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1 WHO/ DRAFT/ 12 June 2009 2
ENGLISH ONLY 3
4
5
Guidelines on evaluation of similar biotherapeutic products (SBPs) 6
7
Proposed guidelines 8
9
NOTE: 10
11
This document has been prepared for the purpose of inviting comments and suggestions on the 12
proposals contained therein, which will then be considered by the Expert Committee on 13
Biological Standardization (ECBS). Publication of this early draft is to provide information 14
about the proposed WHO approach for evaluation of similar biotherapeutic products to a broad 15
audience and to improve transparency of the consultation process. 16
17
A previous draft (WHO/BS/08.2101) was presented to the ECBS in October 2008. The 18
Committee affirmed that the guiding principles outlined in the document will contribute to the 19
assurance of the quality, safety and efficacy of similar biotherapeutic products worldwide and 20
recommended further development of the document. Following the ECBS advice, an updated 21
draft has been prepared for public consultation. After receiving comments from this consultative 22
process, as well as from invited reviewers, further revision of the draft guidelines will be 23
undertaken and presented to the ECBS 2009. Final draft for submission to the ECBS (BS 24
document) will be posted on WHO Biologicals website (http://www.who.int/biologicals/en/) for 25
public consultation in August 2009. 26
27
The text in its present form does not necessarily represent an agreed formulation of the 28
Expert Committee. Comments proposing modifications to this text MUST be received by 15 29 July 2009 and should be addressed to the World Health Organization, 1211 Geneva 27, 30
Switzerland, attention: Quality Safety and Standards (QSS). Comments may also be submitted 31
electronically to the Responsible Officer: Dr Ivana Knezevic at email: [email protected]. 32
33 The outcome of the deliberations of the Expert Committee will be published in the WHO 34
Technical Report Series. The final agreed formulation of the document will be edited to be in 35
conformity with the "WHO style guide" (WHO/IMD/PUB/04.1). 36
37
© World Health Organization 2009 38
All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health 39 Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: 40 [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for 41
WHO/DRAFT/12 June 2009
Page 2 noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-42 mail: [email protected]). 43
44
The designations employed and the presentation of the material in this publication do not imply the expression of any 45 opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, 46 city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps 47 represent approximate border lines for which there may not yet be full agreement. 48 49 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 50 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. 51 Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 52 53 All reasonable precautions have been taken by the World Health Organization to verify the information contained in 54 this publication. However, the published material is being distributed without warranty of any kind, either expressed 55 or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the 56 World Health Organization be liable for damages arising from its use. 57
58 The named authors [or editors as appropriate] alone are responsible for the views expressed in this publication. 59
WHO/DRAFT/12 June 2009
Page 3
60
61
Table of contents 62
63
1. Introduction..........................................................................................................4 64
2. Aim .......................................................................................................................5 65
3. Scope......................................................................................................................5 66
4. Glossary ................................................................................................................5 67
5. Key principles for the licensing of SBPs ............................................................8 68
6. Reference biotherapeutic product ......................................................................9 69
7. Regulatory considerations.................................................................................11 70
8. Quality.................................................................................................................14 71
9. Non-clinical evaluation ......................................................................................22 72
10. Clinical evaluation ...........................................................................................25 73
11. Pharmacovigilance...........................................................................................35 74
12. Other considerations........................................................................................36 75
Authors and acknowledgements...........................................................................37 76
References ...............................................................................................................40 77
WHO/DRAFT/12 June 2009
Page 4
1 Introduction 78
Biotherapeutic products (biotherapeutics) have a successful record in treating many life-79
threatening and chronic diseases. However, their cost has often been high, thereby limiting their 80
access to patients, particularly in developing countries. Recently, the expiration of patents and/or 81
data protection for the first major group of originator’s biotherapeutics has ushered in an era of 82
products that are designed to be ‘similar’ to a licensed originator product. These products rely, in 83
part, for their licensing on prior information regarding safety and efficacy obtained with the 84
originator products. The clinical experience and established safety profile of the originator 85
products should contribute to the development of similar biotherapeutic products (SBPs). The 86
amount and extent of data required for the licensing of SBPs is likely to be less than is normally 87
required for the originator products. A variety of terms, such as 'biosimilar products', 'follow-on 88
protein products' and 'subsequent-entry biologics' have been coined by different jurisdictions to 89
describe these products. 90
The term 'generic' medicine is used to describe chemical, small molecule medicinal products that 91
are structurally and therapeutically equivalent to an originator product whose patent and/or data 92
protection period has expired. The demonstration of bioequivalence of the generic medicine with 93
the reference product is usually appropriate to infer therapeutic equivalence between the generic 94
medicine and the reference product. However, the approach established for generic medicines is 95
not suitable for development, evaluation and licensing of SBPs since biotherapeutics usually 96
consist of relatively large, and complex proteins that are difficult to characterize. 97
As part of its mandate for assuring global quality, safety and efficacy of biotherapeutics, the 98
World Health Organization (WHO) provides globally accepted norms and standards for the 99
evaluation of these products 1, 2
. Written standards established through the Expert Committee on 100
Biological Standardization (ECBS) serve as a basis for setting national requirements for 101
production, quality control and overall regulation of biological medicines. In addition, 102
International Standards for measurement are essential tools for the establishment of potency for 103
biological medicines worldwide 3. Often they are used as primary standards for calibration of the 104
secondary standards that are directly used in the biological assays. 105
An increasingly wide range of SBPs are under development or are already licensed in many 106
countries and a need for guidelines for their evaluation and overall regulation was formally 107
WHO/DRAFT/12 June 2009
Page 5
recognized by the WHO in 2007 4. This document is intended to provide guidance for the 108
development and evaluation of such biotherapeutics. 109
It is essential that the standard of evidence supporting the decisions to license SBPs be sufficient 110
to ensure that the product meets acceptable levels of quality, safety and efficacy to ensure public 111
health. Also, it is expected that the elaboration of the data requirements and considerations for 112
the licensing of these products will facilitate development of and worldwide access to 113
biotherapeutics of assured quality at more affordable prices. In most cases, their authorization 114
will be evaluated on a case-by-case basis, and the amount of data required by a National 115
Regulatory Authority (NRA) may vary. However, it is expected that a guideline on the scientific 116
principles for evaluation of SBPs will help harmonize the requirements worldwide and will lead 117
to greater ease and speed of approval and assurance of the quality, safety and efficacy of these 118
products. 119
120
2 Aim 121
The intention of this document is to provide a globally acceptable set of principles to be applied 122
to the licensing of safe, efficacious, and high quality biotherapeutics that are claimed to be 123
similar to already licensed biotherapeutics and therefore may rely, in part, on information from 124
the already licensed products whose patents have expired. This guideline can be adopted as a 125
whole, or partially, by NRAs worldwide or used as a basis for establishing national regulatory 126
frameworks for licensure of these products. 127
128
3 Scope 129
This guideline applies to well-established and well-characterized biotherapeutic products such as 130
recombinant DNA-derived therapeutic proteins. 131
Vaccines and plasma derived products are excluded from the scope of this document because 132
they are highly complex and generally less well characterized entities. 133
134
4 Glossary 135
The definitions given below apply to the terms used in this guideline. They may have different 136
meanings in other contexts. 137
WHO/DRAFT/12 June 2009
Page 6
Comparable 138
Absence of any relevant differences at the level of quality, safety or efficacy between two 139
biotherapeutics. 140
Comparability exercise 141
Comparison of a biotherapeutic product with a licensed originator product with the goal to 142
establish similar quality, efficacy and safety. 143
Drug product 144
A pharmaceutical product type that contains a drug substance, generally in association with 145
excipients. 146
Drug substance 147
The active pharmaceutical ingredient and associated molecules that may be subsequently 148
formulated, with excipients, to produce the drug product. It can be composed of the desired 149
product, product-related substances, and product- and process-related impurities. It may also 150
contain excipients including other components such as buffers. 151
Equivalent 152
Equal or virtually identical in the parameter of interest. Equivalent efficacy of two medicinal 153
products means they have similar (no better and no worse) efficacy and any observed differences 154
are of no clinical relevance. 155
Generic medicine 156
A generic medicine contains the same active ingredient as and is bioequivalent to an originator 157
prescription medicine, and is subject to all applicable data protection periods and/or intellectual 158
property rights of the originator product. Since generic medicines are identical in the active 159
substance, dose, strength, route of administration, safety, efficacy, and intended use, they can be 160
substituted for the originator product. 161
Immunogenicity 162
The ability of a substance to trigger an immune response or reaction (e.g., development of 163
specific antibodies, T cell response, allergic or anaphylactic reaction). 164
Impurity 165
Any component present in the drug substance or drug product that is not the desired product, a 166
product-related substance, or excipient including buffer components. It may be either process- or 167
product-related. 168
WHO/DRAFT/12 June 2009
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Interchangeability 169
Refers to the medical practice of switching one medicine for another that is equivalent, in a given 170
clinical setting. 171
Non-inferior 172
Not inferior to a comparator in the parameter of interest. Non-inferiority trial is a trial with the 173
primary objective of showing that the response to the investigational product is not clinically 174
inferior to a comparator. 175
Originator product 176
A medicine which has been licensed by the national regulatory authorities on the basis of a full 177
registration dossier; i.e., the approved indication(s) for use were granted based on own quality, 178
efficacy and safety data. 179
Pharmacovigilance 180
The science and activities relating to the detection, assessment, understanding and prevention of 181
adverse effects or any other drug related problems. 182
Reference biotherapeutic product (RBP) 183
A reference biotherapeutic product is used as the comparator for head-to-head studies with the 184
similar biotherapeutic product in order to show similarity in terms of quality, safety and efficacy. 185
Only an originator product that was licensed on the basis of a full registration dossier can serve 186
as a RBP. 187
Similar biotherapeutic product (SBP) 188
A biotherapeutic product claimed to be “similar” in terms of quality, safety and efficacy to an 189
already licensed reference biotherapeutic product, which is an originator product marketed by an 190
independent manufacturer. 191
Substitutability 192
Refers to the practice of automatically substituting one medicine for another equivalent medicine 193
at the pharmacy. 194
Well-established biotherapeutic product 195
Well-established biotherapeutic product is the one that has been marketed for a suitable period of 196
time with a proven efficacy and safety. 197
198
WHO/DRAFT/12 June 2009
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5 Key principles for the licensing of SBPs 199
a. The basis for a product being licensed as a SBP hinges on its demonstrated similarity to a 200
suitable RBP, which will then provide a basis for a reduction in the non-clinical and 201
clinical information needed to support the market authorization of the SBP. 202
b. The development of a SBP involves a stepwise approach of comparability exercise 203
starting with comparison of the quality characteristics of the SBP and RBP followed by 204
non-clinical and clinical studies. Demonstration of similarity of a SBP to a RBP in terms 205
of quality is a prerequisite for the reduction of the non-clinical and clinical data set 206
required for licensure. If major differences are found in the quality, non-clinical, or 207
clinical studies, the product will not be likely to qualify as a SBP and a more extensive 208
non-clinical and clinical data set will likely be required to support the application for 209
licensure. 210
c. SBPs are not “generic medicines” and many characteristics associated with the 211
authorization process and marketed use of generic medicines generally do not apply. 212
d. SBPs, like other biotherapeutic products, require effective regulatory oversight for the 213
management of their potential risks and in order to maximize their benefits. Hence, only 214
NRAs with experience and expertise in biotherapeutic products should license SBPs. The 215
NRA is responsible for determining a suitable regulatory framework for licensing SBPs. 216
The NRA may choose to utilize or amend existing pathways or develop a new pathway 217
for this purpose. The licensing of SBPs should be consistent with the laws and 218
regulations for patents, intellectual property, and data protection (where they exist). 219
e. The decision to allow automatic substitution of a SBP for a RBP should be made on a 220
national level taking into account potential safety issues with the product or class of 221
products. Decisions on interchangeability should be based on appropriate scientific and 222
clinical data and is beyond the scope of this document. 223
224
WHO/DRAFT/12 June 2009
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6 Reference biotherapeutic product 225
To support licensure of a SBP, the SBP is studied in head-to-head comparison with a licensed 226
originator product that is used as the comparator to establish similarity of the SBP. This 227
comparator is the RBP. 228
Comprehensive information on the RBP provides the basis for establishing the safety, quality, 229
and effectiveness profile to which the SBP is compared. The RBP also provides the basis for 230
dose selection and route of administration, and is utilized in the comparability studies required to 231
support the licensing application. The demonstration of an acceptable level of similarity between 232
the SBP and RBP provides the rationale for utilizing a reduced non-clinical and clinical data set 233
to support the application for market authorization of the SBP. Hence the RBP is central to the 234
licensing of a SBP. 235
The choice of a RBP is of critical importance for the evaluation of SBP. The rationale for the 236
choice of the RBP should be provided by the manufacturer of the SBP in the submission to the 237
NRA. Considerations by a NRA on its policy on RBPs should include the nature of the biologics 238
industry in the country, the availability of nationally licensed RBPs, and may include, as 239
appropriate, the laws or regulations for patents, intellectual property, and/or data protection. The 240
latter tends to be intrinsically linked with policies for innovative drug development. Traditionally, 241
NRAs have required the use of a nationally licensed reference product for licensing of generic 242
medicines. This practice may not be feasible for countries lacking nationally-licensed RBPs. 243
NRAs may need to consider establishing additional criteria to guide the acceptability of using a 244
RBP licensed or resourced in other countries. 245
246
WHO/DRAFT/12 June 2009
Page 10
Considerations for choice of reference biotherapeutic product 247
248
Since the choice of a RBP is essential to the development of a SBP, the following should be 249
considered. 250
251
• The RBP should have been marketed for a suitable duration and have a volume of 252
marketed use such that the demonstration of similarity to it brings into relevance a 253
substantial body of acceptable data regarding the safety and efficacy. 254
• The manufacturer needs to demonstrate that the chosen RBP is suitable to support the 255
application for marketing authorization. 256
• The RBP should be licensed based on a full quality, safety, and efficacy data. Therefore a 257
SBP should not be considered as a choice for RBP. 258
• The same RBP should be used throughout the development of the SBP (i.e., for the 259
comparative quality, non-clinical, and clinical studies). 260
• The active substance of the RBP and the SBP must be shown to be similar. 261
• The dosage form and route of administration of the SBP should be the same as that of the 262
RBP. 263
• The following factors should be considered in the choice of a RBP that is marketed in 264
another jurisdiction; 265
o The RBP should be widely marketed in another jurisdiction which has regulatory 266
standards and principles for evaluation of biotherapeutic products, post-market 267
surveillance activities, and approaches to establishing comparability that are 268
consistent with those of the NRA. 269
o The laws and regulations for patents, data protection and intellectual property 270
should be consistent between the different jurisdictions. 271
o The acceptance of a RBP for evaluation of a SBP in a country does not imply 272
approval for use of the RBP by the NRA of that country. 273
274
WHO/DRAFT/12 June 2009
Page 11
7 Regulatory Considerations 275
One of the responsibilities of a NRA is to set up appropriate regulatory oversight for the 276
licensing of SBPs that are developed and/or authorized for sale in their country. As development 277
of biotherapeutic products is a rapidly evolving area, regular review of the NRAs for their 278
licensing, the adequacy of the regulations for providing oversight, and the processes and policies 279
that constitute the regulatory framework is an essential component of a well-functioning and up-280
to-date regulatory oversight for biotherapeutics. 281
A NRA may possess the regulatory authority for authorization of all new drugs and as such may 282
not need to amend its regulations to authorize SBPs. However, the EU has specifically amended 283
its regulations to provide an abbreviated pathway for SBPs (biosimilars) 5, 6, 7, 8
. This issue is 284
subject of discussion in a number of other countries where development of SBPs is ongoing. For 285
instance, Health Canada has recently developed their guideline. National guidelines in some 286
other countries are also being developed. Although US FDA did not issue guidelines, their 287
perspective on the assessment of Follow-on Protein Products was published 9. In most instances, 288
NRAs will need to provide guidance to manufacturers on the information needed and regulatory 289
requirements for the authorization of SBPs. A majority of countries will either be using their 290
existing legislation and applicable regulations or they will amend or develop entirely novel 291
frameworks for the authorization of SBPs. In most jurisdictions, regulations for licensing 292
subsequent entry versions of biotherapeutic products are intricately linked with policies for 293
innovation. Hence a NRA will need to coordinate with other stakeholders for consistency. 294
295
Scientific considerations and concept for licensing of SBPs 296
297
For the licensing of generic medicines, the regulatory framework is well-established in most 298
countries. Demonstration of bioequivalence of the generic medicine with the reference product is 299
usually appropriate to infer (conclude) therapeutic equivalence between the generic and the 300
reference product. However, the generic approach is not suitable for the licensing of SBPs since 301
WHO/DRAFT/12 June 2009
Page 12
biotherapeutic products usually consist of relatively large and complex entities that are difficult 302
to characterize. In addition, SBPs are manufactured and controlled according to their own 303
development since the manufacturer of a SBP normally does not have access to all the necessary 304
manufacturing information on the originator product. However, even minor differences in the 305
manufacturing process may affect the pharmacokinetics, pharmacodynamics, efficacy and/or 306
safety of biotherapeutic products. As a result, it has been agreed that the normal method for 307
licensing generic medicines through bioequivalence studies alone is not scientifically appropriate 308
for SBPs. Decision making regarding the licensing of SBPs should be based on scientific 309
evidence. The onus is on a manufacturer of a SBP to provide the necessary evidence to support 310
all aspects of an application for licensing. 311
As with any drug development program, the development of a SBP involves a stepwise approach 312
starting with characterization and evaluation of quality attributes of the product and followed by 313
non-clinical and clinical studies. Comprehensive characterization and comparison at the quality 314
level are the basis for possible data reduction in the non-clinical and clinical development. If 315
differences between the SBP and the RBP are found at any step, the underlying reasons for the 316
differences should be investigated. Differences should always be explained and justified and may 317
lead to the requirement of additional data (e.g., safety data). 318
In addition to the quality data, SBPs require non-clinical and clinical data generated with the 319
product itself. The amount of additional data considered necessary will depend on the product or 320
class of products, the extent of characterization possible by state-of-the-art analytical methods, 321
on observed or potential differences between the SBP and the RBP, and on the clinical 322
experience with the product class (e.g., safety/immunogenicity concerns in a specific indication). 323
A case by case approach is clearly needed for each class of products. 324
A SBP is intended to be similar to a licensed biotherapeutic product for which there is a 325
substantial public record of safety and efficacy. The ability for the SBP to be authorized based on 326
reduced non-clinical and clinical data depends on its demonstrated similarity to an appropriate 327
RBP. Manufacturers should demonstrate a full understanding of their product, consistent and 328
robust manufacture of their product, and submit a full quality dossier that includes a complete 329
characterization of the product. The comparability exercise in the quality part represents an 330
additional element to the ‘traditional’ full quality dossier. The reduction in data requirements is 331
WHO/DRAFT/12 June 2009
Page 13
therefore only possible for the non-clinical and/or clinical parts of the development program. The 332
dosage form and route of administration of the SBP should be the same as for the RBP. 333
Studies must be comparative in nature employing analytical strategies (methods) that are 334
sensitive to detect potential differences between the SBP and the RBP. Main clinical studies 335
should use the final formulation derived from the final process material of the SBP. Otherwise, 336
additional evidence of comparability will be required to demonstrate that the SBP to be marketed 337
is comparable to that used in the main clinical studies. 338
If similarity between the SBP and the RBP has been convincingly demonstrated, the SBP may be 339
approved for use in other clinical indications of the RBP that have not directly been tested in 340
clinical trials if appropriate scientific justification for such extrapolation is provided by the 341
manufacturer (see section 10.7). Significant differences between the SBP and the chosen RBP 342
detected during the comparability exercise would be an indication that the products are not 343
similar and full non-clinical and clinical data may be required to support the application for 344
licensing. 345
346
Comparability exercise 347
348
The comparability exercise for a SBP is designed to show that the SBP has highly similar quality 349
attributes when compared to the RBP. However, it also includes the non-clinical and clinical 350
studies to provide an integrated set of comparative data. The comparability data at the level of 351
quality can be considered to be an additional set of data over that which is normally required for 352
an originator product developed as a new and independent product. This is the basis for reducing 353
the non-clinical and clinical data requirements. 354
Although the quality comparisons are undertaken at various points throughout the quality dossier, 355
a distinction should be made between usual data requirements and those presented as part of the 356
comparability exercises. It may be useful to present these as a separate section in the quality 357
module. The quality expert acting on behalf of the SBP manufacturer should provide a specific 358
review of the quality comparability data. 359
360
WHO/DRAFT/12 June 2009
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8 Quality 361
The quality comparison showing molecular similarity between the SBP and the RBP provides 362
the underlying rationale for predicting that the clinical safety and efficacy profile of the RBP 363
should also apply to the SBP so that the extent of the non-clinical and clinical data required with 364
the SBP can be reduced. Development of an SBP involves thorough characterization of a number 365
of representative lots of the RBP and then engineering a manufacturing process that will 366
reproduce a product that is highly similar to the RBP in all critical product quality attributes; i.e., 367
those product attributes that may impact clinical performance. The quality comparison between 368
the SBP and the RBP is the basis for allowing extrapolation of clinical safety and efficacy data 369
for the RBP to the SBP. A SBP is generally derived from a separate and independent master cell 370
bank using independent manufacturing processes and control. These should be selected and 371
designed to meet the required comparability criteria. A full quality dossier for both drug 372
substance and drug product is always required, which complies with the standards as required by 373
NRAs for originator products. 374
Increased knowledge of the relationship between biochemical, physicochemical, and biological 375
properties of the product and clinical outcomes will facilitate development of a SBP. Due to the 376
heterogeneous nature of proteins (especially those with extensive post-translational 377
modifications such as glycoprotein), the limitations of some analytical techniques, and the 378
sometimes unpredictable nature of the clinical consequences of differences in protein 379
structural/physico-chemical properties, the evaluation of comparability will have to be carried 380
out independently for each product. For example, oxidation of certain methionine residues in one 381
protein may have no impact on clinical activity whereas in another protein it may significantly 382
decrease the intrinsic biological activity of the protein, or may increase its immunogenicity. 383
Thus, differences in the levels of Met oxidation in the RBP and SBP would need to be evaluated 384
differently for different proteins. 385
To evaluate comparability, the manufacturer should carry out a comprehensive physicochemical 386
and biological characterization of the SBP in head-to-head comparisons with the RBP. All 387
aspects of product quality and heterogeneity should be assessed (see characterization below). 388
A high degree of similarity between the SBP and the RBP is the basis for reducing non-clinical 389
and clinical requirements for licensing. However, some differences are likely to be found, e.g., 390
WHO/DRAFT/12 June 2009
Page 15
due to differences in impurities or excipients. Such differences should be assessed for their 391
potential impact on clinical safety and efficacy of the SBP and a justification, e.g., own study 392
results or literature data, for allowing such differences provided. Differences of unknown clinical 393
relevance, particularly regarding safety, may have to be addressed in additional studies pre- or 394
post-marketing. Differences in critical product quality attributes (i.e., those that are known to 395
have potential impact on clinical activity) will add to the clinical testing required for the SBP. 396
For example, if differences are found in glycosylation patterns that alter the biodistribution of the 397
product and thereby change the dosing scheme, then dose-finding studies for the product would 398
likely be required. Similarly, since differences in fucosylation of the Fc portion of monoclonal 399
antibodies are known to impact receptor binding and biological activity in vivo, the impact on 400
clinical efficacy and/or safety of differences between the SBP and RBP would likely need to be 401
evaluated with appropriate clinical studies. Other differences between the SBP and RBP may be 402
acceptable, and would not trigger the need for extra clinical evaluation. For example, a 403
therapeutic protein that has lower levels of protein aggregates would, in most cases, be predicted 404
to have a better safety profile than the RBP and would not need added clinical evaluation. Along 405
the same lines, if heterogeneity in the N-terminal amino acids is known, with sufficient 406
documentation, not to affect the bioactivity, biodistribution, or immunogenicity of the RBP or 407
similar products in its class, then there may be no need for added clinical safety or efficacy 408
studies based upon differences in this portion of the RPB and SBP. 409
Due to the unavailability of drug substance for the RBP, the SBP manufacturer will usually be 410
using commercial drug product for the comparability exercise. The commercial drug product will, 411
by definition, be in the final dosage form containing the active substance(s) formulated with 412
excipients. It should be verified that these do not interfere with analytical methods and thereby 413
impact the test results. If the active substance in the RBP needs to be purified from a formulated 414
reference drug product in order to be suitable for characterization, studies must be carried out to 415
demonstrate that product heterogeneity and relevant attributes of the active moiety are not 416
affected by the isolation process. The approach employed to isolate and compare the SBP to the 417
RBP should be justified and demonstrated, with data, to be appropriate for the intended purpose. 418
Where possible, the product should be tested with and without manipulation. 419
420
421
WHO/DRAFT/12 June 2009
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8.1 Manufacturing process 422
423
Manufacture of a SBP should be based on a comprehensively designed production process taking 424
all relevant guidelines into account. The manufacturer needs to demonstrate the consistency and 425
robustness of the manufacturing process by implementing Good Manufacturing Practices 10
, 426
modern quality control and assurance procedures, in-process controls, and process validation. 427
The manufacturing process should meet the same standards as required by the NRA for 428
originator products. The manufacturing process should be optimized to minimize differences 429
between the SBP and RBP in order to (a) maximize the ability to reduce the clinical testing 430
requirements for the SBP based upon the clinical history of the RBP, and (b) minimize any 431
predictable impact on the clinical safety and efficacy of the product. Some differences between 432
the SBP and RBP are expected and may be acceptable, provided, appropriate justification with 433
regard to lack of impact on clinical performance is given. 434
It is understood that a manufacturer developing a SBP does not have access to confidential 435
details of the manufacturing process of the RBP such that the process will differ from the 436
licensed process for the RBP (unless there is a contractual arrangement with the manufacturer of 437
the RBP). The manufacturing process for a SBP should employ state-of-the-art science and 438
technology to achieve a high quality SBP that is as similar as possible to the RBP. This will 439
involve evaluating the RBP extensively prior to developing the manufacturing process for the 440
SBP. The SBP manufacturer should assemble all available knowledge of the RBP concerning the 441
type of host cell and expression system, formulation, stability profile, and container closure 442
system used for marketing the RBP. The SBP manufacturer should then determine the potential 443
impact of changing any one of these elements on product quality, safety and efficacy and apply 444
this knowledge to the design of the manufacturing process. The rationale for accepting these 445
differences needs to be justified based upon sound science and clinical experience, either with 446
the SBP, or the RBP. 447
As a general rule, the product should be expressed and produced in the same host cell type as the 448
RBP (e.g., E.coli, CHO cells, etc) in order to minimize the potential for important changes to 449
critical quality attributes of the protein and to avoid introduction of certain types of process-450
related impurities (e.g., host cell proteins, endotoxins, yeast mannans) that could impact clinical 451
outcomes and immunogenicity. The host cell type for manufacture of the SBP should only be 452
WHO/DRAFT/12 June 2009
Page 17
changed if the manufacturer can demonstrate convincingly that the structure of the molecule is 453
not affected or that the clinical profile of the product will not change. For example, somatropin 454
produced in yeast cells appears to have similar characteristics to somatropin expressed in E. coli. 455
In most cases, however, the use of a different host cell type will not be feasible for glycoproteins 456
because glycosylation patterns vary significantly between different host cell types. Novel host 457
cell production systems should not be used for the SBP. 458
A complete description and data package should be provided that delineates the manufacturing 459
process, starting with development of expression vectors and cell banks, cell culture/ 460
fermentation, harvest, purification and modification reactions, filling into bulk or final containers, 461
and storage. The development studies conducted to establish and validate the dosage form, 462
formulation, and container closure system (including integrity to prevent microbial 463
contamination) and usage instructions should be also documented (see relevant guidelines such 464
as ICH). 465
466
8.2 Characterization 467
468
Characterization should start with the RBP to set the target for the SBP. The manufacturing 469
process should then be optimized, and the characterization of the SBP carried out using 470
appropriate, state-of-the-art biochemical, biophysical, and biological analytical techniques. For 471
the active ingredient(s) (i.e., the desired product), details should be provided on primary and 472
higher-order structure, post-translational modifications (including but not limited to glycoforms), 473
biological activity, purity, impurities, product-related (active) substances (variants), and 474
immunochemical properties, where relevant. 475
When conducting a comparability exercise, head-to-head characterization studies are required to 476
compare the SBP and the RBP. If any differences between the SBP and the RBP are found, they 477
should be evaluated for their potential impact on safety and efficacy of the SBP. The acceptance 478
limit for allowable differences should be set in advance by the manufacturer and a justification 479
for allowing such differences should be provided. This determination will be based upon 480
knowledge of the relationship between product quality attributes and clinical activity of the RBP 481
and related products, the clinical history of the RBP, and lot-to-lot differences for commercial 482
lots of the RBP. For example, quality attributes such as composition and profile of glycosylation, 483
WHO/DRAFT/12 June 2009
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biological activity which known to be related to clinical activity (e.g., insulin), and receptor 484
binding activity should determine the acceptance limit for differences before performing 485
comparability exercise. 486
Knowledge of the analytical limitations of each technique used to characterize the product (e.g., 487
limits of sensitivity, resolving power) should be applied when making a determination of 488
similarity. Representative raw data should be provided for all complex analytical methods (e.g., 489
high quality reproductions of gels, chromatograms, etc) in addition to tabular data summarizing 490
the complete data set and showing the results of all release and characterization analyses carried 491
out on the SBP and the RBP. 492
The following criteria should be considered when conducting the comparability exercise: 493
494
8.2.1 Physicochemical Properties 495
The physicochemical characterization should include the determination of primary and higher 496
order structure (secondary/tertiary/quaternary) and other biophysical properties. An inherent 497
degree of structural heterogeneity occurs in proteins due to the biosynthesis process such that 498
the RBP and the SBP are likely to contain a mixture of post-translationally modified forms. 499
Appropriate efforts should be made to investigate, identify and quantify these forms. 500
501
8.2.2 Biological Activity 502
Biological assays serve multiple purposes in the assessment of product quality and are required 503
for characterization, batch analyses, and immunogenicity assessments. Ideally, the bioassay will 504
reflect the understood mechanism of action of the protein and will thus serve as a link to clinical 505
activity. A bioassay is a quality measure of the ‘function’ of the protein product and can be used 506
to determine whether a product variant has the appropriate level of activity (i.e., a product-507
related substance) or is inactive (and is therefore defined as an impurity). The biological assay 508
also complements the physicochemical analyses by confirming the correct higher order structure 509
of the molecule. Thus, the use of a relevant biological assay(s) with appropriate precision and 510
accuracy provides an important means of confirming that a significant functional difference does 511
not exist between the SBP and the RBP. In addition, a relevant bioassay is essential for 512
determining whether antibodies that develop in response to the product have neutralizing activity 513
that impacts the biological activity of the product and/or endogenous counterparts to the product. 514
WHO/DRAFT/12 June 2009
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For a product with multiple biological activities, manufacturers should perform, as part of 515
product characterization, a set of relevant functional assays designed to evaluate the range of 516
activities of the product. For example, certain proteins possess multiple functional domains that 517
express enzymatic and receptor-binding activities. In such situations, manufacturers should 518
evaluate and compare all relevant functional activities of the SBP and RBP. 519
The results of the biological assay(s) should be provided and expressed in units of activity. 520
Where possible (e.g., for in vitro biochemical assays such as enzyme assays or binding assays), 521
the results may be expressed as specific activities (e.g., units/mg protein). Assays should be 522
calibrated against an international or national reference standard, when available and appropriate. 523
524
8.2.3 Immunochemical Properties 525
When immunochemical properties are part of the characterization (e.g., for antibodies or 526
antibody-based products), the manufacturer should confirm that the SBP is comparable to the 527
RBP in terms of specificity, affinity, binding kinetics, and Fc functional activity, where relevant. 528
529
8.2.4 Impurities 530
Process- and product-related impurities should be identified, quantified and compared between 531
the SBP and RBP. Some differences may be expected because the proteins are produced by 532
different manufacturing processes. If differences are observed in the impurity profile of the SBP 533
relative to the RBP, the differences should be evaluated to assess the potential impact on safety 534
and efficacy of the product. This should include evaluation of the potential impact on 535
immunogenicity of the product. It is critical to have suitable assays for process-related impurities, 536
specific to the cell line used for production. 537
538
8.3 Specifications 539
540
Specifications are employed to verify the routine quality of the drug substance and drug product 541
rather than to fully characterize them. As for any biotherapeutic product, specifications for a SBP 542
should be set as described in established guidelines and monographs, where these exist. It should 543
be noted that pharmacopoeial monographs may only provide a minimum set of requirements for 544
a particular product and additional test parameters may be required. Reference to analytical 545
WHO/DRAFT/12 June 2009
Page 20
methods used and acceptance limits for each test parameter of the SBP should be provided and 546
justified. All analytical methods referenced in the specification should be validated; the 547
corresponding validation should be documented. 548
Specifications for a SBP will not be the same as for the RBP since different analytical procedures 549
and laboratories will be used for the assays. Nonetheless, the specifications should capture and 550
control key product quality attributes known for the RBP (e.g., correct identity; purity, potency; 551
molecular heterogeneity in terms of size, charge, and hydrophobicity, if relevant; degree of 552
sialylation; inter-molecular disulfide bonding and number of individual polypeptide chains; 553
glycosylation of a functional domain; aggregate levels). The setting of specifications should be 554
based upon the manufacturer’s experience with the SBP (e.g., manufacturing history; assay 555
capability; safety and efficacy profile of the product) and the experimental results obtained by 556
testing and comparing the SBP and RBP. Sufficient lots of SBP should be employed in setting 557
specifications. The manufacturer should demonstrate, whenever possible, that the limits set for a 558
given specification are not significantly wider than the range of variability of the RBP over the 559
shelf-life of the product, unless justified. 560
561
8.4 Analytical techniques 562
563
Although the power of analytical methods for characterization of proteins has increased 564
dramatically over the past few decades, there are still obstacles to completely characterizing 565
complex biotherapeutic products. A battery of state-of-the-art analyses is needed to determine 566
structure, function, purity, and heterogeneity of the products. The methods employed should 567
separate and analyze different variants of the product based upon different underlying chemical, 568
physical, and biological properties of protein molecules. For example, PAGE, ion exchange 569
chromatography, isoelectric focusing, and capillary electrophoresis all separate proteins based 570
upon charge, but they do so under different conditions and based upon different physicochemical 571
properties. As a result, one method may detect variants that another method does not detect. The 572
goal of the comparability investigation is to be as comprehensive as possible in order to 573
minimize the possibility of undetected differences between the RBP and SBP that may impact 574
clinical activity. The analytical limitations of each technique (e.g., limits of sensitivity, resolving 575
WHO/DRAFT/12 June 2009
Page 21
power) should be considered when making a determination of similarity between a SBP and a 576
RBP. 577
The measurement of quality attributes in characterization studies (versus in the specifications) 578
does not necessarily require the use of validated assays, but the assays should be scientifically 579
sound and qualified; i.e., they should provide results that are meaningful and reliable. The 580
methods used to measure quality attributes for lot release should be validated in accordance with 581
relevant guidelines, as appropriate. A complete description of the analytical techniques employed 582
for release and characterization of the product should be provided in the license application. 583
584
8.5 Stability 585
586
The stability studies should be in compliance with relevant guidance as recommended by the 587
NRA. Studies should be carried out to show which release and characterization methods are 588
stability-indicating for the product. Generally, stability studies should be summarized in an 589
appropriate format such as tables, and they should include results from accelerated degradation 590
studies and studies under various stress conditions (e.g., temperature, light, humidity, mechanical 591
agitation). Accelerated stability studies comprise an important element of the determination of 592
similarity between a SBP and a RBP because they can reveal otherwise-hidden properties of a 593
product that warrant additional evaluation. They are also important for identifying the 594
degradation pathways of a protein product. The results obtained from accelerated stability studies 595
may show the additional controls should be employed in the manufacturing process and during 596
shipping and storage of the product in order to ensure the integrity of the product. Head-to-head 597
accelerated stability studies comparing the SBP to the RBP will be of value in determining the 598
similarity of the products by showing comparable degradation profiles. Representative raw data 599
showing the degradation profiles for the product should be provided in the license application. 600
The stability data should support the conclusions regarding the recommended storage and 601
shipping conditions and the shelf life/storage period for the drug substance, drug product, and 602
process intermediates that may be stored for significant periods of time. Stability studies on drug 603
substance should be carried out using containers and conditions that are representative of the 604
actual storage containers and conditions. Stability studies on drug product should be carried out 605
in the intended drug product container-closure system. Real time/real temperature stability 606
WHO/DRAFT/12 June 2009
Page 22
studies will determine the licensed storage conditions and expiration dating for the product. This 607
may or may not be the same as for the RBP. 608
9 Non-clinical evaluation 609
The non-clinical part of the guideline addresses the pharmaco-toxicological assessment of the 610
SBP. The establishment of safety and efficacy of a SBP usually requires the generation of some 611
non-clinical data with the SBP. In general, the demonstration of a high degree of molecular 612
similarity between the SBP and RBP should significantly reduce the need for non-clinical studies 613
since the RBP will already have a significant clinical history. Non-clinical studies, if considered 614
necessary (see below), should be conducted with the final formulation of the SBP intended for 615
clinical use, unless otherwise justified. 616
The design of an appropriate non-clinical study program requires a clear understanding of the 617
product characteristics. Results from the physico-chemical and biological characterization 618
studies should be reviewed from the point-of-view of potential impact on efficacy and safety. 619
When developing a SBP some existing guidelines may be relevant and should therefore be taken 620
into account; e.g., the ´Note for preclinical safety evaluation of biotechnology-derived 621
pharmaceuticals` (ICH S6) 11
. 622
Problems in the non-clinical evaluation of SBPs containing biotechnology-derived recombinant 623
proteins as active substance are often related to the fact that these products 624
- may show species-specific pharmacodynamic activity such that it is sometimes difficult to 625
identify a relevant species for pharmacodynamic and toxicological evaluation 626
- will, as ´foreign proteins`, usually elicit an antibody response in long-term animal studies. Thus, 627
the results of subchronic or chronic repeat dose studies may be difficult to interpret due to the 628
formation of antibody complexes with the active substance. 629
630
WHO/DRAFT/12 June 2009
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9.1 Special considerations 631
632
Non-clinical evaluation of a new biotherapeutics normally encompasses a broad spectrum of 633
pharmacodynamic, pharmacokinetic and toxicological studies 11
. For SBPs, however, as long as 634
the quality (including bioactivity) of the SBP is sufficiently similar to an appropriate RBP, the 635
minimum requirements for non-clinical studies are head-to-head comparative toxicology studies. 636
The amount of additional non-clinical data required to establish safety and efficacy of a SBP is 637
considered to be highly dependent on the product and substance-class related factors. Factors that 638
often elicit the need for additional non-clinical studies include, but are not restricted to: 639
- Quality-related factors: 640
• Significant differences in the cell expression system compared with the RBP, 641
• The presence of a complex mixture of less well characterized product- and/or process-642
related impurities 643
• International reference standards unavailable 644
- Factors related to pharmaco-toxicological properties of the active substance 645
• Mechanism(s) of drug action are unknown or poorly understood 646
• The active substance is associated with significant toxicity and/or has a narrow therapeutic 647
index 648
Depending on these factors, the spectrum of studies required to establish safety and efficacy of 649
the SBP may vary considerably and should be defined on a case-by-case basis. In the case of a 650
highly complex active substance that is difficult to characterize by analytical techniques and 651
which possesses a narrow therapeutic index, the non-clinical development program may 652
encompass a significant portion of the spectrum of studies described in relevant guidelines such 653
as ICH S6 11
. On the other hand, for products for which the active substance and the impurity 654
profile are well characterized by analytical means and which possess a wide therapeutic index, 655
the non-clinical development program will likely be more limited. Most SBPs will meet this 656
latter criterion since, at present, only well-characterized proteins with a good benefit:risk ratio 657
should be developed as SBPs. 658
WHO/DRAFT/12 June 2009
Page 24
The non-clinical studies constitute a part of the overall comparability exercise. Therefore, the 659
studies should be comparative in nature and designed to detect differences in response between 660
the SBP and the RBP and not just the response to the SBP alone. 661
662
In vitro studies: 663
Assays like receptor-binding studies or cell-based assays (e.g., cell-proliferation or cytotoxicity 664
assays) should normally be undertaken in order to establish comparability of the 665
biological/pharmacodynamic activity of the SBP and RBP. Such data are already available from 666
the biological assays described in the quality part of the dossier. Reference to these studies can 667
be made in the non-clinical part of the dossier. 668
669
In vivo studies: 670
Animal studies should be designed to maximize the information obtained. Such studies should be 671
comparative in nature (see above), should be performed in (a) species known to be relevant (i.e., 672
a species in which the RBP has been shown to possess pharmacodynamic and/or toxicological 673
activity) and employ state-of-the-art technology. Where the model allows, consideration should 674
be given to monitoring a number of endpoints such as: 675
- Biological/pharmacodynamic activity relevant to the clinical application. These data should be 676
available from biological assays described in the quality part of the dossier and reference to these 677
studies can be made in the non-clinical part of the dossier. 678
- Non-clinical toxicity as determined in at least one repeat dose toxicity study with a relevant 679
species and including toxicokinetic measurements. These measurements should include 680
determination and characterization of antibody responses, including anti-product antibody titres, 681
cross reactivity with homologuous endogenous proteins, and product neutralizing capacity. The 682
duration of the studies should be sufficiently long to allow detection of relevant differences in 683
toxicity and antibody responses between the SBP and RBP. 684
685
Besides being a part of the overall comparability exercise, the comparative repeat-dose toxicity 686
study is considered to provide reassurance that no ´unexpected` toxicity will occur during 687
clinical use of the SBP. If performed with the final formulation intended for clinical use, the 688
WHO/DRAFT/12 June 2009
Page 25
repeat-dose toxicity study will, in principle, allow for detection of potential toxicity associated 689
with both the active substance and product- and process-related impurities. 690
Although the predictive value of animal models for immunogenicity in humans is considered low, 691
antibody measurements, if applicable, should be included in the repeat-dose toxicity study to aid 692
in the interpretation of the toxicokinetic data and to help assess, as part of the overall 693
comparability exercise, whether important differences in structure or immunogenic impurities 694
exist between the SBP and RBP (i.e., the immunological response may be sensitive to 695
differences not detected by laboratory analytical procedures). 696
Depending on the route of administration, local tolerance may need to be evaluated. If feasible, 697
this evaluation may be performed as part of the described repeat-dose toxicity study. 698
On the basis of the demonstration of similarity between the SBP and RBP by the additional 699
comparability exercise performed as part of the quality evaluation, normally other routine 700
toxicological studies such as safety pharmacology, reproductive toxicology, genotoxicity and 701
carcinogenicity studies are not generally requirements for the non-clinical testing of a SBP, 702
unless triggered by results of the repeat-dose toxicity study or the local tolerance study and/or by 703
other known toxicological properties of the RBP (e.g., known adverse effects of the RBP on 704
reproductive function). 705
706
10 Clinical evaluation 707
The main/pivotal clinical data should be generated using the product derived from the final 708
manufacturing process and therefore reflecting the product for which marketing authorization is 709
being sought. Any deviation from this recommendation needs to be justified and additional 710
bridging data may be required, such as from PK studies comparing the PK profiles of the 711
products from the previous and final formulations, 712
Clinical studies should be designed to demonstrate comparable safety and efficacy of the SBP to 713
the RBP and therefore need to employ testing strategies that are sensitive enough to detect 714
relevant differences between the products, if present (see below). 715
The clinical comparability exercise is a stepwise procedure that should begin with 716
pharmacokinetic and pharmacodynamic studies followed by the pivotal clinical trials. 717
WHO/DRAFT/12 June 2009
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718
10.1 Pharmacokinetic (PK) studies 719
720
The PK profile is an essential part of the basic description of a medicinal product and should 721
always be investigated. PK studies should generally be performed for the routes of 722
administration applied for and using doses within the therapeutic dosing range recommended for 723
the RBP. 724
PK studies must be comparative in nature and should be designed to enable detection of potential 725
differences between the SBP and the chosen RBP. This is usually best achieved by performing 726
single-dose, cross-over PK studies in a homogenous study population and by using a dose where 727
the sensitivity to detect differences is largest. For example, for a medicinal product with 728
saturable absorption (saturation kinetics), the lowest therapeutic dose would be most appropriate, 729
provided that the employed assay can measure the resulting drug plasma levels with sufficient 730
accuracy and precision. In order to reduce variability not related to differences between products, 731
PK studies should normally be performed in healthy volunteers. If the investigated active 732
substance is known to have adverse effects and the pharmacological effects or risks are 733
considered unacceptable for healthy volunteers, it may be necessary to perform the PK studies in 734
the proposed patient population. 735
In general, single dose PK studies will suffice. However, in cases of dose or time-dependent 736
pharmacokinetics, resulting in markedly higher concentrations at steady-state than expected from 737
single dose data, a potential difference in the extent of absorption of the SBP and RBP may be 738
larger at steady-state than after single dose administration. In such cases, it may be advisable for 739
the manufacturer to perform an additional comparative multiple dose study to ensure similar PK 740
profiles also at steady-state before commencing the confirmatory clinical trial(s). In steady-state 741
PK studies, the administration scheme should preferably use the highest customary dosage 742
recommended for the RBP. 743
The choice of single-dose studies, steady-state studies, or repeated determination of PK 744
parameters and the study population should be justified by the manufacturer. The cross-over 745
design reduces inter-subject variability and therefore, compared to the parallel design, reduces 746
the sample size necessary to show equivalent PK profiles of the SBP and RBP. The treatment 747
phases should be separated by an adequate wash-out phase to avoid carry-over effects. The 748
WHO/DRAFT/12 June 2009
Page 27
cross-over design may not appropriate for biological medicinal products with a long half-life or 749
for proteins for which formation of anti-product antibodies is likely. In parallel designs, care 750
should be taken to avoid relevant imbalances in all prognostic variables between treatment 751
groups that may affect the pharmacokinetics of the active substance (e.g., ethnic origin, smoking 752
status, extensive/poor metabolic status of the study population). 753
PK comparison of the SBP and the RBP should not only include absorption/bioavailability but 754
should also include elimination characteristics; i.e., clearance and/or elimination half-life, since 755
differences in elimination rate of the SBP and the RBP may exist. 756
Acceptance criteria for the demonstration of similar PK between the SBP and the RBP should be 757
pre-defined and appropriately justified. It is noted that the criteria used in standard clinical PK 758
comparability studies (bioequivalence studies) were developed for chemically-derived, orally 759
administered products and may not necessarily be applicable for biological medicinal products. 760
Due to the lack of established acceptance criteria designed for biologicals, the traditional 80-761
125% equivalence range is often used. However, if the 90% confidence intervals of the ratio of 762
the population geometric means (test/reference) for the main parameters under consideration 763
(usually rate and extent of absorption) fall outside that range, the SBP may still be considered 764
similar to the RBP based on similar PD, efficacy and safety data. 765
Other PK studies, such as interaction studies (with drugs likely to be used concomitantly) or 766
studies in special populations (e.g., children, the elderly and patients with renal or hepatic 767
insufficiency) are not usually required for a SBP. 768
Historically, the PK evaluation of peptide or protein products has suffered from limitations in the 769
assay methodology thus limiting the usefulness of such studies. Special emphasis should 770
therefore be given to the analytical method selected and its capability to detect and follow the 771
time course of the protein (the parent molecule and/or degradation products) in a complex 772
biological matrix that contains many other proteins. The method should be optimized to have 773
satisfactory specificity, sensitivity and a range of quantification with adequate accuracy and 774
precision. 775
In some cases, the presence of measurable concentrations of endogenous protein may 776
substantially affect the measurement of the concentration-time profile of the administered 777
exogenous protein. In such cases, the manufacturer should describe and justify the approach to 778
minimize the influence of the endogenous protein on the results. 779
WHO/DRAFT/12 June 2009
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780
10.2 Pharmacodynamic (PD) studies 781
782
Although comparative clinical trials are usually required for demonstration of similar efficacy 783
and safety of the SBP and RBP, it may be advisable for the manufacturer to ensure similar PD 784
profiles before proceeding to clinical trials, particularly if a difference in PK profiles of unknown 785
clinical relevance has been detected. 786
In many cases, PD parameters are investigated in the context of combined PK/PD studies. Such 787
studies may provide useful information on the relationship between dose/exposure and effect, 788
particularly if performed at different dose levels. In the comparative PD studies, PD effects 789
should be investigated in a suitable patient population using a dose/doses within the steep part of 790
the dose-response curve in order to best detect potential differences between the SBPs and the 791
RBP. PD markers should be selected based on their clinical relevance. 792
793
10.3 Confirmatory pharmacokinetic/pharmacodynamic (PK/PD) studies 794
795
Usually, clinical trials are required to demonstrate similar efficacy between the SBP and the RBP. 796
In certain cases, however, comparative PK/PD studies may suffice, provided that 1) the PK and 797
PD properties of the RBP are well characterized, 2) at least one PD marker is an accepted 798
surrogate marker for efficacy, and 3) the relationship between dose/exposure, the relevant PD 799
marker(s) and response/efficacy of the RBP is established. Euglycaemic clamp studies would be 800
an example for acceptable confirmatory PK/PD studies for the comparison of efficacy of two 801
insulins. In addition, absolute neutrophil count is the relevant PD marker for the activity of 802
granulocyte colony stimulating factor (G-CSF) and could be used in PK/PD studies in healthy 803
volunteers to demonstrate similar efficacy of two G-CSF-containing medicinal products. 804
The study population and dosage should represent a test system that is known to be sensitive to 805
detect potential differences between the SBP and the RBP. For example, in the case of insulin, 806
the study population should consist of non-obese healthy volunteers or patients with type 1 807
diabetes rather than insulin-resistant patients with type 2 diabetes. Otherwise, it will be necessary 808
to investigate a relevant dose range to demonstrate that the test system is discriminatory 12
. In 809
WHO/DRAFT/12 June 2009
Page 29
addition, the acceptance ranges for demonstration of similarity in confirmatory PK and PD 810
parameters should be pre-defined and appropriately justified. 811
812
10.4 Efficacy studies 813
814
Dose finding studies are not required for a SBP. Demonstration of comparable potency, PK and 815
PD profiles provide the basis for the use of the posology of the RBP in the confirmatory clinical 816
trial(s). 817
Similar efficacy of the SBP and the chosen RBP will usually have to be demonstrated in 818
adequately powered, randomized, and parallel group clinical trial(s). The principles of such trials 819
are laid down in relevant ICH guidelines 12, 13
. Clinical studies should preferably be double-blind 820
or at a minimum observer-blind. In the absence of any blinding, careful justification will be 821
required to prove that the trial results are free from significant bias 6. 822
Potential differences between the SBP and the RBP should be investigated in a sensitive and 823
preferably well-established model. For example, in the case of growth hormone (GH), treatment-824
naïve children with GH deficiency usually represent the most appropriate study population as 825
opposed to children with non GH-deficient short stature that are usually less sensitive to the 826
effects of GH. Although adult patients with GH deficiency could also be considered a “sensitive” 827
population, the endpoint used to measure effects of GH treatment (i.e., body composition) is less 828
sensitive than the one used in children (i.e., longitudinal growth) and an equivalence/non-829
inferiority margin is difficult to define. 830
In principle, equivalence or non-inferiority studies may be acceptable for the comparison of 831
efficacy and safety of the SBP with the RBP. Equivalence/non-inferiority margins have to be 832
pre-specified and justified based on clinical relevance; i.e., the selected margin should represent 833
the largest difference in efficacy that would not matter in clinical practice. Treatment differences 834
within this margin would thus be acceptable because they have no clinical relevance. For 835
example, for Silapo (epoetin zeta) the EMEA accepted equivalence margins of 80-125% for the 836
treatment difference in epoetin dose because such differences within this range were shown to 837
have no major impact on hemoglobin concentrations and were within the batch-to-batch 838
variability of the reference product (epoetin alfa). 839
WHO/DRAFT/12 June 2009
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Similar efficacy implies that similar treatment effects can be achieved with similar dosages. 840
Therefore, in cases for which the medicinal product is titrated according to treatment response 841
(e.g., epoetin, insulin) rather than given at a fixed dosage (e.g., somatropin in GH-deficient 842
children), equivalence/non-inferiority should be demonstrated not only with regard to treatment 843
response but also with regard to dosage. This is best achieved by defining a combined primary 844
endpoint that also includes the dosage. 845
Equivalence trials are strongly recommended for medicinal products with a narrow safety margin 846
(therapeutic index), such as insulin, to ensure that the SBP is not less and not more effective than 847
the RBP when used at the same dosage. For medicinal products with a wide safety margin, a 848
non-inferiority trial may also be appropriate for demonstration of similar efficacy of the SBP and 849
RBP. It should, however, be considered that non-inferior efficacy does not exclude the 850
possibility of superior efficacy of the SBP compared to the RBP. In such cases, sufficient 851
reassurance should be provided by the manufacturer that superior efficacy of the SBP would not 852
be associated with additional adverse events if used at the same dosage as the RBP, particularly 853
if the SBP and the RBP are considered interchangeable. This could be achieved, for example, by 854
including a key safety variable as a co-primary endpoint with a well-defined non-inferiority 855
margin. 856
Whereas several examples exist for licensing of SBPs based on equivalence trials (e.g., 857
recombinant human GH, epoetin and G-CSF in the EU), experience with non-inferiority trials for 858
this purpose is limited and mainly based on theoretical considerations. An additional advantage 859
of demonstration of equivalent efficacy (rather than non-inferior efficacy) is that this would 860
provide a stronger rationale for the possibility of extrapolation of efficacy data to other 861
indications of the RBP, particularly if these include different dosages than the one(s) tested in the 862
clinical trial (see section 10.7). However, if there is no disadvantage to increased efficacy in any 863
indication (e.g., for a cancer treatment or an anti-infective), then non-inferiority trials may still 864
support extrapolation to other indications. 865
866
Special statistic consideration about sample size 867
868
Equivalence trials should not require a larger sample size compared to non-inferiority trials if the 869
efficacy of the SBP and RBP is reasonably expected to be similar based on the quality 870
WHO/DRAFT/12 June 2009
Page 31
comparison of the products. In clinical research, the type 1 error for a wrong or false positive 871
conclusion (e.g., erroneously accepting the test drug as an alternative to the reference drug in a 872
non-inferiority trial) is usually set at 2.5%. The type 1 error is set at 5% for the two-sided 873
procedure and is designed to prevent the wrong conclusion that the test drug is either better or 874
worse than a placebo or the active comparator. Since a drug will not be acceptable if it is inferior 875
to a placebo or the active comparator, the error of a false positive conclusion is still limited to 876
2.5%. 877
For products that are demonstrated to be highly similar at the molecular level and for which no 878
important clinical differences are expected, there is no formal difference between equivalence 879
and non-inferiority designs, where the non-inferiority (irrelevance) margin would be specified on 880
one side (i.e., to exclude the possibility that the efficacy of the SBP is worse than the efficacy of 881
the RBP) and the equivalence margin would be specified on two sides (i.e., to exclude that the 882
possibility that the efficacy of the SBP is either worse or better than that of the RBP). In case 883
both drugs are equally effective (as they should be), the chosen approach would be irrelevant. A 884
larger sample-size would only be required, if the SBP would be known or suspected to be less 885
effective than the RBP. In a non-inferiority study, the sample-size could be reduced if the SBP is 886
suspected of being more efficacious than the RBP. This, however, may be seen as a contradiction 887
to the concept that the amount of clinical data required for evaluation of a SBP can be reduced 888
based upon similarity to the RBP, and to justify the treatment recommendation based on 889
similarity arguments. On the other hand, this approach would be acceptable if the manufacturer 890
can provide reassurance that better efficacy will not come at the price of lessened or lowered 891
tolerability. 892
893
10.5 Safety 894
895
Pre-licensing safety data should be obtained in a sufficient number of patients to characterize the 896
safety profile of the SBP. Usually, safety data obtained from the efficacy trial(s) will suffice (i.e., 897
trials that are powered for their primary efficacy endpoint(s)). Comparison with the RBP should 898
include type, frequency and severity of adverse events/reactions. For cases in which similar 899
efficacy is demonstrated in confirmatory PK/PD studies but safety data relevant for the target 900
population cannot be deduced from these studies, safety data in the target population are still 901
WHO/DRAFT/12 June 2009
Page 32
needed. For example, for two soluble insulins, the euglycaemic clamp study is considered the 902
most sensitive method to detect differences in efficacy. However, immunogenicity and local 903
tolerance of subcutaneously administered SBP cannot be assessed in such studies and should 904
therefore preferably be evaluated in the target population. 905
Safety data should preferably be comparative. Comparison with an external control group is 906
usually hampered by differences in the investigated patient population and concomitant therapy, 907
observation period and/or reporting. 908
Safety data obtained from the clinical trials can be expected to mainly detect frequent and short-909
term adverse events/reactions. Such data are usually sufficient pre-licensing, but further close 910
monitoring of clinical safety of the SBP may be necessary in the post-marketing phase (see 911
section 11). 912
913
10.6 Immunogenicity 914
915
Immunogenicity of biotherapeutic products should always be investigated pre-authorization. 916
Even if efficacy and safety of a SBP and RBP have been shown to be similar, immunogenicity 917
may still be different. 918
The immune response against a biotherapeutic is influenced by many factors such as the nature 919
of the active substance, product- and process-related impurities, excipients and stability of the 920
product, route of administration, dosing regimen, and patient-, disease- and/or therapy-related 921
factors 14
. 922
The consequences of unwanted immunogenicity may vary considerably, ranging from clinically 923
irrelevant to serious and life-threatening. Although neutralizing antibodies directly alter the 924
pharmacodynamic effect of a product (i.e., by directly blocking the bioactivity of the protein), 925
binding antibodies often affect pharmacokinetics and thereby also influence pharmacodynamics. 926
Thus, an altered effect of the product due to anti-product antibody formation might be a 927
composite of pharmacokinetic, pharmacodynamic and safety effects. 928
Immunogenicity of a biotherapeutic should always be investigated in humans since animal data 929
are usually not predictive of the immune response in human. The frequency and type of 930
antibodies induced as well as possible clinical consequences of the immune response should be 931
compared for the SBP and the RBP. Comparison with an external control group is not considered 932
WHO/DRAFT/12 June 2009
Page 33
appropriate because this is usually hampered by differences in the investigated patient population, 933
observation period, sampling time points, assays employed, and interpretation of results. 934
Generally, the amount of immunogenicity data obtained from the comparative efficacy trial(s) 935
(i.e., trials that are powered for their primary efficacy endpoint) will allow detection of a marked 936
increase in immunogenicity of the SBP compared to the RBP and will be sufficient pre-licensing. 937
Where clinically meaningful or even serious antibody development has been encountered with 938
the RBP or the substance class but is too rare to be captured pre-licensing (e.g., cross-reacting 939
neutralizing anti-epoetin antibodies causing pure red cell aplasia), a specific risk management 940
plan (RMP) for the SBP may be necessary to assess this specific risk post-marketing (see section 941
11). In case similar efficacy is demonstrated in confirmatory PK/PD study(ies), immunogenicity 942
data in the target population are still needed (see section 10.5). If the manufacturer intends to 943
extrapolate efficacy and safety data to other approved indications of the RBP (see section 10.7), 944
care should be taken to ensure that immunogenicity is investigated in the patient population that 945
carries the highest risk of an immune response and immune-related adverse events. 946
The manufacturer will need to justify their antibody testing strategy including the selection, 947
assessment, and characterization of assays, identification of appropriate sampling time points 948
including baseline, sample volumes and sample processing/storage as well as selection of 949
statistical methods for analysis of data. Antibody assays need to be validated for their intended 950
purpose. A screening assay of sufficient sensitivity should be used for antibody detection and a 951
neutralization assay should be available for further characterization of antibodies, if present. 952
Possible interference of the circulating antigen with the antibody assay(s) should be taken into 953
account. Detected antibodies need to be further characterized and their potential clinical 954
implications regarding safety, efficacy and pharmacokinetics evaluated. For example, the isotype 955
of the antibodies should be determined if they may be predictive of safety (e.g., development of 956
IgE antibodies correlates with the development of allergic and anaphylactic responses. If the 957
antibody incidence is higher with the use of the SBP compared to the RBP, the reason for the 958
difference needs to be investigated. Special attention should be paid to the possibility that the 959
immune response seriously affects the endogenous protein and its unique biological function. 960
The required observation period for immunogenicity testing will depend on the intended duration 961
of therapy and the expected time of antibody development and should be justified by the 962
manufacturer. In the case of chronic administration, one-year data will usually be appropriate 963
WHO/DRAFT/12 June 2009
Page 34
pre-licensing to assess antibody incidence and possible clinical implications. This is, for example, 964
the case for somatropin-containing products, where antibody development usually occurs within 965
the first 6-9 months of treatment but potential effects on growth are only seen later. In some 966
cases, shorter observation periods may be sufficient; e.g., for insulins, where most susceptible 967
patients will develop antibodies within the first 6 months of treatment and clinical consequences, 968
if any, would usually be at around the same time as antibody development. If considered 969
clinically relevant, development of antibody titers, their persistence over time, potential changes 970
in the character of the antibody response and the possible clinical implications should be 971
assessed pre- and post-marketing. 972
Since pre-licensing immunogenicity data are often limited, further characterization of the 973
immunogenicity profile may be necessary post-marketing, particularly, if rare antibody-related 974
serious adverse events may occur that are not likely to be detected in the pre-marketing phase. 975
976
10.7 Extrapolation of efficacy and safety data to other clinical indications 977
978
If similar efficacy and safety of the SBP and RBP have been demonstrated for a particular 979
clinical indication, extrapolation of these data to other indications of the RBP (not studied using 980
independent clinical studies with the SBP) may be possible if all of the following conditions are 981
fulfilled: 982
• A sensitive clinical test model has been used that is able to detect potential differences 983
between the SBP and the RBP 984
• The mechanism of action and/or involved receptor(s) are the same; e.g., GH action in 985
different conditions of short stature in children; erythropoiesis-stimulating action of epoetins 986
in different conditions associated with anaemia or for the purpose of autologous blood 987
donation 988
• Safety and immunogenicity have been sufficiently characterized and there are no 989
unique/additional safety issues expected for the indication(s) for which clinical data on the 990
SBP are not being provided 991
WHO/DRAFT/12 June 2009
Page 35
• If the efficacy trial used a non-inferiority study design and demonstrated that relevant 992
inferiority with regard to efficacy and safety can be excluded, the manufacturer should 993
provide a convincing argument that this finding can be applied to the extrapolated indications 994
If these prerequisites for extrapolation of efficacy and safety data to other indication(s) of the 995
RBP are not fulfilled, the manufacturer will need to submit own clinical data to support the 996
desired indication(s). 997
998
11 Pharmacovigilance 999
As for most biological medicines, data from pre-authorization clinical studies are usually too 1000
limited to identify all potential unwanted effects of a SBP. In particular, rare adverse events are 1001
unlikely to be encountered in the limited clinical trial populations being tested with the SBP. 1002
Therefore, further close monitoring of the clinical safety of these products in all approved 1003
indications and a continued benefit-risk assessment is necessary in the post-marketing phase. 1004
The manufacturer should submit a safety specification and pharmacovigilance plan at the time of 1005
submission of the marketing authorization application. The principles of pharmacovigilance 1006
planning can be found in relevant guidelines such as ICH E2E 15
. The safety specification should 1007
describe important identified or potential safety issues for the RBP, the substance class and/or 1008
any that are specific for the SBP. The pharmacovigilance plan should describe the planned post-1009
marketing activities and methods based on the safety specification 16
. In some cases, risk 1010
minimization measures such as educational material for patients and/or treating physicians may 1011
enhance the safe use of the SBP. 1012
Any specific safety monitoring imposed on the RBP or product class should be incorporated into 1013
the pharmacovigilance plan for the SBP, unless a compelling justification can be provided to 1014
show that this is not necessary. Moreover, potential additional risks identified during the review 1015
of the data obtained with the SBP should be subject to further safety monitoring (e.g., increased 1016
immunogenicity that might result from a difference in the glycosylation profile). The NRAs 1017
should closely monitor the compliance with the marketing commitments, where appropriate, and 1018
pharmacovigilance obligations. 1019
WHO/DRAFT/12 June 2009
Page 36
Post-marketing safety reports should include all information on product tolerability received by 1020
the marketing authorization holder. The safety information must be evaluated in a scientific 1021
manner and should include evaluation of the frequency and causality of adverse events. 1022
Manufacturers should ensure that, at the time of the marketing authorization, they have in place 1023
an appropriate pharmacovigilance system including the services of a qualified person responsible 1024
for monitoring pharmacovigilance and the necessary means for the notification of adverse 1025
reactions that occur in any of the countries where the product is marketed. 1026
In addition, as for all biotherapeutics, an adequate system is necessary to ensure specific 1027
identification of the SBPs. The NRA shall ensure the ability to identify any biotherapeutics 1028
marketed in their territory which is the subject of adverse reaction reports. This implies that an 1029
adverse reaction report for any biotherapeutic should include, in addition to the International 1030
Nonproprietary Names (INN) 16
, other indicators such as proprietary (brand) name, 1031
manufacturer’s name, lot number and country of origin. 1032
1033
12 Other Considerations 1034
Prescribing information 1035
The prescribing information for the SBP should be as similar as possible to that of the RBP 1036
except for product-specific aspects, such as different excipient(s). This is particularly important 1037
for posology and safety-related information, including contraindications, warnings and adverse 1038
events. However, if the SBP has fewer indications than the RBP, the related text in various 1039
sections may be omitted unless it is considered important to inform doctors and patients about 1040
certain risks; e.g., because of potential or likely off-label use. In such cases it should be clearly 1041
stated in the prescribing information that the SBP is not indicated for use in the specific 1042
indication(s). If applicable, study results should be presented in a way that enables readers to 1043
clearly distinguish the data obtained from studies with the SBP from those obtained with the 1044
RBP. 1045
1046
1047
WHO/DRAFT/12 June 2009
Page 37
Authors and acknowledgements 1048
The scientific basis for the evaluation and regulation of similar biotherapeutic products was 1049
discussed and agreement for developing WHO Guidelines reached at the first WHO Informal 1050
Consultation on Regulatory Evaluation of Therapeutic Biological Medicinal Products held in 1051
Geneva, 19-20 April 2007, attended by the following participants: 1052
Dr. A. Bristow, Dr. E. Gray, Dr. R. Thorpe, and Dr. J. S Robertson, National Institute for 1053
Biological Standardization and Control, Potters Bar, London, UK; Dr. M. Cheraghali, Iran Blood 1054
Transfusion Organization, Tehran, Iran; Dr. L. G. Castanheira and Dr. G. Garcia de Oliveira, 1055
Agencia Nacional da Vigilancia Sanitaria, Brasília, Brazil; Dr. E. Griffiths and Dr. K. Nyarko, 1056
Health Canada, Ottawa, Canada; Dr. U. Kalinke, Paul-Ehrlich-Institut, Langen, Germany; Dr. T. 1057
Kawanishi and Dr. T. Yamaguchi, National Institute for Health and Science, Tokyo, Japan; Dr. J. 1058
C. Krayenbühl and Ms M. Schmid-Appert, Swissmedic, Bern, Switzerland; Ms M. Poulis, 1059
Therapeutic Goods Administration, Wooden, Australia; Dr. H. Schellekens, Utrecht University, 1060
Utrecht, Netherlands; Dr. Y. Sohn, Korea Food and Drug Administration, Seoul, Republic of 1061
Korea; Dr. J. Southern, Ministry of Health, CapeTown, South Africa; Dr. K. Webber, Food and 1062
Drug Administration, Silverspring, Maryland, USA; Dr. M. Weise, Federal Institute for Drugs 1063
and Medical Devices, Bonn, Germany; Dr. S. P. Gogoi, Ministry of Health & Family Welfare, 1064
Guwahati, India; Dr. W. Junzhi, National Institute for the Control of Pharmaceutical and 1065
Biological Products, Beijing, China; Dr. P. Richardson, European Medicines Agency, London, 1066
UK; Dr. S. Gairola, Serum Institute of India Ltd, Pune, India, Representative of the Developing 1067
Country Vaccine Manufacturing Network (DVCMN); Dr. J. Mascaro, Hoffman La Roche, Basel, 1068
Switzerland, Representative of the International Federation of Pharmaceutical Manufacturers and 1069
Associations (IFPMA); Dr. A. Fox, Amgen, Cambridge, UK, Representative of IFPMA; Dr. R. 1070
Krause, IFPMA, Geneva, Switzerland; Dr. M. Schiestl, Sandoz, Kundl/ Tirol, Austria, 1071
Representative of the European Generic medicines Association (EGA); Ms S. Kox, EGA, 1072
Brussels, Belgium; Dr. A. Eshkol, International Association for Biologicals (IABS), Geneva, 1073
Switzerland; Dr. R. Balocco-Mattavelli, Dr. S. Lasseur, Dr. J. Dong, Quality Assurance and 1074
Safety of Medicines unit, Medicines Policy and Standards Department, World Health 1075
Organization, Geneva, Switzerland; Dr. D. Wood, Dr. I. Knezevic, Dr. J. Joung, Quality, Safety 1076
and Standards unit, Immunization, Vaccines and Biologicals Department, World Health 1077
Organization, Geneva, Switzerland. 1078
WHO/DRAFT/12 June 2009
Page 38
1079
The first draft of the guidelines was developed by the members of the WHO drafting group on 1080
similar biotherapeutic products following the meeting held at the Federal Institute for Drugs and 1081
Medical devices (BfArM), Bonn, Germany, on 5 - 7 March 2008, attended by: 1082
Dr Hans-Karl Heim, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany; 1083
Dr Kwasi Nyarko, Policy and Promotion Division, Centre for Policy and Regulatory Affairs 1084
Biologics and Genetic Therapies Direcctorate, Health Canada, Ottawa, Canada; Dr Yeowon 1085
Sohn, Recombinant Products Team, Korea Food and Drug Administration, Seoul, Republic of 1086
Korea; Dr Martina Weise, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, 1087
Germany; Dr Elwyn Griffiths, Biologics and Genetic Therapies, Biologics and Genetic 1088
Therapies Directorate, Health Canada, Ottawa, Canada; Dr. Ivana Knezevic, Dr. Jeewon Joung, 1089
Quality, Safety and Standards unit, Immunization, Vaccines and Biologicals Department, World 1090
Health Organization, Geneva, Switzerland. 1091
1092
The second draft of these guidelines (BS/08.2101) was prepared by Dr Kwasi Nyarko, Policy 1093
and Promotion Division, Centre for Policy and Regulatory Affairs Biologics and Genetic 1094
Therapies Direcctorate, Health Canada, Ottawa, Canada; Dr Martina Weise, Federal Institute 1095
for Drugs and Medical Devices (BfArM), Bonn, Germany; Dr Elwyn Griffiths, Biologics and 1096
Genetic Therapies, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, 1097
Canada; Dr. Emily Shacter, Food and Drug Administration, Bethesda, Maryland, USA; Dr. 1098
Ivana Knezevic, Dr. Jeewon Joung, Quality, Safety and Standards unit, Immunization, Vaccines 1099
and Biologicals Department, World Health Organization, Geneva, Switzerland, after a WHO 1100
Informal Consultation on Regulatory Evaluation of Therapeutic Biological Medicines in Seoul, 1101
Rep of Korea, 27-29 May, 2008, and acknowledgements are due to the following participants: 1102
Dr. R. Thorpe, and Dr. M. Wadhwa, National Institute for Biological Standardization and 1103
Control, Potters Bar, London, UK; Dr. M. Cheraghali, Iran Blood Transfusion Organization, 1104
Tehran, Iran; Dr. P. Thanaphollert, Food and Drug Administration, Nonthaburi, Thailand; Dr. E. 1105
Griffiths and Dr. K. Nyarko, Health Canada, Ottawa, Canada; Dr. T. Yamaguchi, National 1106
Institute for Health and Science, Tokyo, Japan; Dr. Y. Sohn and Dr S. Hong, Korea Food and 1107
Drug Administration, Seoul, Republic of Korea; Dr. J. Southern, Ministry of Health, CapeTown, 1108
WHO/DRAFT/12 June 2009
Page 39
South Africa; Dr. E. Shacter, Food and Drug Administration, Bethesda, Maryland, USA; Dr. M. 1109
Weise and Dr. H. Heim, Federal Institute for Drugs and Medical Devices, Bonn, Germany; Dr. S. 1110
P. Gogoi, Ministry of Health & Family Welfare, Guwahati, India; Dr. W. Junzhi, National 1111
Institute for the Control of Pharmaceutical and Biological Products, Beijing, China; Dr. P. 1112
Richardson, European Medicines Agency, London, UK; Dr. S. Gairola, Serum Institute of India 1113
Ltd, Pune, India, Representative of the Developing Country Vaccine Manufacturing Network 1114
(DCVMN); Dr. H. Ji, LG life Science, Seoul, Republic of Korea, representative of DCVMN; Dr. 1115
J. Mascaro, Hoffman La Roche, Basel, Switzerland, Representative of the International 1116
Federation of Pharmaceutical Manufacturers and Associations (IFPMA); Dr. A. Fox, Amgen, 1117
Cambridge, UK, Representative of IFPMA; Dr. R. Krause, IFPMA, Geneva, Switzerland; Dr. M. 1118
Schiestl, Sandoz, Kundl/Tirol, Austria, Representative of the European Generic medicines 1119
Association (EGA); Dr. S. Eisen, TEVA, London, UK, representative of EGA; Ms S. Kox, EGA, 1120
Brussels, Belgium; Dr M. L. Pombo, Pan American Health Organization, Washington DC, USA; 1121
Dr. I. Knezevic, Dr. J. Joung, Quality, Safety and Standards unit, Immunization, Vaccines and 1122
Biologicals Department, World Health Organization, Geneva, Switzerland. 1123
1124
Taking into account comments and advise provided by the ECBS on the BS/08.2101, the third 1125
draft was prepared by the drafting group members following the meeting in Tokyo, Japan, 16 1126
and 18 February, 2009, attended by: 1127
Dr Jeewon Joung, Biologics Bureau, Korea Food and Drug Administration, Seoul, Republic of 1128
Korea; Dr Martina Weise, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, 1129
Germany; Dr Kwasi Nyarko, Centre for Policy and Regulatory Affairs Biologics and Genetic 1130
Therapies Directorate, Health Canada, Ottawa, Canada; Dr. Emily Shacter, Food and Drug 1131
Administration, Bethesda, Maryland, USA; Dr Peter Richardson, European Medicines Agency 1132
(EMEA), Quality of Medicines Sector, London, UK; Dr Seung Hwa Hong, Biologics Bureau, 1133
Korea Food and Drug Administration, Seoul, Republic of Korea; Dr Keith Webber, Office of 1134
Pharmaceutical Science (OPS), US Food and Drug Administration, MD, USA; Dr. Teruhide 1135
Yamaguchi, Division of Biological Chemistry and Biologicals, National Institute of Health 1136
Sciences, Japan; Dr Ivana Knezevic, Dr Hye-Na Kang, FCH/IVB/QSS, World Health 1137
Organization, Geneva, Switzerland. 1138
1139
WHO/DRAFT/12 June 2009
Page 40
Further revision of the draft guidelines, undertaken by the drafting group, led to this draft of the 1140
guidelines which is posted on WHO Biologicals website (http://www.who.int/biologicals/en/) for 1141
public consultation. 1142
1143
1144
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