53 Introduction ........................................................................................................................... 22 54 Rationale ................................................................................................................................ 23 55 Objectives .............................................................................................................................. 23 56

Strategic area 5 – Enhanced Vaccine Safety Communication ...................................................... 29 57 Introduction ........................................................................................................................... 29 58 Rationale ................................................................................................................................ 29 59 Objectives .............................................................................................................................. 30 60

Strategic area 6 - Fragile States and Emergencies ........................................................................ 33 61 Introduction ........................................................................................................................... 33 62 Rationale ................................................................................................................................ 33 63 Objectives .............................................................................................................................. 34 64

Accountability framework ............................................................................................................ 36 65 Rationale.................................................................................................................................... 36 66

Appendix 1: Current WHO Benchmarking Tool sub-indicators of maturity levels ....................... 38 67 68 69


Recognition 70

This draft has been prepared to address the findings from background research published in 71

July 2019 by the Institute for Vaccine Safety (IVS) at Johns Hopkins Bloomberg School of 72

Public Health (Daniel A. Salmon, Matthew Z. Dudley, Tina Proveaux) with support from the 73

WHO Secretariat to the Global Vaccine Safety Initiative (Patrick Zuber, Christine Guillard, 74

Isabelle Sahinovic, Madhava Ram Balakrishnan, Oleg Benes, Houda Langar). 75

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A Drafting Group advised throughout the process: Chair Edwin Asturias (University of 77

Colorado), Adiela Saldaña (Instituto de Salud Pública de Chile), Jane Gidudu (US CDC), Priscilla 78

Nyambayo (Medicines Control Authority of Zimbabwe), Lee Hampton (GAVI), Satinder Aneja 79

(Lady Harding Medical College, Delhi India), Dure Samin Akram (Karachi Pakistan), Gopa 80

Raychaudhuri (US FDA), Ben Hickler (UNICEF), Robb Butler (UNICEF) 81

Subgroups have developed the following sections: 82

Coordination of Safety Systems Adiela Saldaña (chair), José Luis Castro, Marc Ceuppens, 83

Katharina Hartmann, Corinne Jouquelet-Royer, Olga Menang, Jens-Ulrich Stegmann, Sonia 84

Pagliusi, Christine Guillard 85

Governance and System Development Edwin Asturias (chair), Lee Hampton, Sujeet Kumar Jain, 86

Patrick Zuber 87

Regulatory Framework Gopa Raychaudhuri (chair), José Luis Castro, Priscilla Nyambayo, Adiela 88

Saldaña, Christine Guillard 89

AEFI Surveillance and Methodological Enhancements DS Akram (co-chair), Jane Gidudu (co-90

chair), Satinder Aneja, Priscilla Nyambayo, Edwin Asturias, Julianne Gee, Narendra Arora, Houda 91

Langar, Madhava Ram Balakrishnan 92

Enhanced Vaccine Safety Communication (including social networks) Robb Butler (initial 93

chair), Elisabeth Wilhelm (chair since mid-October 2019), Ben Hickler, Lisa Menning, Isabelle 94

Sahinovic 95

Fragile States and Crisis Situations Ananda Amarasinghe (chair), Edinam Agbenu, Alejandro 96

Costa, DS Akram, Sujeet Kumar Jain, Patrick Zuber 97

Accountability Framework Jim Buttery (chair), Lee Hampton, Christoph Steffen and Patrick 98

Zuber 99


Acronyms 100

101 AEFI Adverse events following immunisation 102 ARC AEFI review committee 103 AVSS Active vaccine safety surveillance 104 GACVS Global Advisory Committee on Vaccine Safety 105 GBT Global benchmarking tool 106 GVSB1.0 2012 Global Vaccine Safety Blueprint 107 GVSI Global Vaccine Safety Initiative 108 IHR International Health Regulations 109 ISRR Immunisation stress-related responses 110 JRF WHO UNICEF joint reporting form 111 LLDB Large linked data bases 112 LMIC Low- and middle-income countries 113 NIP National immunisation programme 114 NITAG National Immunization Technical Advisory Group 115 NRA National regulatory authorities 116 SF Substandard and falsified health products 117 UNICEF United Nations Children’s Fund 118 VICP Vaccine injury compensation programme 119 WHO World Health Organization 120 WLA WHO listed authorities 121


Introduction 122

Moving from the minimal and enhanced capacity concept to maturity levels 123 124 The main goals of vaccine safety systems are universal, regardless of country or region. They 125 take into consideration the fact that due to a very low tolerance for adverse reactions related 126 to preventive interventions and the variability of those reactions linked to individual 127 characteristics, vaccines safety profiles need to be continuously monitored and accordingly 128 updated throughout their life cycle. Many rare vaccine reactions or individual vulnerabilities 129 can only be ascertained through observational studies after vaccines have received regulatory 130 approval and are in widespread use. These goals of vaccine safety systems include: 131

• fully characterizing the safety profile of vaccines in use in terms of their risk profile, in 132 support of risk and benefits assessment for public health policies; 133

• detecting adverse reactions when they occur; 134

• determining the biological mechanism for adverse reactions; 135

• managing and treating the adverse reactions that occur; 136

• preventing adverse reactions when possible; 137

• determining when adverse events following immunisation (AEFI) are not caused by 138 vaccines; and 139

• communicating all the above to the media, healthcare providers, policy-makers and the 140 public in an accurate, credible, and timely manner. 141 142

The first Global Vaccine Safety Blueprint published in 2012 (GVSB1.0) described the goals of 143 vaccine safety systems in two parts: minimal capacity and enhanced capacity. The minimal 144 capacity pharmacovigilance resources included: 145

• a national dedicated vaccine pharmacovigilance capacity, with designated staff for this 146 purpose, stable basic funding, clear mandates and well-defined structures and roles, 147 collaborating with the WHO Programme for International Drug Monitoring; 148

• health-care workers and others encouraged to report vaccine safety issues; 149

• a reporting form for individual case safety reports (i.e. a national reporting form for 150 AEFI); 151

• a national database or system for collating, managing and retrieving AEFI reports; 152

• a national AEFI expert review committee (ARC) that is able to provide technical 153 assistance on causality assessment of serious AEFI, and clusters of AEFI, so that 154 unwanted risk can be managed; 155

• a clear strategy for risk communication that identifies risks and benefits to prepare 156 health professionals, caregivers and the public for possible vaccine reactions, by 157 explaining possible coincidental events, encouraging the monitoring of AEFI by all 158 concerned, and with preparedness plans in place to address vaccine safety crises (risk 159 communication is dynamic and needs a feedback loop to all relevant stakeholders); and 160

• implemented and harmonized methods and tools for the monitoring and investigation 161 of AEFI. 162

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The managerial elements listed as strengthening minimal capacity for vaccine safety and 164 guaranteeing its functionality included: 165

• a regulatory framework is in place that defines the provisions for monitoring and 166 management of AEFI; 167

• clear lines of accountability have been identified for the conduct of vaccine safety work; 168

• an institutional development plan is in place for implementation of activities and 169 development of performance indicators; 170

• the institutional development plan is periodically evaluated and revised in order to 171 ensure continuous quality improvement when conducting national vaccine safety 172 activities; and 173

• there is a commitment to sharing information on vaccine safety with other countries. 174 175 Although the minimal capacity goals and elements listed above are critical for any vaccine 176 safety system, their reliance on spontaneous reporting systems leave them unable to perform 177 rapid assessments of causality and provide an adequate public health response to vaccine 178 safety signals and early post-licensure monitoring of novel products. Rapid response to vaccine 179 safety signals is required to identify those rare instances where real adverse reactions occur, so 180 that their impact can be minimized as they emerge. In GVSB1.0, it was determined that 181 countries where an increased level of vaccine safety activity was judged to be necessary, such 182 as those where newly developed vaccines are being introduced or those that manufacture and 183 use prequalified vaccines, should strive for enhanced capacity. In addition to the basic and 184 managerial requirements for minimal capacity described above, enhanced capacity for vaccine 185 safety activity included the following: 186

• the ability to carry out active surveillance (of events of special interest) rather than 187 relying solely on spontaneous reporting of AEFI alone for signal detection; and 188

• the ability to carry out epidemiological studies to test hypotheses. 189 190

GVSB1.0 had three strategic goals: 1/ to assist low and middle income countries (LMIC) have at 191 least minimal capacity for vaccine safety activities; 2/ to enhance capacity for vaccine safety 192 assessment in countries that introduce newly-developed vaccines, that introduce vaccines in 193 settings with novel characteristics, or that both manufacture and use prequalified vaccines; and 194 3/ to establish a global vaccine safety support structure. Those goals remain fully relevant and 195 the GVSB2.0 will maintain them whilst expanding its scope to all WHO member states. 196 197 In addition, GVSB1.0 had eight strategic objectives that aimed to cover all aspects of vaccine 198 safety: 1/ strengthen vaccine safety monitoring in all countries; 2/ strengthen the ability of 199 countries to investigate vaccine safety signals; 3/ develop vaccine safety communication plans 200 at country level to promote awareness of vaccine risks and benefits, understand perceptions of 201 risk and prepare for managing any adverse events and concerns about vaccine safety promptly; 202 4/ develop internationally harmonized tools and methods to support country vaccine safety 203 activities; 5/ promote a legal, regulatory and administrative framework for the safety of 204 vaccines at national, regional and international levels; 6/ strengthen regional and global 205 technical-support platforms that meet countries’ expressed needs; 7/ provide expert advice on 206


vaccine safety issues at national, regional and international level; and 8/ put in place systems 207 for appropriate interaction between national governments, multilateral agencies and 208 manufacturers at national, regional and international level. 209 210 Since the development of GVSB1.0, surveillance of adverse events following immunisation 211 (AEFI) has improved significantly in LMICs, in part due to the creation of tools and methods to 212 assist with pharmacovigilance. While capacity is improving, many of the same challenges from 213 GVSB1.0 remain. Such challenges include: effective collaboration with clear roles and 214 responsibilities and timely provision of safety data pertaining to vaccine quality for National 215 Regulatory Authorities (NRAs) and immunisation programmes including surveillance units and 216 healthcare workers; capacity to exchange information across countries and with industry; and 217 stronger use of strategic communication. 218 219 A landscape analysis was conducted in 2019 by Deloitte Consulting LLP for the World Health 220 Organization (WHO) to obtain input from vaccine safety experts, national regulatory officials, 221 immunisation program managers, global agencies, industry, non-governmental organizations 222 (NGOs), and others regarding the impact and strategic direction of the first Global Vaccine 223 Safety Blueprint (GVSB1.0) in 2012 and their recommendations for the Global Vaccine Safety 224 Blueprint 2.0 (GVSB2.0). This analysis found that, although many of the challenges discovered 225 during the creation of GVSB1.0 remain, new challenges related to hesitancy and emergencies 226 have arisen, and opportunities exist to focus GVSB2.0 to maximize its impact and utility for the 227 next decade. 228 229 An important objective of the second Blueprint is to provide the best scientific data to increase 230 public understanding of the distinction between real and coincidental AEFIs. Better vaccine 231 safety data will assist with addressing this challenge, as will improved communication efforts, 232 such as using social networks as a tool to share scientific and accurate vaccine safety 233 information to proactively combat the rise of misinformation. Another challenge is the 234 increasing number of conflicts, outbreaks, and other emergencies across the globe. GVSB2.0 235 provides guidance on monitoring vaccine safety in conflict settings and managing crisis 236 communications during an outbreak. 237 238 To build upon GVSB1.0 rather than repeating this comprehensive approach, GVSB2.0 focuses 239 on several key priorities to maximize impact in the next decade. The strategic focus areas for 240 GVSB2.0 include: 241

• Regulatory framework 242

• AEFI surveillance (including detection, investigation, causality assessment, prevention, 243 and compensation) 244

• Enhanced vaccine safety communication 245

• Coordination of safety systems 246

• Fragile states and crisis situations 247 248 Beyond these strategic focus areas, GVSB2.0 emphasizes country ownership, in line with the 249 Immunization Agenda 2030 framework. The strategic area on governance and systems 250


development discusses features such as expert advisory structures, resources, and funding 251 (including for active surveillance and hypothesis-testing capacity). GVSB2.0 also emphasizes the 252 need for and development of an accountability framework; specifically, a monitoring and 253 evaluation framework to monitor progress with each strategic focus area over time, using a 254 stepwise process of graduating national programs. 255 256 GVSB2.0 expands upon the dichotomous minimal and enhanced capacity concept by 257 incorporating the concept of maturity level (ML). This concept was adapted from the 258 International Organization for Standardization (ISO) Standard 9004: “Quality management – 259 Quality of an organization – Guidance to achieve sustained success” (available from: 260 https://www.iso.org/standard/70397.html). Maturity levels allow WHO and regulatory 261 authorities to assess the “maturity” of a regulatory system, using a scale from 1 to 4 (Figure 262 1/Appendix). 263 264

265 Figure 1. Maturity levels concept adapted to the national regulatory functions (including the 266

pharmacovigilance function) 267 268 The WHO has developed a Global Benchmarking Tool (GBT) to evaluate national regulatory 269 systems using the maturity level concept (available from: 270 https://www.who.int/medicines/regulation/benchmarking_tool/en/). Based on the maturity 271 level of a national regulatory system, the WHO can differentiate the approach to drive public 272 health impact in that country. 273

https://www.iso.org/standard/70397.html

https://www.who.int/medicines/regulation/benchmarking_tool/en/


274 In GVSB2.0, the pharmacovigilance resources and managerial elements for each of the four 275 maturity levels were reorganized, instead of just minimal versus enhanced capacity. This 276 updated breakdown is presented below. 277 278 279

Table 1: Summarized current WHO Benchmarking Tool vigilance sub-indicators of maturity levels 280 (full version in annex 1) 281 282

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Maturity levels

Indicators Level 1 sub-indicators Level 2 sub-indicators Level 3 sub-indicators Level 4 sub-indicators

VL01 Legal provisions, regulations and guidelines required to define regulatory framework of vigilance

Legal provisions for a national vigilance system exist. They require the manufacturers to set up a vigilance system of their medical products and periodically report data and reliance on vigilance‐related decisions from other bodies

Legal provisions allow NRA to require manufacturers to conduct specific safety studies

Legal provisions require manufacturers to designate an individual person in charge of vigilance. Guidelines available for planning, conducting, monitoring, and reporting of vigilance activities

VL02 Arrangement for effective organization and good governance

Defined organizational structure with clear roles and responsibilities

Documented procedures to ensure among all relevant stakeholders

VL03 Human resources to perform vigilance activities

Sufficient competent staff with adequate job descriptions, training plan implemented and documented.

VL04 Procedures established and implemented to perform vigilance activities

Staff access to relevant information resources is ensured

Procedures for collection, investigation and assessment of AEFIs are implemented, include a risk approach and access to expert committees for review of serious concerns

Standard procedures are implemented for the national vigilance system, include regular assessment of risk‐benefit balance and active vigilance activities

VL05 Regular performance monitoring

Vigilance information used in timely manner to update regulatory decisions

Performance indicators for vigilance activities implemented

VL06 Transparency, accountability and communication

Vigilance activities appropriately communicated to the public

Mechanism for regular feedback complemented with a risk communication plan and data shared with international partners


Strategic area 1 - Governance and systems development 284

Introduction 285 Implementing the Blueprint 2.0 will require continued close collaboration between global 286 vaccine safety stakeholders. In 2009, the Global Advisory Committee on Vaccine Safety 287 identified several organizations that are available in support of WHO member states for vaccine 288 safety work1. They are involved with capacity building and tools development, signal detection 289 and evaluation, analysis and response and individual products monitoring. Those organizations 290 are active internationally, either for a group of countries or at the global level. They include 291 governmental institutions (immunisation programmes, pharmacovigilance centres and agencies 292 involved in regulatory activities); intergovernmental organizations (including WHO and UNICEF), 293 international nongovernmental organizations and academic institutions; international industry 294 associations/umbrella organizations that have a demonstrated interest and experience; and 295 WHO Collaborating Centres. Optimizing the work of a broad and diverse group of partners 296 requires an agile coordination mechanism for governance and funding. The first Global Vaccine 297 Safety Blueprint (GVSB1.0) was endorsed by SAGE in 2012. The establishment of the Global 298 Vaccine Safety Initiative in 2013 focused on increasing the capacity of the LMIC and enable 299 them to achieve a minimal standard. 300 301

GOVERNANCE 302

Rationale 303 Through the Global Vaccine Safety Initiative (GVSI) partners have implemented the first global 304 vaccine safety Blueprint. The GVSI is not a legal entity, it is a WHO mechanism for enhancing 305 vaccine safety by providing a framework for WHO to convene its member states and partners 306 for the implementation of the Global Vaccine Safety Blueprint. As a forum for collaboration 307 between vaccine safety stakeholders, the GVSI highlights existing tools and resources, creates 308 synergies, and prevents duplication of efforts and wasted resources towards the achievement 309 of its mission. 310 311 Over time, the GVSI implementation has evolved from attempts to develop and implement 312 work plans, to periodic calls with a planning group that later became a strategic priority group 313 and various information mechanisms. GVSI has conducted seven general meetings and its terms 314 of reference are available2. There is a need to further structure the GVSI and better monitor its 315 progress. For that purpose, the Blueprint 2.0 also includes an accountability framework chapter 316 and proposes to establish a GVSI Observatory to develop indicators of vaccine safety 317 surveillance, provide continued progress monitoring, and link to vaccine safety resources for 318 GVSI members. 319 320

1 Global Advisory Committee on Vaccine Safety (GACVS); WHO secretariat. Global safety of vaccines: strengthening systems for monitoring, management and the role of GACVS. Expert Rev Vaccines. 2009;8(6):705-716 2 https://www.who.int/vaccine_safety/initiative/gvsi_tors_18aug2014.pdf?ua=1

https://www.who.int/vaccine_safety/initiative/gvsi_tors_18aug2014.pdf?ua=1


Objectives 321 The main objective of governance and systems development is to provide the structure for 322 effective decision-making in support of vaccine safety for immunisations. This includes the 323 systems framework and springboard for development of capacities and feedback that allows its 324 maturity and function at the national, regional, and global levels. 325 326 Strategies 327

• Strengthen the GVSI with dedicated secretarial resource 328

• Report on accountability framework at each GVSI general meetings 329 330

SYSTEM FUNDING AND FINANCING 331

Rationale 332 Vaccine safety systems serve both to minimize risks from vaccination by identifying and 333 preventing serious adverse events from immunization and to maintain public confidence in 334 immunization systems by addressing concerns about the safety of vaccines. In both cases, 335 funding of vaccine safety systems helps avoid costly negative outcomes, such as the medical 336 care of cases of serious adverse events from immunization and the medical and social costs of 337 cases of vaccine preventable diseases that result from declining immunization rates following a 338 loss of public confidence in an immunization program. Given the important roles of vaccine 339 safety systems in immunization programs, adequate resources need to be provided for their 340 operations that do not compete with other health and non-health needs. 341 342 Many vaccine safety activities can potentially be integrated with other immunization program 343 activities, providing potential efficiencies in the performance of those activities, although it is 344 important that such integration not come at the expense of objective detection, reporting, and 345 response to adverse events following immunizations. For example, the same health care 346 workers who identify, treat, and report cases of vaccine preventable diseases can also treat, 347 identify, and report adverse events following immunizations. Field epidemiologists who 348 investigate cases of infectious diseases can also conduct initial investigations of adverse events 349 following immunization. Risk communication systems that can address epidemics of vaccine 350 preventable diseases can also address concerns about vaccine safety. The clear majority of 351 changes in vaccines, vaccination devices, and vaccination programme practices made in 352 response to the findings of vaccine safety systems will be carried out and funded through 353 vaccine development, production, procurement, delivery channels. Nevertheless, some 354 activities are specific to vaccine safety and require dedicated resources, including the 355 development of vaccine safety guidelines and training materials on the identification, 356 treatment, and reporting of adverse events following immunization; the operations of causality 357 assessment committees, including in-depth examinations of potential causes of serious AEFIs 358 and deaths; and responses to newly identified vaccine safety risks, such as the recall of 359


problematic vaccine lots. In countries that choose to operate them, vaccine injury 360 compensation programs3,4 also require resources. 361 362 Although passive vaccine safety surveillance is needed in and throughout all countries, funding 363 is also needed for active surveillance sites conducting detailed post-marketing surveillance for 364 vaccine adverse events. However, a few such sites may generate sufficient data for entire 365 regions or, in some cases, the entire world, so not all countries need to maintain such active 366 surveillance. For new vaccines, such active surveillance is often most valuable when conducted 367 in the first few countries to introduce a vaccine. Other countries may then learn from those first 368 countries’ experiences and forgo conducting active surveillance themselves. Similar 369 considerations apply for active surveillance to determine background rates of potential adverse 370 events. Given the resources needed for the high-quality data generated by active surveillance 371 and the small number of active surveillance sites usually needed for assessing a given new 372 vaccine, it can be reasonable to have different funding sources and implementing groups for 373 passive and active surveillance. 374 375 For vaccine safety systems to maintain the objectivity and public confidence that are essential 376 for successful operation, it is important that their sources of funding avoid creating any real or 377 apparent conflicts of interest. As a result, public vaccine safety systems should not receive 378 voluntary contributions from private individuals and organizations that have a financial interest 379 in the findings of vaccine safety systems, and such private individuals and organizations should 380 not control public organizations’ decisions about funding vaccine safety work. However, public 381 organizations, such as NRAs, may require manufacturers to conduct or fund specific safety 382 studies as needed, and manufacturers may choose to fund individual sites to conduct active 383 post-marketing surveillance for vaccine adverse events, potentially including determination of 384 adverse event background rates. In either case, ultimate responsibility and authority for making 385 specific vaccine safety policy decisions remain with public organizations. Funding for public 386 vaccine safety systems should give vaccine safety staff, especially the staff involved with 387 vaccine safety specific activities described above, considerable autonomy to set their priorities 388 and approaches for minimizing serious adverse events following immunization and addressing 389 concerns about the safety of vaccines. At the same time, those vaccine safety staff must use 390 such autonomy carefully, e.g., not favor certain manufacturers or groups over others for 391 commercial or political reasons. 392 393 Objectives 394

1. Encourage provision of adequate resources for public vaccine safety systems’ 395 operations 396

Given the many competing demands for resources and the need for funding sources to be 397 compatible with public vaccine safety systems maintaining objectivity and public confidence, 398 mobilizing adequate resources for vaccine safety systems’ operations can be difficult. However, 399

3 Mungwira RG, Maure CG, Zuber PLF. Economic and immunisation safety surveillance characteristics of countries implementing no-fault compensation programmes for vaccine injuries. Vaccine 2019; 37: 4370-7. 4 Evans G. Vaccine injury compensation programs worldwide. Vaccine 1999;17 (Suppl 3): S25–35.


evidence of the value of strong vaccine systems and the potential consequences of the lack of 400 such systems, combined with persistence on behalf of vaccine safety advocates, can facilitate 401 the mobilization of sufficient resources, particularly in countries with growing economies, 402 government resources, and health budgets. 403 404 Vaccine safety is sometimes compared to preventive maintenance or an insurance policy where 405 the direct benefits are only apparent when a vaccine safety disaster occurs. Documentation of 406 past vaccine safety disasters and their effects can help to illustrate to budget authorities the 407 potential consequences of inadequate vaccine safety resources. Conversely, documentation of 408 potential vaccine safety disasters averted or contained through the work of effective vaccine 409 safety systems can help to illustrate to budget authorities the value of providing adequate 410 vaccine safety resources. Such documentation can emphasize that vaccine safety systems 411 provide not only direct benefits of preventing adverse reactions but also indirect benefits in 412 helping avoid the medical and social costs of cases of vaccine preventable diseases that result 413 from declining immunization rates following a loss of public confidence in an immunization 414 program. Given the global nature of vaccination production and distribution, events in one 415 country can be very instructive for other countries. 416 417 Strategies 418

• Develop clear vaccine safety system use cases for communications with budget 419 authorities 420

• Systematically document vaccine safety disasters and successes and their consequences 421 for use in communications with budget authorities 422

423 2. Describe public vaccine safety funding options appropriate for countries’ regulatory 424

systems’ levels of maturity 425 Even within the limits imposed by the need for public vaccine safety system funding sources to 426 be compatible with those systems maintaining objectivity and public confidence, there are 427 multiple reasonable potential sources of funding for such systems, including: 428

• General government tax revenue 429

• Taxes on specific goods or services from which revenue are derived for vaccine safety 430 systems, such as excise taxes on vaccine, i.e., a tax on each unit of vaccine purchased 431

• Donations from multilateral international organizations or foreign governments 432

• Donations from non-governmental organizations that are not controlled by private 433 individuals and organizations that have a financial interest in the findings of vaccine 434 safety systems 435

436 The relative proportion of funding for vaccine safety systems can vary considerably across 437 countries, particularly given how vaccine safety systems are organized, the scale of their 438 activities, and government revenues and spending priorities. Guidance for countries on how to 439 choose among these options could help them most effectively and efficiently access and use 440 funding for vaccine safety. 441 442


Strategies 443

• Establish a financing task force that will advise WHO on funding mechanisms for the GVSI 444 and their oversight 445

• Develop guidance for countries on mobilizing funding for vaccine safety work aligned with 446 country maturity model 447

448

ADDRESS INJURIES CAUSED BY VACCINE REACTIONS 449

As countries keep expanding vaccines use and strengthen their safety surveillance with 450 investigative capacity, occasional severe vaccine reactions are identified. The need for 451 management of vaccine injuries is fundamental yet approaches vary substantially between 452 countries depending on factors such as the healthcare and social services systems. Fair and 453 appropriate compensation also requires capacity to determine which AEFIs are caused by 454 vaccines. 455 456 Progress with vaccine safety surveillance will increase demands for properly managing vaccine 457 and examine the relevance of injury compensation schemes. Such programs will have to take 458 into consideration the diversity of countries with regards to economic capacity, performance of 459 immunisation programs, and availability of social welfare programs. 460 461 This issue is no longer limited to the most affluent countries5. Vaccine injury compensation 462 programs (VICPs) are no-fault schemes established to compensate individuals who may have 463 experience a vaccine-related injury due to the inherent risks of vaccination. VICPs waive the 464 need for accessing compensation of vaccine-related injuries through litigation. To date only a 465 few WHO-member states have implemented such programmes6,7

. 466 467 Strategy 468

• Develop guidance on vaccine injury management based on available evidence and 469 national circumstances. 470

471

5 National Vaccine Injury Compensation Program, Health Resources & Services Administration, USA https://www.hrsa.gov/vaccine-compensation/data/index.html 6 Weekly epidemiological record. 25 January 2019, No 4, 2019, 94, 45–52 https://apps.who.int/iris/bitstream/handle/10665/279829/WER9404.pdf?ua=1 7 Clare Looker & Heath Kelly Bulletin of the World Health Organization No-fault compensation following adverse events attributed to vaccination: a review of international programmes https://www.who.int/bulletin/volumes/89/5/10-081901/en/


Strategic area 2 - Coordination of Safety Systems 472

Introduction 473 There are multiple stakeholders within a vaccine safety system and each of them contributes 474 significantly to the system’s operation. To ensure effective vaccine safety, adequate 475 coordination between public and private sectors is required. Both sectors contribute to keep 476 vaccine safety profiles updated throughout a product life cycle. Collaborative mechanisms can 477 help develop comprehensive approaches and achieve optimization of resources. 478 479

Rationale 480 The importance of close collaboration between regulators and industry is well recognized in 481 vaccine pharmacovigilance activities, and guidance has been developed for jointly planning 482 those activities. However, the ability of vaccine manufacturers to obtain information about AEFI 483 remains limited in several settings. 484 485 Information about the safety of a vaccine may be generated by various stakeholders (vaccine 486 recipients, health care workers, scientific community, immunisation programmes, national 487 regulatory authorities, vaccine manufacturers), and may reach several different immunisation 488 stakeholders – including national governments (through their immunisation programmes, 489 regulatory authorities and others), multilateral agencies and the manufacturers. 490 It is essential to ensure harmonised and standardised approaches in generating and 491 communicating the data generated to relevant stakeholders. 492 493

Objectives 494 495 1. Strengthened coordination and exchange of information between vaccine manufacturers 496 and national regulatory authorities at local, regional and global level 497 Vaccine manufacturers and marketing authorization holders are accountable for the safety, 498 quality and effectiveness of the products that receive a marketing authorization during the 499 entire product lifecycle. National Regulatory Agencies (NRA) are responsible for safety 500 monitoring of each vaccine authorized on their territory including assessment of the safety, 501 quality and effectiveness of the products, and the monitoring of those conditions in the post 502 marketing phase. 503 504 Close collaboration and exchange of information between regulators and vaccine 505 manufacturers is therefore key in vaccine pharmacovigilance activities, to keep the vaccine 506 safety profile updated and to be able to act upon any safety concerns. 507 508 Strategies: 509

• Implement mechanisms for systematic and timely exchange of vaccine safety related 510 information (individual case reports, safety signals, findings from post‐marketing 511 studies and any changes about risk-benefit profile of the vaccine) between vaccine 512 manufacturers and public health authorities at local, regional and global level. 513


• Develop mechanisms for systematic and timely exchange of vaccine safety related 514 information (individual case reports, safety signals, findings from post‐marketing 515 studies) from public health authorities to the relevant vaccine manufacturer to ensure 516 that the manufacturer can maintain the safety profile of its products, at local, regional 517 and global level. 518

519 2. Strengthened coordination and exchange of information within the health authorities at 520 local, regional and global levels 521 Effective vaccine safety systems require broad collaboration within national health systems and 522 internationally. Independent expert advisory bodies provide advice on vaccine safety issues 523 and can also guide the development of stronger national and international systems. They 524 provide expertise in multiple areas relevant to the conduct of vaccine pharmacovigilance such 525 as clinical medicine, epidemiology, regulation, pathology, statistics and methodology. National 526 authorities, as secretary to those bodies inform and propose priority agenda items. Currently a 527 global body has been in place for 20 years, the Global Advisory Committee on Vaccine Safety 528 (GACVS) and national vaccine safety committees are available in an increasing number of 529 countries. Regional relays and collaborative mechanisms across levels should be considered. In 530 addition, global networks of voluntary experts have provided extremely valuable tools for 531 harmonization of vaccine pharmacovigilance (Brighton Collaboration, CIOMS working groups) 532 and have the potential of catalysing new initiatives such as distributed data networks. 533 534 Strategies 535

• Develop and independent national advisory bodies for vaccines safety. 536

• Promote global alignment of methods and collaboration between national and global 537

advisory bodies and examine the need and relevance of similar regional committees. 538

• Promote global expert collaborative networks in support of vaccine pharmacovigilance. 539

540 3. Collaboration between scientific community and health authorities 541 Information on all post marketing safety studies, ongoing and completed, should be made 542 publicly available to ensure transparency, avoid duplication of efforts, inform the scientific 543 community, and facilitate access to all generated evidences. 544 545 Strategies: 546

• Establish a global registry of vaccine pharmacovigilance studies. 547

548 4. Communication between health authorities and the population they serve 549 The NRA, immunisation programme or other competent authorities should establish 550 mechanisms of communication with the public on vaccine safety issues, as well as 551 communication on the benefits of vaccination and the safety profile of vaccines. The public 552 should be provided with sources of validated information on vaccines safety. 553


The population should be sensitized about the importance of vaccine safety surveillance and 554 should be encouraged to report AEFIs and other safety-related issues to authorities and vaccine 555 manufacturers either directly or via healthcare professionals or local authorities and should be 556 knowledgeable about the means of reporting. 557

Strategies 558 • Establish communication channels between regulatory authorities, immunisation 559

programmes and other authorities at local, regional and global levels, so the population 560 is informed about vaccine safety issues and can report any concern. 561

562


Strategic area 3 - Regulatory framework 563

Introduction 564 National Regulatory Authorities (NRAs) are responsible for ensuring the quality, safety, and 565 effectiveness of medicines, vaccines, and other medical products used within a country 566 throughout the product lifecycle. Vaccines must be registered or authorised by the NRA in 567 country before they can be used in the national population. Marketing authorisation (MA) is 568 determined based on an assessment that there are adequate data to support that the benefits 569 outweigh the risks in the populations indicated for use. However, it is essential to have 570 continuous post-registration oversight of quality, safety, and effectiveness of vaccines with 571 periodic assessment of benefit and risk to ensure benefits of the vaccine continue to outweigh 572 the potential risks (life-cycle management). The NRA and immunisation programme have 573 specific roles and collective responsibility in assuring vaccine safety post-registration. 574 575 A well-functioning regulatory system based on laws, regulations, and well-defined procedures is 576 required to have effective oversight of vaccine safety throughout the product life-cycle. This 577 requires investment in systems, processes, infrastructures, administrative support, and human 578 capacity with relevant scientific knowledge and technical expertise. The investment in 579 resources must be sustainable for the long-term stability of a regulatory system. Approaches 580 for assuring vaccine safety should be practical, risk-based, fit for purpose, and continually 581 improving to take advantage of new science and technology. Available tools (e.g., the global 582 benchmarking tool - GBT) should be utilized to strengthen pharmacovigilance capacity as a 583 fundamental component of a well-functioning, integrated regulatory system. 584 585 Regional regulatory harmonization and collaboration initiatives facilitate sharing of information 586 and leveraging knowledge to support public health decisions including matters related to 587 vaccine safety. These principles are applicable for all regulatory authorities but are especially 588 important as a practical measure for small and less resourced countries. 589 590

Rationale 591 Legal requirements and regulations should be in place to support an effective adverse event 592 surveillance system, with clear description of roles and responsibilities, efficient coordination 593 among public health officials and stakeholders, adequate flow of information, and transparency 594 in decision-making. The regulatory system should have a framework for reliance and 595 collaboration to make effective use of regulatory resources. The GBT has criteria for assessing 596 whether an NRA has legal provisions and regulations that allow recognition and/or reliance for 597 vaccine safety decisions, reports or information from other countries, regions or international 598 bodies. 599 600 Safety monitoring of a medical product is required from pre- to post-marketing phases and 601 involves engagement of manufacturers, MA holders, and NRAs. Regulators have a key role in 602 reviewing risk management plans prior to marketing authorization and making risk-based 603 recommendations for safety surveillance post-registration. Safety monitoring systems, 604


processes, and adequate investment in human resources are essential for effective safety 605 monitoring and maintaining public confidence in vaccines. 606 607 NRAs must have the authority to act, if warranted. Communication and information sharing 608 with immunisation programme and other key institutions enhances the NRA’s ability to make 609 science-based decisions to protect public health. Regulators should have authority to require 610 safety studies from manufacturers, MA holders, and importers of vaccines and the 611 independence to investigate potential safety signals and assure continued safety of vaccines 612 post-registration. 613 614 Building pharmacovigilance capacity is fundamental to assuring vaccine safety post-licensure. 615 The GBT is an effective tool to generate and analyse evidence of regulatory system 616 performance. WHO is developing a process intended to promote trust, confidence, and a 617 transparent and evidence-based approach that would allow NRAs to rely on work of other 618 NRAs, including decision making related to vaccine safety. The option to practice reliance would 619 increase efficiency and allow more effective use of regulatory resources especially in limited 620 resource settings. 621 622 NRAs and immunisation programs must address product quality issues including the problem of 623 substandard and falsified (SF) products on the market. Countries should have a mechanism in 624 place for prevention, detection, and response to SF products, including SF vaccines which have 625 been an increasing concern. Reporting to global alert system should be encouraged, and there 626 should be mechanisms to exchange information on SF or suspected SF products. 627 628 629

Objectives 630 1. All countries have provisions to establish vaccine pharmacovigilance, including laws, 631 regulations, infrastructure, and lines of accountability 632 Components of a well-functioning, integrated pharmacovigilance system include legal 633 provisions, systems for data collection and storage, mechanisms for communication of vaccine 634 safety information among critical stakeholders (e.g., NRAs, immunisation programmes, vaccine 635 manufacturers and MAH etc.), adequate human resources and technical expertise to assess 636 safety data, transparency in decision-making and actions, and timely and accurate 637 communication on vaccine safety issues with the public. In many countries, vaccine 638 pharmacovigilance systems are supported by regulatory provisions with clearly defined lines of 639 accountability. However, many countries still lack such provisions and have either a limited or 640 no pharmacovigilance system. 641 642 Each country should establish requirements for vaccine pharmacovigilance that allow timely 643 identification, investigation and appropriate communication of the most serious vaccine safety 644 problems. Harmonization or convergence of regulations, guidelines, data collection and analysis 645 tools, databases, and processes facilitates collaboration and opportunity for reliance on 646 decisions of trusted partners (e.g., other NRAs), as appropriate. 647 648


Strategies 649

• Establish a set of legal provisions, regulations, and guidelines which provide a mandate 650 and guidance to implement all activities related to vaccine safety monitoring over the 651 life-cycle of the product. Laws, regulations, and guidelines should meet international 652 standards, and be publicly available for transparency. 653

• Establish legal provisions and regulations to allow recognition and/or reliance on 654 decisions from other countries and regional networks or international bodies on vaccine 655 safety issues. 656

• Ensure good communication, transparency, and outreach to the national population, 657 regional and international partners, and accountability for the decisions and actions of 658 the NRA. 659

• Incorporate the principle of continuous improvement in strengthening the vaccine 660 safety surveillance system and capacity to assess vaccine safety data for decision 661 making. 662

663 2. Ensure vaccine pharmacovigilance is a national, regional, and international responsibility 664 International Health Regulations (IHR) aim to assess the ability of national systems and 665 resources to meet at least minimum core capacities for vaccine safety surveillance and 666 response to disease outbreaks including events that constitute a “public health emergency of 667 international concern”. 668 669 In an increasingly globalized market, the same vaccines are being licensed in countries all over 670 the world. 671

• Vaccine safety is a national, regional and international responsibility. 672

• Regulatory and public health decisions should be made utilizing all available data. 673

• Vaccine safety data from one country is important to others that are using the same or 674 similar product. As countries develop their legal, regulatory, and administrative 675 structures for monitoring vaccine safety, and as worldwide AEFI data are pooled and 676 analysed (e.g. through the Programme for International Drug Monitoring), the 677 information generated should be shared with decision-makers at national, regional, and 678 international levels. 679

680 Strategies 681

• Develop and expand regulatory networks for information and experience exchange and 682 promote harmonization or convergence of approaches. 683

• Exchange vaccine safety data through national, regional, and global platforms including 684 the Programme for International Drug Monitoring. 685

686 3. Develop human resources to perform regulatory vigilance activities 687 Health product regulation demands the application of sound scientific (including but not limited 688 to medical, pharmaceutical, biological and chemical) knowledge and specific technical skills, 689 and operating within a legal framework. Like other parts of the health system, a well-690 functioning regulatory system needs a qualified workforce. Making scientifically sound 691


decisions about the safety, effectiveness and quality of medical products is increasingly 692 complex – even qualified health care professionals such as pharmacists and medical doctors 693 cannot carry out these functions without specialized training. Given the rapid pace of advances 694 and innovation in technology and methodologies, it is important for regulators to stay abreast 695 of the science that underpins development and regulation of these complex biological 696 products. Specific technical training, conducted on a continual basis, is essential to maintain an 697 efficient and effective workforce. 698 699 Strategies 700

• Promote the development and implementation of a “Global competency framework for 701 regulators” to support training and professional development of regulatory staff. 702

• Ensure all entities that have a role in vigilance activities are adequately resourced with a 703 well-trained, experienced, and skilled workforce that has expertise in areas required to 704 perform the vigilance function, including appropriate managerial capacities. 705

• Encourage sharing of expertise among technical staff from different countries to build 706 capacity through networking. 707


Strategic area 4 – Surveillance of adverse events 708

following immunisation (AEFI) 709

710

Introduction 711 The goal of AEFI surveillance is early detection, analysis of adverse events, appropriate and 712 timey response to decrease the negative impact on the health of individuals and immunisation 713 programmes. Clinical trial data used by regulators for licensure ensure that the vaccine benefits 714 outweigh the risks in the populations studied. However, clinical trials cannot evaluate 715 uncommon AEFIs, outcomes that are delayed, that occur beyond study follow-up, and AEFIs 716 among subpopulations that were excluded from such trials or not included with adequate 717 numbers for statistical power. Post-licensure surveillance fills these gaps. 718 719 Current status 720 The GVSB 1.0 laid the framework for minimal capacity for AEFI surveillance including AEFI 721 reporting, investigation, data management, causality assessment and communications. To 722 evaluate the performance of different countries in achieving minimal capacity, WHO developed 723 the reporting ratio for minimal capacity as a surrogate indicator8. A country is said to have a 724 minimum vaccine safety system in place if it reports at least 10 AEFI cases (serious and non-725 serious cases) for 100,000 surviving infants per year. Even though this is a crude indicator to 726 evaluate the country performances, it enabled global monitoring of AEFI reporting over the last 727 decade. The countries able to reach this reporting level rose from 80 in 2010 to 120 in 2018. 728 729 Vaccine safety surveillance systems were further strengthened as LMIC countries were 730 supported to establish their national and subnational AEFI Committees and efforts undertaken 731 to build their functional capacities. This included standardizing the reporting processes through 732 the identification of core variables and development of additional standardized tools and 733 methods for surveillance9 and associated training10. The national surveillance systems were 734 further harmonized through several countries developing their national vaccine safety 735 guidelines aligned to the global vaccine safety surveillance principles11. 736 737 At the Global level, aggregate vaccine safety data are transmitted primarily by National 738 Immunisation Programs through the WHO UNICEF JRF12 and case-based data are transmitted 739 primarily by NRAs or National pharmacovigilance centres through the WHO Programme on 740 International Drug monitoring13. Efforts to collaborate across these main stakeholders are 741 encouraged to consolidate available national data sets. 742 743

8 Global Vaccine Action Plan Monitoring, Evaluation & Accountability Secretariat Annual Report 2018 Chapter 8 page 77 https://www.who.int/immunization/global_vaccine_action_plan/web_gvap_secretariat_report_2018.pdf?ua=1 9 AEFI core variables https://www.who.int/vaccine_safety/news/HL_1/en/; AEFI reporting form; AEFI investigation form https://www.who.int/vaccine_safety/initiative/investigation/AEFI_Investigation_form_2Dec14.pdf; 10 AEFI investigation e-learning https://vaccine-safety-training.org/investigation/; AEFI data management training http://gvsi-aefi-tools.org/aefidata/training/index1.html 11 Global Manual on Surveillance of Adverse Events Following Immunization https://www.who.int/vaccine_safety/publications/aefi_surveillance/en/ 12 https://www.who.int/immunization/monitoring_surveillance/routine/reporting/en/ 13 https://www.who.int/medicines/areas/quality_safety/safety_efficacy/National_PV_Centres_Map/en/

https://www.who.int/immunization/global_vaccine_action_plan/web_gvap_secretariat_report_2018.pdf?ua=1

https://www.who.int/vaccine_safety/news/HL_1/en/

https://www.who.int/vaccine_safety/initiative/investigation/AEFI_Investigation_form_2Dec14.pdf

https://vaccine-safety-training.org/investigation/

http://gvsi-aefi-tools.org/aefidata/training/index1.html

http://gvsi-aefi-tools.org/aefidata/training/index1.html

https://www.who.int/vaccine_safety/publications/aefi_surveillance/en/

https://www.who.int/immunization/monitoring_surveillance/routine/reporting/en/

https://www.who.int/medicines/areas/quality_safety/safety_efficacy/National_PV_Centres_Map/en/


Rationale 744 The 201914 landscape analysis indicated that while efforts have borne fruit in the areas of 745 notification and reporting, greater progress is still needed in the areas of investigation, capacity 746 for data analysis, causality assessment and communication related to AEFI. This is corroborated 747 by the feedback that active surveillance, causality assessment and methods for vaccine safety 748 are key areas to prioritize for the next decade. 749 750

Objectives 751 In addition to the guiding principles outlined in GVSB 1.0, there are several additional objectives 752 to achieve high quality AEFI surveillance. These objectives may be accomplished at the local, 753 national or regional levels. 754

755 1. Detect and refine vaccine safety signals that warrant further investigation 756 The past decade has witnessed the development of national reporting forms using WHO 757 approved core variables in many countries. Electronic reporting15 is replacing paper reporting in 758 several countries. Over time, web-based and electronic platforms that are more accurate and 759 reliable are being adapted by countries causing challenges in recording and processing data in a 760 common database. Free and open source software such as DHIS216 are enabling the integration 761 and visualisation of vaccine safety data with overall immunisation databases as well as 762 integration with other national health programs. 763 764 The AEFI reporting patterns over the last decade have changed and immunisation stress-related 765 responses (ISRR) are being increasingly reported particularly among older children and adults 766 interrupting immunisation programs in several countries17. New vaccine introductions such as 767 typhoid, malaria and dengue and use of vaccines in non-traditional settings such as epidemic 768 settings (Ebola) and special populations (pregnancy) have brought new challenges for AEFI 769 detection as all these were first introduced in LMICs18. 770 771 Vaccine safety signals typically arise when unexpected events in terms of type, frequency, 772 severity or seriousness are reported in clinical trials or passive or active surveillance systems or 773 special studies establish temporal relationship between vaccine(s) and AEFI without 774 establishing a causal relationship (true vaccine adverse reaction). By careful review of clinical 775 trial data, potential signals can be investigated once the vaccine is licensed, recommended and 776 more widely used in the population. In populations served by passive surveillance systems the 777 identification of unique AEFI patterns or the identification of higher rates of reported AEFIs 778 than what would be expected can flag a signal; however, doing so can be challenging as it 779 requires ascertaining estimates of under-reporting to the passive surveillance system and 780

14 https://www.who.int/vaccine_safety/publications/2019_Landscape_Analysis.pdf?ua=1 15 Vaccine Adverse Events Information Management System https://www.who.int/vaccine_safety/publications/GVSI_meeting2_india_Nov_2013_report.pdf?ua=1 16 https://academy.dhis2.org/ 17 Anxiety-related adverse events following immunization (AEFI): A systematic review of published clusters of illness https://www.sciencedirect.com/science/article/pii/S0264410X17315761 18https://www.intechopen.com/books/dengue-immunopathology-and-control-strategies/roadmap-for-the-introduction-of-a-new-dengue-vaccine; https://www.coalitionagainsttyphoid.org/who-recommends-use-of-first-typhoid-conjugate-vaccine/; https://academic.oup.com/jid/article/217/suppl_1/S6/4999145

https://www.who.int/vaccine_safety/publications/GVSI_meeting2_india_Nov_2013_report.pdf?ua=1

https://academy.dhis2.org/

https://www.sciencedirect.com/science/article/pii/S0264410X17315761

https://www.intechopen.com/books/dengue-immunopathology-and-control-strategies/roadmap-for-the-introduction-of-a-new-dengue-vaccine

https://www.coalitionagainsttyphoid.org/who-recommends-use-of-first-typhoid-conjugate-vaccine/

https://academic.oup.com/jid/article/217/suppl_1/S6/4999145


knowledge of background rates of the disease of interest in such populations. Public concerns 781 or reports by social media can alert immunisation programs to initiate surveys and review 782 passive reports received to ascertain signals. In all these situations, signals need to be refined 783 for specificity and spurious reports need to be ruled out. Signals for intussusception following 784 Rotashield rotavirus vaccine19 and narcolepsy following Pandemrix influenza vaccine20 have 785 been confirmed as true vaccine reactions. Postural orthostatic tachycardia syndrome (POTS), 786 chronic fatigue syndrome (CFS) and complex regional pain syndrome (CRPS) after HPV 787 vaccines21 were identified as spurious signals on investigation. 788 789 Collaboration of multiple countries for active surveillance22 using pooled data have yielded 790 information on measles-containing vaccines and aseptic meningitis and idiopathic 791 thrombocytopenic purpura23. Similar multi-centre studies have examined the association of 792 rotavirus vaccines and intussusception24. Special active surveillance studies are needed for new 793 vaccines that are introduced in LMICs such as typhoid conjugate, malaria, Ebola, and dengue. 794 Active surveillance and sentinel sites are conducive to identifying signals and establishing 795 causality and require investments to establish in some LMICs. 796 797 Strategies 798

• Use passive surveillance systems as primary pillar for AEFI reporting (minimum 799 requirements and electronic reporting should continue; passive reporting should be 800 stimulated by making stakeholders aware of the system). 801

• Regularly review reports submitted to passive systems to identify rates and unexpected 802 patterns, with special attention to serious outcomes such as death, disabilities, life 803 threating events, and programmatic errors. 804

• Identify and quantify public concerns surrounding vaccines through cross-sectional 805 surveys and monitoring of social media. 806

• Develop and implement a framework and process at country level to refine vaccine 807 safety signals and determine which should be prioritized for more rigorous evaluation 808 and assessment of the risk. 809

• Measure and characterize background rates of disease that may become temporally 810 associated with vaccines and AEFIs in active surveillance and sentinel systems. 811

• Coordinate existing active surveillance and sentinel nationally, regionally and globally to 812 take advantage of variability in vaccination practices and increase power and timeliness. 813

• Characterize background rates of disease that may become temporally associated with 814 vaccination. 815

816 817

19 Historical information as RotaShield® was taken off U.S. market in 1999 https://www.cdc.gov/vaccines/vpd-vac/rotavirus/vac-rotashield-historical.htm 20 Narcolepsy Associated with Pandemrix Vaccine. https://www.ncbi.nlm.nih.gov/pubmed/29855798 21 A cluster analysis of serious adverse event reports after human papillomavirus (HPV) vaccination in Danish girls and young women, September 2009 to August 2017 https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2019.24.19.1800380 22 Operational lessons learned in conducting a multi-country collaboration for vaccine safety signal verification and hypothesis testing: The global vaccine safety multi country collaboration initiative. https://www.ncbi.nlm.nih.gov/pubmed/28780118 23 Enhancing global vaccine pharmacovigilance: Proof-of-concept study on aseptic meningitis and immune thrombocytopenic purpura following measles-mumps containing vaccination https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656178/ 24 Tate JE et al. Evaluation of intussusception after monovalent rotavirus vaccination in Africa. N Engl J Med. 2018 Apr 19;378(16):1521-1528

https://www.cdc.gov/vaccines/vpd-vac/rotavirus/vac-rotashield-historical.htm

https://www.ncbi.nlm.nih.gov/pubmed/29855798

https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2019.24.19.1800380


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656178/



2. Investigate AEFIs and assess causal relationship 818 The frequency of AEFI investigations has improved over the last decade. Capacity has been 819 built in many countries to investigate serious AEFIs. However, the quality of the field 820 investigations being conducted have not always been able to provide high quality information 821 for AEFI causality assessments. 822 823 The clinical diagnosis and circumstances of occurrence, particularly of serious AEFI and deaths, 824 should be investigated with the participation of local health leaders and an independent group 825 of experts that does not include the immunisation program, regulators or the manufacturer 826 considering conflict of interest; however, such stakeholders can assist AEFI investigations on 827 specific request by the experts as they can provide relevant information. 828 829 Fully independent and specifically trained national AEFI committees have the capacity to 830 perform investigations on their own. Ideally members of such committees should be 831 represented at the NITAG as well as the multi-country Regional AEFI committees. In large 832 countries it is recommended to have subnational AEFI committees to address locally emerging 833 vaccine safety challenges. 834 835 Determining whether an individual AEFI is associated with the vaccine can be difficult and 836 requires varied approaches. Rarely, a laboratory test can definitively determine that the AEFI is 837 a vaccine reaction (e.g. vaccine associated paralytic polio - VAPP). In most situations, more 838 rigorous studies are needed to determine if the vaccine is associated with the AEFI beyond 839 temporality and to explore potential biological mechanisms. Associations can be explored using 840 methodological approaches such as cohort, case-control, and self-controlled designs25. These 841 study designs can be accomplished on an ad hoc basis. Timeliness, study validity and efficiency 842 can be improved through active vaccine safety surveillance (AVSS)26. 843 844 Different data sources may be accessed for conducting AVSS; including Large-linked automated 845 databases (LLDB), registries and sentinel site-based surveillance. LLDBs can combine vaccine 846 exposure data, health outcome data and socio-demographic data at the individual level from 847 different sources using unique patient identifiers in a defined population. By combining 848 multiple databases, LLDBs allow quick analysis of large, heterogeneous study populations, 849 increasing the statistical power and allowing for investigations into rare AEFIs27,28. An 850 alternative route to AVSS may be collection of data from sentinel sites that may be population 851 based or hospital based29. 852 853 Strategies 854

• Develop systems to investigate AEFI thoroughly to provide high quality data for causality 855 assessment. 856

25 M. A. Baker et al., “A Vaccine Study Design Selection Framework for the Postlicensure Rapid Immunization Safety Monitoring Program,” Am. J. Epidemiol., vol. 181, no. 8, pp. 608–618, Apr. 2015. 26 https://cioms.ch/wp-content/uploads/2017/06/Dr-R%C3%A4go_-Kuala_Lumpur-2017-1.pdf 27 G. Trifirò et al., “Combining multiple healthcare databases for postmarketing drug and vaccine safety surveillance: why and how?,” J. Intern. Med., vol. 275, no. 6, pp. 551–561, Jun. 2014. 28 M. M. McNeil et al., “The Vaccine Safety Datalink: successes and challenges monitoring vaccine safety,” Vaccine, vol. 32, no. 42, pp. 5390–5398, Sep. 2014. 29 The Immunization Programme Monitoring-Active (IMPACT) system in Canada

https://cioms.ch/wp-content/uploads/2017/06/Dr-R%C3%A4go_-Kuala_Lumpur-2017-1.pdf


• Establish in-country process to evaluate vaccine safety signals rapidly and rigorously for 857 further assessment of risk. 858

• Develop active surveillance and sentinel systems. 859 860

3. Conduct individual and population level AEFI causality assessment 861 AEFI causality assessment is the systematic evaluation of the information obtained about an 862 AEFI to determine the likelihood that the event might have been caused by the vaccine(s) or 863 vaccination. On the individual-level, clinical assessment can lead to a determination as to 864 whether the vaccine caused the AEFI in that individual. Such assessments should be conducted 865 by national AEFI committees and other expert groups30 that are independent of conflicts of 866 interest with the ministries of health, industry and the immunisation program. 867 868 Procedures for AEFI causality assessment have been streamlined in the last decade and the 869 national AEFI committees of several countries use the revised WHO AEFI causality assessment 870 classification31 and the online tools32 for assessment. Standardized case definitions such as 871 those developed by the Brighton Collaboration and algorithms are essential to ensure 872 standards and specificity. 873 874 Population causality assessments determine if the vaccine(s) can cause the AEFI and, if so, at 875 what frequency. Factors considered in population level causality assessments include temporal 876 association, exclusion of alternative explanations, prior evidence, proof of association, 877 consistency of the association, specificity, and biological plausibility. 878 879 Strategies 880

• Establish expert committees with clear terms of reference for causality assessment of 881 serious AEFIs, clusters of AEFI and other vaccine-related events that cause public 882 concerns. 883

• When indicated, conduct special studies, under guidance of such committees, to 884 evaluate if a confirmed signal represents a true vaccine adverse reaction. 885

• Establish national strategies and processes to utilize appropriate methodological tools33 886 which have been developed. 887 888

4. Prevent vaccination-related reactions 889 Vaccine product related AEFI and quality defect related AEFI can be minimised by rigorous 890 quality control during the manufacturing processes. Industry should maintain the highest 891 standards of rigorous testing in the pre-license phase (1 to 3) as well as active surveillance 892 during phase 4. Traceability helps identify falsified vaccine. Risk management plans are the 893 backbone of post-licensure monitoring. 894 895

30 Clinical Immunization Safety Assessment (CISA) Network https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/cisa/index.html . 31revised WHO AEFI causality assessment classification https://www.who.int/vaccine_safety/publications/gvs_aefi/en/ 32 AEFI causality assessment software - http://gvsi-aefi-tools.org/new/ 33 https://www.who.int/vaccine_safety/initiative/tools/en/

https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/cisa/index.html

https://www.who.int/vaccine_safety/publications/gvs_aefi/en/

http://gvsi-aefi-tools.org/new/

https://www.who.int/vaccine_safety/initiative/tools/en/


At immunisation centres, managing vaccine product related reactions such as anaphylaxis 896 needs emergency kits and trained staff to identify and respond. A conducive ambience and 897 environment will reduce ISRRs. Behavioural and pharmacological approaches help to alleviate 898 pain and anxiety. Beneficiaries and parents should be sensitised using appropriate 899 communication strategies by vaccinators to identify and manage common minor reactions (e.g. 900 fever and pain at the site of injection) and counselled on seeking medical care for severe 901 symptoms. Monitoring minor AEFI is important as doing so may identify quality or batch related 902 issues. 903 904 Immunization-related errors can be serious, result in death or long-term disabilities. They also 905 negatively impact confidence in immunization programmes. Yet, they are fully preventable with 906 adequate training, supervision, monitoring, and tools. Suitable training on the principles of 907 vaccine storage, handling and administration to all relevant staff are critical. Supportive 908 supervision and suitable documentation will ensure that proper procedures are followed. 909 Updated technologies need to be used for maintaining and monitoring cold chain. Innovative 910 engineering and product design of vaccine packaging, vaccine storage, and vaccination devices 911 can help eliminate potential sources of immunization-related errors. 912 913 Strategies 914

• Use information from vaccine safety signal detection, investigation, and causality 915 assessments to address and prevent vaccination-related injuries. 916

• Request manufacturers to consistently provide very safe and effective vaccines, vaccine 917 packaging, vaccine storage, and vaccination devices through research, innovation and 918 quality control. 919

• Provide appropriate training and resources to health staff to ensure that vaccines are 920 administered in a safe and conducive environment. 921

• Communicate on the risks prior to vaccination in a manner that is salient and address 922 concerns of the vaccine recipient, their care givers and the public. 923 924

5. Strengthened capacity to address vaccine related events and communication response 925 Routine and special situations such as vaccination campaigns or school immunization should be 926 accompanied by appropriate vaccine safety messages. It is also necessary to prepare suitable 927 communication plans to anticipate and address unique situations such as clusters of AEFIs and 928 maintain adherence from communities and vaccine recipients to the program. 929 930 Strategies 931

1. Develop a vaccination safety communication plan that includes both routine risk 932

communication and crisis communication components: 933

• Risk communication prior to vaccination includes concerns of vaccine recipient and 934 their care givers 935

• Messages and frameworks to facilitate a rapid response to any event 936

• Identification of channels for information dissemination to reach audiences across a 937 diverse range of segmented stakeholder and population groups 938


• Sufficient human and financial capacity 939

• Coordination processes, including stakeholder engagement plans. 940 941 Refer also to Chapter 5 for more detailed guidelines on communication. 942


Strategic area 5 – Enhanced Vaccine Safety 943

Communication 944

Introduction 945 Vaccine safety communications is an essential component of every step of an immunisation 946 program’s interactions with health workers, their patients, community leaders and influencers, 947 the media and the public34. Vaccine safety concerns are strongly associated with vaccine 948 hesitancy, acceptance and demand. These concerns impact the degree of trust and confidence 949 of the public, healthcare community and decision makers in vaccines and the services that 950 deliver them. Therefore, assuring that every country has the capacity, infrastructure and 951 resources to communicate about vaccine safety and benefits is critical to building trust as well 952 as maintaining and increasing immunisation coverage.35 953 954

Rationale 955 As the number of vaccines on routine immunisation schedules grows to prevent more diseases, 956 and as communities see less of the devastating consequences of vaccine-preventable diseases, 957 heightened scrutiny of AEFIs or other vaccine safety concerns will result. These concerns must 958 be tracked, taken seriously and misconceptions corrected. This includes prompt and 959 appropriate advice to the regulators, to health workers and to communities, who have a right 960 to know about any potential vaccine risks, no matter how small they may be, including very 961 rare risks. Patients and the public also have a right to know about any uncertainties, particularly 962 those at the launch of a new vaccine. That requires dedicated resources, financial and technical 963 in nature, to adequately communicate facts about AEFIs and address issues of vaccine 964 ingredients and purity, manufacturing, safety studies, regulation and policy as they relate to 965 individuals and their informed decision to vaccinate. 966

Strategies for communication about vaccine safety are necessary throughout the life cycle of all 967 vaccine products and not only as part of crisis management. Where vaccine safety risk 968 communication involves communicating the benefits of vaccination, as well as potential risks 969 before and during a vaccination session (as a preparation for possible AEFI), vaccine safety crisis 970 communication involves communicating about vaccine safety updates and benefits of 971 immunisation after an AEFI or a vaccine-related event (which can include other events that can 972 damage vaccine confidence, usually linked to vaccine safety), which has triggered public 973 concern. This needs to be understood as mutually reinforcing strategies that aim to mitigate 974 future negative outcomes affecting the immunisation program or vaccine uptake. 975 976

The media, as an amplifier of vaccine safety concerns and misinformation, plays a crucial role in 977 vaccine safety risk and crisis communication. Understanding traditional, social and digital 978

34 Employing strong communication principles and strategies is not a substitute for evidence‐based risk analysis. This chapter

should be considered a companion to Blueprint 2.0 and guidance related to safety management, surveillance, capacity,

preparedness and management of response to adverse events. 35 For further guidance on how to communicate about vaccine safety and related crises consult the WHO Vaccine safety communication library; available at: www.euro.who.int/vaccinesafetycommunication.


media, monitoring the real‐time manifestation and emergence of vaccine safety concerns and 979 facilitating informed dialogue and discussion with media gatekeepers, are important for 980 authorities to gauge public sentiment, appropriately and effectively use media channels, 981 communicate in a timely fashion, and assure accurate media reporting of vaccine safety related 982 events. Engaging media as an ally and assuring that reliable vaccine safety information is 983 accessible and commensurate with audience health literacy, is critical in any context. During 984 crises, the principles of being first, right, credible, empathetic, respectful, consistent and 985 providing clear messages and calls to action when necessary are critical. Having a willingness to 986 admit mistakes when wrong is also essential for maintaining public confidence in the 987 immunisation program. 988 989

Ultimately, vaccine safety communication aims to build individual and public trust and protect 990 immunization programs. In this way, vaccine safety communication contributes significantly to 991 addressing concerns related to vaccine safety that may contribute to hesitancy and promoting 992 demand for vaccination. The goal of vaccine safety communication is to ensure that 993 stakeholders are part of a real-time feedback loop, especially in case of an AEFI, and that 994 stakeholders can access the information they need to trust vaccines and have access to the 995 services and authorities that deliver them to make an informed choice. 996 997

Objectives 998 1. Strengthen the capacity and infrastructure to communicate vaccine safety and manage the 999 communication response to vaccine safety related events, including AEFIs 1000 An effective approach to vaccine safety communication requires integrating it into every 1001 component touching vaccine safety: AEFI surveillance, AEFI or vaccine related event response, 1002 AEFI preparedness, AEFI causality assessment, health worker training, immunisation policies 1003 and mandates, NITAGs, routine immunisation communication, demand generation, and data 1004 reporting. This calls for strong coordination and capacity, and a dedicated budget to ensure 1005 adequate preparedness and that the response to a vaccine safety‐related event will minimize 1006 and mitigate any negative consequences for confidence. 1007 1008 Strategies 1009

• Establish a dedicated vaccine safety communications committee at the national level 1010

with a scope of work to formulate a shared communication strategy with delineated 1011

roles and responsibilities, able to advocate and secure an appropriate budget, and 1012

coordinate vaccine‐safety risk and crisis communications36 1013

• Conduct capacity needs assessments on a regular basis with follow‐up training and 1014

education activities delivered for health workers, the media and decision‐makers 1015

• Upgrade health professional curricula and in‐service training on vaccine safety related 1016

topics and issues including risk and interpersonal communication 1017

36 For further information on how to establish a vaccine safety coordination mechanism consult “Template terms of reference for a vaccine communication working group” in the WHO Vaccine safety communication library; available at: www.euro.who.int/vaccinesafetycommunication.

http://www.euro.who.int/en/health-topics/disease-prevention/vaccines-and-immunization/publications/2017/template-terms-of-reference-for-a-vaccine-communication-working-group-2017

http://www.euro.who.int/en/health-topics/disease-prevention/vaccines-and-immunization/publications/2017/template-terms-of-reference-for-a-vaccine-communication-working-group-2017


• Regularly engage the media on an ongoing basis and prior to introducing new vaccines 1018

• Support the development of trustworthy websites for vaccine safety information at the 1019

national level, to be supported by the VSN 1020

1021

2. Identify and characterize vaccine safety concerns among the public, healthcare workers 1022 and other stakeholders as potential safety signals warranting further investigation and a 1023 communications response 1024 Vaccine safety concerns among segments of the public, healthcare workers and other 1025 stakeholders are potential safety signals that may warrant additional investigations. Public 1026 concerns by themselves may require vaccine safety systems to evaluate AEFIs. In other 1027 situations, vaccine safety concerns may be held more broadly, also warranting further 1028 investigations. Vaccine safety systems must be able to detect these safety signals rapidly and 1029 characterize them so that those that need to be investigated can be prioritized and addressed 1030 scientifically. There is substantial variability in how to most efficiently and effectively identify 1031 and characterize these vaccine safety concerns depending on the setting (sub-national and 1032 national) as well as the population or subpopulation of interest. Countries should conduct 1033 evidence-based research and assessments to develop tools and resources for the potential use 1034 of media, web-based, and social media analytics to identify understand emerging concerns and 1035 sentiments about vaccines and guide communication responses. 1036 1037 Strategies 1038

• Conduct cross‐sectional studies of the public, healthcare workers and other potential 1039

stakeholders to understand perceptions related to vaccine safety 1040

• Monitor traditional and social media to characterize public vaccine safety concerns37 1041

1042 3. Provide timely short and precise messages describing what is known, what is not known, 1043 and what is being done to fill these gaps to NRA, NITAGs, AEFIs committees, vaccine 1044 companies, health workers, the media and the public. 1045 AEFI passive surveillance systems, investigation of signals, and causality assessments require 1046 timely communications to all interested parties. NRAs and NITAGs require this information to 1047 determine if there are any changes to the risk and benefit profile of the vaccine. Vaccine 1048 manufacturers require this information for similar reasons, including making changes to the 1049 product and conducting their own analyses and communications. Health workers, the media 1050 and the public will often be interested in this information and can have an expectation that 1051 such information will be shared with them in a timely manner. It is essential that these vaccine 1052 safety communications are evidence‐based and tailored to the target audience. Often, vaccine 1053 safety communications are incorporated into broader vaccine communications that includes a 1054 wider explanation of vaccine benefits. Nonetheless, the purpose of vaccine safety 1055

37 For further information on how to monitor public opinion consult the WHO Vaccine safety communication library; available at: www.euro.who.int/vaccinesafetycommunication.


communications in context of a crisis must focus on what is known, what is not known and 1056 what is being done to fill these gaps. 1057 1058 Strategies 1059

• Develop a vaccine safety communication plan or strategy that includes both routine risk 1060

communication and crisis communication components: 1061

o Severity grading of the safety issue rubric for all major contingencies including 1062 vaccine safety 1063

o Standing messaging and messaging frameworks to facilitate a rapid response to 1064

any likely event 1065

o Identification of channels for information dissemination including online/digital 1066

communication to address vaccine misinformation 1067

o Target audiences across a diverse range of segmented stakeholder and 1068

population groups 1069

o Develop, evaluate and widely implement effective vaccine communication 1070

strategies taking advantage of insights from social sciences, psychology, science 1071

communication and other disciplines 1072

o Develop specific strategies for outreach to vaccine-hesitant and other vulnerable 1073

communities working through engagement with established community leaders 1074

• Manage a monitoring and evaluation framework 1075

o Ensure sufficient human and financial capacity to handle communications-1076

related issues, especially in crises 1077

o Adequate coordination processes, including stakeholder engagement plans. 1078

Include clear national and subnational vaccine safety communication roles and 1079

responsibilities, with standard operating procedures, at each step of the process 1080

within AEFI surveillance and response plans 1081


Strategic area 6 - Fragile States and Emergencies 1082

Introduction 1083 Fragile states have characteristics that substantially impair their economic and social 1084 performance. These include weak governance, limited administrative capacity, chronic 1085 humanitarian crises, persistent social tensions, and often, violence or the legacy of armed 1086 conflict and civil war38. Emergency is defined as a situation impacting the lives and well-being of 1087 many people or significant percentage of a population and requiring substantial multi-sectoral 1088 assistance. For WHO to respond, there must be clear health consequences, 39usually defined in 1089 time and space, and requiring threshold values to be recognized, which implies rules of 1090 engagement and an exit strategy. 1091 1092

Rationale 1093 Vaccine safety monitoring in fragile states and crisis such as humanitarian emergencies pose 1094 specific challenges as they may cause major disruptions in the delivery of all routine health 1095 services, including routine vaccination programmes. Thus, many of these services need to be 1096 addressed on an emergency basis and re-established as quickly as possible. Further, prevention 1097 of additional AEFI cases should not be neglected which is particularly important in a protracted 1098 crisis. Security and logistics issues are more challenging in such situations and have important 1099 implications for population access to health services and for providing quality assured safe 1100 vaccines by health providers to the population. This may result with an inability to deliver full 1101 series of vaccinations and may prompt consideration of viable alternatives and in several 1102 instances may result in greater frequency of immunisation and programmatic errors causing 1103 vaccine adverse reactions. Vaccine safety particularly using strategies such as mass vaccination 1104 campaigns, expanded target age groups, and reduced courses for certain vaccines warrant 1105 greater consideration than they might in other circumstances, whether routine vaccination 1106 services remain functional40. This warrants the need of staff preparedness and training to 1107 minimise avoidable immunisation and programmatic errors to avoid vaccine safety crisis, 1108 particularly in emergencies. 1109 1110 When vaccines are procured for use in these situations, particularly from non-conventional 1111 sources such as donations, it is mandatory that the products considered meet international 1112 standards of quality and safety, and preferably have obtained WHO prequalification. However, 1113 under certain circumstances, non-prequalified vaccines may be approved3. Information on 1114 safety needs to be assessed carefully, weighing the risks against the benefits of the vaccine. The 1115

38 Definition from International Monetary Fund https://www.ilo.org/wcmsp5/groups/public/---ed emp/documents/terminology/wcms_504528.pdf 39 Taken from Emergency response framework of WHO https://www.who.int/hac/about/erf.pdf 40 Vaccination in Acute Humanitarian Emergencies A framework for decision making https://apps.who.int/iris/bitstream/handle/10665/255575/WHO-IVB-17.03-eng.pdf;jsessionid=04C19A5493EB57A02CF77726FEC48397?sequence=1

https://www.ilo.org/wcmsp5/groups/public/---ed%20emp/documents/terminology/wcms_504528.pdf

https://www.who.int/hac/about/erf_.pdf

https://apps.who.int/iris/bitstream/handle/10665/255575/WHO-IVB-17.03-eng.pdf;jsessionid=04C19A5493EB57A02CF77726FEC48397?sequence=1

https://apps.who.int/iris/bitstream/handle/10665/255575/WHO-IVB-17.03-eng.pdf;jsessionid=04C19A5493EB57A02CF77726FEC48397?sequence=1


risk-benefit ratio may vary among situations but, in emergencies, where morbidity and 1116 mortality are high, the expected benefits may far outweigh the risk of adverse events. 1117 1118 Many different vaccines can be considered depending on risk of potential outbreaks (cholera, 1119 diphtheria, hepatitis, measles, meningococcal disease, poliomyelitis, typhoid fever, and yellow 1120 fever in particular). It is important that health care providers are familiar with the safety 1121 profiles of these vaccine use as well as their administration. 1122 1123 Immunisation errors can occur in these situations depending on the quality of immunisation 1124 services, including cold chain, supervision and monitoring. Vaccination in unfamiliar 1125 environments using unfamiliar techniques further enhance the risk. The lack of qualified and 1126 well-trained staff is another risk factor. Vaccines supplied and donated during emergencies may 1127 not have undergone standard regulatory evaluations and may not meet international 1128 requirements such as labelling and off-label use. 1129 1130 Vaccinations (both routine and disease specific) also must be considered in the face of 1131 emerging infectious diseases such as Ebola, Zika, Middle-East respiratory syndrome (MERS), 1132 severe acute respiratory syndrome (SARS). It is always challenging as often there are no 1133 licensed candidate vaccines available for use against emerging infectious disease in outbreak 1134 proportions, and health care providers are occupied with emergency response. Prevention and 1135 control of emerging infectious diseases in fragile states and in emergencies are highly 1136 challenging due to prevailing disrupted infrastructure, health care services and, sometimes, 1137 even general insecurity. High risk for frontline workers and immediate contacts of case patients 1138 justify utilisation of novel vaccines with limited record of utilisation in humans. In those 1139 circumstance it is essential that vaccine administration is complemented with active safety 1140 monitoring. 1141 1142 Vaccine safety needs to be incorporated into microplanning processes for vaccination in such 1143 situations, specific communication strategies embedded into the vaccine roll-out to ensure that 1144 populations are not only aware of the protecting aspects but also the risks involved. The risk of 1145 public outrage and media criticism over serious vaccine safety events can be extremely 1146 sensitive politically. It is therefore critical that health authorities clearly recognized the purpose 1147 of vaccine pharmacovigilance and be prepared to support it. 1148 1149

Objectives 1150 1. Use vaccine safety monitoring as a quality assurance mechanism for vaccination 1151

activities in fragile states and under emergency circumstances 1152

Fragile states and emergencies are often involved with interruption of routine health services 1153 and problematic infrastructure. Nonetheless, there may be remaining infrastructure and 1154 resources that can be used to accomplish necessary components of the vaccine 1155 pharmacovigilance, in part or in whole. There are three possible strategies: 1156 1157 1158


Strategies 1159

• Ensure that only WHO prequalified or approved quality assured vaccine are used in 1160

fragile states or during emergencies 1161

• Ensure that national guidelines and micro plans incorporating safety surveillance, 1162

communications and response on vaccine safety are in place in fragile states or during 1163

emergencies 1164

• Ensure continuing spontaneous reporting of AEFI as part of the vaccination activity, 1165

identify sentinel sites for enhanced or active surveillance to supplement passive 1166

reporting 1167

1168 2. Monitor the safety of novel vaccines during emergencies related to emerging 1169

infectious diseases 1170

Introduction of novel vaccines in emergency situations requires oversight by NRAs. The 1171 response to emerging infectious diseases benefits from additional resources by regional and 1172 international partners for prevention and control response. Using additional resources to 1173 establish and implement active safety surveillance of vaccine recipients is desirable as there is 1174 limited record of utilisation of the novel vaccines utilized in those settings. 1175 1176 Strategy 1177

• Develop guidelines and standard operating procedures with national, regional and 1178

global regulatory networks for vaccine pharmacovigilance of novel vaccines in 1179

emergency use 1180

• Ensure that active safety surveillance is set-up prior to introducing novel vaccine in an 1181

emergency response 1182

Global Vaccine Safety Blueprint (GVSB) 2.0 Drafting Group 4 Nov 2019

Accountability framework 1183

RATIONALE 1184

Global vaccine pharmacovigilance is a complex network of multiple interconnected systems. 1185 Within each of these systems, including health, legislative, regulatory, governmental, industry, 1186 media and community, multiple levels and stakeholders are typically involved, ranging from 1187 local community level, jurisdictional, national, regional and global. Within each of these levels 1188 health care workers ranging from local immunisation teams to clinicians treating potential AEFI, 1189 patients, parents and other community members need to be engaged and motivated using a 1190 variety of strategies. Additionally, the level of maturity of these systems varies widely across 1191 settings, with pharmacovigilance challenges varying accordingly. 1192 1193 For the key clients of Global Vaccine Pharmacovigilance to be able to benchmark their maturity 1194 levels, measure progress and develop practical strategies for improving that maturity, a 1195 framework for accountability has been recognised as a practical and effective way of identifying 1196 and measuring the key steps leading to improved pharmacovigilance capacity. Additionally, 1197 there are mechanisms by which these outputs and outcomes can be displayed, linked to 1198 illustrations of successful activities that led to them. 1199 1200 The accountabilities and indicators will also be guided by the WHO Global Benchmarking Tool 1201 for Evaluation of National Regulatory System of Medical Products and the Indicator-Based 1202 Pharmacovigilance Assessment Tool: Manual for Conducting Assessments in Developing 1203 Countries. 1204 1205 Each strategic area will identify: 1206

• Clients or beneficiaries 1207

• Primary Stakeholders 1208

• Accountabilities: roles and responsibilities of the partners and relationships, including 1209 coordination of safety systems between industry and governmental bodies 1210

1211 They will develop a high-level logic model with: 1212

• Activities 1213

• Outputs 1214

• Outcomes 1215

The GVSI strategic priority group will coordinate monitoring of the accountability framework 1216 and report at each annual general meeting. An independent GVSI Observatory will be 1217 established. It will provide a as a resource for academia, technical agencies, research networks 1218 to display their methods and findings to enhance reach of investigations and disseminate 1219 findings. Under its terms of reference, the aims of the Observatory are to identify data sources 1220 and present them in a useful format to document: 1221


• Status of vaccine safety monitoring in all countries. 1222

• Ability of countries to evaluate vaccine safety signals. 1223

• Availability of vaccine safety communication plans at country level to ensure awareness 1224

of vaccine risks and benefits, understand perceptions of risk, and prepare for managing 1225

any AEFI and crises promptly. 1226

• Legal, regulatory and administrative frameworks to ensure compliance with vaccine 1227

pharmacovigilance requirements at national, regional and international levels. 1228

• Availability of regional and global technical support platforms strengthening for a 1229

vaccine pharmacovigilance system that meets countries’ expressed needs. 1230

• Efforts to improve systems for appropriate interaction between national governments, 1231

multilateral agencies, and manufacturers at national, regional and international levels. 1232


Appendix 1: Current WHO Benchmarking Tool sub-indicators of maturity levels

Maturity levels

Indicators

Level 1 sub-indicators Level 2 sub-indicators Level 3 sub-indicators Level 4 sub-indicators

VL01 Legal provisions, regulations and guidelines required to define regulatory framework of vigilance

VL01.01: Legal provisions for a national vigilance system exist VL01.02: Legal provisions and regulations require the manufacturers and/or MAHs to set up a vigilance system of their medical products and periodically report vigilance data to the NRA VL01.03: Guidelines ensure that distributors, importers, exporters, healthcare institutions, consumers and other stakeholders are encouraged to report adverse drug reactions (ADRs) and AEs to the MAH and/or NRA

VL01.04: Legal provisions and regulations allow NRA to require manufacturers and/or MAHs to conduct specific studies on safety and effectiveness under specific conditions

VL01.05: Legal provisions, regulations and guidelines require manufacturers and/or MAHs to designate an individual person to be in charge of vigilance system VL01.06: There are guidelines for planning, conducting, monitoring, and reporting of vigilance activities


VL01.07: Legal provisions and regulations allow recognition and/or reliance on vigilance‐related decisions, reports or information from other countries or regional or international bodies.

VL02 Arrangement for effective organization and good governance

VL02.01: There is a defined organizational structure with clear responsibilities to conduct vigilance activities

VL02.02: Documented procedures and mechanisms are implemented to ensure the involvement, coordination and communication among all stakeholders relevant to vigilance activities

VL03 Human resources to perform vigilance activities

VL03.01: Sufficient competent staff (i.e., education, training, skills and experience) are assigned to perform vigilance activities VL03.02: Duties, functions, and responsibilities of the staff in charge of vigilance activities are established and updated


in the respective job descriptions VL03.03: Training plan developed, implemented and updated at least once a year for staff in charge of vigilance activities VL03.04: The NRA generates and maintains records of staff training activities and training effectiveness verification

VL04 Procedures established and implemented to perform vigilance activities

VL04.05: Staff access to information resources relevant to vigilance processes (e.g., safety information sources and reference materials) is ensured

VL04.01: Vigilance procedures and tools are in place and implemented for collection and assessment of ADRs and AEs VL04.02: Vigilance procedures and tools are in place for investigation, interpretation of and response to ADRs and AEs VL04.04: Risk approach is considered throughout different vigilance activities, including timely response to

VL04.03: Standard procedures exist and are implemented for enforcement of the national vigilance system VL04.07: With respect to vigilance data, assessment of the risk‐benefit balance of medical products is regularly conducted VL04.08: Active vigilance activities, as well as proactive monitoring programmes (when needed) have been


detected signals for risks or benefit VL04.06: The NRA has access to expert committees for review of serious emergent safety concerns, when needed

developed and implemented

VL05 Mechanism in place to monitor regulatory performance and output

VL05.01: Vigilance information is used in timely manner to amend existing regulatory decisions or to issue new regulatory decisions or actions

VL05.02: Performance indicators for vigilance activities are established and implemented

VL06 Mechanism exists to promote transparency, accountability and communication

VL06.01: Vigilance activities and relevant feedback are appropriately communicated to the public

VL06.02: Mechanism for regular feedback to all stakeholders on vigilance events exists and is complemented with a risk communication plan VL06.03: Vigilance data and findings are shared with relevant regional and international partners

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