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Working document QAS/20.851 June 2020
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DRAFT WORKING DOCUMENT FOR COMMENTS: 2
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Good reliance practices in regulatory 4
decision-making: 5
high-level principles and 6
recommendations 7
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Please send your comments to Mrs Marie Valentin, Technical Officer, Regulatory Convergence and Networks, Regulation and Safety ([email protected]), with a copy to Mrs Carolyn Doucelin ([email protected]) before 24 July 2020. Please use our attached Comments Table for this purpose.
Our working documents are sent out electronically and they will also be placed on the WHO Medicines website (http://www.who.int/medicines/areas/quality_safety/quality_assurance/guidelines/en/) for comments under the “Current projects” link. If you wish to receive all our draft guidelines, please send your email address to [email protected] and your name will be added to our electronic mailing list.
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© W o rld Health Organization 2020 10
All rights reserved. 11
This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft 12 may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in 13 any form or by any means outside these individuals and organizations (including the organizations' concerned sta ff and member 14 organizations) without the permission of the World Health Organization. The draft should not be displayed on any website. 15
Please send any request for permission to: Dr Sabine Kopp, Team Lead, Norms and Standards for Pharmaceuticals, Technical 16 Standards and Specifications, Department of Health Products Policy and Standards, World Health Organization, CH -1211 Geneva 17 27, Switzerland, email: [email protected]. The designations employed and the presentation of the material in this draft do not 18 imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of an y 19 country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on 20 maps represent approximate border lines for which there may not yet be full agreement. 21
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended 22 by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions 23 excepted, the names of proprietary products are distinguished by initial capital letters. 24
All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. 25
However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibi lit y 26 for the interpretation and the use of the material lies with the reader. In no event shall the World Health Organization be liable 27 for damages arising from its use. 28
This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 29
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Working document QAS/20.851 page 2
SCHEDULE FOR DRAFT WORKING DOCUMENT QAS/20.851: 31
Good reliance practices in regulatory decision-making: 32
high-level principles and recommendations 33
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Description of activity Date
Presentation of the concept to the 53rd Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP).
22-26 October 2018
Consultation with National Regulatory Authorities and regulatory organizations regarding the nature, structure and overall contents of a document outlining Good Reliance Practice was conducted in a meeting in Geneva, Switzerland.
19 September 2019
Presentation and update of the various new activities regarding the development of new good practices in the area of regulatory science to 54th ECSPP.
14-18 October 2019
Development of the Good Reliance Practice working document. Until 31 March 2020
Targeted consultation among participants of the consultative meeting
held on 19 September 2019. 21 April – 15 May 2020
Consolidation of comments received. 18 May – 31 May 2020
First public consultation. 9 June – 24 July 2020
Consolidation of comments received and revision of working document
by WHO. July – August 2020
Second public consultation. August –September 2020
Consolidation of comments received and revision of the working document by WHO.
September – October 2020
Presentation to the 55th ECSPP with a proposal for adoption. 12-16 October 2020
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Working document QAS/20.851 page 3
Good reliance practices in 39
regulatory decision-making: 40
high-level principles and 41
recommendations 42
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1. Acronyms 44
2. Background 45
3. Introduction 46
4. Purpose 47
5. Scope 48
6. Definitions and key concepts 49
6.1 Definitions 50
6.2 Key concepts 51
7. Principles underpinning good reliance practices 52
8. Considerations 53
8.1 General considerations 54
8.2 Barriers 55
8.3 Enablers 56
9. Conclusions 57
References 58
Annex 1: Examples 59
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1. Acronyms 62
63
ACSS Australia-Canada-Singapore-Switzerland Consortium
AMRH African Medical Products Regulatory Harmonisation
APEC Asia-Pacific Economic Cooperation
API Active Pharmaceutical Ingredient
ASEAN Association of Southeast Asian Nations
AVAREF African Vaccine Regulatory Forum
CEP Certificate of Suitability to the monographs of the European Pharmacopoeia
CPQ Confirmation of active pharmaceutical ingredient Prequalification
COFEPRIS Comisión Federal para la Protección Contra Riesgos Sanitarios (Mexico)
CRP Collaborative Registration Procedure
EAC East African Community
ECOWAS Economic Community of West African States
ECSPP Expert Committee on Specifications for Pharmaceutical Preparations
EMA European Medicines Agency
EU European Union
EU-M4 all European Union Medicines for all
GBT Global Benchmarking Tool
GCP Good Clinical Practices
GMP Good Manufacturing Practices
GRP Good Regulatory Practices
GRelP Good Reliance Practices
ICH International Council on Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use
IMDRF International Medical Device Regulators Forum
IPRP International Pharmaceutical Regulators Programme
MAGHP Marketing Authorization for Global Health Products
MERCOSUR Southern Common Market
MDSAP Medical Device Single Audit Program
NRA National Regulatory Authority; for the purpose of this document, this term also
includes regional regulatory authorities such as the European Medicines Agency
(EMA)
Working document QAS/20.851 page 5
OMCL Official Medicines Control Laboratories
PAHO Pan American Health Organization
PANDRH Pan American Network for Drug Regulatory Harmonization
PIC/S Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-
operation Scheme
ASEAN PPWG ASEAN Pharmaceutical Products Working Group
REC Regional Economic Communities in Africa
SEARN South-East Asia Regulatory Network
SADC Southern African Development Community
SRA
UHC
Stringent Regulatory Authority (1)
Universal Health Coverage
WAHO West African Health Organization
WHO World Health Organization
WLA WHO Listed Authorities
WHO-NNB WHO-National Control Laboratory Network for Biologicals
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2. Background 66
67
The World Health Organization (WHO) supports the implementation of reliance on other 68
regulators’ work as a general principle in order to make the best use of available resources and expertise. 69
This principle enables leveraging the output of others whenever possible while placing a greater focus 70
at the national level on value added regulatory activities that cannot be undertaken by other authorities, 71
such as in-country vigilance activities and oversight of local manufacturing and distribution. Reliance 72
approaches facilitate timely access to safe, effective and quality-assured medical products and can help 73
in regulatory preparedness and response, particularly during public heath emergencies. 74
75
Good Reliance Practices (GReIP) are anchored in the overarching Good Regulatory Practices (GRP) (2) 76
which provide a means for establishing sound, affordable and effective regulation of medical products 77
as an important part of health system strengthening. If implemented effectively, GRP can lead to 78
consistent regulatory processes, sound regulatory decision-making, increased efficiency of regulatory 79
systems and better public health outcomes. 80
81
An ongoing initiative at WHO aims at establishing and implementing a framework for evaluating national 82
regulatory authorities (NRAs) and designating those that meet a specific standard as WHO-Listed 83
Authorities (WLAs) (3). Based on benchmarking using the WHO Global Benchmarking Tool (GBT) (4), 84
WHO will assess the NRA’s regulatory performance and maturity level in order to qualify an NRA as a 85
WLA and thereby provide a globally recognized, evidence-based and transparent system that can be 86
used by NRAs as a reference to practise reliance. 87
88
The WHO held a consultative meeting in September 2019 in order to solicit input on the nature, 89
structure and overall content of a document outlining GRelP. The meeting concluded that the Pan 90
American Health Organization (PAHO)/Pan American Network for Drug Regulatory Harmonization 91
(PANDRH) concept note and recommendations on regulatory reliance principles (5) should be used as a 92
starting point for the development of a WHO GRelP document. The high-level document would be 93
complemented in a second step by a repository of case studies, practice guides and examples of practical 94
applications of GReIP. 95
96
97
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3. Introduction 98
99
The United Nations Sustainable Development Goals and the drive for Universal Health Coverage (UHC) 100
require that patients have access to quality-assured medical products, hence, strong regulatory systems 101
for medical products remain a critical element of well-functioning health systems and an important 102
contributor to improving access and ultimately achieving UHC. 103
104
It is widely recognized, however, that regulatory systems can be very resource-intensive. Establishing 105
and sustaining mature regulatory systems is a high resourced enterprise that requires skilled human 106
resources and significant public investments. Moreover, the globalization of markets, the sophistication 107
of health technologies, the rapid evolution of regulatory science and the increasing complexity of supply 108
chains have led regulators to recognize the importance of international cooperation in order to ensure 109
the safety, quality and efficacy of locally used products. In view of the extent and complexity of 110
regulatory oversight required to address these challenges, NRAs must consider enhanced, innovative 111
and more effective forms of collaboration in order to make the best use of the available resources and 112
expertise, avoid duplication and concentrate their regulatory efforts and resources where most needed. 113
114
Reliance represents a smarter way of regulating medical products in a modern regulat ory world. 115
Towards this end, countries are encouraged to formulate and implement strategies to strengthen their 116
regulatory systems consistently with GRP, including pursuing regulatory cooperation and convergence, 117
as well as reliance. Reliance brings benefit to the industry, patients and consumers, national 118
governments, as well as the donor community, and international development partners by facilitating 119
and accelerating access to quality medical products. 120
121
There is a long history of enhancing the efficiency of regulatory systems through reliance. The WHO 122
Certification scheme on the quality of pharmaceutical products moving in international commerce (6), 123
introduced by WHO in 1969, is a form of reliance providing assurance to countries participating in the 124
Scheme about the quality of pharmaceutical products. The European Union (EU) introduced the mutual 125
recognition procedure for marketing authorizations between Member States in 1995, and outcomes of 126
Good Manufacturing Practice (GMP) inspections have been shared for years in the context of the 127
Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme (PIC/S) and 128
mutual recognition agreements. 129
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The use of reliance was more recently investigated by WHO through a survey conducted on behalf of 130
the International Pharmaceutical Regulators Programme (IPRP) (7). The results showed that regulatory 131
reliance is a broadly accepted and widely practiced approach in the area of medical products, especially 132
among the participating well-resourced regulatory authorities. At the same time, responses also 133
reflected an evolving situation marked by varying degrees of experience and promise in the use of 134
reliance-based approaches. While the use of reliance in some regions may be characterized as an 135
emerging trend, the commonly stated goals are to bring efficiency, to help strengthen regulatory 136
systems and to optimize the use of resources. The results and suggestions from this survey were taken 137
into account for the preparation of this document. 138
139
Given the increased prevalence and importance of reliance in the regulation of medical products, 140
countries have requested WHO to develop practical guidance on the topic while ensuring that 141
approaches meet the intended objectives. This document, and the companion documents that will 142
follow, are intended to assist countries in implementing a sound, evidence-based and effective approach 143
to reliance. 144
145
4. Purpose 146
147
The objective of this document is to promote a more effective and efficient approach to regulation as 148
part of a “smart regulation” approach, thereby promoting access to quality-assured medical products. 149
150
It aims at presenting the overarching principles under which regulatory reliance in the field of oversight 151
of medical products should operate and use reliance as a tool for effective regulation and regulatory 152
system strengthening. 153
154
This document is intended to provide high-level guidance, definitions, key concepts and considerations 155
in order to guide reliance activities, illustrative examples of reliance approaches and conclusions. It will 156
be complemented by a “reliance toolbox” consisting of practice guides, case studies and a 157
comprehensive repository of examples. 158
159
160
161
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5. Scope 162
163
This document covers reliance activities in the field of regulatory oversight of medical products 164
(i.e. medicines, vaccines, blood and blood products and medical devices including in-vitro diagnostics), 165
addressing all regulatory functions spanning the full life cycle of a medical product. 166
167
In addition, this document is intended for all NRAs, irrespective of their level of maturity or resources, 168
as well as policy makers, governments, the industry and other developers of medical products, and other 169
relevant stakeholders. 170
171
6. Definitions and key concepts 172
173
6.1 Definitions 174
175
Definitions are essential to ensure a common understanding of concepts and clarity in interpreting 176
guidance related to reliance. In addition to the definitions provided below, reference is made to the 177
WHO Guideline on good regulatory practices: Guidelines for national regulatory authorities for medical 178
products (2), which includes definitions for harmonization, convergence and other relevant terms. 179
180
abridged regulatory pathways. Abridged regulatory pathways are regulatory procedures facilitated by 181
the use of reliance, whereby the regulatory decision is solely or widely based on the application of 182
reliance. Normally this would also involve some degree of work by the relying NRA (see “risk-based 183
approach”, p. 13 ). The expectation is that the use of reliance in these pathways would save resources 184
and shorten the timelines compared to the standard pathways, while ensuring that the standards for 185
regulatory oversight are maintained. 186
187
assessment. For the purpose of this document, the term “assessment” covers the outcome of any 188
evaluation conducted for a regulatory function (e.g. evaluation for a clinical trial application, evaluation 189
of an initial authorization for a medical product or any subsequent post-authorization changes, 190
evaluation of safety data, evaluation as part of an inspection, etc.). 191
192
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equivalence of regulatory systems. Equivalence (or comparability) of regulatory systems implies a high 193
degree of similarity between two regulatory systems as established and documented through objective 194
evidence. Equivalence can be established using criteria and approaches such as similarity of the 195
regulatory framework and practices, adherence to the same international guidelines and standards, 196
experience gained through the use of assessments for regulatory decision-making, joint activities and 197
exchange of staff, among others. The expectation is that equivalent regulatory systems should lead to 198
similar standards and levels of regulatory oversight or “level of control”. 199
200
joint activity. A joint activity is a process whereby a regulatory function is conducted by two or more 201
NRAs in collaboration in order to share their assessments, benefit from each other’s expertise and 202
discuss any shortcomings of the data being evaluated. For example, a joint assessment is a procedure 203
in which the same application is simultaneously submitted to two or more NRAs in order for the 204
(assigned) NRAs to conduct their evaluations in parallel and share their respective scientific assessments 205
with each other. The NRAs participating in the joint assessment can combine their list of questions or 206
deficiencies to send to the manufacturer and base their respective independent regulatory decision on 207
the outcome of these assessments. Similarly, a joint inspection is an inspection involving two or more 208
NRAs sharing the activities and assessment performed during an inspection. 209
210
recognition. The acceptance of the regulatory decision of another regulator or other trusted institution. 211
Recognition should be based on evidence of conformity that the regulatory requirements of the 212
reference regulatory authority is sufficient to meet the regulatory requirements of the relying authority. 213
Recognition may be unilateral or mutual and may, in the latter case, be the subject of a mutual 214
recognition agreement. 215
216
reference regulatory authority. For the purpose of this document, the reference regulatory authority is 217
a national or regional authority being relied upon by another regulatory authority. 218
219
reliance. The act whereby the NRA in one jurisdiction may take into account and give significant weight 220
to assessments performed by another NRA or trusted institution, or to any other authoritative 221
information in reaching its own decision. The relying authority remains independent, responsible and 222
accountable regarding the decisions taken, even when it relies on the decisions and information of 223
others. 224
225
226
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work-sharing . Work-sharing is a process by which NRAs of two or more jurisdictions share activities to 227
accomplish a specific regulatory task. The opportunities for work-sharing include but are not limited to: 228
jointly assessing applications for authorization of clinical trials, marketing authorizations or product 229
manufacturing site inspections, joint work in the post-marketing surveillance of medical product quality 230
and safety, joint development of technical guidelines or regulatory standards, and collaboration on 231
information platforms and technology. Work-sharing also entails the exchange of information 232
consistent with the provisions of existing agreements and compliant with each agency's or institution’s 233
legislative framework for sharing such information with other NRAs. 234
235
6.2 Key concepts 236
237
The diagram below illustrates some of the key concepts explained in the document, notably how NRAs 238
can gain efficiencies in their regulatory operations and how they avoid duplication by increasing the use 239
of reliance approaches. 240
241
242
243
244
245
246
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reliance versus recognition. Reliance may take many forms and reflect varying degrees of application in 247
recognizing or taking account of the assessments, decisions or any other authoritative information 248
available from other authorities and institutions. Recognition may be seen as a special and more 249
complete form of reliance whereby one regulatory authority relies on the decisions of another 250
regulatory authority, system or institution, obviating the need for additional regulatory assessment in 251
reaching its own decision. Recognition usually requires formal and enabling legal provisions. 252
253
unilateral vs. mutual reliance/recognition. Reliance can be unilateral, for example, when a country 254
chooses to rely on the assessment from another country unilaterally and without reciprocity. In other 255
cases, reliance may be based on binding mutual agreements or treaties negotiated at the level of 256
governments. These agreements may take considerable time and resources to set up as the regulatory 257
systems involved need to be mutually assessed and shown to be equivalent before implementation. The 258
demonstration of equivalence (or comparability) of regulatory systems is normally a prerequisite to 259
mutual reliance and recognition. 260
261
life cycle approach. The concept of reliance for regulatory oversight of medical products can be applied 262
across the full life cycle of medical products, from clinical trial authorization to marketing authorization, 263
including post-authorization procedures, vigilance, inspections, testing and lot release. While reliance 264
approaches are widely used for the initial authorization of medical products, it is equally important to 265
consider the use of reliance for pharmacovigilance and post-authorization activities given the substantial 266
regulatory resources required for evaluating safety and variations over the product life cycle. Reviewing 267
post-authorization changes to a product approved by a different authority may present some challenges. 268
Therefore, if an NRA has relied upon another NRA’s decision for its initial approval, there is a strong 269
benefit for similar reliance measures for post-authorization changes and pharmacovigilance activities. 270
This also avoids the situation of different changes being accepted in the originating and receiving 271
countries over time. 272
273
Reliance has also been shown to offer significant advantages in avoiding duplication in the field of 274
inspections and lot release between countries. 275
276
risk-based approach. Each NRA should define its own strategy regarding the appropriate risk-based 277
approach to reliance that considers factors, such as the type and source of products evaluated, the level 278
of resources and expertise available in the NRA, the public health needs and priorities of the country, 279
Working document QAS/20.851 page 13
and opportunities for reliance. Using marketing authorization as an example, one could envisage four 280
models and levels of reliance involving an increasing degree of additional assessment by the relying NRA: 281
• Confirmation of sameness of the product to ensure that the medical product is the same as the 282
one that had been assessed by the reference regulatory authority. 283
• Verification of applicability of the assessment outcomes of another authority for regulatory 284
decision-making in the national context, for example, in terms of legal and regulatory settings, 285
benefit-risk assessment, unmet medical needs, risk management plans and any quality-related 286
specificities such as climatic zones for product stability. 287
• Abridged assessment of the quality, safety and efficacy/performance data taking into account 288
information in the assessment reports of the reference regulatory authority. 289
• Joint assessment or work-sharing between two or more regulatory authorities. This could take 290
various forms, including a primary review by one authority followed by a joint assessment 291
session to finalize the assessment report and comments, or a distribution of the different 292
modules (quality, non-clinical and safety/efficacy) between authorities. 293
294
Similar models can also be developed or used for other regulatory functions (e.g. inspection). 295
296
regional reliance mechanisms. In some regions, an assessment for medical products can be conducted 297
centrally based on a regional regulatory system for a group of countries. The decision is then 298
implemented in all the countries that are part of the regional system, such as the authorization system 299
in the EU, the Gulf Health Council (GHC) and the Caribbean Regulatory System (CRS). 300
301
7. Principles underpinning good reliance practices 302
303
In developing a strategy on the use of reliance in regulatory functions, an NRA should consider possible 304
approaches in the context of the needs and characteristics of the national health and regulatory system. 305
The decision to practise reliance should take into consideration the existing capacities, regulatory 306
systems’ needs, the availability of an authority that the NRA can rely upon with confidence, and how 307
reliance can complement these capacities to drive efficiencies and the optimal use of resources. 308
Reliance is not a lesser form of regulatory oversight but rather a strategy seeking to make the best use 309
of the available resources in any given setting. This would allow the allocation of resources to other 310
areas of regulatory functions, such as vigilance and post-authorization activities, and increase the 311
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effectiveness of the local regulatory oversight. In addition, reliance can lead to more evidence-based 312
and better quality decisions. 313
314
The following principles are meant to complement and expand upon the basic principles of GRP and are 315
based on the principles presented in the PAHO/ PANDRH concept note and recommendations on 316
regulatory reliance principles (5). 317
318
a) Universality 319
320
Reliance applies to all NRAs irrespective of their levels of maturity or resources. Lack of resources or 321
capacity are not the exclusive drivers for reliance. Indeed, reliance is relevant for all resource settings, 322
representing an increasingly important mechanism for improving regulatory efficiency and effectiveness. 323
324
b) Sovereignty of decision-making 325
326
The decision to practise reliance, and how best to implement reliance, rests with the country. Reliance 327
does not imply dependence. In applying reliance in their daily practice, NRAs maintain independence, 328
sovereignty and accountability in regulatory decision-making. 329
330
c) Transparency 331
332
Transparency is a key enabler to adopting new, more efficient ways of conducting regulatory operations, 333
both locally and internationally. NRAs should be transparent regarding the standards, processes and 334
approaches adopted in implementing reliance measures. In addition, the basis and rationale for relying 335
on a specific entity should be disclosed and fully understood by all parties. 336
337
Furthermore, it is incumbent upon NRAs to practise transparency in regulatory operations and decisions, 338
not only as a fundamental principle of GRP and “open government”, but also towards building trust and 339
maximizing opportunities for cooperation and reliance as part of a shared regulatory community 340
responsibility. In other words, regulatory authorities are an increasingly important audience and 341
beneficiaries of measures that promote transparency in regulation through the publishing and sharing 342
of regulatory information. 343
344
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d) Respect of national and regional legal basis 345
346
Reliance practices should be coherent with national and regional legal frameworks and medical 347
products’ policy and supported by clear mandates and regulations that enable the efficient 348
implementation of reliance as part of government policy on good regulat ion. The driving force behind 349
the adoption of these legal frameworks should be the efficiencies and capacity to be gained by reliance, 350
not the minimization of resources for regulatory functions. Where regulations giving explicit legal 351
footing and visibility to reliance practice do not exist, reliance may still be adopted through the 352
interpretation of existing regulations provided that the legal framework does not preclude the 353
application of reliance approaches by the NRA. Implementing reliance can be done through policy 354
changes as long as it is broadly consistent with the legislation. If prohibitions to apply reliance exist, 355
they should be considered for revision. 356
357
e) Consistency 358
359
Reliance on a specific assessment or decision from another authority should be established for specific 360
and well-defined categories of products and processes. The scope of regulatory activities where reliance 361
may be practised should be clearly defined and the process for practising reliance should be transparent 362
and predictable. Thus, it is expected that reliance shall be applied consistently for products/processes 363
in the same predetermined categories. 364
365
f) Competency 366
367
The implementation of reliance approaches requires that NRAs have built the necessary competencies 368
for critical decision-making. Setting up the reliance approach will normally require the involvement of 369
senior regulatory staff and managers who are competent to make the best use of foreign information 370
in the local context. NRAs should also maintain the appropriate scientific expertise of their staff needed 371
for activities where they do not apply reliance, for example, such as in post-marketing surveillance 372
activities. 373
374
Equally, authorities being relied upon should possess and maintain competencies and operate within a 375
robust and transparent regulatory system, underpinned by international standards and practices as well 376
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as a well-functioning quality system. Competencies may be benchmarked using transparent processes 377
to develop trust and build confidence in the reference authorities. 378
379
8. Considerations 380
381
A number of considerations can guide reliance approaches and facilitate their successful 382
implementation. These considerations include general aspects as well as barriers that NRAs need to 383
overcome and enablers that will help in implementing reliance approaches. The non-exhaustive list of 384
considerations presented below will be further elaborated in the case studies, practice guides and the 385
reliance repository. 386
387
8.1 General considerations 388
389
a) Reliance anchored in a national regulatory authority strategy 390
391
In addition to having a legal basis supporting, or at least not precluding reliance approaches (see above 392
under “Principles underpinning good reliance practices”), the application of reliance should be anchored 393
in the NRA’s strategy, endorsed by senior management and in the respective higher-level National Policy 394
in order to provide a mandate, direction and expectations to NRA staff, guiding them in their day-to-day 395
work. The strategy should be further detailed in procedures and integrated in processes to ensure that 396
maximum benefits accrue. It should also include considerations on a sustainable funding model for the 397
NRA when implementing reliance. The strategy should be published in order to make it accessible and 398
understandable to external stakeholders. Additionally, the implementation of reliance should be 399
supported by training and periodic reviews in order to ensure that standards are being maintained, to 400
assess whether or not objectives are being met, and to make refinements where warranted. 401
402
NRAs that are practising reliance should establish and publish a list of reference regulatory authorities 403
together with the criteria used for identifying them. In order to qualify reference regulatory authorities, 404
an NRA may refer to an assessment performed by an independent organization (e.g. WHO 405
Benchmarking, International Organization for Standardization (ISO) accreditation, etc.). 406
407
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WHO encourages NRAs to monitor and evaluate the impact of regulatory reliance in their country and 408
region and to share their experiences with other regulatory authorities. Where possible, specific 409
measurement of the impact of reliance is encouraged, for example, in terms of cost savings, efficiencies 410
in the number of products reaching markets, a redirection of scarce resources to areas of higher 411
regulatory risks, and so on. 412
413
b) Cultural change 414
415
The implementation of reliance approaches means moving to a more innovative, effective way of 416
working, based on trust and relying on other NRA outputs. It is essential that the benefits of the strategy 417
be understood and supported at the operational level and that staff expected to implement reliance 418
approaches have input into their development. 419
420
This will require effective preparation, messaging and support from management and peers that 421
articulates the importance of reliance in better addressing workload pressures without minimizing the 422
rigor of regulatory work or causing the loss of scientific and regulatory competence and capacity. In fact, 423
the use of assessments and information from other trusted regulatory authorities can help build capacity 424
and competence (e.g. through networking, twinning, staff visits/staff exchanges, etc.). Furthermore, 425
the effective use of such information within the local context requires skills, ability and experience. Thus, 426
the skill set needed to practice reliance will need to be developed in the NRA’s workforce. 427
428
It also requires that upper management, reviewers, inspectors and other staff build confidence and trust 429
in work that has been done by other NRAs or trusted authorities. Building trust in other NRAs’ work 430
requires time and a change in the culture within the relying NRA. Some regulatory authorities and 431
systems already practise reliance and that experience should be leveraged to promote acceptance and 432
avoid pitfalls. 433
434
Trust should also be built with the public and healthcare professionals in order to inform and assure 435
them that the use of reliance offers a more efficient and effective regulatory oversight. 436
437
438
439
440
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c) Flexibility in approach: “one size doesn’t fit all” 441
442
Following the principles listed above, reliance strategies should be tailored to the needs of the national 443
health and regulatory systems. NRAs may choose to rely on others as part of their routine regulatory 444
oversight and/or during special circumstances such as public health emergencies. Reliance is a tool 445
offering flexibility to NRAs. Whatever the approach, the NRA needs to consider its own capacities and 446
to establish clear goals when adopting reliance. 447
448
d) Implementing reliance needs investment 449
450
As stated above, reliance should increase the efficiency and effectiveness of a regulatory system in a 451
country and/or region. Nevertheless, it is important to recognize that the implementation of reliance 452
approaches will first require time and investment. This may include but may not be limited to: legislative 453
changes and the development of guidance documents, the development of approaches and elaboration 454
of procedures and processes, confidence-building through parallel or joint reviews and supported by 455
staff exchanges, the training of staff, dialogue with industry and other stakeholders, as well as the 456
establishment of, or access to, information-sharing platforms. To the best extent possible, the use of 457
publicly available information should also be pursued. 458
459
e) “Sameness” of the product in different jurisdictions 460
461
One of the most critical aspects when applying reliance is the verification of the “sameness” of the 462
medical product in different jurisdictions. Reliance can only be applied if the NRAs have the assurance 463
that the medical product assessed by the reference regulatory authority is the same as the one 464
submitted to the NRA, intending to use a foreign assessment as the basis for its own assessment and 465
regulatory decision-making. The role of the manufacturer is essential here in order to confirm the 466
sameness of a product and to provide the same documentation to different NRAs. As part of the process, 467
the manufacturer should confirm in the application that the product is the same and that the dossier 468
contains the same information as much as possible, taking into consideration any potential national 469
requirements. 470
471
When addressing the sameness of the medical product, all relevant aspects have to be considered in 472
order to confirm that the product is the same (e.g. same qualitative and quantitative composition, same 473
Working document QAS/20.851 page 19
strength, same pharmaceutical form, same manufacturing process and site of production, etc.). 474
Additionally, supporting safety, efficacy and quality studies, indications and conditions of use, and so on, 475
should be the same. The impact of potential justified differences should be assessed by the 476
manufacturer and the relying NRA in determining the merit of using foreign regulatory reports or 477
decisions. 478
479
f) The role of industry 480
481
Industry plays a crucial role in the successful application of reliance mechanisms by NRAs. While industry 482
is widely supportive of reliance as a concept and practice that can bring about efficiency gains, industry 483
must also have clear guidance on its application and see meaningful benefits. 484
485
Industry’s support and stringent adherence to the factors that give validity to the reliance process is vital 486
for filing applications in multiple countries or regions, ensuring the sameness of products submitted to 487
reference regulatory authorities and relying NRAs, and sharing unredacted and complete information. 488
489
g) Reliance in case of a public health emergency 490
491
In case of a public health emergency, reliance approaches represent an even more essential tool and 492
should be applied to accelerate access to medical products needed in the context of the emergency. 493
494
8.2 Barriers 495
496
a) Lack of political will 497
498
The lack of political will and support at government level can make it difficult for NRAs to implement 499
reliance in their daily practice, even if a legal basis is established supporting (or not precluding) reliance 500
and NRAs’ support reliance as a strategy and approach. 501
502
503
504
505
Working document QAS/20.851 page 20
b) Lack of accessible information and confidentiality of information 506
507
The lack of access to assessments of reference regulatory authorities can pose a major barrier to 508
implementing effective reliance strategies. Reference regulatory authorities should strive to make 509
assessments and other regulatory information publicly available whenever possible. 510
511
Sensitive, non-public information included in unredacted assessment or inspection reports can also be 512
shared between regulatory authorities upon request. This may include confidential, commercial, trade 513
secret or personal information. In some circumstances, the sharing of such information may require the 514
prior consent of the manufacturer. Given the sensitivity of such information, NRAs may require that 515
confidentiality agreements be signed which govern the exchange, management and disclosure of such 516
information. Such information should always be exchanged using secure channels or information-517
sharing platforms. 518
519
Non-public regulatory reports might also be obtained directly from the manufacturer when the 520
company is able to access these reports from the reference regulatory authority. In that case, 521
manufacturers are encouraged to submit complete and unredacted reports to NRAs. 522
523
c) Other considerations 524
525
Additional barriers can include language, differences in country-specific regulatory requirements and 526
evidentiary standards, the level of detail in regulatory reports and, as previously noted, internal 527
resistance and insufficient knowledge of the reference regulatory authority and how it operates. All 528
such factors should be considered in developing the appropriate reliance strategies, as will be further 529
elucidated in the companion documents to follow. 530
531
8.3 Enablers 532
533
a) Trust 534
535
Trust is a critical element since the reliance requires confidence that the regulatory outcome is based 536
on strong regulatory processes and standards and is, thus, trustworthy. Consequently, initiatives that 537
Working document QAS/20.851 page 21
foster trust among regulatory authorities are essential to promoting reliance . Trust comes from 538
increasing familiarity and understanding in what stands behind regulatory outputs. By sharing 539
information, including the standards applied to regulatory decisions, working together and learning each 540
other’s ways of working, confidence can be built which thereafter leads to the effective use of reliance 541
in regulatory work. Trust can be built in phases, starting with reliance using the exchange of reports and 542
moving to work-sharing or joint assessments. Regulatory authorities may also consider using 543
applications of lower risk to initiate reliance processes. 544
545
b) Convergence and harmonization 546
547
Convergence and the harmonization of requirements and standards are important enablers of 548
regulatory cooperation and reliance. The more requirements and standards are alike, the more 549
opportunity for collaboration and reliance exists. 550
551
The differences in standards and practices, however, do not prevent one authority from relying on 552
another, particularly when the relying authority has limited capacity and expertise. The system upon 553
which an NRA relies should be at least equivalent to or superior to the standards it applies. As a matter 554
of good practice, NRAs should preferably rely on assessments or decisions from reference regulatory 555
authorities that apply international standards and guidelines (e.g. guidelines of the International Council 556
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), WHO 557
guidelines). 558
559
c) Information-sharing and dialogue between regulators 560
561
Information-sharing is an essential part of reliance and NRAs are encouraged to share information and 562
good practices with other NRAs as much as possible. The increasing dialogue between regulators is seen 563
in the growing number of international initiatives such as the IPRP or the International Conference of 564
Drug Regulatory Authorities (ICDRA), as well as regulatory information- and work-sharing networks such 565
as PANDRH, the South-East Asia Regulatory Network (SEARN), regulatory networks in the Regional 566
Economic Communities (RECs) under the African Medicines Regulatory Harmonisation (AMRH) Initiative 567
or the Association of Southeast Asian Nations (ASEAN) Pharmaceutical Products Working Group (PPWG), 568
and so on, which are great facilitators for reliance. 569
570
Working document QAS/20.851 page 22
d) Economic or legal integration 571
572
In situations where there is economic or legal integration in a region or for a group of countries, reliance 573
is facilitated and strengthened by the existing mutual provisions, such as the EU, the Eurasian Economic 574
Union, RECs in Africa, ASEAN, the Asia-Pacific Economic Cooperation (APEC) or the Southern Common 575
Market (MERCOSUR). 576
577
e) Engagement of stakeholders 578
579
All relevant stakeholders, including industry, healthcare professionals, policy makers and the public, 580
should be engaged and/or informed in order to increase the understanding and acceptance of reliance 581
approaches as they present some clear benefits for all parties involved. Communications and 582
engagement with stakeholders should be tailored to the target audience. 583
584
9. Conclusions 585
586
Reliance is seen by a growing number of regulatory authorities as an important means of improving the 587
efficiency and effectiveness of regulatory operations in the oversight of medical products. It allows 588
NRAs to make the best use of resources, build capacity, increase the quality of regulatory decisions, 589
reduce duplication of effort and, ultimately, promote access to safe, efficacious and quality-assured 590
medical products. By adopting reliance measures whenever possible within a well-structured 591
framework, underpinned by national or regional policies and strategies, regulators may focus their 592
resources on key activities that cannot be undertaken by others and that contribute to public health. 593
594
Reliance represents a “smarter” form of regulation based on constructive regional and international 595
collaboration, one that will also facilitate and promote convergence and the use of common 596
international standards. 597
598
Reliance does not represent a less stringent form of regulation nor an outsourcing of regulatory 599
mandates or a compromise to independence. On the contrary, the decision to “regulate through 600
reliance” is the hallmark of a modern and efficient regulatory authority. 601
602
Working document QAS/20.851 page 23
The inclusion of reliance-related provisions as part of their flexible regulatory pathways is encouraged 603
and should be considered for all regulatory functions over the medical product life cycle, as appropriate. 604
The principles and considerations presented in this document should be taken into consideration when 605
implementing regulatory reliance frameworks or strategies. While reliance may be viewed as a 606
particularly useful strategy for regulatory authorities with very limited resources and capacity, it is 607
equally relevant for well-resourced NRAs. It is an approach to be used by all NRAs and, as such, should 608
become an integral part of regulatory operations and regulatory lexicon. 609
610
611
Working document QAS/20.851 page 24
Annex 1: Examples 612
613
Regulatory reliance can take many forms and encompasses a broad array of regulatory approaches and 614
practices that can involve two or more regulatory authorities. In addition, it can be limited to a discrete 615
regulatory process or function or include the full scope of regulatory functions over the entire life cycle 616
of a medical product. 617
618
There are many examples around the world that illustrate the current use of reliance and the diverse 619
models in which national regulatory authorities (NRAs) leverage the work done by others. 620
621
Examples are given below to illustrate the different points addressed in this document and to show the 622
use of reliance in the different regulatory functions. The list below is not exhaustive but just an 623
illustration of the current practices of reliance taking place globally. It may be replaced in future by a 624
comprehensive repository of reliance approaches to be established as a part of the Good Reliance 625
Practices (GRelP) toolbox. 626
627
a) Clinical trials 628
629
Work-sharing for clinical trial assessment is happening in some regions, such as the Voluntary 630
Harmonisation Procedure in the European Union (8) and via the African Vaccine Regulatory 631
Forum (AVAREF) (9). By assessing clinical trial applications together, NRAs, and in some cases ethic 632
committees from different countries, can benefit from the assessments performed by the different 633
participating countries with a view to facilitating and ensuring the robustness of the approval process 634
across countries. The AVAREF platform has been instrumental in building the capacity of regulators and 635
ethics committees, promoting the use of international standards and expediting clinical trial 636
assessments and decisions for medical products of high public health interest in both emergency and 637
normal circumstances. Towards this end, a guideline and platform for joint assessment of clinical trials 638
applications, as well as Good Clinical Practices (GCP) site inspections, have been developed and 639
implemented in order to facilitate product development, regulatory decision-making and access to 640
promising new medical products. 641
642
643
644
Working document QAS/20.851 page 25
b) Marketing authorization 645
646
Abridged regulatory pathways using reliance for initial marketing authorization 647
648
Several pathways are available through stringent regulatory authorit ies (SRAs) or the World Health 649
Organization (WHO) in order to enable the use of an abridged reliance pathway. The EU Article 58, also 650
referred to as European Union Medicines for all (EU-M4 all) (10), the Swissmedic Marketing 651
Authorisation for Global Health Products (MAGHP) (11) procedures and the WHO Collaborative 652
Registration Procedure (CRP) (12) are three examples of abridged regulatory pathways using reliance to 653
facilitate the registration of medicinal products in target countries. 654
655
In addition to facilitating in-country registration, the EU Article 58 and the Swissmedic MAGHP 656
procedures provide experts from target NRAs the opportunity to both observe and participate actively 657
in the assessment procedures, with the aim of building their own capacities and to establish confidence 658
in the processes. 659
660
The CRP facilitates the assessment and accelerates the national registration of WHO prequalified 661
medical products and medicines approved by an SRA. The CRP operates by providing unredacted 662
assessment, inspection and performance evaluation (in the case of in vitro diagnostics) reports upon 663
request (and with the consent of the manufacturer) to participating NRAs, primarily in low- and middle-664
income countries. The procedures are detailed in WHO guidelines, which also include guidance on how 665
receiving NRAs can make the most efficient use of the reports in reaching their own decisions. 666
Participating NRAs are expected to reach a decision on authorization within 90 calendar days (regulatory 667
time). The CRP tool has shown to be successful in both accelerating decisions in countries and building 668
the capacity of regulatory authorities. 669
670
Quality information 671
672
Many NRAs, as well as the WHO Prequalification Programme (WHO PQ), recognize Certificates of 673
Suitability to the monographs of the European Pharmacopoeia (CEP) (13) for active pharmaceutical 674
ingredients (API) as a validation of the quality of a certain API. Some countries also recognize the 675
Confirmation of API Prequalification (CPQ) issued by the WHO PQ for APIs (14). These two examples not 676
only provide assured mechanisms of reliance, but also reduce the documentation requirements for 677
Working document QAS/20.851 page 26
countries that recognize these certificates. Where a CEP or CPQ is issued, the receiving NRA does not 678
have to duplicate the API assessment but can focus on specific sections not covered under CEP or CPQ. 679
680
Work-sharing 681
682
The Australia-Canada-Singapore-Switzerland Consortium (ACSS Consortium) (15) is a coalition which 683
was formed in 2007 by “like-minded” medium-sized regulatory authorities in order to promote work-684
sharing based on greater regulatory collaboration and the alignment of regulatory requirements. The 685
ACSS Consortium explores opportunities for information- and work-sharing initiatives in areas including 686
biosimilar products, complementary medicines, generic medicines, new prescription medicines, medical 687
devices and information technology. The Consortium capitalizes on each country's area of strength, 688
addresses gaps in science, knowledge and expertise and leverages resources to help expedite risk 689
assessment processes, all the while maintaining or raising quality and safety standards. The Consortium 690
builds on existing international networks, initiatives and mechanisms in order to advance work- and 691
information-sharing along health product life cycles. 692
693
Joint assessments 694
695
Joint assessments can provide significant benefits to NRAs by sharing the workload, building capacity by 696
bringing broader experience and expertise to bear, and helping to build trust in one another’s 697
assessments and decision-making processes. Similarly, industry can benefit from a common review 698
process and set of questions in terms of both resource and time-savings as compared to interacting 699
separately with multiple countries. In recognition of these benefits, a growing number of joint 700
assessment initiatives have been established within the framework of regional regulatory networks, 701
sometimes driven by the higher-level priorities of economic blocks seeking to create common markets. 702
Examples of joint assessments initiatives include, for example, those in the Regional Economic 703
Communities in Africa (East African Community (EAC) (16), ZAZIBONA (17) in the Southern African 704
Development Community (SADC), the Economic Community of West African States (ECOWAS)/West 705
African Health Organization (WAHO) (18), as well as the Association of Southeast Asian Nations (ASEAN) 706
Joint Assessment Coordinating Group (19), and so on. 707
708
709
710
711
Working document QAS/20.851 page 27
Unilateral recognition 712
713
The Mexican Federal Commission for the Protection against Sanitary Risk (COFEPRIS) has implemented 714
a unilateral recognition of marketing authorizations from reference regulatory authorities (20). This 715
Agreement recognizes the requirements and procedures authorized by the reference health authorities 716
as being equivalent for the purposes of evaluation of the marketing authorization applications for 717
allopathic medicinal products, biological medicinal products, vaccines and blood products in Mexico. 718
719
Mutual recognition 720
721
The EU system is an example of highly integrated regulatory cooperation and its multiple regulatory 722
pathways depend heavily on work-sharing, recognition and other forms of reliance. The various routes 723
to the approval of medicines in the EU system are based on a single assessment system so that any 724
assessment report from any of the agencies in the EU network can be used as a basis for reliance by 725
other regulators. In this specific case, a strong and common legal framework and harmonized regulatory 726
standards shared among all EU countries enabled and facilitated reliance. 727
728
c) Post-authorization procedures 729
730
When an NRA has relied upon another NRA for their initial approval, similar reliance measures should 731
be considered for post-authorization changes such as variations. In the case of CRP, for example, the 732
participating NRAs for prequalified products are informed by WHO of any variations approved by WHO 733
Prequalification Team. 734
735
d) Testing and lot release 736
737
Network of Official Medicines Control Laboratories 738
739
The Network of Official Medicines Control Laboratories (OMCLs) support regulatory authorities in 740
controlling the quality of medicinal products available on the market. Collaboration within the Council 741
of Europe’s General European OMCL Network (GEON) (21) makes the best use of resources via resource 742
pooling and avoids duplication of work or testing. Some of the main goals of the Network are to set 743
Working document QAS/20.851 page 28
mutual recognition, within the members of the networks, of tests carried out by OMCLs at the national 744
level, coordinate activities among the OMCLs, and facilitate knowledge and work-sharing. 745
746
Lot release and quality monitoring of vaccines and other biotherapeutic products 747
748
Launched in 2017, the WHO-National Control Laboratory Network for Biologicals (WHO-NNB) (22) brings 749
together National Control Laboratories (NCLs) and NRAs of vaccine-producing and vaccine-recipient 750
countries, WHO contract laboratories, manufacturer associations, WHO Regional Offices and other 751
stakeholders, including donors. The Network works towards the effective use of globally available 752
resources in providing a platform and infrastructure for the exchange of quality and technical 753
information. The main objective of the Network is to facilitate the access to and availability of 754
prequalified vaccines (or other biotherapeutic products) through reliance on the batch release of the 755
respective Network member NRAs/NCLs by recipient countries, thereby reducing redundant testing and 756
contributing to more cost-effective testing and more effective regulatory oversight. 757
758
e) Pharmacovigilance 759
760
In the field of pharmacovigilance, the exchange and sharing of data is critical. More than 100 Member 761
States contribute by sharing their safety data to the WHO Global database of individual case safety 762
reports (ICSR) - VigiBase - developed and maintained by the Uppsala Monitoring Center (UMC) (23). 763
Member States rely upon this resource (and thereby, on each-others’ data) as a single point of 764
pharmacovigilance information, to confirm and validate signals of adverse events with medicines and 765
vaccines that they may have observed within their own jurisdictions. 766
767
f) Inspections 768
769
In the field of inspections, governments and NRAs in different regions and parts of the world have 770
worked on mutual recognition agreements in order to rely on each other’s inspection outcomes, 771
avoiding the duplication of inspections and making the best use of resources (e.g. EU Mutual Recognition 772
Agreements (24) with Australia, Canada, Japan, Switzerland and the United States of America (USA); 773
ASEAN Mutual Recognition Agreement (25), etc.). 774
775
Working document QAS/20.851 page 29
The Pharmaceutical Inspection Co-operation Scheme (PIC/S) (26) is a non-binding, informal co-operative 776
arrangement between regulatory authorities in the field of Good Manufacturing Practice (GMP) of 777
medicinal products for human or veterinary use. It aims at facilitating cooperation and networking 778
between competent authorities, regional and international organisations, thus increasing mutual 779
confidence regarding GMP inspections. 780
781
Reliance is also an important aspect for conducting desktop assessment of compliance with relevant 782
good practice guidelines and requirements, as described in the respective WHO guidance (27). 783
784
g) Examples in the field of medical devices 785
786
The use of reliance is equally prevalent in the regulation of medical devices. An example of this is the 787
Medical Device Single Audit Program (MDSAP) (28) originally developed through the auspices of the 788
International Medical Device Regulators Forum (IMDRF). Under this program, the regulatory authorities 789
of Australia, Brazil, Canada, Japan and the USA have pooled their resources in order to develop and 790
implement a robust system of oversight of third party auditing organizations that, in turn, conduct audits 791
of the quality management systems of medical device manufacturers. The MDSAP allows an auditing 792
organization recognized by the Program to conduct a single regulatory audit that satisfies the relevant 793
requirements of the regulatory authorities participating in the program. Collective regulatory resources 794
are directed at establishing and maintaining the oversight of auditing organizations, providing a more 795
effective use of limited regulatory resources. Employing a single audit program allows regulatory 796
authorities to efficiently leverage resources and streamline the regulatory process without 797
compromising public health and to promote more aligned and consistent regulatory requirements. 798
799
Vigilance 800
801
The IMDRF has also set guidance for the exchange of information between national competent 802
authorities with respect to medical device safety (29). The system focuses on incidents that represent 803
a serious public health threat that goes beyond borders in order to inform other NRAs of such. 804
805
806
Working document QAS/20.851 page 30
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