Guidelines on clinical evaluation of vaccines: regulatory ...€¦ · 1 2 3 WHO/BS/2016.2287 4...

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WHO/BS/2016.2287 3

ENGLISH ONLY 4

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Guidelines on clinical evaluation of vaccines: regulatory expectations 7

Proposed revision of WHO TRS 924, Annex 1 8

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NOTE: 10

11 This document has been prepared for the purpose of inviting comments and suggestions on the proposals 12 contained therein, which will then be considered by the Expert Committee on Biological Standardization 13 (ECBS). Publication of this early draft is to provide information about the proposed Guidelines on 14 Clinical Evaluation of Vaccines: Regulatory Expectations, to a broad audience and to improve 15 transparency of the consultation process. 16 17 The text in its present form does not necessarily represent an agreed formulation of the Expert 18 Committee. Written comments proposing modifications to this text MUST be received by 19 16 September 2016 in the Comment Form available separately and should be addressed to the World 20 Health Organization, 1211 Geneva 27, Switzerland, attention: Department of Essential Medicines and 21 Health Products (EMP). Comments may also be submitted electronically to the Responsible Officer: Dr 22 Ivana Knezevic at email: [email protected]. 23 24 The outcome of the deliberations of the Expert Committee on Biological Standardization will be 25 published in the WHO Technical Report Series. The final agreed formulation of the document will be 26 edited to be in conformity with the "WHO style guide" (WHO/IMD/PUB/04.1). 27

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© World Health Organization 2016 29

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health 30 Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: 31 [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for non-32 commercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: 33 [email protected]). 34

The designations employed and the presentation of the material in this publication do not imply the expression of any 35 opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or 36 area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent 37

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WHO/BS/2016.2287

approximate border lines for which there may not yet be full agreement. 38 39 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 40 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 41 and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 42 43 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this 44 publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. 45 The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 46 Organization be liable for damages arising from its use. 47

48 The named authors [or editors as appropriate] alone are responsible for the views expressed in this publication. 49

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Recommendations and guidelines published by WHO are intended to be scientific and advisory in

nature. Each of the following sections constitutes guidance for national regulatory authorities (NRAs)

and for manufacturers of biological products. If an NRA so desires, these Guidelines may be adopted

as definitive national requirements, or modifications may be justified and made by the NRA. It is

recommended that modifications to these Guidelines be made only on condition that modifications

ensure that the vaccine is at least as safe and efficacious as that prepared in accordance with the

recommendations set out below. The parts of each section printed in small type are comments or

examples for additional guidance intended for manufacturers and NRAs, which may benefit from

those details.

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Contents 55

56

1. Introduction 57

2. Scope 58

3. Glossary 59

4. Vaccine clinical development programmes 60

4.1 General considerations 61

4.1.1 Consultation with national regulatory authorities 62

4.1.2 Use of independent data monitoring committees 63

4.1.3 Registering and reporting clinical trials 64

4.2 Pre-licensure clinical development programmes 65

4.2.1 Initial trials 66

4.2.2 Pivotal trials 67

4.3 Post-licensure clinical evaluations 68

5. Immunogenicity 69


5.2 Characterization of the immune response 71

5.3 Measuring the immune response 72

5.3.1 Collection of specimens 73

5.3.2 Immunological parameters 74

5.3.2.1 Humoral immune response 75

5.3.2.2 Cell-mediated immune response 76

5.3.3 Assays 77

5.4 Determination and use of immunological correlates of protection 78

5.4.1 Immunological correlates of protection and their uses 79

5.4.2 Establishing an immunological correlate of protection 80

5.5 Immunogenicity trials 81

5.5.1 Objectives 82

5.5.2 General considerations for trial designs 83

5.5.2.1 Endpoints 84

5.5.2.2 Trials designed to detect superiority 85

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5.5.2.3 Trials designed to detect non-inferiority 86

5.5.3 Analysis and interpretation 87

5.6 Specific uses of immunogenicity trials 88

5.6.1 Selection of formulation and posology 89

5.6.1.1 Selecting the formulation and posology for initial licensure 90

5.6.1.2 Amending or adding posologies after initial licensure 91

5.6.1.3 Post-primary doses 92

5.6.2 Using immunogenicity data to predict efficacy 93

5.6.2.1 Bridging to efficacy data 94

5.6.2.2 Other approaches 95

5.6.3 Co-administration trials 96

5.6.4 Immunization of pregnant women 97

5.6.4.1 Aims of immunization during pregnancy 98

5.6.4.2 Safety and immunogenicity in pregnancy 99

5.6.4.3 Passive protection of infants 100

5.6.5 Changes to the manufacturing process 101

5.6.6 Lot-to-lot consistency trials 102

6. Efficacy and effectiveness 103

6.1 General considerations for efficacy trials 104

6.2 Types of efficacy trials 105

6.2.1 Human challenge trials 106

6.2.2 Initial efficacy trials 107

6.2.3 Pivotal efficacy trials 108

6.3 Design and conduct of efficacy trials 109

6.3.1 Selection of trial sites 110

6.3.2 Candidate (test) vaccine group(s) 111

6.3.3 Control (reference) group(s) 112

6.3.3.1 Control groups not vaccinated against the infectious disease to be 113

prevented 114

6.3.3.2 Control groups vaccinated against the infectious disease to be 115

prevented 116

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6.3.4 Trial designs 117

6.1.4.1 Randomization 118

6.1.4.2 Types of trial design 119

6.3.5 Clinical endpoints 120

6.3.5.1 Primary endpoints 121

6.3.5.2 Secondary endpoints 122

6.3.6 Case definition 123

6.3.7 Case ascertainment 124

6.3.8 Duration of follow-up 125

6.3.9 Analysis of efficacy 126

6.3.9.1 Sample size calculation 127

6.3.9.2 Analysis populations 128

6.3.9.3 Primary analysis 129

6.3.9.4 Other analyses 130

6.3.9.5 Other issues 131

6.4 Approaches to determination of effectiveness 132

7. Safety 133


7.2 Assessment of safety in clinical trials 135

7.2.1 Safety outcomes as primary or secondary endpoints 136

7.2.1.1 Safety outcomes as primary endpoints 137

7.2.1.2 Safety outcomes as secondary endpoints 138

7.2.2 Recording and reporting adverse events 139

7.2.2.1 Methods 140

7.2.2.2 Solicited signs and symptoms 141

7.2.2.3 Unsolicited adverse events 142

7.2.2.4 Other investigations 143

7.2.3 Categorization of adverse events 144

7.2.3.1 Causality 145

7.2.3.2 Severity 146

7.2.3.3 Other categorization 147

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7.2.4 Adverse event reporting rates within and between trials 148

7.3 Size of the pre-licensure safety database 149

7.4 Post-licensure safety surveillance 150

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Authors and acknowledgements 152

References 153

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1. Introduction 155

156

This guideline is intended to replace WHO’s Guidelines on clinical evaluation of vaccines: 157

regulatory expectations, which was adopted by the Expert Committee on Biological 158

Standardization (ECBS) in 2001 and published as Annex 1 in the WHO Technical Report Series, 159

No. 924 (1). The document of 2001 provided guidance for the clinical evaluation of vaccines as 160

well as for WHO vaccine prequalification. 161

162

Since 2001, more than 20 vaccine-specific documents that include a section on clinical 163

evaluation have been adopted by the ECBS. They are all intended to be read in conjunction with 164

Annex 1 of the WHO Technical Report Series, No. 924 (2). These include documents that 165

address both oral and inactivated polio vaccines [OPV, IPV], whole cell pertussis and acellular 166

pertussis vaccines, meningococcal conjugate vaccines for serotypes A and C, pneumococcal 167

conjugate vaccines, and vaccines intended to prevent diseases due to rotaviruses, dengue viruses, 168

human papillomaviruses and malaria parasites. 169

170

This guideline has been prepared to reflect the scientific and regulatory experience that has been 171

gained from vaccine clinical development programmes since the adoption of the above-172

mentioned version in 2001. It is intended for use by national regulatory authorities (NRAs), 173

companies developing and holding licences for vaccines, clinical researchers and investigators. It 174

takes into account the content of clinical development programmes, clinical trial designs, the 175

interpretation of trial results and post-licensing activities. 176

177

The main changes (modification or expansion of previous text and additional issues covered) in 178

this revision compared to the version of 2001 (1) include, but are not limited to, the following: 179

180

Immunogenicity 181

general principles for comparative immunogenicity studies, including selection of the 182

comparators, endpoints and acceptance criteria for concluding non-inferiority or 183

superiority of immune responses; 184

situations in which age de-escalation studies are not necessary; 185

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assessment of the need for and timing of post-primary doses; 186

use of different vaccines for priming and boosting; 187

assessment of the ability of vaccines to elicit immune memory or to cause hypo-188

responsiveness; 189

use of immunogenicity data to predict vaccine efficacy, with or without bridging to 190

efficacy data; 191

the derivation and uses of immunological correlates of protection (ICPs); 192

vaccination of pregnant women to protect them and/or their infants; 193

194

Efficacy and effectiveness 195

the need for, and feasibility of, conducting vaccine efficacy studies; 196

selection of appropriate control groups in different circumstances; 197

comparison of extended and parent versions of vaccines; 198

prediction of vaccine efficacy when there is no ICP and vaccine efficacy studies are not 199

feasible; 200

preliminary and pivotal vaccine efficacy studies and their design; 201

vaccines with modest efficacy and/or that provide a short duration of protection; 202

extrapolation of data between geographically/genetically diverse populations; 203

the role and potential value of human challenge studies; 204

the role of sponsors and public health authorities in generating vaccine effectiveness 205

data; 206

207

Safety 208

detailed consideration of the collection and analysis of safety data from clinical trials; 209

consideration of size of the pre-licensure database by type of vaccine and its novelty; 210

consideration of the safety database by population subgroup; 211

special safety considerations by vaccine construct; 212

circumstances of limited pre-licensure safety data; 213

use of vaccine registries and disease or pregnancy registries; 214

issues regarding vaccine pharmacovigilance activities. 215

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216

Because a separate document on nonclinical evaluation of vaccines was established in 2003 (3), 217

the section on that topic in the 2001 version of Guidelines on clinical evaluation of vaccines: 218

regulatory expectations has been removed. Furthermore, the structure of the document has 219

changed. In particular, a number of methodological considerations have been incorporated into 220

relevant sections and subsections rather than being described in a separate section. In line with 221

the changes made in the document, the glossary and references have been updated. 222

223

WHO has also made several other guidelines and reports of relevance available to clinical 224

development programmes for vaccines. These should be consulted as appropriate. They include: 225

Good clinical practice for trials on pharmaceutical products (4) 226

Good manufacturing practice for pharmaceutical preparations (5) 227

Good manufacturing practice for biological products (6) 228

Guidelines on nonclinical evaluation of vaccines (3) 229

Guidelines on nonclinical evaluation of vaccine adjuvants and adjuvanted vaccines (7) 230

Guidelines on procedures and data requirements for changes to approved vaccines (8) 231

Guidelines for independent lot release of vaccines by regulatory authorities (9) 232

Recommendations for the evaluation of animal cell cultures as substrates for the 233

manufacture of biological medicinal products and for the characterization of cell banks 234

(10) 235

Clinical Considerations for Evaluation of Vaccines for Prequalification (11) 236

The WHO manual Immunization in practice (12) 237

WHO expert consultation on the use of placebos in vaccine trials (13). 238

239

Furthermore, guidance on various aspects of pre-licensure clinical development programmes for 240

vaccines and post-licensure assessment is also available from several other bodies, such as the 241

International Conference on Harmonization (ICH), the European Medicines Agency (EMA), the 242

United States Food and Drug Administration (FDA) and the United Kingdom’s Medical 243

Research Council (MRC). These WHO guidelines are intended to complement these other 244

documents. 245

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246

2. Scope 247

248

This guideline considers clinical development programmes for vaccines that are intended to 249

prevent clinical disease in humans by eliciting protective immune responses. The protective 250

immune response to vaccination may be directed against one or more specific antigenic 251

components of microorganisms or against substances produced and secreted by them (e.g. 252

toxins) that are responsible for clinical disease. The clinical disease prevented by vaccination 253

may be an acute infectious disease and/or a disease that results from chronic infection with an 254

infectious agent. 255

256

This guideline is applicable to the clinical development of: 257

new candidate vaccines; 258

licensed vaccines; 259

vaccines that are given by any route of administration; 260

vaccines that may be given before exposure or shortly after known or presumed exposure 261

to an infectious agent to prevent the onset of clinical disease. 262

263

The guideline is applicable to vaccines which contain one of more of the following: 264

microorganisms that have been inactivated by chemical and/or physical means; 265

live microorganisms that are not virulent in humans as a result of attenuation processes or 266

specific genetic modification; 267

antigenic substances that have been derived from microorganisms (these may be purified 268

from microorganisms and used in their natural state, or they may be modified (e.g. 269

detoxified by chemical or physical means, aggregated or polymerized); 270

antigens that have been manufactured by synthetic processes or produced by live 271

organisms using recombinant RNA or DNA technology; 272

antigens (however manufactured) that have been chemically conjugated to a carrier 273

molecule to modify the interaction of the antigen with the host immune system; 274

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antigens that are expressed by another microorganism which itself does not cause clinical 275

disease but acts as a live vector (e.g. live viral vectored vaccines, live attenuated chimeric 276

vaccines). 277

In addition, although naked DNA vaccines are not specifically discussed in this guideline, the 278

principles and development programmes outlined are broadly applicable. 279

280

This guideline does not apply to: 281

therapeutic vaccines (i.e. intended for treatment of disease); 282

vaccines intended for any purpose other than the prevention of clinical disease due to 283

infectious agents. 284

285

3. Glossary 286

287

The definitions given below apply to the terms used in this guideline. They may have different 288

meanings in other contexts. 289

290

Adverse event (AE) 291

Any untoward medical occurrence in a participant in a clinical trial. An AE does not necessarily 292

have a causal relationship with the vaccine. 293

294

Adverse event following immunization (AEFI) 295

Any untoward medical occurrence that follows immunization using a licensed vaccine outside of 296

a clinical trial setting. An AEFI does not necessarily have a causal relationship with the use of 297

the vaccine. The AEFI may be any unfavourable or unintended sign, abnormal laboratory 298

finding, symptom or disease. 299

300

Adverse event of special interest (AESI) 301

A clinically important untoward medical occurrence that is known to occur following 302

administration of the type of vaccine under study (e.g. hypotonic-hyporesponsive episodes, 303

febrile convulsions) or that is considered to be a possible risk on the basis of knowledge of the 304

content of the vaccine and/or its interaction with the host immune system (e.g. auto-immune 305

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disease, antibody-dependent enhanced clinical disease). 306

307

Attack rate 308

The proportion of the population that is exposed to an infectious agent and that develops 309

clinically manifest disease. 310

311

Blinding 312

A procedure by which one or more parties involved in a clinical trial are kept unaware of the 313

treatment assignment(s). In double-blind trials the trial subjects and their caregivers, the 314

investigator(s) and other study site staff (with the possible exception of those who administer the 315

vaccines if they are visually different) and the sponsor’s staff are unaware of the treatment 316

assignment. Unblinding of the treatment assignment should not occur before completion of the 317

primary analysis. The criteria to be fulfilled before unblinding should be stated in the protocol. 318

319

Booster dose 320

A dose that is given at a certain interval after completion of the primary series that is intended to 321

boost immunity to, and therefore prolong protection against, the disease that is to be prevented. 322

323

Case ascertainment 324

The method adopted for detecting cases of the disease that is targeted for prevention by 325

vaccination in a vaccine efficacy trial or in a study of vaccine effectiveness. 326

327

Case definition 328

The predefined clinical and/or laboratory criteria that must be fulfilled to confirm a case of a 329

clinically manifest disease in a vaccine efficacy trial or in a study of vaccine effectiveness. 330

331

Cluster randomization 332

Randomization of subjects by group (e.g. by household or by community) as opposed to 333

randomization of individual subjects within a clinical trial. 334

335

Geometric mean concentration 336

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The average antibody concentration for a group of subjects calculated by multiplying all values 337

and taking the nth root of this number, where n is the number of subjects with data. 338

339

Geometric mean titre 340

The average antibody titre for a group of subjects calculated by multiplying all values and taking 341

the nth root of this number, where n is the number of subjects with data. 342

343

Good clinical practice (GCP) 344

GCP is a process that incorporates established ethical and scientific quality standards for the 345

design, conduct, recording and reporting of clinical research that involves the participation of 346

human subjects. Compliance with GCP provides public assurance that the rights, safety and well-347

being of research subjects are protected and respected, consistent with the principles enunciated 348

in the Declaration of Helsinki and other internationally recognized ethical guidelines, and also 349

ensures the integrity of clinical research data. 350

351

Good manufacturing practice (GMP) 352

GMP is the aspect of quality assurance that ensures that medicinal products are consistently 353

produced and controlled to the quality standards appropriate to their intended use and as required 354

by the product specification. 355

356

Immunological correlate of protection (ICP) 357

An ICP is most commonly defined as a type and amount of immunological response that 358

correlates with vaccine-induced protection against a clinically apparent infectious disease and 359

that is considered predictive of clinical efficacy. For some types of vaccines the ICP may be 360

the type and amount of immunological response that correlates with vaccine-induced 361

protection against infection (e.g. hepatitis A and B vaccines). The ICP may be mechanistic (i.e. 362

causative for protection, such as antibody that results in virus neutralization or serum 363

bactericidal antibody) or it may be non-mechanistic (i.e. a non-causative immune response that 364

is present in persons protected by vaccination but is not the cause of protection, such as serum 365

immunoglobulin G [IgG] against varicella-zoster virus [VZV] in the context of prevention of 366

herpes zoster). 367

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368

Immune memory 369

An immunological phenomenon in which the primary contact between the host immune system 370

and an antigen results in a T-cell-dependent immune response, often referred to as priming of the 371

immune system. Effective priming results in the development of antigen-specific memory B-372

cells and an anamnestic (memory) immune response to post-primary doses, which are commonly 373

referred to as booster doses. 374

375

Immunogenicity 376

The capacity of a vaccine to elicit a measurable immune response. 377

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Initial trial 379

A clinical trial that is not intended to serve as a pivotal trial. Initial trials are usually conducted 380

to obtain information on the safety and immunogenicity of candidate vaccine formulations and 381

to select the formulation(s) and regimen(s) for evaluation in pivotal trials. Initial trials may also 382

serve to inform the design of pivotal trials (e.g. by identifying the most appropriate populations 383

and endpoints for further study). On occasion, an initial trial may provide a preliminary 384

evaluation of vaccine efficacy. 385

386

New candidate vaccine 387

Examples of new candidate vaccines from the regulatory standpoint include: 388

a vaccine that contains a new antigenic component (i.e. not previously used in a licensed 389

vaccine); 390

a vaccine that contains a new adjuvant; 391

a vaccine that contains antigen(s) ± adjuvant(s) not previously combined together in a 392

vaccine; 393

a vaccine with the same antigenic component(s) ± adjuvant as a licensed vaccine that is 394

produced by a different manufacturer (including situations in which seed lots or bulk 395

antigenic components used to make a licensed vaccine are supplied to other 396

manufacturers for their own vaccine production). 397

398

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Non-inferiority trial 399

The objective of a non-inferiority trial is to compare a new active treatment with a reference 400

active treatment with a view to demonstrating that the new treatment is not clinically worse with 401

regard to a specified endpoint (which may relate to safety, immunogenicity or efficacy). In non-402

inferiority trials that compare immunogenicity or efficacy it is assumed that the reference 403

treatment has been established to have a significant clinical effect (against placebo). These trials 404

are frequently used in situations where a comparison between a new active treatment and a 405

placebo control may be considered unethical. In the context of clinical development programmes 406

for vaccines, non-inferiority trials may also compare the same vaccine when given to different 407

populations, by different routes and/or or using different regimens. 408

409

Pharmacovigilance 410

The science and activities relating to the detection, assessment, understanding and prevention 411

of adverse effects or any other possible drug-related problems (14). 412

413

Pivotal trials 414

Pivotal clinical trials provide the major evidence in support of licensure. 415

416

Posology 417

The vaccine posology for a specific route of administration and target population includes: 418

the dose content and volume delivered per dose; 419

the dose regimen (i.e. the number of doses to be given in the primary series and, if 420

applicable, after the primary series); 421

the dose schedule (i.e. the dose intervals to be adhered to within the primary series and 422

between the primary series and any further doses). 423

424

Post-licensure safety surveillance 425

A system for monitoring AEFIs in the post-licensure period. 426

427

Post-primary doses 428

Additional doses of vaccine given after a time interval following the primary series of 429

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vaccination, which may or may not boost the immune response. 430

431

Primary vaccination 432

The first vaccination or the initial series of vaccinations intended to establish clinical protection. 433

434

Protocol 435

A document that states the background, rationale and objectives of the clinical trial and describes 436

its designs, methodology and organization, including statistical considerations and the conditions 437

under which it is to be performed and managed. The protocol should be signed and dated by the 438

investigator, the institution involved and the sponsor. 439

440

Randomization 441

In its simplest form, randomization is a process by which n individuals are assigned to a test (nT) 442

or control (nC) treatment so that all possible groups of size n = nT + nC have equal probability of 443

occurring. Thus, randomization avoids systematic bias in the assignment of treatment. 444

445

Responder 446

A trial subject who develops an immune response (humoral or cellular) that meets or exceeds a 447

predefined threshold value using a specific assay. This term is may be applied whether or not 448

there is an established ICP and when the clinical relevance of achieving or exceeding the 449

predefined response is unknown. 450

451

Responder rate 452

The responder rate is the percentage of subjects in a treatment group with immune responses that 453

meet (or exceed) a predefined immune response. 454

455

Serious adverse event (SAE) or SAE following immunization (SAEFI) 456

An AE is serious when it results in death, admission to hospital, prolongation of a hospital stay, 457

persistent or significant disability or incapacity, is otherwise life-threatening, or results in a 458

congenital abnormality/birth defect. Some NRAs may have additional or alternative criteria that 459

must be met. SAEs are such events that occur during clinical trials. SAEFIs are such events that 460

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occur during post-licensure safety surveillance. 461

462

Seroconversion 463

A predefined increase in serum antibody concentration or titre. In subjects with no detectable 464

antibody (below the lower limit of detection [LLOD]) or no quantifiable antibody (below the 465

lower limit of quantification [LLOQ]) prior to vaccination, seroconversion is usually defined as 466

achieving a quantifiable antibody level post-vaccination. In subjects with quantifiable antibody 467

prior to vaccination, seroconversion is commonly defined by a predefined fold-increase from 468

pre- to post-vaccination. 469

470

Sponsor 471

The individual, company, institution or organization that takes responsibility for the initiation, 472

management and conduct of a clinical trial. The sponsor of a clinical trial may not be the entity 473

that applies for a licence to place the same product on the market and/or the entity that holds the 474

licence (i.e. is responsible for post-licensing safety reporting) in any one jurisdiction. 475

476

Superiority trial 477

A trial with the primary objective of demonstrating that a test group is superior to a reference 478

group on the basis of the primary endpoint. In the context of vaccine development the primary 479

endpoint may be a safety parameter (e.g. occurrence of a specific type of AE), a clinical 480

condition (e.g. occurrence of a specific infectious disease) or an immunological parameter (e.g. a 481

measure of the immune response to one or more antigenic components of the vaccine). 482

483

Vaccine efficacy 484

Vaccine efficacy measures direct protection (i.e. protection induced by vaccination in the 485

vaccinated population sample). 486

487

Vaccine efficacy is most commonly a measure of the proportionate reduction in disease attack 488

rate (AR) between the control group that did not receive vaccination against the infectious 489

disease under study (ARU) and the vaccinated (ARV) group(s). Vaccine efficacy can be 490

calculated from the relative risk (RR) of disease among the vaccinated group as (ARU-491

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ARV/ARU) x 100 and (1-RR) x 100. This estimate may be referred to as absolute vaccine 492

efficacy. 493

494

Alternatively, vaccine efficacy may be defined as a measure of the proportionate reduction in 495

disease attack rate between a control group that is vaccinated against the infectious disease under 496

study and the group vaccinated with the candidate vaccine. This estimate may be referred to as 497

relative vaccine efficacy. 498

499

Vaccine effectiveness 500

Vaccine effectiveness is an estimate of the protection conferred by vaccination. It is usually 501

obtained by monitoring the disease to be prevented by the vaccine during routine use in a 502

specific population. Vaccine effectiveness measures both direct and indirect protection (i.e. the 503

estimate may in part reflect protection of unvaccinated persons secondary to the effect of use of 504

the vaccine in the vaccinated population). 505

506

Vaccine vector 507

A vaccine vector is a genetically engineered microorganism (which may be replication 508

competent or incompetent) that expresses one or more foreign antigen(s) (e.g. antigens derived 509

from a different microorganism). 510

511

4. Vaccine clinical development programmes 512

513

This section covers: 514

General considerations for clinical programmes, including: 515

- consultations with regulatory authorities 516

- use of independent data review committees 517

- registering and reporting clinical trials. 518

Typical clinical development programmes for new candidate vaccines, including: 519

- main objectives of the clinical development programme 520

- factors that determine the extent and content of the programme 521

- initial trials 522

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- pivotal trials. 523

Post-licensure clinical trials. 524

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527

4.1.1 Consultation with national regulatory authorities 528

529

It is strongly recommended that dialogue with the appropriate NRAs occurs at regular intervals 530

during the pre-licensure clinical development programme to agree on the content and extent of 531

the initial application dossier. This is especially important in the following cases: 532

a. The clinical programme proposes a novel approach to any aspect of development for which 533

there is no precedent or guidance available. 534

b. The proposed programme conflicts with existing guidance to which the NRAs involved 535

would usually refer when considering programme suitability. 536

c. Particular difficulties are foreseen in providing evidence to support an expectation of 537

vaccine efficacy (i.e. there is no immunological correlate of protection and a vaccine 538

efficacy study is not feasible). 539

d. There are other special considerations for the total content of the pre-licensure programme 540

(e.g. when different vaccine constructs are to be used for priming and boosting). 541

542

Appropriate NRAs should be consulted when planning clinical trials that are intended to support 543

a revision of the prescribing information. In addition, changes to the manufacturing process of a 544

vaccine before or after initial licensure should be discussed with NRAs to establish whether or 545

not clinical trials are required. When issues of vaccine safety or effectiveness arise in the post-546

licensure period, consultation with NRAs is essential to determine any actions that are needed. 547

548

4.1.2 Use of independent monitoring committees 549

550

The members of an independent monitoring committee should not include persons who are 551

employed by the sponsor of the clinical trial. The same or different independent monitoring 552

committees may be appointed to oversee one or more aspects of a clinical trial. The 553

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responsibilities of an independent monitoring committee may include one or more of the 554

following: 555

ongoing review of safety data; 556

oversight of planned interim analyses of safety and/or efficacy and recommending to the 557

sponsor that a trial is terminated early in accordance with predefined stopping rules; 558

determination of the eligibility of individual subjects for inclusion in the primary analysis 559

population or other analysis population(s), as defined in the protocol; 560

adjudication to determine whether cases of clinically apparent infections meet the 561

predefined case definition for inclusion in analyses of efficacy; 562

adjudication to determine whether reports of AEs meet the criteria for specified types of 563

AEs and AESIs and/or to determine causality. 564

565

4.1.3 Registering and reporting clinical trials 566

567

Before any clinical trial is initiated (i.e. before the first subject receives the first medical 568

intervention in the trial), details of the trial should be registered in a publicly available, free-to-569

access, searchable clinical trial registry. The registry should comply with individual NRA 570

requirements and, as a minimum, should comply with the WHO internationally agreed standards. 571

572

The entry into the clinical trial registry site should be updated as necessary to include final 573

enrolment numbers achieved and the date of actual study completion. A definition of study 574

completion for this purpose should be included in the protocol. For example, this may be defined 575

as the point in time when data analyses have been completed to address the major study 576

objectives. If a clinical trial is terminated prematurely, the entry should be updated to reflect this 577

with a report of the numbers enrolled up to the point of termination. 578

579

The key outcomes of a clinical trial must be posted in the results section of the entry in the 580

clinical trial registry and/or posted on a publicly available, free-to-access, searchable website 581

(e.g. that of the trial sponsor or principal investigator). It is recommended that posting of these 582

results should usually occur within 12 months of completion or termination of the study, or in 583

accordance with the relevant NRA requirements. Depending on individual NRA requirements, 584

WHO/BS/2016.2287

some or all regulatory submissions may need to include a listing of all completed and ongoing 585

trials conducted with the vaccine by the sponsor. It is recommended that any trials that are 586

known to the sponsor (e.g. from searching registries or from publications) that were initiated by 587

persons other than the sponsor (e.g. by a public health body, academic institution or another 588

company that used the product as a comparator) should be included. 589

590

4.2 Pre-licensure clinical development programmes 591

592

The main objective of the pre-licensure clinical development programme is to accumulate 593

adequate data to support initial licensure and appropriate use. The essential elements of the 594

programme are: 595

to describe the interaction between the vaccine and the host immune response (Section 596

5); 597

to identify safe and effective dose regimens and schedules (Sections 5 and 6); 598

to estimate vaccine efficacy by directly measuring efficacy and/or to provide evidence of 599

vaccine efficacy based on immune responses (Sections 5 and 6); 600

to describe the safety profile (Section 7); 601

to assess co-administration with other vaccines if this is relevant (Section 5). 602

603

The content and extent of the pre-licensure clinical development programme will reflect how 604

much is already known about the antigenic components and adjuvants in the vaccine. Some 605

important factors include: 606

the number of the antigenic components (e.g. from the same or from several infectious 607

organisms); 608

the nature of the antigenic components (e.g. manufactured with or without genetic 609

modification, live attenuated, live vectored); 610

the inclusion of an adjuvant; 611

the disease(s) to be prevented and the available options for evaluating vaccine efficacy 612

(e.g. by conducting vaccine efficacy trials or providing other evidence of efficacy on the 613

basis of immune responses); 614

WHO/BS/2016.2287

the target populations for use (e.g. infants, older persons, pregnant women); 615

the route of administration; 616

the likelihood of co-administration with other vaccines in routine use; 617

any vaccine-specific safety issues that may be anticipated. 618

619

4.2.1 Initial trials 620

621

The clinical programme for new candidate vaccines usually commences with an exploration of 622

the safety of different amounts of the antigen(s) in each dose of candidate vaccine formulations, 623

with or without an adjuvant. It is usual that immune responses to the antigenic components are 624

also explored. These are commonly referred to as Phase 1 trials. In most cases the first clinical 625

trials are conducted in healthy adults. It may be appropriate, if feasible, that the first trials are 626

confined to subjects who have no history of previous exposure to the organism(s) against which 627

the candidate vaccine is intended to protect. 628

629

Further safety and immunogenicity trials that are conducted to build on the Phase 1 trial results 630

are commonly referred to as Phase 2 trials. In most cases these trials are conducted in subjects 631

who are representative of the intended target population for the vaccine at the time of initial 632

licensure. For vaccines intended for a broad age range, it may not be necessary in all instances to 633

apply an age de-escalation approach (e.g. to move from adults to adolescents, then to children 634

aged 612 years, followed by younger children, toddlers and finally infants) to sequential trials 635

or to groups within trials. For instance, if a vaccine has negligible potential benefit for older 636

children, it may be acceptable in some cases to proceed directly from trials in adults to trials in 637

younger children, including infants and toddlers. 638

639

These trials are usually designed to provide sufficient safety and immunogenicity data to support 640

selection of one or more candidate formulations for evaluation in pivotal trials (i.e. to select the 641

amount(s) of antigenic component(s) and, where applicable, adjuvant in each dose). 642

643

4.2.2 Pivotal trials 644

Pivotal trials are intended to provide robust clinical evidence in support of licensure. They are 645

WHO/BS/2016.2287

commonly referred to as Phase 3 trials. There may be exceptional cases in which initial licensure 646

is based on a Phase 2 trial that has been designed to provide robust statistical conclusions. It is 647

usual that the investigational formulations used in pivotal trials are manufactured using validated 648

processes and undergo lot release in the same way as intended for the commercial product. 649

650

651

Pivotal trials may be designed to provide an estimate of vaccine efficacy or to provide an 652

indication of the ability of the vaccine to prevent clinical disease on the basis of immunogenicity 653

data (see 6.1). On occasion, an assessment of a specific safety aspect may be the primary, or a 654

co-primary, objective in a pivotal trial (see 7.2.1). 655

656

4.3 Post-licensure clinical evaluations 657

658

After initial licensure: 659

It is essential to monitor vaccine safety in routine use (Section 7). 660

Studies designed to address specific safety issues that were identified as potential 661

concerns from pre-licensure trials may need to be conducted. 662

It is commonly appropriate to evaluate vaccine effectiveness (Section 6). 663

Further trials may be conducted and the data may be used to extend or to otherwise 664

modify the use of the vaccine through revision of the prescribing information. 665

666

5. Immunogenicity 667

668

This section covers: 669

The range of immunogenicity data that may be collected throughout the pre- and post-670

licensure clinical development programme. 671

Collection of specimens for immunogenicity trials. 672

Characterization of the immune response to a new candidate vaccine. 673

Selection of the immune parameters to be measured. 674

Assays for measuring humoral and cellular immune responses. 675

Identification and uses of immunological correlates of protection. 676

WHO/BS/2016.2287

Objectives and designs of immunogenicity trials. 677

Considerations for some specific types of immunogenicity trials, including: 678

- trials to identify formulations and posologies (primary and post-primary) 679

- comparative immunogenicity trials to bridge efficacy 680

- trials to extend or modify use 681

- co-administration trials 682

- trials in which pregnant women are vaccinated 683

- trials to support major changes to the manufacturing process 684

- lot-to-lot consistency trials 685

686


688

Immunogenicity trials are conducted at all stages of pre-licensure vaccine development and 689

additional trials may be conducted in the post-licensure period. The evaluation of immune 690

responses rests on the collection of adequate specimens at appropriate time intervals and the 691

measurement of immune parameters most relevant to the vaccine. In the clinical development 692

programme for new candidate vaccines that contain microorganisms or antigens not previously 693

included in human vaccines the immunogenicity trials should provide a detailed understanding 694

of the immune response to vaccination. 695

696

Pre-licensure and post-licensure clinical trials commonly evaluate and compare immune 697

responses between trial groups to address a range of objectives. Depending on the objectives, 698

stage of development and trial population, the comparisons may be made with placebo, with 699

other formulations or regimens of the same vaccine, with licensed vaccines, or with a 700

combination of these. In trials that are primarily intended to estimate vaccine efficacy and/or 701

safety, assessment of immune response is usually a secondary objective. In vaccine efficacy 702

trials it is important that data on immune responses are collected to support analyses of the 703

relationship between immunogenicity and efficacy, which may lead to identification of ICPs. 704

705

5.2 Characterization of the immune response 706

707

WHO/BS/2016.2287

For microorganisms and antigens that have not been used previously in human vaccines, a 708

thorough investigation of their interaction with the human immune system should be conducted 709

as part of the overall clinical development programme. For microorganisms and antigens that are 710

already in licensed vaccines, it is not usually necessary to repeat these types of investigations but 711

consideration should be given to conducting at least some trials in certain circumstances (e.g. 712

when a new adjuvant is to be added to known antigens, a different method of attenuation is used, 713

a different carrier protein is used for antigen conjugation, or an antigen previously obtained by 714

purification from cultures is to be manufactured using recombinant technology). 715

716

The range of investigations conducted should take into account what is known about the immune 717

response that results from natural exposure and whether or not this provides partial or complete 718

protection and, if so, whether it is temporary or lifelong. The range of investigations should also 719

consider the characteristics of the infecting microorganism (e.g. whether there are multiple 720

subtypes that cause human disease) and the content of the vaccine (15). Investigations may 721

include some or all of the following: 722

determination of the amount, class, subclass and function (e.g. neutralization of viruses or 723

toxins, bactericidal activity, opsonophagocytosis) of antibody elicited by the vaccine; 724

description of the magnitude of the humoral and cell-mediated immune response to initial 725

and sequential doses, and changes in the magnitude of responses with time elapsed since 726

vaccination; 727

assessment of the ability of the vaccine to elicit a T-cell-dependent primary immune 728

response, with induction of immune memory (i.e. priming of the immune system) giving rise 729

to anamnestic responses i) on natural exposure, ii) after further doses of the same vaccine, 730

and/or iii) after further doses of a vaccine that contains closely related but non-identical 731

microorganisms or antigens (i.e. cross-priming); 732

assessment of the specificity and cross-reactivity of the immune response; 733

assessment of changes in antibody avidity with sequential doses, which may be useful when 734

investigating priming; 735

evaluation of factors that could influence the immune responses, such as the effect of 736

maternal antibody on the infant immune response to some antigens, pre-existing immunity 737

to the same or very similar organisms, and natural or vaccine-elicited antibody against a live 738

WHO/BS/2016.2287

viral vector 739

740

5.3 Measuring the immune response 741

742

5.3.1 Collection of specimens 743

744

Immune responses to vaccination are routinely measured in serum (humoral immune responses) 745

and blood (cellular immune responses). For some vaccines it may be of interest to explore 746

immune responses in other body fluids that are relevant to the site at which the target 747

microorganism infects and/or replicates (e.g. in nasal washes or cervical mucus), especially if it 748

is known or suspected that the systemic immune response does not show a strong correlation 749

with protective efficacy for the type of vaccine under trial (e.g. intranasal vaccination against 750

influenza). Nevertheless, specimens other than sera have not to date provided data that have been 751

pivotal in regulatory decision-making processes and have not resulted in identification of ICPs. 752

Therefore the rest of this section focuses on the collection of blood samples. 753

754

Pre-vaccination samples should be collected from all subjects in the initial immunogenicity 755

trials, after which it may be justifiable to omit these samples or to obtain them from subsets (e.g. 756

if the initial trials indicate that antibody is rarely detectable or quantifiable prior to vaccination in 757

the target population). Pre-vaccination sampling remains essential if it is expected that the target 758

population will have some degree of pre-existing immunity due to natural exposure and/or 759

vaccination history, since the assessment of the immune response will need to take into account 760

seroconversion rates and increments in geometric mean titres or concentrations from pre- to post-761

vaccination. Pre-vaccination sampling is also necessary if it is known or suspected that pre-762

existing immune status may have an impact on the magnitude of the immune response to 763

vaccination that is positive (e.g. because pre-existing antibody reflects past priming) or negative 764

(e.g. due to maternal antibody interfering with primary vaccination with certain antigens in 765

infants) . 766

767

The timing of post-vaccination sampling should be based on what is already known about the 768

peak immune response and antibody decay curve after initial and, if applicable, sequential doses 769

WHO/BS/2016.2287

(e.g. for vaccines that elicit priming, the rise in antibody after a booster dose is usually much 770

more rapid compared to the rise after earlier doses). For antigens not previously used in human 771

vaccines, sampling times may be based initially on nonclinical data and then adjusted when 772

antibody kinetic data that are specific to the antigen(s) under trial have been generated. As 773

information is accumulated, the number and volume of samples taken from individual subjects 774

may be reduced to the minimum considered necessary to address the trial objectives. 775

776

5.3.2 Immunological parameters 777

778

Immunological parameters are measures that describe the humoral immune response (e.g. 779

antibody concentrations or antibody titres, depending on the assay output) or the cell-mediated 780

immune response (e.g. percentages of sensitized T-cells). To date, immunological parameters 781

other than those that measure the humoral immune response have not played a pivotal or major 782

role in vaccine licensure, so the focus is usually on determination of antibody levels. 783

For known microorganisms or antigens in a candidate vaccine, the range of parameters to be 784

measured in clinical trials is usually selected on the basis of prior experience and whether or 785

not there is an established ICP. 786

For microorganisms or antigens not previously included in human vaccines, the selection of 787

parameters to be measured should take into account what is known about natural immunity. 788

For some infectious diseases, the nature of the immune response to infection in animal 789

models may also be useful for parameter selection. In later clinical trials, after 790

characterization of the immune response, the parameters to be measured may be modified. 791

792

5.3.2.1 Humoral immune response 793

794

The humoral immune response is assessed from the post-vaccination appearance of, or increase 795

after pre-vaccination in, antibody directed at specific microorganisms or antigens in the vaccine. 796

Most weight is usually placed on functional antibody responses (e.g. serum bactericidal 797

antibody [SBA], toxin or virus neutralizing antibody, opsonophagocytic antibody [OPA]), 798

but an appropriate assay may not be available (e.g. for typhoid vaccines based on the Vi 799

polysaccharide) or the only available assays may have low feasibility for application to large 800

WHO/BS/2016.2287

numbers of samples (e.g. because they are very labour-intensive or require high-level 801

biocontainment facilities). 802

Alternatively, or in addition to the determination of functional antibody, the immune 803

response may be assessed by measuring total antibody (e.g. total IgG measured by ELISA) 804

that binds to selected antigens (or, on occasion, to specific epitopes). Only a proportion of 805

the total antibody detected may be functional. 806

807

The following should be taken into consideration when deciding how to measure the humoral 808

immune response: 809

a. If a correlation has already been established between total and functional antibody responses 810

to a specific microorganism or antigen, it may be acceptable to measure only total IgG in 811

further trials (e.g. antibody to tetanus toxin). However, determination of functional immune 812

responses might be important for specific age groups or target populations where it is known 813

or suspected that the binding and the functional capacity of the antibodies elicited differs 814

(e.g. pneumococcal conjugate vaccines in older persons). 815

b. For antigens for which there is an established ICP, it may suffice to measure only the 816

relevant functional antibody (e.g. SBA for meningococcal vaccines) or total IgG (e.g. for 817

antibody to tetanus toxin) response. 818

c. If the ICP is based on total IgG, there may be instances in which there is still merit in 819

measuring functional antibody (e.g. for antibody to diphtheria toxin for which a micro-820

neutralization assay is available). 821

d. If there is no ICP, the functional antibody response should be measured if this is feasible. 822

e. Occasionally there may be more than one immunological parameter that can measure 823

functional antibody but one is considered to be a more definitive measure than the other (e.g. 824

neutralizing antibody to influenza virus versus antibody that inhibits haemagglutination). In 825

this case the more definitive parameter may be determined at least in a subset. 826

f. For some vaccines against certain viruses there is a potential that some of the total antibody 827

detected has no protective effect (e.g. is non-neutralizing) but that it could enhance cellular 828

infection by wild-type virus and result in an increased risk of severe disease after 829

vaccination (e.g. this may apply to dengue vaccines). To assess this possibility, the routine 830

measurement of total antibody to assess the humoral immune response to vaccination should 831

WHO/BS/2016.2287

be supported by other detailed investigations. 832

833

5.3.2.2 Cell-mediated immune response 834

835

For some types of infectious disease (such as tuberculosis) the assessment of the cell-mediated 836

immune response may have a major role in the assessment of the interaction between the 837

vaccine and the human immune system. In many other settings, the evaluation of the cellular 838

immune response may serve to support the findings based on the humoral immune response (for 839

instance, when assessing the benefit of adding an adjuvant or when evaluating the degree of 840

cross-priming elicited by a vaccine). 841

842

The cell-mediated immune response is most commonly assessed by detecting and quantifying 843

sensitized T-cells in blood from trial subjects. These investigations may also serve to 844

characterize the predominant cytokines released and to detect differences in sensitization 845

between T-cell subpopulations. Several methods may be used. These are typically based on 846

measuring the production of a range of cytokines following in vitro stimulation of T-cells with 847

individual or pooled antigens. 848

849

The results may provide useful comparisons between treatment groups within any one study 850

(e.g. they could describe the effect, if any, of an adjuvant) based on comparing rates of 851

“responders”, defined by a magnitude of change in the assay readout from pre- to post-852

vaccination. If there are marked discrepancies in the patterns of responses observed between 853

cell-mediated and humoral responses (e.g. if adding an adjuvant has a major effect on antibody 854

levels but does not increase the percentages of sensitized cells in one or more T-cell subsets) the 855

findings should be carefully considered and discussed. 856

857

5.3.3 Assays 858

859

Assays of functional or total antibody that are used to report immune responses to vaccination 860

(whether to the candidate vaccine or to co-administered vaccines) in trials intended to support 861

licensure (i.e. in pivotal trials) may be: 862

WHO/BS/2016.2287

commercially-available assays specifically designed and intended for quantification of 863

antibody that are considered acceptable to NRAs (i.e. they have been marketed following a 864

robust regulatory review by the same NRA or by other NRAs); 865

assays that are not commercially available but have been validated according to principles 866

similar to those recommended for quantitative lot release assays in the ICH Q2 (R1) 867

document Validation of analytical procedures: text and methodology (16); 868

assays that are not commercially available but have been shown to be comparable to a 869

reference assay (e.g. to an assay established in a WHO reference laboratory, or to an assay 870

that is established in a recognized public health laboratory and that has been used previously 871

to support clinical trials that have been pivotal for licensure). 872

In each case, it is expected that WHO International Standards and reference reagents will be 873

used in assay runs if these exist. Any omission of their use should be adequately justified. 874

875

Initial trials that explore the immune response may report data using assays that have yet to be 876

validated or which are not subsequently validated. The use of these assays should be justified 877

and they should be qualified for the intended use. Results obtained using assays that have not 878

been fully validated should not be used to make specific claims regarding clinical effect. 879

880

Clinical trial protocols should specify which assays will be used. Clinical trial reports should 881

include a summary of the assay methodology and its commercial or other validation status. For 882

assays that are not commercially available, any available validation reports should be provided. 883

884

The same assays should preferably be used in the same laboratories throughout the clinical 885

development programme (including pre- and post-licensure trials) for an individual vaccine. It is 886

also preferable that each assay (whether it measures the response to the candidate vaccine or to a 887

concomitant vaccine) is run by one central laboratory. If this is not possible (e.g. because 888

different laboratories have to be used, assays change over time, or a switch is made to an 889

improved and/or more suitable assay), the new and original assays should be shown to be 890

comparable or the impact of any differences should be evaluated and the use of a new assay 891

justified. It is recommended that, as a minimum, a selection of stored sera (e.g. covering a range 892

of low to high results when using the previous assay) should be re-run using the previous and 893

WHO/BS/2016.2287

new assays in parallel. The number of sera retested should be sufficient to support a statistical 894

assessment of assay comparability and/or reproducibility. 895

896

The microorganisms (e.g. in assays of SBA, OPA and virus neutralization) and the antigens (e.g. 897

in ELISAs and for in vitro stimulation of sensitized T-cells) used in the assay may affect both the 898

result and the interpretation of the result. For instance: 899

It is important to use purified antigen to avoid the possibility that the assay detects and 900

measures antibody to any extraneous antigenic substances that may be in the vaccine. 901

For vaccines that contain antigens from multiple strains of the same pathogen (e.g. multiple 902

bacterial capsular types), the assays selected (whether separate or multiplex) should 903

determine the immune response to each antigen. 904

Although it is usually acceptable to conduct routine testing using the same microorganisms 905

or antigens as those present in the vaccine, it may be very informative to perform additional 906

testing, at least in subsets of samples, using circulating wild-type organisms or antigens 907

derived from them in the assay. It is not expected that these additional assays will 908

necessarily be validated since they are exploratory in nature. The results of additional testing 909

can provide an indication as to whether the results of routine testing could represent an 910

overestimate of the immune response to circulating strains. This additional testing can also 911

provide an assessment of the cross-reactivity of the immune responses elicited by the 912

vaccine to other organisms of the same genus or species (e.g. to different flaviviruses, 913

different clades of influenza virus, or different HPV types), and can guide the need to 914

replace or add strains or antigens in a vaccine to improve or maintain its protective effect. 915

916

5.4 Identification and use of immunological correlates of protection 917

918

5.4.1 Immunological correlates of protection and their uses 919

920

All established ICPs are based on humoral immune response parameters that measure 921

functional or total IgG antibody. Examples of well-established ICPs include those for antibody 922

to diphtheria and tetanus toxoids, polioviruses, hepatitis B virus and H. influenzae type b 923

capsular polysaccharide (17). In most cases, established ICPs have been shown to correlate 924

WHO/BS/2016.2287

with prevention of clinically apparent infectious disease, but for some pathogens the ICP 925

correlates with prevention of documented infection (e.g. hepatitis A and hepatitis B). 926

927

Subsections 5.5.2 and 5.5.3 consider trial endpoints and the approach to analysis and 928

interpretation of immunogenicity data in the presence or absence of an ICP and situations in 929

which alternative approaches may be appropriate. For instance, for some infectious diseases, 930

vaccine-elicited protection against clinical disease shows a broad correlation with a specific 931

immunological parameter (e.g. with serum neutralizing antibody elicited by HPV vaccines), but 932

no cut-off value has been identified that shows a strong statistical correlation with protection in 933

the short or longer term in individuals or populations. In some other instances there is an 934

indication of a threshold value that seems broadly to predict protection but the evidence is 935

insufficient to regard this as an ICP. For some other infectious diseases there is no well-936

established correlation between vaccine-elicited protection and measurable immune parameters 937

(e.g. for acellular pertussis vaccines). 938

939

5.4.2 Establishing an ICP 940

941

Documentation of the immune response to natural infection, the duration of protection after 942

clinically apparent infection (i.e. whether natural protection is lifelong [solid immunity], 943

temporary or absent) and the specificity of protection (i.e. whether the individual is protected 944

only against specific subtypes of a microorganism) should be taken into account when 945

attempting to establish an ICP from clinical data. For example, to date, widely-accepted clinical 946

ICPs have been established on the basis of one or more of the following: 947

serosurveillance and disease prevalence in specific populations; 948

passive protection using antibody derived from immune humans or manufactured using 949

recombinant technology; 950

efficacy trials; 951

effectiveness trials; 952

investigation of vaccine failure in immunosuppressed populations. 953

954

In the majority of cases, clinical ICPs have been determined from vaccine efficacy trials that 955

WHO/BS/2016.2287

were initiated pre-licensure, often with long-term follow-up of subjects that extended into the 956

post-licensure period. Efficacy trial protocols should plan to collect sufficient information to 957

allow for analyses of the relationship between immune parameters and protection against 958

clinically apparent disease. At the minimum this requires collection of post-vaccination samples 959

from all, or from a substantial subset of, the vaccinated and control groups. Serial collection of 960

samples over the longer term, along with follow-up surveillance for vaccine breakthrough cases, 961

has also served to support identification of ICPs. 962

963

To investigate the predictive capacity of a putative ICP, protocols should predefine the 964

assessments to be applied to all cases of the disease to be prevented that occur in the vaccinated 965

and control groups. These assessments should include investigation of the immune status of 966

subjects as well as microbiological studies with the infecting microorganisms whenever these 967

have been recovered. For breakthrough cases from which both post-vaccination sera and 968

organisms have been recovered, it is recommended that, whenever feasible, functional antibody 969

(or, if not possible, total antibody) should be determined for individuals against their own 970

pathogen. An exploration of vaccine-elicited cell-mediated responses in individuals against their 971

own pathogen may also be useful and, for some types of infectious diseases (such as 972

tuberculosis), may be very important for further understanding vaccine-associated protection. 973

These data may be very important for investigating the broad applicability of the ICP, depending 974

on host and organism factors. 975

976

A single clinical ICP identified from a vaccine efficacy trial in a defined population may not 977

necessarily be applicable to other vaccine constructs intended to prevent the same infectious 978

disease. In addition, an ICP may not be applicable to other populations and disease settings. For 979

example, putative ICPs have sometimes differed between populations of different ethnicities 980

with variable natural exposure histories for subtypes of a single microorganism. Thus, the 981

reliance that is placed on a clinical ICP, even if regarded as well-supported by the evidence, 982

should take into account details of the efficacy trials from which it was derived. 983

984

Clinical ICPs have also been derived from, or further supported by, data collected during use of a 985

vaccine to control an outbreak and from analyses of effectiveness data. The methods used to 986

WHO/BS/2016.2287

derive ICPs from these types of data have been very variable. The estimates may in part reflect 987

the type of immunization programme put in place and the extent to which protection of 988

individual persons relies on herd immunity rather than the initial and persisting immune response 989

in the individual. Therefore the wider applicability of ICPs derived from interventional or routine 990

use should be viewed in the light of how and in what setting the estimates were obtained. 991

992

If it is not possible to derive a clinical ICP, the interpretation of the human immune response 993

data may take into account what is known about immunological parameters that correlate with 994

protection in relevant animal models and any nonclinical ICPs that have been identified (e.g. 995

from trials that assess passive protection and active immunization). This approach may be the 996

only option available for interpreting immune responses to some new candidate vaccines. 997

Nevertheless, ICPs derived wholly from nonclinical data should be viewed with caution and 998

attempts should be made to obtain a clinical ICP whenever the opportunity arises (e.g. when the 999

vaccine is used in the context of an outbreak). 1000

1001

If conducted, human challenge trials may also provide preliminary evidence supporting an ICP. 1002

Nevertheless, these trials are usually conducted in non-immune healthy adults who are 1003

challenged with organisms that are not identical to, and do not behave like, virulent wild-types. 1004

Consequently these trials may point to a correlation between a specific immunological parameter 1005

and protection, and this can be further investigated during the clinical development programme. 1006

1007

5.5 Immunogenicity trials 1008

1009

5.5.1 Objectives 1010

1011

The objectives of immunogenicity trials include (but are not limited to): 1012

i) to select vaccine formulations and posologies (including primary and booster doses) 1013

(subsection 5.6.1); 1014

ii) to compare immune responses documented in a specific population, and using one 1015

vaccine formulation and posology, to immune responses to the same vaccine when used 1016

in other settings (e.g. different populations) or with alternative posologies, or a different 1017

WHO/BS/2016.2287

vaccine intended to protect against the same infectious disease(s) (subsection 5.6.2); 1018

iii) to support co-administration with other vaccines (subsection 5.6.3); 1019

iv) to support maternal immunization (subsection 5.6.4); 1020

v) to support major changes to the manufacturing process (subsection 5.6.5); 1021

vi) to assess lot-to-lot consistency (8) (subsection 5.6.6). 1022

1023

5.5.2 General considerations for trial designs 1024

1025

Immunogenicity trials are almost without exception comparative trials. For candidate vaccines 1026

containing antigens for which there are well-established ICPs that can be applied to interpret 1027

the results sponsors may sometimes question the value of including a comparative arm. 1028

Nevertheless, there is great value in conducting a randomized controlled trial. For instance, the 1029

inclusion of a control group that receives a licensed vaccine provides assurance of the 1030

adequacy of the trial procedures and methods, including the assays, and facilitates 1031

interpretation of data in circumstances in which unexpected results (e.g. low immune response 1032

to one or more antigens, high rates of specific AEs, or unexpected AEs) are observed. 1033

1034

Comparative trials include those in which all subjects receive the same vaccine formulation but 1035

there are differences between groups in terms of how or to whom the vaccine is administered 1036

(e.g. using a different dose or dose interval, administering the vaccine to different age groups) 1037

and trials in which one or more group(s) receives an alternative treatment, which may be placebo 1038

and/or another licensed vaccine. 1039

1040

The design of comparative immunogenicity trials is driven by the characteristics of the vaccine, 1041

the trial objectives, the stage of clinical development, the trial population, the availability and 1042

acceptability of suitable comparators, and what is known about immune parameters that correlate 1043

with protection (including whether or not there is an established ICP). 1044

1045

In comparative immunogenicity trials, subjects should be randomized to one of the trial groups at 1046

enrolment. This also applies to trials that enrol sequential cohorts of subjects (as in ascending 1047

dose trials in which at least some subjects are assigned to receive placebo or another vaccine). In 1048

WHO/BS/2016.2287

some cases it may be appropriate that subjects who meet certain criteria (e.g. completed all 1049

assigned doses in the initial part of the trial) are re-randomized at a later stage of the trial to 1050

receive a further dose of a test or control treatment. 1051

1052

In all comparative trials the assays should be performed by laboratory staff who are unaware of 1053

the treatment assignment. Whenever possible, comparative immunogenicity trials should be of 1054

double-blind design. If the vaccines to be compared are visually distinguishable, it is preferable 1055

that designated persons at each trial site who are not otherwise involved in the trial should 1056

administer the products. If this is not feasible, or if the vaccines to be compared are given by 1057

different routes or according to different schedules, attempts should be made to maintain 1058

blinding of the trial site staff who conduct the study visits and assessments. 1059

1060

In trials intended to provide only descriptive analyses of the immunogenicity data the trial 1061

sample size is usually based on considerations of feasibility and collection of sufficient safety 1062

data to support the design of sequential trials. Trials that aim to assess superiority or non-1063

inferiority between vaccine groups should be sized according to the intended power and the 1064

predefined margins. It is recommended that protocols and statistical analysis plans for each trial 1065

should be developed in conjunction with an appropriately experienced statistician. 1066

1067

5.5.2.1 Endpoints 1068

1069

The choice of the primary trial endpoint and the range of other endpoints for immunogenicity 1070

trials should take into account subsections 5.2, 5.3 and 5.4. Protocols should predefine the 1071

primary, co-primary, secondary and any other endpoints (which may be designated tertiary or 1072

exploratory). Co-primary endpoints may be appropriate in some cases, namely: 1073

The vaccine is intended to protect against multiple subtypes of the same microorganism (e.g. 1074

human papillomavirus vaccines, pneumococcal conjugate vaccines). 1075

The vaccine contains multiple microorganisms (such as measles, mumps, rubella vaccine) or 1076

multiple antigens (such as combination vaccines used for the primary immunization series in 1077

infants). 1078

1079

WHO/BS/2016.2287

The following should be taken into consideration when selecting the primary endpoint(s) 1080

following primary vaccination: 1081

1082

When an ICP has been established, the primary endpoint is usually the percentage of 1083

subjects that achieves an antibody level at or above the ICP, which is sometimes referred 1084

to as the seroprotection rate. 1085

When there is no established ICP, the primary endpoint or the co-primary endpoints 1086

is/are usually based on a measure of the humoral immune response. 1087

In some instances there may not be an ICP but there may be evidence to support the 1088

application of a threshold value (i.e. the primary endpoint may be the percentage of 1089

subjects that achieves antibody levels at or above the threshold value). 1090

If there is no ICP or threshold value that can be applied, it may be appropriate to base 1091

the primary endpoint on the seroconversion rate or on some other definition of the 1092

magnitude of the immune response that differentiates responders from non-1093

responders. Comparisons of post-vaccination seropositivity rates may also be 1094

informative if pre-vaccination rates are very low. 1095

1096

Following administration of a vaccine to subjects who are already primed against one or more 1097

microorganisms or antigens in the vaccine, an anamnestic (memory) immune response is 1098

anticipated. Thus the seroprotection, seroconversion (fold-rise from pre-boost to post-boost) and 1099

seropositivity rates after the booster dose are likely to be very high. In these cases, and in other 1100

situations in which post-vaccination seroprotection and/or seroconversion rates are expected to 1101

be very high (i.e. the vaccine is very immunogenic), the most sensitive immunological parameter 1102

for detecting differences between groups may be the geometric mean concentration or titre. 1103

1104

After primary vaccination and after any additional doses, the results of all immunological 1105

parameters measured should be reported, including reverse cumulative distributions, regardless 1106

of the predefined primary and secondary endpoints. 1107

1108

5.5.2.2 Trials designed to detect superiority 1109

1110

WHO/BS/2016.2287

Trials intended to detect superiority of immune responses are most often conducted during the 1111

selection of candidate vaccine formulations and posologies for further clinical investigation. It is 1112

common for these trials to plan to assess whether a specific candidate vaccine formulation elicits 1113

superior immune responses compared to no vaccination against the disease to be prevented 1114

and/or compared to alternative formulations of the candidate vaccine. Initial dose selection trials 1115

are not usually formally powered to demonstrate superiority but this may be considered for 1116

larger trials that are intended to select a final formulation and posology for further investigation. 1117

1118

An assessment of superiority may be applicable when an adjuvant is proposed for inclusion in 1119

the vaccine (e.g. to demonstrate that the immune response to at least one of the antigenic 1120

components in an adjuvanted formulation is superior to the response in the absence of the 1121

adjuvant). 1122

1123

Protocols should predefine the magnitude of the difference between vaccine groups or vaccine 1124

and control groups that will be regarded as evidence of superiority. The difference should be 1125

selected in such a way that it provides some evidence of a potential clinical advantage. 1126

1127

5.5.2.3 Trials designed to detect non-inferiority 1128

1129

Most comparative immunogenicity trials are intended to show that the test vaccinated groups 1130

achieve comparable immune responses to the selected reference groups. If these trials are 1131

intended to be pivotal, they should be designed and powered to demonstrate non-inferiority using 1132

a predefined and justifiable non-inferiority margin. 1133

1134

Factors to consider with regard to the stringency of the non-inferiority margin include the 1135

clinical relevance of the endpoint, seriousness of the disease to be prevented, vulnerability of the 1136

target population, availability of a well-established ICP, and the performance characteristics of 1137

the assay(s). A stringent margin may be appropriate when the vaccine is intended to prevent 1138

severe or life-threatening diseases and/or it will be used in particularly vulnerable populations 1139

(e.g. infants and pregnant women). A stringent margin could also be considered when there is 1140

potential for a downward drift in immunogenicity such as that which could occur when a new 1141

WHO/BS/2016.2287

candidate vaccine can be compared only with vaccines that were approved on the basis of non-1142

inferiority trials. In contrast, if a new candidate vaccine is known to offer substantial benefits in 1143

terms of safety or improved coverage, margins that are less stringent may be considered. As a 1144

result of these considerations it is possible that different non-inferiority margins may be 1145

considered appropriate for interpreting immune responses to any one specific antigenic 1146

component in different settings. 1147

1148

When comparing seroprotection rates, seroconversion rates or percentages of vaccines with 1149

immune responses that are above a predefined threshold, NRAs have often accepted 1150

predefined non-inferiority margins of 5% or 10%. There is very rarely any justification 1151

provided for the margin, nor is there any discussion of the possible consequences if a candidate 1152

vaccine elicits seroprotection or seroconversion rates or percentages with responses above a 1153

predefined threshold that are lower than those in the licensed vaccine group to such an extent 1154

that the lower 95% confidence interval around the difference (test–reference) approaches the 1155

margin. In the absence of adequate justification for the predefined margin, the implications of 1156

the actual 95% confidence intervals that are observed should be reviewed in light of the 1157

considerations described above. 1158

1159

When it is proposed to demonstrate non-inferiority between vaccine groups based on GMT or 1160

GMC ratios for antibody titres or concentrations, it is suggested that the lower bound of the 1161

95% confidence interval around the ratio (test versus reference vaccine) should not fall below 1162

0.67. Under certain circumstances, NRAs may consider allowing a lower bound (e.g. 0.5) or 1163

alternative criteria. The selection of a criterion should take into account whether or not an ICP 1164

has been identified. In addition, any marked separations between the reverse cumulative 1165

distributions of antibody titres or concentrations should be discussed in terms of potential 1166

clinical implications, including those which occur at the lower or upper ends of the curves. 1167

1168

5.5.3 Analysis and interpretation 1169

1170

A statistical analysis plan should be finalized before closing the trial database and unblinding 1171

treatment assignments (if these were blinded). This should include any planned interim analyses, 1172

WHO/BS/2016.2287

which should be adequately addressed in terms of purpose, timing and any statistical adjustments 1173

required. 1174

1175

The immunogenicity data from all subjects with at least one result for any immunological 1176

parameter measured in the trial should be included in the clinical trial report. The analysis of the 1177

immune response based on any one parameter is commonly restricted to all subjects with a pre-1178

vaccination measurement (if this is to be obtained from all subjects) and at least one post-1179

vaccination measurement. Protocols may also restrict the primary analysis population to subjects 1180

with pre- and post-vaccination results, or those with post-vaccination results who received all the 1181

assigned doses within predefined windows of the intended schedule and had no other major 1182

protocol violations (i.e. they met the inclusion and exclusion criteria). Other analysis populations 1183

of interest may be predefined in accordance with the primary or secondary objectives (e.g. age 1184

subgroups, pre-vaccination serostatus). Whatever the predefined primary analysis population, all 1185

available immunogenicity data should be presented in the clinical trial report. 1186

1187

If a trial fails to meet the predefined criteria for superiority and/or non-inferiority with respect to 1188

any of the antigenic components, the possible reasons for the result and the clinical implications 1189

of it should be carefully considered before proceeding with clinical development or licensure. 1190

The considerations may take into account the basis for setting the predefined criteria (e.g. Does 1191

failure to meet the criteria strongly imply that lower efficacy may result?), the comparisons made 1192

for all other immune parameters measured (e.g. Were criteria not met for only one or a few of 1193

many antigenic components of the vaccine?), any differences in composition between the test 1194

and the comparator vaccines that could explain the result, the severity of the disease(s) to be 1195

prevented and the overall anticipated benefits of vaccine, including its safety profile. Subsection 1196

5.6 provides some further examples and issues for consideration. 1197

1198

Additional analyses of the data that were not pre-specified in the protocol and/or the statistical 1199

analysis plan (i.e. post hoc analyses) should generally be avoided. If conducted, they should 1200

usually be viewed with caution, although the results may stimulate further clinical trials to 1201

investigate specific issues. 1202

1203

WHO/BS/2016.2287

5.6 Specific uses of immunogenicity trials 1204

1205

5.6.1 Selection of formulation and posology 1206

1207

The vaccine formulation is determined by the numbers of microorganisms or amounts of 1208

antigens and, if applicable, the amount of adjuvant that is to be delivered in each dose, as well as 1209

the route of administration. 1210

1211

The vaccine posology for a specific route of administration includes: 1212

the dose content (as for formulation) and volume delivered per dose; 1213

the dose regimen (number of doses to be given in the primary series and, if applicable, after 1214

the primary series); 1215

the dose schedule (dose intervals within the primary series and between the primary series 1216

and any further doses). 1217

1218

The posology for any one vaccine may vary between target populations (e.g. age groups and 1219

according to prior vaccination history) in one or more aspects (content, regimen or schedule). 1220

1221

The following subsections outline the immunogenicity data that are usually generated to support 1222

the vaccine formulation and posology and to assess the need for, and immune response to, 1223

additional doses of the vaccine after completion of the primary series. See also Section 7, which 1224

addresses the importance of the safety profile when selecting vaccine formulations and 1225

posologies. 1226

1227

5.6.1.1 Selecting the formulation and posology for initial licensure 1228

1229

The vaccine formulation and posology that is initially approved should be supported by safety 1230

and immunogenicity data, with or without efficacy data, collected throughout the pre-licensure 1231

clinical development programme. At the time of initial licensure the data should at least support 1232

the formulation and posology for the primary series, which may consist of one or more doses. 1233

1234

WHO/BS/2016.2287

Depending on the intended formulation of the new candidate vaccine, the following 1235

considerations may apply: 1236

1237

i) When a new candidate vaccine contains any microorganisms or antigens not previously 1238

used in human vaccines, with or without others already used in human vaccines, the 1239

initial trials may explore the immune responses to different amounts of each of the new 1240

microorganisms or antigens when given alone to non-immune healthy adult subjects. 1241

These trials can be used to describe the doseresponse curve and may indicate a plateau 1242

for the immune responses above a certain dose level. The next trials usually evaluate 1243

immune responses to further doses at various dose intervals in order to evaluate the 1244

kinetics of the immune response and any increment in immune response that is achieved 1245

by further doses. The transition from trials in healthy adults to trials in subjects in the 1246

target age range at the time of initial licensure should occur as soon as this can be 1247

supported, taking into account the safety profile. 1248

1249

However, evaluating the immune response to each of the new microorganisms or 1250

antigens alone may not be a feasible undertaking. For example, if the vaccine construct is 1251

manufactured in such a way that production of individual antigens is not feasible, the 1252

evaluation of the appropriate vaccine dose may be based solely on studies with the entire 1253

construct. Another example concerns vaccines intended to protect against multiple 1254

subtypes of an organism. In this case, the use of microorganisms or antigens that could be 1255

regarded as broadly representative in the first trials may provide some idea of the likely 1256

response to other subtypes. Further trials may then explore formulations that contain 1257

increasing numbers of the subtypes with the objective of assessing the effect of 1258

combining them into a single product on the immune response. 1259

1260

ii) For new candidate vaccines that contain known antigenic components not previously 1261

combined in a single vaccine, the initial trials are usually conducted in subjects within the 1262

age ranges approved for licensed vaccines that contain some or all of the same antigenic 1263

components. The aim is to demonstrate non-inferiority of immune responses to each of 1264

the intended antigenic components when combined in a candidate formulation with co-1265

WHO/BS/2016.2287

administration of licensed vaccines that together provide all of the same antigenic 1266

components. The same approach applies whenever the antigenic components are not 1267

combined into a single formulation, but the contents of more than one product have to be 1268

mixed immediately before administration to avoid a detrimental physico-chemical 1269

interaction. 1270

1271

iii) For new candidate vaccines that contain known – and one or more new – antigenic 1272

components, the initial trials may aim to demonstrate non-inferiority of immune 1273

responses to each of the known antigenic components when combined into a candidate 1274

formulation with separate administrations of known and new antigenic components. It 1275

may also be informative to include a control group that receives co-administration of 1276

known and new antigenic components. The exact design depends on the availability of a 1277

single licensed vaccine that contains the known antigenic components and whether more 1278

than one licensed vaccine has to be given. 1279

1280

iv) For vaccine formulations to which an adjuvant is to be added, there should be adequate 1281

data already available (which may apply to known adjuvants) or data should be generated 1282

(new adjuvants or when using any adjuvant with a new antigenic component) to describe 1283

the effect of the adjuvant on the immune responses. Some, or a major part, of the 1284

evidence supporting addition of an adjuvant may come from nonclinical studies. The 1285

addition of an adjuvant, which may or may not elicit superior immune responses to one 1286

or more antigens, should not have a potentially detrimental effect on responses to any 1287

antigenic components. Addition of an adjuvant may allow for the use of a much lower 1288

dose of an antigenic component to achieve the desired level of immune response, and it 1289

may also broaden the immune response (e.g. it may result in higher immune responses to 1290

antigens closely related to those in the vaccine). Trials should evaluate a sufficient range 1291

of combinations of antigenic components and adjuvants to support the final selected 1292

formulation (i.e. the ratio of adjuvant to antigenic components). 1293

1294

v) The total data generated should be explored to identify the criteria that should be applied 1295

to the release and stability specifications and to determination of an appropriate shelf-life 1296

WHO/BS/2016.2287

for the vaccine. This is usually of particular importance to vaccines that contain live 1297

microorganisms. Depending on data already generated, it may be necessary to conduct 1298

additional trials with formulations known to contain a range of microorganism numbers 1299

or antigen doses in order to identify appropriate limits at the end of the shelf-life. 1300

1301

vi) Comparative immunogenicity trials may be needed to determine schedules that are 1302

appropriate for specific target populations, taking into account the urgency to achieve 1303

protective immunity (i.e. trials based on diseases to be prevented and their 1304

epidemiology). The data generated across all the trials should determine the minimum 1305

period that should elapse between doses as well as the effects of delaying doses to 1306

support acceptable windows around scheduled doses. Additionally, for some vaccines it 1307

may be useful to explore the shortest time frame within which doses may be completed 1308

without a detrimental effect on the final immune response (e.g. for vaccines for travellers 1309

who may need to depart at short notice and for vaccines intended to provide post-1310

exposure prophylaxis). 1311

1312

Assessment of the effects of dose interval and the total time taken to complete the 1313

primary series is a particular issue for vaccines intended for use in infants as there is a 1314

very wide range of schedules in use in different countries (e.g. 3-dose schedules include 1315

6-10-14 weeks and 2-4-6 months). In general, experience indicates that the magnitude of 1316

the post-primary series immune responses broadly correlates with the age of infants at the 1317

time of the final dose. 1318

1319

vii) All data generated in accordance with points i) to vi) should be taken into account when 1320

selecting the final formulation and posology or posologies. The selection process is more 1321

straightforward if there are established ICPs that can be applied to the interpretation of 1322

the results for at least some of the antigenic components. In the absence of an ICP, the 1323

posology may be selected on the basis of consideration of any plateau effects that are 1324

observed and the safety profile of various doses and regimens. 1325

1326

It is not unusual for the final selected formulation and posology to represent, at least to 1327

WHO/BS/2016.2287

some extent, a compromise between immunogenicity and safety or, for combination 1328

vaccines, a compromise between the potential benefits of a vaccine that can protect 1329

against multiple types of infectious disease and some negative effects on immune 1330

response that may occur. These negative effects may result from a physicochemical 1331

interaction between vaccine components and/or a negative immune interference effect of 1332

some antigenic components. Such negative effects may be accompanied by enhanced 1333

immune responses to other vaccine components. The rationale for the final selection 1334

should be carefully discussed in the application dossier. 1335

1336

5.6.1.2 Amending or adding posologies after initial licensure 1337

1338

Clinical trials conducted after first licensure may be designed to address one or more of the 1339

following situations: 1340

Change to the number of doses or dose intervals. In this case the control group should be 1341

vaccinated using the licensed posology and the trial should be conducted in a population 1342

for which the vaccine is already licensed. 1343

Use of the licensed posology in a new population (e.g. in subjects who are younger or 1344

older than the currently licensed age group; or in subjects with specific underlying 1345

conditions, such as immunosuppression). In this case the trial should compare use of the 1346

licensed posology in the new target population with use in the population for which the 1347

vaccine is already licensed. 1348

Use of an alternative to the licensed posology in a new population. In this case the 1349

alternative posology administered to the new population should be directly compared 1350

with the licensed posology in the population for which the vaccine is already licensed. 1351

Support for alternative routes of administration for the licensed formulation (e.g. adding 1352

subcutaneous or intradermal injection to intramuscular use). 1353

1354

Post-licensure clinical trials may also be conducted to support changes in formulation. 1355

Formulation changes other than adding or removing a preservative or removing thiomersal from 1356

the manufacturing process usually result in a modified product that is considered to be a new 1357

candidate vaccine from a regulatory standpoint (i.e. it would require a new application dossier 1358

WHO/BS/2016.2287

and adequate trials to support separate licensure). 1359

1360

5.6.1.3 Post-primary doses 1361

1362

a. Need for post-primary doses 1363

1364

The need to administer additional doses, and the timing of these doses, may be determined 1365

before and/or after first licensure. 1366

1367

If experience with other similar vaccines clearly indicates that additional doses of a new 1368

candidate vaccine will be needed, the clinical development programme should incorporate this in 1369

the overall assessment of immune responses. 1370

1371

If it is not known whether post-primary doses of a new candidate vaccine will be needed to 1372

maintain protection, it is preferable that this should be determined from long-term follow-up of 1373

subjects who were enrolled in efficacy trials and/or from post-licensure effectiveness studies. 1374

Although the long-term monitoring of antibody persistence is important, these data alone cannot 1375

determine if another dose is needed unless there is evidence, or a strong reason to expect, that 1376

failure to maintain circulating antibody above a certain level (e.g. above the ICP if there is one) 1377

is associated with a risk of breakthrough disease (even if the primary series of the vaccine 1378

elicited an immune memory response). 1379

1380

Until it is clear whether or not additional doses are needed, it is prudent to plan to obtain data on 1381

the immune response to additional doses at different intervals after the last dose of the primary 1382

series in order that data will be available should it become clear that an additional dose is 1383

required. 1384

1385

b. Assessment of prior priming 1386

1387

Not all vaccines elicit a T-cell-dependent immune response that results in priming of the immune 1388

system and an anamnestic (memory) response to further doses. Not all primed individuals have 1389

WHO/BS/2016.2287

detectable humoral immunity against the relevant organism or the toxin that causes clinical 1390

disease. When assessing the immune response to additional doses and determining whether or 1391

not the primary series elicited immune memory, the following should be taken into account: 1392

Trials in which additional doses are administered may be extension phases of primary 1393

series trials or new trials in subjects with documented vaccine histories. 1394

When assessing whether the primary series elicited immune memory, the optimal design 1395

is to compare subjects who previously completed a full primary series of the candidate 1396

vaccine with a control group consisting of subjects not previously vaccinated. Control 1397

subjects should be matched for age and for any host or demographic factors that might 1398

have an impact on their immune response (e.g. they should be resident in similar areas so 1399

that any natural exposure is likely to be similar). 1400

If the new candidate vaccine elicited immune memory in the primary series, the immune 1401

response to the additional (i.e. booster) dose should usually be superior (on the basis of 1402

comparisons of the geometric mean concentrations or titres of antibody) to that observed 1403

in individuals who have not been vaccinated against the disease to be prevented. The 1404

percentages that achieve seropositivity or seroprotection (as defined) may not differ 1405

between the two groups if a single dose of the vaccine is highly immunogenic even in 1406

unprimed individuals. 1407

The immune response to the additional dose in primed and unprimed subjects may also 1408

be differentiated on the basis of the rapidity of the rise in antibody levels (faster in 1409

primed) and in terms of antibody avidity (greater in primed). 1410

If the immune response as measured by geometric mean antibody concentrations or titres 1411

in the vaccine-primed group is not superior to that in controls, this does not always mean 1412

that the primary series did not elicit immune memory. For example, the immune response 1413

in the vaccinated group may not be superior to the immune response in the control group 1414

when natural priming has occurred in a substantial proportion of subjects not previously 1415

vaccinated against the disease to be prevented, in which case the rapidity of response and 1416

measurements of avidity may also not be distinguishable between groups. If natural 1417

priming has occurred it may or may not be detectable from pre-vaccination antibody 1418

levels in the control group. 1419

If an immune memory response is elicited in the primary series, it may be possible to 1420

WHO/BS/2016.2287

achieve a robust anamnestic response using a much lower dose of an antigenic 1421

component compared to the primary series. A lower boosting dose may also provide a 1422

better safety profile (e.g. as occurs with diphtheria toxoid). 1423

For polysaccharide-protein conjugate vaccines that elicit immune memory, it may be 1424

informative to compare boosting with the same type of conjugate used for priming with 1425

an alternative conjugate (e.g. to prime with a tetanus toxoid conjugate and boost with a 1426

CRM197 conjugate and vice versa). 1427

It may also be informative to assess the ability of a candidate vaccine to achieve cross-1428

priming by using heterologous antigenic components for priming and boosting. This may 1429

be assessed by comparing boosting with the same vaccine used to prime with 1430

administration of a formulation (which may be a licensed vaccine or an unlicensed 1431

product manufactured specifically for the trial) containing a different microorganism or 1432

antigen that is known to be closely related but not identical to that in the vaccine (e.g. 1433

material derived from an influenza virus of a different clade). 1434

Elicitation of an immune memory response to a vector for an antigen after the first 1435

dose(s) may sometimes interfere with or wholly prevent the immune response to the 1436

antigen after subsequent doses (e.g. this may be observed when using certain 1437

adenoviruses capable of infecting humans as live viral vectors). It is essential to 1438

understand whether or not this occurs since it may necessitate the use of a different vector 1439

for the antigen or an entirely different vaccine construct to deliver subsequent doses. 1440

Some antigens elicit immune hypo-responsiveness to further doses. The best known 1441

examples are some of the unconjugated meningococcal and pneumococcal 1442

polysaccharides (18, 19). In the past these were sometimes administered to assess 1443

whether corresponding conjugated polysaccharides had elicited immune memory in the 1444

primary series, based on the premise that this would better mimic the immune response to 1445

natural exposure compared to administration of a further dose of the conjugate. This 1446

practice is not recommended since it is possible that a dose of unconjugated 1447

polysaccharide could result in blunted immune responses to further doses of the 1448

conjugate. 1449

Studies of cell-mediated immunity may provide supportive evidence that the primary 1450

series elicited immune memory and may be particularly useful for assessing cross-1451

WHO/BS/2016.2287

priming. 1452

1453

5.6.2 Using immunogenicity data to predict efficacy 1454

1455

5.6.2.1 Bridging to efficacy data 1456

1457

Immunogenicity data may be used to provide evidence of efficacy when: 1458

There is a well-established ICP that can be used to interpret the immune responses to a 1459

specific antigenic component. 1460

It is possible to use immune responses to bridge to estimates of vaccine efficacy obtained 1461

from prior well-designed clinical trials (i.e. to conduct bridging trials). 1462

1463

Two main situations should be considered when using immunogenicity data to bridge to 1464

estimates of vaccine efficacy obtained in prior clinical trials. In both cases comparative 1465

immunogenicity trials designed to demonstrate non-inferiority are recommended. The choice of 1466

comparator is a critical factor for interpretation of the results. 1467

1468

i) Modifying the use of the vaccine for which efficacy has been estimated 1469

1470

As described in Section 6, vaccine efficacy trials are usually conducted in specific target 1471

populations – characterized by factors such as age, region (which may define endemicity of some 1472

infectious diseases) and health status – using the intended final vaccine posology. Before or after 1473

initial licensure, trials may be conducted with the aim of extending the use of the vaccine to 1474

other populations and/or to support alternative posologies. 1475

1476

When a different age group or posology is proposed it is usually very clear that a bridging trial is 1477

necessary. Careful consideration is required to decide whether or not a bridging trial is necessary 1478

to support use in regions other than where the estimate of efficacy was obtained. Bridging trials 1479

may be required for licensure if there are compelling scientific reasons to expect that the immune 1480

response to the vaccine, and therefore its efficacy, could be significantly different because of 1481

host factors (such as common underlying conditions that may affect immune responses) and/or 1482

WHO/BS/2016.2287

geographical factors (such as distribution of subtypes of organisms and levels of natural 1483

exposure). Additionally, for trials in infants there is the possibility that high levels of maternal 1484

antibody could interfere with responses to the primary series. 1485

1486

The trial design most commonly involves a direct comparison between the new population 1487

and/or posology and a control group in which subjects representative of the efficacy trial 1488

population receive the previously-studied posology. It may also be acceptable to make a cross-1489

trial (indirect) comparison with the immunogenicity data that were obtained during the efficacy 1490

trial, in which case the vaccine formulation and assay used should be the same as those used in 1491

the efficacy trial whenever possible. 1492

1493

If the exact vaccine used in the efficacy trial is no longer available, the comparator 1494

should be as similar as possible to the original vaccine that was evaluated. Over time, it 1495

may be that the only bridge back to the efficacy data is via a comparison with a licensed 1496

vaccine that was itself licensed on the basis of a bridging efficacy trial. As the number of 1497

bridging steps that has occurred between the original efficacy data and the licensed 1498

comparator vaccine increases, so the reliance that may be placed on a demonstration of 1499

non-inferiority to predict efficacy is weakened. This consideration also applies when the 1500

vaccine for which efficacy was estimated contained a certain number of subtypes but was 1501

later extended on the basis of bridging to the efficacy documented for the original 1502

subtypes and the extended vaccine has replaced the original vaccine in the market. 1503

If the assay has changed and has not been, or cannot be, directly compared to the original 1504

assay used during the efficacy trial, it may be possible to re-assay stored sera collected 1505

during the prior efficacy trial in parallel with the sera from the new trial population. 1506

1507

If it remains unknown which immunological parameter best correlates with efficacy, it is 1508

preferable that the primary comparison between vaccines is based on functional antibody 1509

whenever this is feasible. 1510

1511

ii) Inferring the efficacy of a new candidate vaccine 1512

1513

WHO/BS/2016.2287

In this case the main evidence of efficacy for licensure comes from one or more bridging 1514

efficacy trials. The same considerations regarding primary comparison, choice of comparative 1515

vaccine and assay apply as described above. 1516

1517

If the new candidate vaccine is an extended version of a licensed vaccine (i.e. it contains 1518

additional subtypes compared to the licensed product) and/or it contains subtypes of an organism 1519

that have not previously been included in any licensed vaccine, the interpretation of the immune 1520

responses to the added or new subtypes is not straightforward. Approaches that could be 1521

considered include comparing immune responses to each added or new subtype with the mean 1522

immune response to all subtypes or with the lowest immune response to any individual subtype 1523

included in a vaccine for which efficacy was demonstrated. Although these approaches may 1524

provide a route to licensure, the limitations of these comparisons in predicting efficacy should be 1525

taken into account when considering the overall benefitrisk relationship for the new vaccine. 1526

Collection of effectiveness data in the post-licensure period is recommended. 1527

1528

5.6.2.2 Other approaches 1529

1530

When there is no ICP and it is not possible to bridge to a prior demonstration of efficacy, the 1531

evidence that may be provided to support likely vaccine efficacy must be considered and 1532

discussed with NRAs on a case-by-case basis. In each case the strength of evidence that may be 1533

provided should be weighed against the advantages of having a licensed vaccine – one that has 1534

been subjected to a full review of quality and nonclinical data and for which it is considered that 1535

there are adequate clinical safety and immunogenicity data – available for use when needed. 1536

1537

Some of the possible approaches may include establishing a nonclinical model of efficacy that is 1538

thought to be relevant to the human infection and identifying which immunological parameter 1539

best correlates with protection (and, if possible, a putative ICP). Data on immune responses that 1540

occur in response to natural infection and the resulting protection against further disease may be 1541

useful, as may any passive protection data that are available from nonclinical or clinical trials. If 1542

a vaccine has already been licensed on the basis of evidence derived from one of these 1543

approaches, any plans for trials to support changes to the vaccine usage are subject to the same 1544

WHO/BS/2016.2287

issues. 1545

1546

5.6.3 Co-administration trials 1547

1548

Comparative immunogenicity trials that are intended to support co-administration of a vaccine 1549

with one or more other vaccines should demonstrate non-inferiority for immune responses to 1550

each of the co-administered antigenic components in the group that receives co-administered 1551

vaccines compared with the groups that receive each vaccine given alone. The immunological 1552

parameters applied to each comparison may differ, depending on the vaccine content. 1553

1554

When multiple licensed products contain the same antigenic components that could be co-1555

administered with the vaccine under trial (e.g. combination vaccines intended for the routine 1556

infant primary immunization series) it is not feasible, nor is it usually necessary, to assess co-1557

administration with each licensed product. The vaccine(s) chosen for trials should be as 1558

representative as possible (e.g. in terms of antigen content) of the range of licensed products. 1559

1560

A particular issue arises when there are several different types of polysaccharide-protein 1561

conjugate vaccines available that may be co-administered with the vaccine under trial. When the 1562

vaccine under trial contains protein that is the same as, or similar to, that in available conjugate 1563

vaccines, it is important to appreciate that the results obtained with any one conjugate may not be 1564

applicable to other types of conjugate (e.g. lack of immune interference with a tetanus toxoid 1565

conjugate does not rule out the fact that this could occur when a different protein is used in the 1566

conjugate). 1567

1568

If multiple doses of the co-administered vaccines are needed, it is usual to make the comparison 1569

between groups only after completion of all doses. The schedule at which the vaccines are co-1570

administered may also be a concern if there are several possibilities (e.g. as in the case of 1571

vaccines for the primary immunization series in infants and for vaccines against hepatitis A and 1572

B). Consideration may be given to using a schedule that is most likely to detect an effect if there 1573

is one. 1574

1575

WHO/BS/2016.2287

Trials that assess the effects of co-administration may be randomized parallel group trials in 1576

which different groups of subjects receive the vaccine under trial alone, the vaccine intended for 1577

co-administration and both together, or the trials may have a staggered administration design. 1578

Staggered administration is necessary when it is not possible to withhold any antigenic 1579

components to be co-administered (e.g. during the infant primary schedule). In staggered 1580

administration trials, the final dose and post-dose sampling occurs later compared to the co-1581

administration group which, in infants, could have some impact on the magnitude of the immune 1582

response. 1583

1584

5.6.4 Immunization of pregnant women 1585

1586

Whenever the target population for a vaccine includes women of childbearing age there is a 1587

need to consider the importance of generating data in pregnant women. The considerations 1588

should take into account the nature of the vaccine construct (e.g. whether the vaccine contains 1589

a live organism that is replication-competent), whether pregnant women can reasonably avoid 1590

exposure to an infectious agent (e.g. by not travelling) and whether they may have the same 1591

risk of exposure but a greater risk of experiencing severe disease compared to non-pregnant 1592

women of the same age. 1593

1594

Not all vaccines are, or need to be, evaluated in trials in pregnant women. If there is no or very 1595

limited experience with a vaccine in pregnant women, NRAs may consider whether nonclinical 1596

data and any data available from the clinical use of the vaccine and very similar vaccines could 1597

be provided in the prescribing information. 1598

1599

5.6.4.1 Aims of immunization during pregnancy 1600

1601

Immunization of women during pregnancy may benefit the mother and the infant for a limited 1602

postnatal period by means of placental transfer of maternal antibody (e.g. influenza, acellular 1603

pertussis and tetanus). In other cases immunization of women during pregnancy may benefit the 1604

infant with no or negligible benefit to the mother (e.g. respiratory syncytial virus and 1605

Streptococcus group B). 1606

WHO/BS/2016.2287

1607

It is also possible that immunization during pregnancy could prevent an infection occurring in 1608

the mother and so protect the fetus from the consequences of infection in utero. 1609

1610

5.6.4.2 Safety and immunogenicity in pregnancy 1611

1612

Before conducting trials in pregnant women, safety and immunogenicity data should be available 1613

from clinical trials conducted in non-pregnant women of childbearing age (20). Once there are 1614

adequate relevant nonclinical data with satisfactory findings and some clinical data on safety and 1615

immune responses in non-pregnant women, data may be obtained from pregnant women, 1616

covering a representative age range, so that the effects of pregnancy on the immune response can 1617

be evaluated. The doses tested initially in pregnant women should be based on the non-pregnant 1618

adult data but may need to be adjusted (in terms of antigen dose or dose regimen) after review of 1619

results from initial trials due to the effects of pregnancy on the immune system. 1620

1621

In all trials conducted in pregnant women, adequate mechanisms should be in place to document 1622

the outcome of the pregnancy, including the duration of gestation at time of delivery, the 1623

condition of the infant at birth and the presence of any congenital conditions (subsection 7.4). 1624

1625

5.6.4.3 Passive protection of infants 1626

1627

If the vaccine is proposed for protection of the infant by placental transfer of maternal antibody, 1628

the trials may evaluate maternal immunization during the third trimester. 1629

1630

If, in a substantial proportion of pregnant women, there is already evidence of humoral immunity 1631

against the infectious disease to be prevented, so that the aim of vaccination during pregnancy is 1632

to increase the amount of antibody transferred to the fetus, the trials in pregnant women may 1633

need to include exploration of dose regimens in seropositive and seronegative subjects. 1634

1635

Dose-finding trials in pregnant women should include measurement of antibody levels in cord 1636

blood samples taken at delivery. The number of samples obtained should be sufficient to provide 1637

WHO/BS/2016.2287

an estimate of inter-individual variability. Additional investigations may include the collection of 1638

cord blood covering a range of times between maternal vaccination and delivery. The cord blood 1639

levels in infants born to vaccinated mothers who receive the final selected vaccine posology 1640

should be superior to those in infants born to mothers who were not vaccinated. Secondary 1641

analyses could examine whether this finding also applies within subsets of mothers who were 1642

seronegative or seropositive prior to vaccination. 1643

1644

To avoid multiple bleeds in individual infants when evaluating the duration of detectable 1645

maternal antibody, mothers may be randomized so that their infants are sampled once or a few 1646

times at defined intervals. The total data collected can be used to describe the antibody decay 1647

curve. These data are particularly important when it is planned that passive protection via 1648

maternal antibody will be followed by active vaccination of infants against the same antigen(s) 1649

because of the possibility that high levels of maternal antibody may interfere with the infant 1650

immune response. 1651

1652

If an ICP is established for the infectious disease to be prevented, the aim of the immunogenicity 1653

trials should be to identify a maternal vaccination regimen that results in cord blood levels that 1654

exceed the ICP in a high proportion of newborn infants. If no ICP exists, there should be 1655

discussion with NRAs regarding whether vaccine efficacy should be estimated in a pre-licensure 1656

efficacy trial or whether an evaluation of vaccine effectiveness may suffice. 1657

1658

5.6.5 Changes to the manufacturing process 1659

1660

Changes made to the product composition (e.g. addition of, removal of, or change in 1661

preservatives) or to manufacture (changes to process, site or scale) during the pre-licensure 1662

clinical development programme or after licensure do not always need to be supported by 1663

comparative clinical immunogenicity trials between the prior and the newer products. 1664

1665

For instance, it is common for the scale of manufacture to change during the pre-licensure 1666

development programme, but this step alone would not be expected to have a clinically 1667

significant effect in the absence of other changes. Any clinical effects of changes to the 1668

WHO/BS/2016.2287

manufacturing process during the pre-licensure programme may not matter if the pivotal trials 1669

use vaccine made using the final process. If this is not the case, and for all changes that are made 1670

post-licensure, consideration must be given to whether a clinical trial to compare vaccine 1671

manufactured using the prior and new processes is required. This decision must be taken on a 1672

case-by-case basis after a full evaluation of the in vitro data, and any nonclinical in vivo data 1673

describing and supporting the change. A single lot of vaccine made using each process may be 1674

sufficient for the comparison, but on occasion data may be required from multiple lots. 1675

1676

In the post-licensure period there may be many changes to the manufacturing process over time. 1677

Whereas each one of these changes may be considered too minor to merit the conduct of a 1678

clinical trial, the product that results from multiple minor changes could be substantially 1679

different from that which was initially licensed. Therefore, when considering the merit of a 1680

clinical trial, it may be important to consider the full history of changes that have been allowed 1681

without clinical data and whether the sum total of the changes could have a clinical impact. In 1682

this situation, when many years have passed, a clinical trial of the current vaccine compared to 1683

the original licensed vaccine will not be possible. If disease surveillance suggests that there could 1684

be a problem with vaccine effectiveness, a clinical trial that compares the current vaccine with 1685

another licensed vaccine may be considered useful. 1686

1687

5.6.6 Lot-to-lot consistency trials 1688

1689

Lot-to-lot consistency trials are conducted to provide an assessment of manufacturing 1690

consistency in addition to the information provided on the manufacturing process. Clinical lot-to-1691

lot consistency trials may or may not be considered necessary. Such trials may be considered 1692

particularly useful for certain types of vaccines where there is inherent variability in the 1693

manufacture of the product. 1694

1695

Whether or not a clinical lot-to-lot consistency trial is conducted, the consistency of 1696

manufacturing for the vaccine lots used in clinical trials should be both demonstrated and well 1697

documented. The lots used in clinical trials should be adequately representative of the 1698

formulation intended for marketing. 1699

WHO/BS/2016.2287

1700

If a lot-to-lot consistency trial is conducted, the usual expectation is that the 95% confidence 1701

interval around each pair-wise comparison of the post-vaccination geometric mean 1702

concentrations/titres falls within predefined limits. The clinical implications of results that show 1703

that one or more comparisons do not meet the predefined criteria set around the ratios should be 1704

considered in light of all available clinical immune response data. 1705

1706

6. Efficacy and effectiveness 1707

1708

This section considers: 1709

Approaches to determination of efficacy. 1710

Human challenge trials. 1711

Initial and pivotal efficacy trials. 1712

Design and conduct of efficacy trials, including control groups. 1713

Approaches to determination of vaccine effectiveness. 1714

1715

6.1 General considerations for efficacy trials 1716

1717

The need for and feasibility of evaluating the protective efficacy of a candidate vaccine should 1718

be considered at an early stage of vaccine development because the conclusion will determine 1719

the overall content of the pre-licensure clinical programme and will have an impact on its 1720

duration. In all application dossiers that do not include an evaluation of vaccine efficacy, the 1721

sponsor should provide sound justification for the lack of such data, taking into account the 1722

following points: 1723

1724

a) Efficacy data are not required 1725

1726

Vaccine efficacy trials are not necessary if it is established that clinical immunological data can 1727

be used to predict protection against disease. For instance, if there is an established 1728

immunological correlate for protection against a specific disease (e.g. anti-toxin levels against 1729

diphtheria and tetanus toxins, antibody against hepatitis B surface antigen) the candidate vaccine 1730

WHO/BS/2016.2287

should be shown to elicit satisfactory responses based on the relevant correlate(s). 1731

1732

b) Efficacy data are usually required 1733

1734

Vaccine efficacy trials are usually required whenever a new candidate vaccine is developed with 1735

intent to protect against an infectious disease and one or more of the following apply: 1736

There is no established immunological correlate of protection that could be used to predict 1737

the efficacy of the new candidate vaccine. 1738

There is no existing licensed vaccine of documented efficacy against a specific infectious 1739

disease to allow for bridging the efficacy documented for a licensed vaccine to that of a new 1740

candidate vaccine. 1741

Use of immune responses to bridge the documented efficacy of a licensed vaccine to a new 1742

candidate vaccine is not considered to be possible because there is no known relationship 1743

between specific immune response parameters and efficacy. 1744

There are sound scientific reasons to expect that vaccine efficacy cannot be assumed to be 1745

similar between the population(s) included in the prior efficacy trial(s) with a candidate 1746

vaccine and one or more other populations. 1747

There are sound scientific reasons to expect that vaccine efficacy that has been demonstrated 1748

for a vaccine against disease due to specific strains of a pathogen (e.g. serotypes, subtypes) 1749

cannot be assumed to apply to other strains that are prevalent in certain regions. 1750

1751

c) Efficacy data cannot be provided 1752

1753

In some instances in which efficacy data are usually required it may not be feasible to conduct 1754

efficacy trials. For instance, if the new candidate vaccine is intended to prevent an infectious 1755

disease that: 1756

does not currently occur (e.g. smallpox); 1757

occurs in unpredictable and short-lived outbreaks that do not allow enough time for the 1758

conduct of appropriately-designed trials to provide a robust estimation of vaccine 1759

efficacy (e.g. some viral haemorrhagic fevers); 1760

WHO/BS/2016.2287

occurs at a rate that is too low for vaccine efficacy to be evaluated in a reasonably-sized 1761

trial population and period of time. This situation may apply: 1762

because of natural rarity of the infectious disease (e.g. plague, anthrax, meningitis 1763

due to N. meningitidis type B); 1764

because of rarity of the disease resulting from the widespread use of effective 1765

vaccines (in this case the numbers required to obtain a robust estimate of vaccine 1766

efficacy may be too large to permit completion in any reasonable time frame). 1767

1768

If it is not feasible to perform vaccine efficacy trials and there is no immunological correlate of 1769

protection, it may be possible to obtain evidence in support of vaccine efficacy and/or to derive 1770

an immunological marker of protection from one or more of the following: 1771

nonclinical efficacy trials; 1772

passive protection trials – i.e. trials which assess the effects of administering normal 1773

or hyper-immune human gamma globulin or convalescent sera (the results may 1774

point to the sufficiency of humoral immunity for prevention of clinical disease and 1775

may suggest a minimum protective antibody level that could be used as a 1776

benchmark in clinical trials with candidate vaccines); 1777

comparison of immunological responses with those seen in past trials of similar 1778

vaccines with proven protective efficacy (e.g. acellular pertussis vaccines) even if 1779

the relationship between immune responses to one or more antigenic components 1780

and efficacy remains unknown; 1781

human challenge trials. 1782

1783

6.2 Types of efficacy trials 1784

1785

6.2.1 Human challenge trials 1786

1787

Human challenge trials, in which subjects are deliberately exposed to an infectious agent in a 1788

controlled setting, are not always feasible or appropriate. However, in some settings it may be 1789

useful and appropriate to obtain an assessment of vaccine efficacy from human challenge trials. 1790

If they are performed, human challenge trials may be of particular use: 1791

WHO/BS/2016.2287

when there is no appropriate nonclinical model (e.g. when a candidate vaccine is 1792

intended to protect against an infectious disease that is confined to humans); 1793

when there is no known ICP; 1794

when vaccine efficacy trials are not feasible. 1795

1796

6.2.2 Initial efficacy trials 1797

1798

If conducted, initial vaccine efficacy trials may provide an estimate of the magnitude of 1799

protection that can be achieved by the new candidate vaccine. However, initial efficacy trials are 1800

not usually designed and powered to provide robust estimates of vaccine efficacy. These trials 1801

may be used to inform the design of pivotal trials. For example: 1802

by evaluating the efficacy of different doses and dose regimens; 1803

by estimating efficacy on the basis of a range of efficacy variables; 1804

by analysing efficacy on the basis of various case definitions in order to identify or 1805

refine the most appropriate case definition; 1806

by exploring efficacy in specific subgroups in order to decide if there is a need to 1807

design pivotal trials specifically to further evaluate efficacy in specific subgroups.; 1808

by assessing the method of case ascertainment for feasibility in larger and more 1809

geographically diverse trials; 1810

by using immunogenicity and efficacy data to support a provisional assessment of 1811

potential correlates of protection. 1812

1813

If the candidate vaccine is intended to prevent a severe and/or life-threatening infectious disease 1814

for which there is no vaccine, or no satisfactory vaccine is already available, individual NRAs 1815

may agree to accept an initial application for licensure based on one or more initial efficacy 1816

trial(s). In these cases it is essential that sponsors and NRAs should discuss and agree the main 1817

features of the design of the trials before initiation, including the sample size, so that, subject to 1818

promising results, the data may be considered robust and sufficient. 1819

1820

The availability of a licensed vaccine has potentially important implications for the acceptability 1821

WHO/BS/2016.2287

and feasibility of initiating or completing additional efficacy trials that include a control group 1822

that does not receive active vaccination. These issues should be discussed between NRAs and 1823

sponsors so that expectations for completion of additional efficacy trials are agreed prior to the 1824

start of trials that could potentially support initial licensure. 1825

1826

6.2.3 Pivotal efficacy trials 1827

1828

Pivotal vaccine efficacy trials are designed and powered to provide statistically robust estimates 1829

of vaccine efficacy to support licensure. Pivotal efficacy trials may evaluate a single vaccination 1830

regimen, or more than one regimen, and may or may not include evaluations of efficacy before 1831

and after booster doses. 1832

1833

6.3 Design and conduct of efficacy trials 1834

1835

The protective efficacy of a vaccine against a specific infectious disease is usually determined in 1836

trials that compare the incidence of disease after vaccination relative to the incidence of disease 1837

in the control group that has not been vaccinated. Less frequently, vaccine efficacy may be 1838

determined in a prospective randomized trial which compares the incidence of disease after 1839

vaccination between the group that received the new candidate vaccine and a control group that 1840

received a licensed vaccine intended to prevent the same infectious disease. 1841

1842

The following subsections are applicable to both types of trial. Details of statistical 1843

methodologies are beyond the scope of this guidance and only broad principles are described. It 1844

is recommended that an appropriately experienced statistician should be consulted. 1845

1846

6.3.1 Selection of trial sites 1847

1848

Vaccine efficacy trials require the presence of a sufficient burden of clinical disease to enable 1849

estimates to be obtained from feasible numbers of subjects within a reasonable time frame. The 1850

infectious disease to be prevented may occur at sufficiently high rates to enable efficacy trials to 1851

be conducted only in certain geographical areas. Even when the disease to be prevented is more 1852

WHO/BS/2016.2287

widespread, it may be necessary to confine efficacy trials to specific areas for reasons that may 1853

include feasibility, the need to ensure adequacy of monitoring, and a desire to accumulate 1854

representative numbers of cases due to specific serotypes or subtypes of the relevant pathogen. 1855

1856

Sponsors may have to conduct feasibility assessments in order to ascertain accurately the clinical 1857

disease rates in various age subgroups of populations before selecting trial sites. Any nationally-1858

recommended non-vaccine-related preventive measures that are in place (e.g. prophylactic drug 1859

therapy in high-risk individuals or settings, use of insect repellents and bed-nets) should be 1860

identified. Trials are usually conducted against a background of these measures. 1861

1862

Trial sites need to be sufficiently accessible to allow regular visits for monitoring. Prior to 1863

initiation of the trial, sponsors may have to engage in site capacity-building exercises, including 1864

training of study personnel, and may need to provide essential infrastructure to support the trial 1865

(e.g. adequate blood collection and processing facilities, refrigeration facilities suitable for the 1866

vaccine and/or sera, access to competent laboratories, data-handling capacity and communication 1867

methods to allow electronic randomization schemes, rapid reporting of safety data or other trial 1868

issues to the sponsor). 1869

1870

6.3.2 Candidate (test) vaccine group(s) 1871

1872

If previous data do not support selection of a single dose or regimen of the candidate vaccine for 1873

assessment of efficacy, trials may include one or more groups in which subjects receive the 1874

candidate vaccine (for instance, more than one dose or schedule may be evaluated). In some 1875

instances, one or more placebo doses may need to be interspersed with candidate vaccine doses 1876

to enable the matching of all regimens under trial in a double-blind design (e.g. if two or three 1877

doses of the candidate vaccine are to be compared with the control group). 1878

1879

6.3.3 Control (reference) group(s) 1880

1881

Control groups comprise all subjects who do not receive the candidate vaccine. Usually only one 1882

control group is enrolled in any one trial. Sometimes it may be important to include more than 1883

WHO/BS/2016.2287

one of the possible types of control groups that are discussed below. 1884

1885

6.3.3.1 Control groups not vaccinated against the infectious disease to be prevented 1886

1887

In most cases, vaccine efficacy trials employ a control group that does not receive vaccination 1888

against the disease to be prevented by the new candidate vaccine. In double-blind trials the 1889

control group may receive: 1890

1891

A true placebo (i.e. material without any pharmacological activity). This has the 1892

advantage of providing safety data against a control that has no pharmacologically active 1893

components. The use of an injectable placebo may not be acceptable to all NRAs, ethics 1894

committees, investigators, trial subjects or their caregivers in some age groups (for 1895

instance, particular objections may be raised against true placebo injections in infants). In 1896

contrast, there is usually no objection to the use of a true placebo when the candidate 1897

vaccine is administered orally or by nasal installation. 1898

1899

If a true placebo is not acceptable the control group may receive a licensed vaccine that 1900

does not prevent the infectious disease under study but may have some benefit for 1901

recipients. In some cases both licensed vaccine and placebo doses may have to be 1902

administered to the control group to match the candidate vaccine regimen. 1903

1904

If there are major objections to the use of placebo injections but no potentially beneficial 1905

licensed vaccine would be suitable for the target age group, the control group may be 1906

randomized to receive no injection. This is an undesirable situation and should be regarded as a 1907

last resort since it precludes the blinding of trial personnel or subjects/caregivers. 1908

1909

6.3.3.2 Control groups vaccinated against the infectious disease to be prevented 1910

1911

In this case the control group receives a vaccine that is already licensed to prevent the same 1912

infectious disease as the candidate vaccine. This approach is used when it is not acceptable to 1913

employ a control group that is not vaccinated against the infectious disease to be prevented 1914

WHO/BS/2016.2287

because there is at least one available licensed efficacious vaccine that is recommended for use 1915

in areas where the disease occurs. 1916

1917

The control group may receive a licensed vaccine that prevents infectious disease due to some, 1918

but not all, of the pathogens responsible for the disease that is to be prevented. In these situations, 1919

the group that receives the licensed vaccine may be regarded as an unvaccinated control group 1920

for the types found only in the candidate vaccine. 1921

1922

It is important that selection of the control vaccine takes into account the available evidence 1923

supporting its efficacy and, if relevant, whether it appears to have similar efficacy against all 1924

serotypes or subtypes of the pathogen involved. When there is more than one available licensed 1925

control vaccine, or the selected control vaccine is unlicensed or is not the product in routine use 1926

in a particular jurisdiction(s), sponsors are advised to discuss selection of the comparator with 1927

the relevant NRA(s). If it is not possible to reach agreement on the use of the same control 1928

vaccine in all regions where efficacy is to be evaluated, consideration should be given to 1929

conducting more than one efficacy trial with a different vaccine used in the control group in each 1930

trial. 1931

1932

Following consultation between the sponsor, NRA, ethics committees, local public health 1933

authorities and investigators, it may be appropriate to use a control group that is not vaccinated 1934

against the disease. For example, this may be the case when the trial is to be conducted in 1935

countries in which: 1936

no vaccine is yet licensed; and/or 1937

no vaccine is included in the routine immunization schedule; and/or 1938

there are sound reasons to consider that no licensed vaccine is likely to provide useful 1939

efficacy (because, for instance, the licensed vaccine does not cover, or is 1940

known/expected to have poor efficacy against, the serotypes or subtypes that are most 1941

prevalent in a specific region). 1942

1943

6.3.4 Trial designs 1944

1945

WHO/BS/2016.2287

6.3.4.1 Randomization 1946

1947

The unit of randomization is most usually the individual. Alternatives include the household or 1948

the cluster under trial (e.g. a school population or a local community). Randomization of groups 1949

or clusters, rather than individuals, may be preferred when it is logistically much easier to 1950

administer the vaccine to groups than to individuals and when estimates of the indirect effects of 1951

vaccination (e.g. herd immunity) are of interest. 1952

When the trial aims to vaccinate pregnant women to protect the infant during the early months of 1953

life, the unit of randomization is the mother. 1954

1955

6.3.4.2 Types of trial design 1956

1957

The simplest design involves randomization of equal numbers of subjects to each candidate 1958

vaccine group and control group (i.e. 1:1). In trials that employ a control group that is not 1959

vaccinated against the disease to be prevented, but some clinical data are available to support the 1960

likely efficacy of the candidate vaccine, it may be appropriate (subject to statistical 1961

considerations and an assessment of the impact on the total trial sample size) to use unbalanced 1962

randomization to reduce the chance that subjects will be randomized to the control group (e.g. 1963

2:1 or 3:1 so that the majority of trial subjects receive the candidate vaccine). 1964

1965

Trials may be planned to follow trial subjects for a fixed period after the last dose of the primary 1966

series. The time at which the primary analysis is conducted should take into account the 1967

anticipated rates of the disease under study in each treatment group, including the unvaccinated 1968

control group if applicable. Other considerations regarding the timing of the primary analysis 1969

may include the possible importance of having some information on the duration of protection 1970

before initial licensure occurs, the feasibility of retaining subjects on trial for prolonged periods, 1971

and whether or not the vaccine could address a pressing unmet need (e.g. in an outbreak situation 1972

when there is no approved vaccine to prevent the disease). 1973

1974

Alternatively, a case-driven approach may be taken based on the anticipated rates of the primary 1975

efficacy endpoint in the control group and the expected or minimum desirable level of efficacy 1976

WHO/BS/2016.2287

of the candidate vaccine. In this design, the primary analysis is conducted once a pre-specified 1977

total number of cases (i.e. in a double-blind setting, based on the anticipated numbers in test and 1978

control groups required to demonstrate the projected vaccine effect) has been detected. 1979

1980

Alternative designs that allow for a comparison with a control group that is not vaccinated 1981

against the disease to be prevented may, at least in the short term, include (among other designs) 1982

the following: 1983

1984

In a step-wedge trial, the candidate vaccine is administered to predefined groups in a 1985

sequential fashion. Each predefined group is a unit of randomization. These may be 1986

geographical groups or groups defined by host factors (e.g. age) or other factors (e.g. 1987

attendance at a specific school or residence within a specific health-care catchment area). 1988

Such a design may be chosen when there is good evidence to indicate that the vaccine 1989

will do more good than harm (affecting the equipoise associated with randomization to a 1990

control group that is not vaccinated against the disease to be prevented) and/or when it is 1991

impossible to deliver the intervention to all trial participants within a short time frame. 1992

1993

In a ring vaccination trial, the direct contacts, and sometimes secondary contacts, of a 1994

case may be randomized to vaccine or control or may be randomized to receive 1995

immediate vaccination or vaccination after a period of delay (21). This type of post-1996

exposure cohort trial usually requires smaller sample sizes than prospective randomized 1997

controlled trials. The validity of this trial design relies on the assumption that there is an 1998

approximately equal chance of vaccinees and non-vaccinees being infected and 1999

developing the infectious disease as a result of contact with an index case. 2000

2001

Ring vaccination trials may be particularly applicable when the infectious disease to be 2002

prevented is associated with a relatively high incidence of secondary cases in susceptible 2003

populations. Therefore the use of this trial design requires prior knowledge of the 2004

infectivity of the infectious agent and the proportion of infections that are clinically 2005

apparent, as well as the general susceptibility of the trial population. 2006

2007

WHO/BS/2016.2287

The follow-up period for subjects after contact with the index case should extend to the upper 2008

limit of the incubation period, taking into account both the period during which the index cases 2009

were infectious and the contact period. The inclusion period for new cases and controls and their 2010

contacts following the detection of the first case should be stated in the protocol. The duration of 2011

the inclusion period should take into account the potential for introducing bias if the disease 2012

incidence changes over time. 2013

2014

6.3.5 Clinical endpoints 2015

2016

The primary endpoint(s) in initial trials may be different from the primary endpoint(s) used in the 2017

pivotal trial(s). 2018

2019

6.3.5.1 Primary endpoints 2020

2021

In most instances, the focus of vaccine efficacy trials is the prevention of clinically apparent 2022

infections that fit the primary case definition based on clinical and laboratory criteria. The 2023

primary endpoint is also usually defined by the time frame in which the case occurred in relation 2024

to dosing. 2025

2026

If an organism causes a range of disease manifestations (e.g. from life-threatening invasive 2027

disease to disease that is not serious if adequately treated or is self-limiting) the primary endpoint 2028

in any one trial should be carefully selected in accordance with the proposed indication(s) for 2029

use. 2030

2031

A candidate vaccine may contain antigens derived from one or several types (serotypes, subtypes 2032

or genotypes) of the same organism. There may also be some possible potential for cross-2033

protection against types not included in the vaccine (e.g. as observed with rotavirus vaccines and 2034

human papilloma virus vaccines). For these types of vaccines, it is usual for the primary endpoint 2035

to comprise cases due to any of the types included in the vaccine, and the trial is powered for this 2036

composite endpoint. It is not usually possible to power the trial to assess efficacy against 2037

individual types in the vaccine or to assess cross-protection against types not in the vaccine. 2038

WHO/BS/2016.2287

2039

Alternative primary endpoints may include: 2040

clinical manifestations of reactivated latent infection (e.g. herpes zoster); 2041

established chronic infections that may be asymptomatic but predispose to 2042

infection-related disease later in life (e.g. chronic hepatitis B infection, persistent 2043

infection with HPV); 2044

other markers that predict progression to clinically apparent disease (e.g. 2045

histological changes that are established precursors of malignant neoplasia). 2046

2047

6.3.5.2 Secondary endpoints 2048

2049

As applicable to the individual candidate vaccine and the definition of the primary endpoint, 2050

important secondary endpoints may include: 2051

cases that occur after each dose, when the vaccine schedule includes multiple doses 2052

and/or a booster; 2053

cases due to each of the individual types of the organism included in the vaccine; 2054

cases due to the organism, regardless of whether the cases are caused by types that 2055

are or are not included in the candidate vaccine; 2056

cases due to non-vaccine types; 2057

cases occurring in groups with host factors of interest (e.g. age, region); 2058

cases meeting various criteria reflecting disease severity; 2059

duration and/or severity of the illness, which may include clinical measurements 2060

(e.g. duration of fever or rash) and laboratory measurements (e.g. duration of 2061

shedding). 2062

2063

One important secondary objective should be to attempt to identify a correlate of protection or a 2064

threshold value if none exists. 2065

2066

Eradication of carriage and/or reduction in disease transmission that is not directly linked to, 2067

and/or accompanied by, a clinical benefit of vaccination to the individual is not usually 2068

WHO/BS/2016.2287

considered to be sufficient to support licensure. Sponsors contemplating trials with these as 2069

primary endpoints are advised to consult widely with NRAs. 2070

2071

6.3.6 Case definition 2072

2073

As part of the predefined primary efficacy endpoint, the protocol should describe the clinical and 2074

laboratory criteria that must be met to define a case. 2075

o If a case is defined as an acute infectious disease, the definition should include the core 2076

clinical features as well as details of the sampling and laboratory processing methods 2077

required to confirm the presence of the target pathogen and/or to detect infection by 2078

serological findings. 2079

o If the endpoint is defined as a consequence of a prior infection (e.g. evidence of 2080

persistence of infection or a histological change), details of sampling (frequency and 2081

method) and grading (if applicable) should be included. 2082

2083

Adequate case definitions should also be provided for secondary endpoints. 2084

2085

6.3.7 Case ascertainment 2086

2087

It is critical that the same methodology for case detection should be applied consistently at all 2088

clinical sites throughout the duration of the trial. Active case ascertainment usually requires 2089

frequent monitoring and contact with trial subjects/caregivers. Passive case ascertainment is 2090

usually based on trial subjects/caregivers presenting to or otherwise contacting a local health-2091

care facility due to the onset of specific symptoms. In this case, contact is commonly triggered 2092

by one or more of a list of signs or symptoms given to trial subjects/caregivers at the time of 2093

randomization and they may be instructed to contact a specific health-care facility. Alternatively, 2094

or in parallel, cases may be detected by monitoring all local clinics and hospitals for cases. 2095

2096

For efficacy endpoints based on clinically apparent disease, the possible range of clinical 2097

presentations will determine the mode of case ascertainment. For instance, this may be hospital-2098

based for cases of life-threatening infections, or community-based for less severe infections. If 2099

WHO/BS/2016.2287

community-based, case detection may depend on family practitioners and on first suspicion of 2100

infection by vaccinated subjects/caregivers. In each case, it is critically important that the 2101

individuals who are most likely to initiate detection of a possible case should have clear 2102

instructions. These may need to cover issues such as criteria for stimulating contact with 2103

designated health-care professionals, telephone contacts, initial investigations, and further 2104

investigations once a case is confirmed. 2105

2106

For efficacy endpoints other than clinically apparent disease, it is essential for subjects to be 2107

monitored at regular intervals to detect clinically non-apparent infections or changes in other 2108

selected markers (e.g. the appearance of histological changes). The frequency of these visits, and 2109

acceptable windows around the visits, should be stated in the trial protocol and carefully 2110

justified. 2111

2112

The appropriate period of case ascertainment during a trial should be determined mainly by the 2113

characteristics of the disease to be prevented and the claim of protection that is sought at the time 2114

of initial licensure. For infectious diseases that have marked seasonality, at least in some 2115

geographical locations, it is usual to plan for a primary analysis when all trial subjects have been 2116

followed through one complete season. In these settings it is usual to conduct an enrolment 2117

campaign over a very short period just before the onset of the expected season. However, it may 2118

be necessary to repeat the exercise before the next season to meet the predefined sample size, in 2119

which case the opportunity should be taken to collect all cases that occur in the second season for 2120

the initial vaccination campaign cohort. 2121

2122

6.3.8 Duration of follow-up 2123

2124

At the time of conducting the primary analysis for the purposes of obtaining initial licensure, the 2125

duration of follow-up in vaccine efficacy trials may be relatively short (e.g. 612 months) and 2126

may be insufficient to detect waning protection, if this exists. Therefore, whenever feasible, case 2127

ascertainment should continue in vaccine efficacy trials with maintenance of the randomized 2128

populations for a sufficient duration to assess waning protection over time. Alternatively, or in 2129

addition, waning protection may be assessed during the post-licensure period. These data may 2130

WHO/BS/2016.2287

serve both to indicate the need for, and optimal timing of, booster doses and to estimate efficacy 2131

after booster doses. 2132

2133

6.3.9 Analysis of efficacy 2134

2135

Detailed plans for the analysis of efficacy, including any interim analyses and/or plans to adjust 2136

the sample size during the study on the basis of specific criteria, should be developed in 2137

conjunction with appropriately experienced statisticians and should be discussed with the NRAs 2138

before the protocol is finalized (and/or during the conduct of the study, as necessary). 2139

2140

6.3.9.1 Sample size calculation 2141

2142

The trial sample size should be calculated on the basis of: 2143

the selected primary efficacy endpoint, which could be a composite of cases due to 2144

any of the organism types, included in the candidate vaccine; 2145

the primary analysis population (see below); and 2146

the primary hypothesis (i.e. superiority or non-inferiority, and the predefined 2147

success criteria). 2148

2149

If the primary analysis population represents a subset of the total randomized population, the 2150

sample size calculation should include an adequate estimation of numbers likely to be excluded 2151

from the primary analysis for various reasons. In addition, a blinded review (e.g. using an IDAC) 2152

of total numbers of persons enrolled who are eligible for the primary analysis population may be 2153

conducted after randomization of a predefined number so that the trial sample size can be 2154

adjusted accordingly. 2155

2156

6.3.9.2 Analysis populations 2157

2158

Clinical efficacy is usually assessed in the total randomized trial population (i.e. those who are 2159

assigned to receive vaccine and/or control) and in predefined subsets of the randomized 2160

population. 2161

WHO/BS/2016.2287

2162

The predefined trial populations should include as a minimum: 2163

all randomized subjects (i.e. the full analysis set); 2164

all vaccinated subjects regardless of the numbers of assigned doses actually 2165

received and whether or not they were administered within the predefined windows; 2166

subsets of all vaccinated subjects, separated according to any evidence of prior 2167

exposure to the infectious disease under trial (e.g. baseline seropositivity versus 2168

seronegativity); 2169

subjects who have generally complied with the protocol and have received all 2170

assigned doses within predefined windows. 2171

2172

Other populations may be appropriate for some predefined secondary or exploratory analyses. 2173

These may include, for instance: 2174

those who completed specific numbers of assigned doses or received all doses 2175

within predefined windows around the scheduled trial visits (i.e. analyses of 2176

efficacy according to adherence to the vaccination regimen); 2177

subgroups defined by demographic factors known or postulated to have an impact 2178

on vaccine efficacy. 2179

2180

6.3.9.3 Primary analysis 2181

2182

It is common in vaccine efficacy trials for the predefined primary analysis to be based on 2183

estimating efficacy in the “per protocol” population and on rates of true vaccine failures – in 2184

other words, the calculation of efficacy takes into account only those cases with onset after a 2185

minimum time has elapsed after completion of the assigned doses. For example, depending on 2186

knowledge of the kinetics of the immune response, true vaccine failures may be limited to cases 2187

with onset more than a specified number of days or weeks after the final dose of the primary 2188

series. In addition, for a vaccine that contains antigens from only certain serotypes or subtypes, 2189

the primary analysis may be based on cases due to vaccine types only. 2190

2191

In trials that compare a candidate vaccine with a group that is not vaccinated against the disease 2192

WHO/BS/2016.2287

to be prevented, the aim is to demonstrate that the lower bound of the 95% confidence interval 2193

around the estimate of vaccine efficacy is above a predefined percentage (which will always be 2194

above zero). The predefined percentage should be selected on the basis of the sponsor’s 2195

expectation of the point estimate of vaccine efficacy, taking into account what might be seen as 2196

the minimum level of efficacy that could be considered clinically important. The sample size 2197

calculation is based on this objective. 2198

2199

In trials that compare a candidate vaccine with an active control, the aim is to demonstrate non-2200

inferiority of the candidate vaccine versus the control vaccine. This requires a predefined non-2201

inferiority margin, which should be justified in accordance with prior estimates of vaccine 2202

efficacy for the disease to be prevented and the level of alpha on which the sample size 2203

calculation depends. If the sponsor also intends to assess superiority of the candidate vaccine 2204

over the active control, the statistical analysis plan should predefine a hierarchical assessment so 2205

that superiority is assessed only after establishing that the non-inferiority has been demonstrated. 2206

2207

6.3.9.4 Other analyses 2208

2209

The full range of secondary and exploratory analyses will depend on the predefined endpoints. 2210

Some of these analyses may be conducted in specific predefined trial populations. For instance, 2211

important sensitivity analyses for supporting the primary analysis include those based on all 2212

proven cases whenever they occurred after randomization and in each analysis population. If the 2213

schedule includes more than one dose, analyses should be conducted to count cases from the 2214

time of each dose for all subjects who were dosed up to that point. 2215

2216

Depending on the case definition, other analyses may be based on cases that met some but not all 2217

of the case definition criteria, cases that were severe and cases that required a medical 2218

consultation or hospitalization. 2219

2220

6.3.9.5 Other issues 2221

2222

Vaccines that contain antigens derived from several serotypes, subtypes or genotypes 2223

WHO/BS/2016.2287

2224

If the primary analysis was confined to cases due to organism types included in the vaccine, 2225

additional analyses should be conducted to evaluate efficacy on the basis of all cases, regardless 2226

of the organism type responsible. If there are sufficient numbers of cases due to organism types 2227

not included in the vaccine, these analyses may provide some indication of cross-protection. 2228

2229

If the data suggest unusually low efficacy against one or more organism types in the vaccine it 2230

may be necessary to explore this issue in further trials. 2231

2232

Magnitude of vaccine efficacy 2233

2234

The point estimate of vaccine efficacy and 95% confidence intervals that are obtained may 2235

indicate that a relatively modest proportion of cases can be prevented. This fact alone does not 2236

preclude licensure provided that the sponsor can substantiate that the vaccine efficacy observed 2237

represents an important clinical benefit (e.g. if the vaccine prevents life-threatening infections for 2238

which there is no very effective specific therapy and for which no vaccine is available). 2239

2240

6.4 Approaches to determination of effectiveness 2241

2242

Vaccine effectiveness reflects direct (vaccine-induced) and indirect (population-related) 2243

protection during routine use. The information gained from assessments of vaccine effectiveness 2244

may be particularly important to further knowledge on the most appropriate mode of use of a 2245

vaccine (e.g. need for booster doses to maintain adequate protection over time). Vaccine 2246

effectiveness is influenced by a number of factors, including: 2247

vaccination coverage of the population; 2248

pre-existing immune status of the population; 2249

differences in types included in a vaccine compared to predominant circulating 2250

types; 2251

changes in circulating predominant types over time; 2252

transmissibility of the pathogen and any effect that the introduction of routine 2253

vaccination may have had on transmission rates. 2254

WHO/BS/2016.2287

2255

Vaccine effectiveness may be estimated in several ways, namely: 2256

In observational cohort studies that describe the occurrence of the disease to be 2257

prevented in the target population over time. However, there is no randomization step 2258

and there is a potential for considerable biases to be introduced. 2259

During phased (e.g. in sequential age or risk groups) introduction of the vaccine into the 2260

target population in which the groups might form the units of randomization (i.e. using a 2261

stepped wedge design). 2262

Using other designs such as, for example, a case test-negative study design. In this 2263

modification of a case control study, subjects with symptoms suggesting the infectious 2264

disease under trial and seeking medical care are tested for the infectious agent of interest. 2265

The cases are those who are positive and controls are those who are negative for the 2266

pathogen of interest. If vaccinated cases are less severely ill and seek care less frequently 2267

than cases that occur in individuals who are not vaccinated against the disease to be 2268

prevented, an appropriate adjustment for illness severity is required to avoid bias in 2269

effectiveness estimates (22). 2270

2271

It may not be possible or appropriate for sponsors to conduct trials to estimate vaccine 2272

effectiveness themselves since regional or national networks may be necessary to ensure that 2273

cases are detected reliably. For some types of disease, the use of data collected by means of 2274

national or international registries may be appropriate. In addition, in some jurisdictions the 2275

estimation of vaccine effectiveness is not considered to fall within the remit of the licence-2276

holder. 2277

2278

Whatever the local requirements and arrangements, sponsors should discuss arrangements for 2279

ongoing disease surveillance and the potential for estimating effectiveness with the public health 2280

authorities in countries where the vaccine is to be used and where appropriate surveillance 2281

systems are in place. The plans for estimation of effectiveness should also be agreed with NRAs 2282

at the time of licensure and the requirements for reporting of effectiveness data to the NRA, 2283

either via the sponsor or directly from a public health authority, should be clarified. 2284

2285

WHO/BS/2016.2287

It may be that reliable estimates of effectiveness can be obtained only in certain countries in 2286

which vaccination campaigns are initiated and where there is already a suitable infrastructure in 2287

place to identify cases. Consequently, it would likely be inappropriate to extrapolate any 2288

estimates of effectiveness that are obtained to other modes of use (such as introducing the same 2289

vaccine to different, or only to highly selected, sectors of the population). 2290

2291

7. Safety 2292

2293

This section considers: 2294

Evaluating safety in clinical trials, including: 2295

- safety as a primary or secondary endpoint 2296

- recording and categorization of adverse events within trials 2297

- size of the pre-licensure safety database 2298

Post-licensure safety surveillance, including: 2299

- spontaneous reporting 2300

- roles of the licence-holders and NRAs. 2301

2302


2304

Safety should be assessed in all clinical trials that are conducted pre- or post-licensure. The 2305

assessment of safety may be the primary objective, a co-primary objective or a secondary 2306

objective in a clinical trial. Since the methods for collection, analysis and interpretation of safety 2307

data during clinical trials contrast with those applicable to post-licensure routine safety 2308

surveillance they are considered separately. 2309

2310

In principle, many of the approaches to documenting and reporting safety data during clinical 2311

trials, and the conduct of pharmacovigilance activities for vaccines, are similar to those for all 2312

medicinal products. The sections that follow should be read in conjunction with the extensive 2313

guidance that is available from many publications and on the websites of WHO, CIOMS, ICH 2314

and individual regulatory bodies. The focus of the sections is on some methods and practices that 2315

are different for vaccines compared to other medicinal products and on some issues that may 2316

WHO/BS/2016.2287

need to be addressed because of the vaccine composition. 2317

2318

7.2 Assessment of safety in clinical trials 2319

2320

7.2.1 Safety outcomes as primary or secondary endpoints 2321

2322

7.2.1.1 Safety outcomes as primary endpoints 2323

2324

When the assessment of safety is a primary objective of a clinical trial it is usual for the primary 2325

analysis to be based on a specific safety endpoint (e.g. rates of a certain AE, or rates of AEs that 2326

may be part of a clinical syndrome of interest) and the trial is powered to address the pre-2327

specified hypothesis. 2328

2329

7.2.1.2 Safety outcomes as secondary endpoints 2330

2331

When the assessment of safety or specific aspects of the safety profile is a secondary objective, 2332

trials are not usually powered a priori to support statistical analyses of endpoints such as rates of 2333

all or of specific AEs. Descriptive comparisons are commonly used to screen for any differences 2334

in AE rates between treatment groups. If statistical analyses of AE rates are conducted, they 2335

should be pre-specified in the protocol and in the statistical analysis plan, with adequate attention 2336

paid to the effects of multiplicity. If any findings indicate statistically significant differences in 2337

rates of AEs (overall or for specific AEs) between treatments, they should be interpreted with 2338

caution since the trial was not primarily designed to address pre-specified hypotheses regarding 2339

safety endpoints. The biological plausibility that AEs that occur more frequently in the new 2340

candidate vaccine group may be related to vaccination should be taken into consideration when 2341

deciding on the need for further pre- or post-licensure clinical trials to investigate and quantify 2342

the potential risks. 2343

2344

7.2.2 Recording and reporting adverse events 2345

2346

7.2.2.1 Methods 2347

WHO/BS/2016.2287

2348

AEs should be reported and recorded by investigators and sponsors according to detailed 2349

procedures described in the trial protocol. AEs should be classified according to a standardized 2350

scheme, such as MedDRA, to categorize AEs by System Organ Class (SOC) and Preferred Term 2351

(PT). If the classification scheme is updated while the trial is being conducted, the clinical trial 2352

report should indicate how the changes affect the tabulations. 2353

2354

Expedited reporting of AEs that meet specific criteria should take place in accordance with the 2355

requirements of individual NRAs relevant to the location of the trial sites. 2356

2357

It is standard practice for vaccinees to be observed immediately after each dose (e.g. for a 2358

defined period, commonly 2060 minutes) for any severe immediate reactions (e.g. severe 2359

hypersensitivity reactions requiring immediate medical attention). 2360

2361

It is usually expected that all AEs are collected from all randomized subjects for defined periods 2362

after each dose: 2363

Solicited signs and symptoms are usually recorded daily in diary cards for at least 47 2364

days after each dose (subsection 7.2.2.2). Longer periods (e.g. 1014 days) may be 2365

appropriate for certain vaccines, such as those which replicate in recipients. 2366

Unsolicited AEs are usually collected for the entire period between each dose or, for 2367

single doses or final doses of regimens, for approximately 4 weeks post-dose (subsection 2368

7.2.2.3). 2369

Serious adverse events (SAEs) and any pre-specified AEs of special interest (AESIs) 2370

should be collected from all trial subjects for at least 6 months after the last dose of 2371

assigned treatment. 2372

For vaccines that contain new adjuvants, it is recommended that there should be follow-2373

up for at least 12 months after the last dose for documentation of any auto-immune 2374

diseases or other immune-mediated AEs. 2375

2376

In trials involving large numbers of subjects (e.g. vaccine efficacy trials), taking into account the 2377

safety profile observed in the previous trials and the numbers from which detailed safety data 2378

WHO/BS/2016.2287

have already been obtained, it may be acceptable for non-serious AEs to be collected from a 2379

representative (and preferably randomized) subset. In this case, all SAEs and any pre-specified 2380

AESIs should be collected from all randomized subjects. It may be acceptable that only SAEs 2381

and AESIs are collected during long-term safety follow-up. 2382

2383

7.2.2.2 Solicited signs and symptoms 2384

2385

After each dose of a vaccine or placebo it is common practice for certain local and systemic AEs 2386

to be documented for a predefined post-dose period by study subjects/caregivers who complete a 2387

daily diary record. These AEs are commonly referred to as “solicited signs and symptoms” since 2388

information on their occurrence is actively sought and they should be listed in the trial protocol. 2389

2390

For injectable vaccines, the local signs and symptoms to be documented usually include as a 2391

minimum pain, redness and swelling at the injection site in all age groups. Pain should be graded 2392

according to a scoring system. Transparent plastic measuring devices may be used to record the 2393

extent of redness and swelling. 2394

2395

Consideration should be given to assessing whether reports of pain are associated with 2396

immediate pain during and just after the injection is made or whether the pain is of later onset. 2397

These data may indicate that attempts should be made to reformulate the vaccine to improve the 2398

local tolerability. 2399

2400

When two or more vaccines are given by injection at the same time, the diary card should ensure 2401

that separate data are recorded for each injection site. Since these sites are usually in different 2402

limbs, the diary card should contain separate records by right and left arm and/or leg. 2403

2404

The systemic signs and symptoms to be collected are determined by the age range in the trial 2405

(e.g. those appropriate for infants will not be wholly applicable to toddlers and older subjects) 2406

and the route of administration (e.g. nausea and vomiting could be solicited symptoms for 2407

vaccines given orally). Fever should be documented using digital thermometers and should be 2408

determined at a specific site (e.g. rectal or axillary in infants). Recordings of fever should be 2409

WHO/BS/2016.2287

required at specific times and for a limited number of days after each dose. For subjective 2410

symptoms (e.g. fatigue and myalgia) a simple scoring system should be included in the diaries to 2411

allow for a grading of severity. 2412

2413

Any self-administered treatments used to address signs or symptoms (such as antipyretic and 2414

analgesic medicines) and any contact with, or treatment administered by, a health-care 2415

professional should be captured. If at the time of each dose a supply of a specific antipyretic or 2416

analgesic was provided for use as needed, or as instructed in accordance with the protocol, the 2417

post-dose usage recorded in the diary should be checked against returned supplies. If prior safety 2418

data suggest that pre-vaccination antipyretic use is appropriate, this can be administered and 2419

recorded by trial staff at the vaccination visit and the diary cards should record any post-2420

vaccination doses administered. 2421

2422

At each trial visit, whether involving face-to-face or telephone contact between the trial 2423

subject/caregiver and site staff, the diary cards should be checked for level of completion and 2424

further instructions given as needed to improve data-recording after the next dose is given. At 2425

face-to-face visits the prior vaccination site(s) should be inspected for any remaining signs such 2426

as induration. Trial subjects or caregivers should also be asked about the maximum extent of 2427

signs (e.g. to determine whether whole limb swelling occurred). Any unresolved local or 2428

systemic signs and symptoms should be recorded and action taken as appropriate. 2429

2430

7.2.2.3 Unsolicited adverse events 2431

2432

Trial subjects/caregivers should be questioned at each visit for the occurrence of any AEs since 2433

the last visit or for predefined periods following the last dose. For each AE, the timing of onset 2434

in relation to vaccination should be captured, as should any consultation with a health-care 2435

professional, whether hospitalization occurred and any treatment that was given (prescribed or 2436

non-prescribed). If the AE is not already resolved, there should be further follow-up to document 2437

the outcome. Sponsors may also wish to record any days off school or off work for trial subjects 2438

and days off work for their caregivers. 2439

2440

WHO/BS/2016.2287

It may be useful to pose specific questions to trial subjects/caregivers at each visit to ensure that 2441

certain AEs or AESIs are captured in a systematic fashion – for instance, to determine whether 2442

persistent inconsolable crying or hypotonic hypo-responsive episodes occurred in infants. Where 2443

well-established and widely-applied definitions of these and other AEs are available, they should 2444

be included in the protocol. 2445

2446

For all AEs that meet the criteria for classification as SAEs, there should be careful 2447

documentation of dates of onset, underlying conditions, concomitant medications and adequate 2448

follow-up to record the outcomes. 2449

2450

7.2.2.4 Other investigations 2451

2452

The collection of data on routine laboratory tests (haematology, chemistry and urinalysis) is not 2453

commonly perceived to be necessary in clinical trials with vaccines. If the sponsor or NRA 2454

considers that there is a good rationale for obtaining these data at certain time points, the results 2455

should be generated in appropriately certified laboratories and reported using well-established 2456

grading scales for abnormalities. 2457

2458

For vaccines that contain live organisms (including attenuated wild types, organisms that have 2459

been genetically engineered to render them non-virulent and/or non-replicative, and live viral 2460

vector vaccines), additional investigations related to safety should include the detection of 2461

viraemia and assessments of shedding (quantity and duration) unless the omission of such studies 2462

can be justified (e.g. on the basis of prior experience with the same or very similar strains and/or 2463

nonclinical data). Organisms recovered from vaccinees may also be subject to genetic analyses 2464

to determine any instances of recombination with wild types and reversion to virulence and/or 2465

replication competency. 2466

2467

The release specifications for vaccines should take into account the safety profile documented 2468

for the highest amount(s) of antigen(s) that have been administered in the clinical trials. It may 2469

be necessary to support the final proposed release specification by conducting a trial with the 2470

primary objective of comparing safety between formulations that contain different numbers of 2471

WHO/BS/2016.2287

live organisms or amounts of antigen(s). 2472

2473

7.2.3 Categorization of adverse events 2474

2475

7.2.3.1 Causality 2476

Section 8.5 of WHO’s Global manual on surveillance of adverse events following immunization 2477

(23) recommends that in clinical trials the investigator should make a judgement about 2478

relatedness to vaccination for all solicited signs and symptoms and unsolicited AEs. The sponsor 2479

may have access to additional information that is not available to investigators and should assess 2480

causality for all SAEs. The assessment of relatedness to vaccination should take into account 2481

factors such as: 2482

plausibility of relatedness, taking into account the vaccine construct (for instance, 2483

live attenuated vaccines may be associated with modified manifestations of natural 2484

infection, such as rashes); 2485

timing in relation to dosing (while most vaccine-related AEs occur within 12 2486

weeks of the dose, there may reasons to suspect that illnesses with onset many 2487

months after the last dose could be related to prior vaccination); 2488

concurrent illnesses common in the trial age group, or documented in the case 2489

report form and the anticipated background rates, if known (this is a particular issue 2490

for vaccines administered to infants and young children in whom intercurrent 2491

illnesses are relatively common); 2492

the frequency with which any one AE occurred in groups that received the 2493

candidate vaccine compared to groups that received another vaccine or placebo; 2494

any correlation between rates of any one AE and dose of antigenic components; 2495

changes in rates of any one AE with sequential doses; 2496

the results of medical investigations (e.g. diagnostic tests for concurrent illnesses) 2497

and of autopsies (e.g. in cases of sudden infant death). 2498

2499

7.2.3.2 Severity 2500

2501

WHO/BS/2016.2287

Sufficient data should be collected for each solicited sign and symptom and unsolicited AE in 2502

order to assess severity. Wherever possible, widely-used grading scales, including scales that 2503

may be age-specific, should be used. The same scales should be applied throughout the clinical 2504

development programme. 2505

2506

7.2.3.3 Other categorization 2507

2508

The classification of AEs as serious and the categorization of frequencies should follow 2509

internationally-accepted conventions, as described in Section 3.1.2 of WHO’s Global manual on 2510

surveillance of adverse events following immunization (23). Frequencies of solicited signs and 2511

symptoms by subject and of AEs in each treatment group should be calculated on the basis of the 2512

denominator of all vaccinated subjects in that group. Calculation of the frequencies of solicited 2513

signs and symptoms after each dose should use the number of subjects who received each dose. 2514

2515

7.2.4 Adverse event reporting rates within and between trials 2516

2517

During any clinical development programme the reporting rates in clinical trials for all AEs, 2518

and/or for specific types of AEs, whether solicited or unsolicited, may demonstrate the following: 2519

2520

i) Differences between candidate vaccines and control groups within a clinical trial. For 2521

example, differences in AE rates may be anticipated between a candidate vaccine and a 2522

placebo group or a group that receives a licensed vaccine that does not have a similar 2523

composition to the candidate vaccine. Any marked differences between a candidate vaccine 2524

and a licensed vaccine that has the same or very similar composition are generally not 2525

anticipated and may require further investigation. 2526

2527

ii) Differences between clinical trials that may be observed in one or both of the candidate 2528

vaccine and control groups for total or specific AE reporting rates. It is important to 2529

consider possible explanations, taking into account whether or not the same effect on the 2530

pattern of reporting rates was observed in groups that received candidate vaccines and 2531

licensed vaccines and whether the study was double-blind or open-label. There may be real 2532

WHO/BS/2016.2287

and anticipated differences in vaccine reactogenicity between trial populations (e.g. age-2533

related differences for specific AEs, such as higher fever rates in trials conducted in infants 2534

and toddlers compared to trials in older children and adults). When there is no clear 2535

explanation for the differences observed, further investigation is merited. For instance, there 2536

may have been incomplete reporting of AEs or data entry errors and there could be cultural 2537

issues that lead to greater reluctance to report side-effects in some regions. 2538

2539

7.3 Size of the pre-licensure safety database 2540

2541

The size of the pre-licensure safety database must be considered on a case-by-case basis. It is not 2542

possible to predefine a minimum number that can be generally applied across vaccine 2543

development programmes. 2544

2545

When considering the pre-licensure safety database, the ability of the sample size to estimate AE 2546

rates with precision is an important factor. For instance, a total database of 3000 subjects across 2547

all trials and populations provides a 95% chance of observing one instance of an AE that occurs 2548

on average in 1 in 1000 subjects. Nevertheless, this figure should not be assumed to be 2549

appropriate in all settings. In particular, this figure should not be applied to application dossiers 2550

for any type of new candidate vaccine without further consideration. When considering the size 2551

of the pre-licensure safety database, factors to take into account include (but are not limited to) 2552

the following: 2553

Fewer than 3000 subjects may be acceptable if the new candidate vaccine consists only 2554

of antigenic components that are already licensed in other vaccines with which there is 2555

considerable experience in routine use. The method of manufacture should also be taken 2556

into account. 2557

The total number exposed in clinical trials may cover many age subgroups, or a single 2558

age group may predominate. In general there should be adequate representation of all 2559

target age groups in the total safety database. In some cases, and depending on the actual 2560

safety profile, it may be acceptable for the majority of subjects included in the safety 2561

database to come from a specific age range. 2562

For specific types of vaccines (e.g. innovative constructs, new adjuvants) or specific 2563

WHO/BS/2016.2287

modes of use (e.g. in a population considered to be vulnerable or otherwise at high risk 2564

that could predispose it to certain AEs) individual NRAs may require that considerably 2565

more than 3000 subjects are exposed prior to initial licensure. 2566

Additional considerations may apply to vaccines that contain antigenic components not 2567

previously used in human vaccines but for which efficacy trials are not possible. For 2568

instance, the safety profile documented in the initial trials may lead to reluctance to 2569

expose large numbers of subjects unnecessarily in the absence of an immediate threat 2570

and/or to expose large numbers in particular population subsets. 2571

2572

7.4 Post-licensure safety surveillance 2573

2574

The requirements of individual NRAs for reporting safety data collected from post-licensure 2575

safety surveillance activities should be consulted. NRAs should provide publicly-available 2576

guidance regarding their requirements for the content and timing of periodic reports of safety 2577

data and for any expedited reporting considered necessary. Licence-holders should demonstrate 2578

that they have adequate capability and appropriate staff to collect, interpret and act upon the 2579

safety data received. 2580

2581

It has become routine at the time of initial licensure for detailed proposals to be in place for post-2582

licensure safety surveillance activities, often in the form of risk management plans. These 2583

documents and proposals are then routinely updated at intervals in line with additional data that 2584

become available. The plans usually outline the safety specification for the vaccine on the basis 2585

of all available safety data at the time of submitting each version of the plan, along with details 2586

of routine and proposed additional pharmacovigilance and risk-minimization activities. 2587

2588

When planning pharmacovigilance activities for a vaccine, it is important to take into account 2589

that, in addition to routine pharmacovigilance (i.e. passive surveillance), important information 2590

may come from other sources, namely: 2591

Data from enhanced safety surveillance (active surveillance) activities, which may be put 2592

in place by public health bodies when a vaccine is introduced into a national routine 2593

immunization programme, or when the use of a vaccine within a programme changes 2594

WHO/BS/2016.2287

significantly (e.g. an entirely different age group is vaccinated for the first time). 2595

Large databases that link information in patient records on vaccination history with 2596

occurrence of specific types of illness can be searched to explore links between specific 2597

vaccines and safety issues in the short and longer term. 2598

Various types of registries exist that are intended to capture details of use in specific 2599

populations. For instance, some registries collect information on exposure of pregnant 2600

women to various types of vaccines and indicate the outcome of the pregnancy 2601

(including rates of spontaneous abortion, premature delivery and congenital 2602

malformations in the infants). There are also registries that capture specific types of 2603

disease that could be of relevance to specific types of vaccines. 2604

2605

The limitations of each of these approaches are well known, thus underlining the need to 2606

consider all sources along with additional data that may come from post-licensure trials. 2607

2608

As with other medicinal products, the same vaccine may be marketed by different licence-2609

holders in various countries and regions, so systems need to be in place at the time of licensure to 2610

facilitate rapid sharing of safety information between licence-holders, between licence-holders 2611

and NRAs, and between NRAs. An additional consideration for vaccines is that when a safety 2612

signal is identified for any one vaccine it may or may not be possible to ascribe the AEFIs 2613

observed to any one antigenic component of the vaccine or to an adjuvant. Furthermore, if there 2614

was concomitant administration of vaccines in some or all cases generating the signal, it may not 2615

be possible to ascribe the AEFI to only one of the products co-administered. The same or very 2616

similar antigenic component(s) or adjuvant in the vaccine(s) from which the signal arose may be 2617

present in several other licensed products marketed worldwide. Ultimately, several different 2618

licence-holders and NRAs without established data-sharing agreements may need to be involved. 2619

As a result, the actions taken, if any, and the speed at which action is taken, are sometimes very 2620

variable between countries. These issues underscore the need for efficient use of electronic 2621

databases to facilitate rapid data-sharing. 2622

2623

Authors and acknowledgements 2624

2625

WHO/BS/2016.2287

The first draft of this document was prepared by a WHO drafting group comprising Dr M. 2626

Powell, Medicines and Healthcare Products Regulatory Agency, London, United Kingdom; Dr 2627

R. Sheets, Consultant, Silver Spring (MD), USA; Dr J. McEwen, Medical Adviser, 2628

Therapeutic Goods Administration, Canberra, Australia; Dr I. Knezevic, Department of 2629

Essential Medicines and Health Products, World Health Organization, Geneva, Switzerland; 2630

and Dr V. Moorthy, Initiative for Vaccine Research, World Health Organization, Geneva, 2631

Switzerland, taking into consideration the discussion and consensus reached at the WHO 2632

Consultation on Clinical Evaluation of Vaccines held on 1718 July 2014 in Geneva, 2633

Switzerland, attended by the following participants: 2634

2635

Dr P. Annunziato, Merck & Co., Kenilworth (NJ), USA; Dr N. Bhat, Program for Appropriate 2636

Technology in Health, Seattle (WA), USA; Dr A. Chatterjee, Biological E Ltd., Hyderabad, 2637

India; Dr K. Chirgwin, Bill & Melinda Gates Foundation, Seattle (WA), USA; Dr G. Coleman, 2638

Health Canada, Ottawa, Canada; Dr D. Tuan Dat, The Company for Vaccines and Biological 2639

Production No. 1 (VABIOTECH), Hanoi, Viet Nam; Dr P.E. Fast, International AIDS Vaccine 2640

Initiative, New York (NY), USA; Dr G. Foglia, Sanofi Pasteur, Swiftwater (PA), USA; Dr 2641

U. Fruth, Initiative for Vaccine Research, World Health Organization, Geneva, Switzerland; Dr 2642

M. Gruber, Center for Biologics Evaluation and Research, United States Food and Drug 2643

Administration, Rockville (MD), USA; Dr P.M. Heaton, Bill & Melinda Gates Foundation, 2644

Seattle (WA), USA; Dr D. Kaslow, Program for Appropriate Technology in Health, 2645

Washington (DC), USA; Dr I. Knezevic, Technologies Standards and Norms, World Health 2646

Organization, Geneva, Switzerland; Dr O. Lapujade, Prequalification Team, World Health 2647

Organization, Geneva, Switzerland; Dr Y.H. Lee, Biopharmaceuticals & Herbal Medicine 2648

Evaluation, Ministry of Food & Drug Safety, Chungcheongbuk-do, Republic of Korea; Dr 2649

D.J.M. Lewis, Institute of Biosciences and Medicine, University of Surrey, Guildford, United 2650

Kingdom; Dr A. Lommel, Paul Ehrlich Institute, Langen, Germany; Dr J. McEwen, 2651

Therapeutic Goods Administration, Canberra, Australia; Dr V. Sathiyamoorthy, Initiative for 2652

Vaccine Research, World Health Organization, Geneva, Switzerland; Dr P. Neels, Vaccine-2653

Advice BVBA, Zoersel, Belgium; Dr M. Nijs, GlaxoSmithKline Biologicals, Wavre, 2654

Belgium; Dr S.A. Nishioka, Department of Science and Technology, Ministry of Health, 2655

Brasilia, Brazil ; Dr A. Podda, Novartis Vaccines Institute for Global Health, Siena, Italy; Dr 2656

WHO/BS/2016.2287

M. Powell, Medicines and Healthcare Products Regulatory Agency, London, United Kingdom; 2657

Dr A. Ramkishan, Central Drugs Standard Control Organization, New Delhi, India; Dr R. 2658

Sheets, Consultant, Silver Spring (MD), USA; Dr J. Shin, Expanded Programme on 2659

Immunization, World Health Organization Regional Office for the Western Pacific, Manila, 2660

Philippines; Dr P. Smith, MRC Tropical Epidemiology Group, London School of Hygiene and 2661

Tropical Medicine, London, United Kingdom; Dr J. Southern, Medicines Control Council, 2662

Cape Town, South Africa; Dr Y. Sun, Paul-Ehrlich-Institut, Langen, Germany; Dr K. 2663

Vannice, Initiative for Vaccine Research, World Health Organization, Geneva, Switzerland; Dr 2664

D. Wood, Technologies Standards and Norms, World Health Organization, Geneva, Switzerland; 2665

Dr Z. Yang, Office of Evaluation III, Center for Drug Evaluation, Beijing, China. 2666

2667

The draft document was posted on the WHO website for the first round of public consultation 2668

from 30 October to 30 November 2015. 2669

2670

The second draft was prepared by a WHO drafting group, taking into account comments 2671

received from following reviewers: 2672

2673

Dr B. Fritzell, BFL Conseils, France; Dr G. Chen, National Institutes of Health, Bethesda (MD), 2674

USA; Dr G. Coleman, Health Canada, Ottawa, Canada; Dr Z. Kusynová (provided consolidated 2675

comments of the International Pharmaceutical Federation), The Hague, Netherlands; Dr M. Nijs, 2676

GlaxoSmithKline Vaccines, Wavre, Belgium; Clinical team of Novilia Sjafri and BioFarma, 2677

Indonesia; Dr Y. Sun, Paul-Ehrlich-Institut, Langen, Germany; I. Uhnoo, Uppsala universitet, 2678

Uppsala, Sweden; Dr T. Yamaguchi, Pharmaceutical and Medical Devices Agency, Tokyo, 2679

Japan; Dr K. Zoon, National Institutes of Health, Bethesda (MD), USA. 2680

2681

The draft document was posted on the WHO website for the second round of public consultation 2682

from 1 February to 15 March 2016. Based on the comments received during the public 2683

consultation and the discussion of the Working Group on clinical evaluation of vaccines, on 3rd

2684

May 2016 at WHO, Geneva, the document WHO/BS/2016.2287 was prepared by the above 2685

mentioned WHO Drafting Group, taking into account comments received from above 2686

consultations. 2687

WHO/BS/2016.2287

2688

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