guidelines on evaluation of similar biotherapeutic products ......6 guidelines on evaluation of...

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

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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


• 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


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


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


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


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


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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1146

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