1 2
WHO/BS/2015.2251 3
ENGLISH ONLY 4
5 EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION 6
Geneva, 12 to 16 October 2015 7
8
9 PROPOSED ADDENDUM TO: WHO TRS 987, Annex 4. 10
Guidelines on the quality, safety and efficacy of biotherapeutic protein products prepared by 11
recombinant DNA technology 12
APPENDIX 7. REGULATORY ASSESSMENT OF APPROVED rDNA-DERIVED 13
BIOTHERAPEUTICS 14
NOTE: 15 16
This document has been prepared for the purpose of inviting comments and suggestions on the 17 proposals contained therein, which will then be considered by the Expert Committee on 18
Biological Standardization (ECBS). Publication of this draft is to provide information about the 19 proposed WHO document on Regulatory Assessment of Approved rDNA-derived Biotherapeutics 20 to a broad audience and to improve transparency of the consultation process. 21
22
The text in its present form does not necessarily represent an agreed formulation of the 23 Expert Committee. Written comments proposing modifications to this text MUST be 24 received by 14 September 2015 in the Comment Form available separately and should be 25
addressed to the World Health Organization, 1211 Geneva 27, Switzerland, attention: Department 26
of Essential Medicines and Health Products (EMP). Comments may also be submitted 27 electronically to the Responsible Officer: Dr Hye-Na Kang at email: [email protected]. 28 The outcome of the deliberations of the Expert Committee will be published in the WHO 29 Technical Report Series. The final agreed formulation of the document will be edited to be in 30 conformity with the "WHO style guide" (WHO/IMD/PUB/04.1). 31
32
© World Health Organization 2015 33
All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health 34 Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: 35 [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for 36 non-commercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-37 mail: [email protected]). 38
WHO/BS/2015.2251
Page 2
The designations employed and the presentation of the material in this publication do not imply the expression of any 1 opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, 2 city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps 3 represent approximate border lines for which there may not yet be full agreement. 4 5 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 6 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. 7 Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 8 9 All reasonable precautions have been taken by the World Health Organization to verify the information contained in 10 this publication. However, the published material is being distributed without warranty of any kind, either expressed or 11 implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the 12 World Health Organization be liable for damages arising from its use. 13
14 The named authors [or editors as appropriate] alone are responsible for the views expressed in this publication. 15 16 17
18 19
20
21
22
This guidance document published by WHO is intended to be scientific and advisory in nature.
Each of the following sections constitutes guidance for national regulatory authorities (NRAs)
and for manufacturers of biological products. If an NRA so desires, this document may be
adopted as definitive national requirements, or modifications may be justified and made by the
NRA. It is recommended that modifications to this document be made only on condition that the
modifications ensure that the product is at least as safe and efficacious as that prepared in
accordance with the principles set out below.
WHO/BS/2015.2251
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Contents 1
2
1. Regulatory expectations for rDNA-derived biotherapeutics, including similar biotherapeutic 3
products ................................................................................................................................ 4 4
2. Review of products on the market ..................................................................................... 5 5
3. Points to consider in a stepwise regulatory assessment ...................................................... 7 6
4. Regulatory actions ............................................................................................................. 9 7
Authors and acknowledgements .......................................................................................... 11 8
References .......................................................................................................................... 15 9
10
WHO/BS/2015.2251
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This appendix considers the regulatory assessment needed for dealing with situations where, for 1
various reasons, rDNA-derived biotherapeutic products were licensed with data packages that do 2
not follow current international regulatory standards for these biologicals – for instance, 3
biotherapeutic products licensed by a generic pathway or with limited analytical, nonclinical 4
and/or clinical data (1, 2). The International Conference of Drug Regulatory Authorities (ICDRA) 5
discussed such situations at its meeting in Singapore in 2010 (3) and requested WHO to assist in 6
developing approaches for evaluating these already-licensed products according to current WHO 7
guidelines. In 2014 the Sixty-seventh World Health Assembly adopted two relevant resolutions: 8
one on critical needs in the biotherapeutics area, aiming to promote access to these products as 9
well as to ensure their quality, safety and efficacy (4), and the other on strengthening of 10
regulatory systems, whereby WHO is requested to provide guidance on strengthening regulatory 11
systems, and especially those dealing with increasingly complex biological products (5). 12
Although this appendix deals primarily with rDNA-derived biotherapeutic protein products, 13
some aspects may also be relevant to other biotherapeutics. 14
15
1. Regulatory expectations for rDNA-derived biotherapeutics, including similar 16
biotherapeutic products 17
Regulatory expectations for rDNA-derived biotherapeutic protein products are found in the main 18
text of these guidelines which were adopted by the WHO Expert Committee on Biological 19
Standardization (ECBS) at its meeting in October 2013 (6). Following considerable international 20
consultation at the global level since 2004, the Guidelines on evaluation of similar 21
biotherapeutic products were adopted by the ECBS in 2009 (7). These guidelines emphasize the 22
need for a head-to-head demonstration of the “similarity” to biotherapeutic products of assured 23
quality, safety and efficacy that have been licensed on the basis of a full licensing dossier. A 24
head-to-head comparability exercise of a candidate similar biotherapeutic product (SBP) with a 25
reference biotherapeutic product (RBP) is essential to justify a reduced nonclinical and clinical 26
package for licensing (7). Studies should be designed to detect any potential difference in quality, 27
nonclinical and clinical attributes between the SBP and RBP rather than simply to confirm safety 28
and efficacy of the two products. It should be ensured that any detected differences have no 29
clinically meaningful impact on product performance. 30
WHO/BS/2015.2251
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If a head-to-head comparison of the SBP with the RBP is not performed throughout the 1
development process as outlined in WHO’s guidelines for SBPs (7), the final product should not 2
be referred to as an SBP (8, 9). SBPs are not “generic medicines” and the approval process used 3
for small molecule generic drugs is not applicable. 4
5
2. Review of products on the market 6
Problems have been identified in some countries where, for various reasons, biotherapeutic 7
products were licensed using data which do not now meet current WHO regulatory expectations 8
– such as biotherapeutics licensed as simple generics or as small molecule drugs. Often little is 9
known about the safety and efficacy of the individual products since, in many cases, 10
pharmacovigilance in the countries concerned is weak and sometimes nonexistent. In addition, 11
the nomenclature of these products is confusing and traceability is poor (10, 11). In some 12
countries, the coexistence on the market of these products and SBPs, as well as rDNA-derived 13
biotherapeutics licensed with full data packages, is a matter of concern. This was the situation for 14
erythropoietin (12) and similarly for heparin (13). Some updating of national regulations has 15
occurred to take account of recognized difficulties and there have also been changes in 16
international regulatory expectations (1417). Special considerations apply to the production and 17
control of biological medicines, including biotherapeutics, which do not apply to chemical drugs. 18
This is because of the biological nature of the starting materials, the manufacturing processes and 19
the test methods needed to characterize batches of the product. Nonclinical and clinical 20
evaluations are key components of the regulatory assessment of all biotherapeutics. Products 21
already approved under the pre-existing regulations will need to be reassessed to ensure that they 22
meet the new requirements. 23
24
National regulatory authorities (NRAs) should undertake a stepwise regulatory review of 25
biotherapeutic products already on the market, as follows: 26
First, NRAs should identify products that have been licensed with data which do not meet 27
current international regulatory standards. 28
WHO/BS/2015.2251
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Second, an assessment of identified products and gaps, based on the product-specific 1
considerations listed in section 3, should be carried out in order to decide the appropriate 2
action to remedy the situation and the timelines for implementing this action. This will 3
inevitably involve a riskbenefit assessment of the situation. 4
Third, manufacturers should submit to the NRA within a defined – but short – period of 5
time a plan of action for dealing with the problem. The plan of action should consist of an 6
analysis of available and missing data in accordance with WHO guidelines (6, 7), as well 7
as a description of measures, which may include interim assessments, and proposed 8
timelines needed to address the identified gaps. 9
Fourth, NRAs should evaluate the plan of action proposed by the manufacturer and agree 10
with the manufacturer on the next steps for generating missing data and their (possibly 11
stepwise) submission to the NRA. 12
Fifth, NRAs should assess in a stepwise approach the data (e.g. quality/manufacturing 13
data) that have been submitted – possibly in several separate packages at different times – 14
and on the basis of the outcome should decide on appropriate regulatory action. 15
The timeline for completing the overall review exercise will depend on the time needed to 16
generate and provide the missing information, taking into consideration the product-specific 17
points outlined in section 3. For example, in 2009 Health Canada clarified the “appropriate 18
regulatory pathway” for dealing with changes in the regulatory oversight of heparins to reflect 19
the fact that in future they would be regulated in Canada as biologicals (biologics) and not as 20
pharmaceutical drugs. In addition, Health Canada announced that any biosimilar heparin 21
submissions should follow Health Canada’s regulatory framework for subsequent entry biologics 22
and not the generic pathway used for small molecule drugs. Health Canada set a transition period 23
to allow manufacturers to update their files to reflect the data required for biological drugs (e.g. 24
12 months in the case of heparin). Manufacturers were also required to identify immediately 25
after the official date of transfer of regulatory authority how much of their licensed product was 26
sold in Canada per year (16). Similar transitional provisions have been made by other NRAs 27
when updating regulations. In Peru, for instance, draft regulations for the registration of 28
biotherapeutics and SBPs using complete dossiers include transitional provisions for products 29
licensed prior to the effective date of the proposed new regulations (17). Mexico recently 30
finalized a regulation covering requirements for biotherapeutics and SBPs. The regulation 31
WHO/BS/2015.2251
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includes a transitional article covering biotherapeutics licensed prior to introduction of the 1
updated regulation. A period of approximately 2 years from the effective date of new regulation 2
is normally anticipated for the entire assessment process. In the first 8 months, existing dossiers 3
and comparative analytical characterization data will be reviewed. After this initial period, the 4
manufacturer may be requested to provide additional nonclinical and clinical data according to a 5
specified timeline. On the basis of the outcome of the assessment, the manufacturer will be 6
recommended a renewal of the licence, risk mitigation or withdrawal of the licence (15). 7
8
3. Points to consider in a stepwise regulatory assessment 9
A particular licensed product should be allowed to remain on the market during the review 10
process. Consideration should be given to the following in deciding appropriate regulatory 11
actions: 12
a) It should be considered that the number of products on the market which have been 13
licensed without adequate quality, nonclinical and/or clinical data and whether there are 14
any therapeutic alternatives on the market which have been either licensed locally with 15
an adequate data package and/or also licensed by an experienced NRA and that meet the 16
standards of the relevant WHO guidelines (see b, below). 17
b) It is important to find out if the product in question is manufactured and licensed in a 18
country with a jurisdiction which has, and follows, well-established regulatory 19
frameworks, including all the principles set out in these guidelines for biotherapeutic 20
products (6) and, where appropriate, in WHO’s guidelines for SBPs (7). Account should 21
also be taken of whether the jurisdiction concerned has considerable experience in the 22
evaluation of biotherapeutic products, SBPs and post-marketing surveillance activities. If 23
a product is manufactured and licensed in a country with considerable experience in these 24
areas, then this provides confidence regarding quality, safety and efficacy. However, it 25
would be important to ascertain whether the actual product on the market in the country 26
with limited regulatory experience is comparable – with respect to manufacturing process 27
and controls, recent good manufacturing practices inspection and labelling – to the 28
product licensed, supplied and used in the manufacturing country with the more 29
WHO/BS/2015.2251
Page 8
experienced jurisdiction. It would also be important to see whether registration of the 1
product in question has been rejected, cancelled or suspended by other stringent NRAs. 2
c) It is also important to know the extent to which the registration dossier of the 3
biotherapeutic product meets the recommendations of WHO’s Guidelines on the quality, 4
safety and efficacy of biotherapeutic protein products prepared by recombinant DNA 5
technology and Guidelines on evaluation of similar biotherapeutic products (6, 7). 6
Attention should be paid to key differences between national requirements and WHO 7
guidelines – such as the lack of a head-to-head comparability exercise for an SBP. The 8
NRA should recommend a critical dataset for re-registration of such products. Changes in 9
regulatory requirements may be needed, as well as amendments to the legal framework of 10
the country concerned, to enable such new requirements to be implemented. 11
d) The level of actual use of the biotherapeutic product (market share or number of patients 12
impacted) should be ascertained. This includes whether the product is essential for 13
treating certain patients and what the clinical outcomes would be if the product were 14
taken off the market. This assessment should cover: the disease that is being treated, 15
whether the condition is life-threatening, the consequences of treating or not treating or 16
stopping treatment in patients already using the product, the risk of switching between 17
therapeutic alternatives, the likelihood (and potential consequences, if any) of supply 18
problems on clinical outcomes should the product be taken off the market, and the type of 19
patient population (paediatric, adult, older persons). 20
e) The seriousness of a potential lack of efficacy should be considered, as should possible 21
safety issues (including higher efficacy) that may result from the continued use of the 22
product under review. This should include an assessment of the severity of the potential 23
impact on a patient of an immunogenic effect arising from the use of the product and an 24
assessment of any adverse effects (e.g. biotherapeutic products that may cause cross-25
reactivity with native proteins, as in the case of pure red cell aplasia caused by 26
erythropoietin (1)). 27
f) The ability of the pharmacovigilance system in the country should be considered to 28
monitor and determine adverse reactions and/or efficacy problems (such as reduced 29
clinical effectiveness) associated with the biotherapeutic product, should they exist. 30
Criteria for the evaluation of functional pharmacovigilance systems can be found in 31
WHO/BS/2015.2251
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WHO’s document The safety of medicines in public health programs: pharmacovigilance 1
an essential tool (18). With poor pharmacovigilance systems in many countries, as well 2
as nomenclature difficulties, it may be impossible to obtain sufficient data to demonstrate 3
that a particular product was the cause of an adverse reaction or that patients may be at 4
risk from the use of products that are clinically untested or are tested with inadequately 5
designed studies. Traceability is a key element in monitoring the safety and efficacy of 6
biologicals as it enables pharmacovigilance measures to be put in place. 7
g) The expertise and capacity of regulators responsible for licensing biotherapeutic products 8
is critically important for the appropriate evaluation of these products. Collaboration 9
between NRAs, including work-sharing agreements and joint reviews with other NRAs, 10
should also be explored (for example, see 2, 19, 20). 11
h) Consideration should be given to transparency with respect to informing health-care 12
professionals, pharmacists and patients of the review process and its timelines. This could 13
be done through website posting, as in Canada (16), or via a symbol and some text in the 14
product information, referring to the need to align the licensing process with current 15
international expectations. 16
17
4. Regulatory actions 18
On the basis of the outcomes of the regulatory assessment, the NRA should make decisions on 19
appropriate actions to be taken. The decisions and actions of NRAs may differ depending on the 20
assessments made according the points listed in section 3, which will be jurisdiction-specific. In 21
a stepwise approach, product supply would not be compromised and authorization might be 22
regularized after the defined time period during which the product would undergo further 23
regulatory evaluation and so long as it is shown to be efficacious and safe. Capacity-building will 24
be needed where resources and expertise are considered inadequate. Where the number and 25
experience of persons available to undertake an overall review is limited, consideration could be 26
given to the possible mentoring, through WHO, of the NRA needing support by an experienced 27
authority that has established processes which follow relevant WHO guidelines. The sharing of 28
information between NRAs regarding the basis for regulatory decisions on biotherapeutic 29
WHO/BS/2015.2251
Page 10
products, including SBPs, is considered an important support for regulatory authorities that are 1
less experienced in dealing with these highly complex products and may accelerate the 2
assessment of the products. Communicating details of what information was reviewed and how it 3
was incorporated into decision-making is also important for prescribers, patients and other 4
stakeholders and can help them gain confidence in biotherapeutic products. The summary basis 5
of decision documents of Health Canada, the European Medicines Agency and the United States 6
Food and Drug Administration are examples of informative documents. The stepwise regulatory 7
assessment approach outlined in this addendum is flexible and is designed to support the 8
accessibility of biotherapeutic products of assured quality, safety and efficacy, as requested in 9
the two resolutions of the Sixty-seventh World Health Assembly in 2014 (4, 5). 10
11
12
WHO/BS/2015.2251
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Authors and acknowledgements 1
The first draft of this document was prepared by Dr E. Griffiths, Consultant, Kingston-upon-2 Thames, United Kingdom; Dr H-N. Kang, World Health Organization, Geneva, Switzerland; and 3 Dr I. Knezevic, World Health Organization, Geneva, Switzerland. 4
5
Comments were recieved from the following reviewers: 6
Mrs A. Abas, Ministry of Health Malaysia, Selangor, Malaysia; Dr W.S. Alhaqaish, Jordan Food 7
and Drug Administration, Amman, Jordan; Dr N. Annibali, Asociación Latinoamericana de 8 Industrias Farmacéuticas, Argentina; Mrs J. Bernat on behalf of the International Federation of 9 Pharmaceutical Manufacturers and Associations, Geneva, Switzerland; Dr B. Boonyapiwat, 10 Ministry of Public Health, Nonthaburi, Thailand; Dr G. Castillero, Ministry of Health, Panama; 11
Dr J.M. Cousiño, Federacion Latinoamericana de la Industria Farmacéutica, Santiago, Chile; Dr 12
F. Muñoz Espinoza, Agencia Nacional de Medicamentos Instituto Nacional de Salud, Santiago, 13 Chile; Dr M.T. Ibarz, Instituto Nacional de Higiene “Rafael Rangel”, Caracas, Venezuela; Dr A. 14 Klein, Health Canada, Ottawa, Canada; Dr C. Njue, Health Canada, Ottawa, Canada; Ms D 15
Pérez, Instituto Nacional de Higiene “Rafael Rangel”, Caracas, Venezuela; Dr G.R. Soni, 16 National Institute of Biologics, Ministry of Health and Family Welfare, Noida, India; Mr H. 17
Vásquez, Dirección General de Medicamentos, Insumos y Drogas, Lima, Perú. 18
19
The second draft was prepared by Dr E. Griffiths, Consultant, Kingston-upon-Thames, United 20 Kingdom; and Dr H-N. Kang, World Health Organization, Geneva, Switzerland; taking into 21 consideration comments recieved from the above reviewers as well as the discussions at the 22
Second WHO Implementation Workshop on Quality Assessment of Similar Biotherapeutic 23 Products held in Xiamen, China, on 28–30 May 2012, attended by: 24
25
Mrs A. Abas, Ministry of Health Malaysia, Selangor, Malaysia; Dr W.S. Alhaqaish, Jordan Food 26 and Drug Administration, Amman, Jordan; Ms J. Archer, Hospira, Thebarton, Australia, 27
representative of the International Generic Pharmaceutical Alliance; Dr B. Boonyapiwat, 28 Ministry of Public Health, Nonthaburi, Thailand; Dr L. Gomes Castanheira, Agência Nacional de 29 Vigilância Sanitária, Brasilia, Brazil; Dr W. Chang, State Food and Drug Administration, Beijing, 30 China; Dr R. Chakrabarti, United States Pharmacopeia - India, Shameerpet, India, representative 31
of the United States Pharmacopoeial Convention; Mr D. Cheng, Beijing Four Rings Bio-32 Pharmaceutical Co., Ltd., Beijing, China; Dr C. Liang, National Institutes for Food and Drug 33 Control, Beijing, China; Dr Y. Choi, Korea Food and Drug Administration, Osong, Republic of 34 Korea; Ms J. Dahlan, National Agency of Drug and Food Control, Jakarta, Indonesia; Mr G. 35 Eich, Amgen Inc. Corporate Services/Global Regulatory Affairs & Safety, Thousand Oaks (CA), 36
USA, representative of the International Federation of Pharmaceutical Manufacturers and 37 Associations; Dr M.H. Friede, World Health Organization, Geneva, Switzerland; Dr K. Gao, 38
National Institutes for Food and Drug Control, Beijing, China; Mr T. Go, Health Sciences 39 Authority, Helios, Singapore; Dr E. Griffiths, Kingston-upon-Thames, United Kingdom; Dr L. 40 Gu, Shenyang Sunshine Pharmacetical Co. Ltd., Shenyang, China; Dr Z. Guo, Chinese 41
WHO/BS/2015.2251
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Pharmacopoeia Commission, Beijing, China, representative of the Chinese Pharmacopoeia; Dr N. 1
Hassannia, Biological Office Food and Drug Organization, Tehran, Iran; Dr K. Ho, Agence 2 Nationale de Sécurité du Médicament et des Produits de Santé, France; Dr S. Hufton, National 3 Institute for Biological Standards and Control, Potters Bar, United Kingdom; Mrs W. Jariyapan, 4 Ministry of Public Health, Nonthaburi, Thailand; Mr R. Jian, Health Sciences Authority, Helios, 5 Singapore; Dr J. Joung, Korea Food and Drug Administration, Osong, Republic of Korea; Dr H-6
N. Kang, World Health Organization, Geneva, Switzerland; Dr Y. Kishioka, Pharmaceutical and 7 Medical Devices Agency, Tokyo, Japan, representative of the Japanese Pharmacopoeia; Dr I. 8 Knezevic, World Health Organization, Geneva, Switzerland; Mr J. Leong, Health Sciences 9 Authority, Helios, Singapore; Dr J. Li, Shanghai CP-Guojian Pharmaceutical Co. Ltd., Shanghai, 10 China; Dr J. Luo, State Food and Drug Administration, Beijing, China; Mrs V. Madrigal, 11
Recepta Biopharma, Sao Paulo, Brazil; Dr C. Njue, Health Canada, Ottawa, Canada; Mrs Y. 12 Hechavarria Nunez, Centro para el Control Estatal de la Calidad de los Medicamentos, Habana, 13 Cuba; Dr P.H. Pan, Innovax Biotech Co. Ltd., Xiamen, China, representative of the Developing 14
Country Vaccine Manufacturing Network; Dr R. Perez, Biotech Pharmaceutical Co. Ltd., Beijing, 15 China; Dr S. Pluschkell, Pfizer Inc., Groton (CT), USA, International Federation of 16 Pharmaceutical Manufacturers and Associations; Prof C. Rao, National Institutes for Food and 17 Drug Control, Beijing, China; Dr M. Schiestl, Sandoz GmbH, Kundl/Tirol, Austria, 18
representative of IGPA; Dr T. Schreitmueller, F. Hoffmann-La Roche, Ltd. Basel, Switzerland, 19 representative of International Federation of Pharmaceutical Manufacturers and Associations; Dr 20
S. Shani, Ministry of Health and Social Welfare, New Delhi, India; Dr Q. Shen, National 21 Institutes for Food and Drug Control, Beijing, China; Dr X. Shen, China Bio-Tech Group, 22 Beijing, China; Dr G.R. Soni, National Institute of Biologics, Ministry of Health and Family 23 Welfare, Noida, India; Dr L. Sun, Xiamen Amoytop Biotech Co. Ltd., Xiamen, China; Dr R. 24 Thorpe, National Institute for Biological Standards and Control, Potters Bar, United Kingdom; 25
Mrs C. Ulm, Mylan GmbH, Zurich, Switzerland, representative of the European Generic 26 Medicines Association; Dr A. Vallin, Centre of Molecular Immunology, Habana, Cuba; Dr J. 27
Wang, Health Canada, Ottawa, Canada; Dr J. Wang, National Institutes for Food and Drug 28 Control, Beijing, China; Dr M. Xu, National Institutes for Food and Drug Control, Beijing, 29 China; Dr S. Zhang, State Food and Drug Administration, Beijing, China. 30
31
The draft document was posted on the WHO Biologicals website for the first round of public 32
consultation from 11 February to 12 March 2014. The draft was also discussed at the First WHO 33 Implementation Workshop on Evaluation of Biotherapeutic Products held in Seoul, Republic of 34
Korea, on 13–14 May 2014. 35
36
The third draft was prepared by Dr E. Griffiths, Consultant, Kingston-upon-Thames, United 37
Kingdom; and Dr H-N. Kang, World Health Organization, Geneva, Switzerland, taking into 38
account comments received from following reviewers: 39
40
Mrs A. Abas, Ministry of Health Malaysia, Selangor, Malaysia; Asociación Latinoamericana de 41 Industrias Farmacéuticas, Buenos Aires, Argentina; Mrs J. Bernat, on behalf of the International 42 Federation of Pharmaceutical Manufacturers and Associations, Geneva, Switzerland; Dr B. 43
WHO/BS/2015.2251
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Boonyapiwat, Ministry of Public Health, Nonthaburi, Thailand; Dr Y. Choi, Ministry of Food 1 and Drug Safety, Osong, Republic of Korea; Dr F. Muñoz Espinoza, Instituto de Salud Publica 2
de Chile, Santiago, Chile; Dr H-K. Heim, Bundesinstitut für Arzneimittel und Medizinprodukte, 3 Bonn, Germany; Dr J. Joung, Ministry of Food and Drug Safety, Osong, Republic of Korea; Dr 4 Y. Kishioka, Pharmaceutical and Medical Devices Agency, Tokyo, Japan; Dr A. Klein, Health 5 Canada, Ottawa, Canada; Dr S. Kox, on behalf of the European Generic Medicines 6 Association, Brussels, Belgium; Dr P. Kurki, Finnish Medicines Agency, Helsinki, Finland; Mrs 7
V. Madrigal, Recepta Biopharma, Sao Paulo, Brazil; Dr C. Njue, Health Canada, Ottawa, 8 Canada; Mrs Y. Hechavarria Nunez, Centro para el Control Estatal de la Calidad de los 9
Medicamentos, Habana, Cuba; Dr J. Shin, World Health Organization Regional Office for the 10 Western Pacific, Manila, Philippines; Dr W. Tan, Genzume Singapore, Singapore; Dr R. Thorpe, 11 Consultant, Welwyn, United Kingdom; Dr J. Wang, Health Canada, Ottawa, Canada; Dr M. 12 Weise, Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany; Dr S. Xie, China 13
Food and Drug Administration, Beijing, China. 14
15
The draft document was posted on the WHO Biologicals website for the second round of public 16 consultation from 16 December 2014 to 30 January 2015. 17
18
The document WHO/BS/2015.2251 was prepared by Dr E Griffiths, Consultant, Kingston-upon-19
Thames, United Kingdom; and Dr H-N. Kang, World Health Organization, Geneva, Switzerland, 20
taking into account comments received from the following reviewers: 21
Dr R. Aaron, Tanzania Food and Drugs Authority, Tanzania; Mrs A. Abas, Ministry of Health 22
Malaysia, Selangor, Malaysia; Dr A. Abdelaziz, Jordan Food And Drug Administration, Amman, 23
Jordan; Dr R. Abete on behalf of Asociacion LatinoAmericana de Industrias Farmaceuticas, 24
Buenos Aires, Argentina; Dr M. Aboulwafa, National Organization for Research and Control of 25
Biological Products, Cairo, Egypt; Mrs J. Bernat, on behalf of the International Federation of 26
Pharmaceutical Manufacturers and Associations, Geneva, Switzerland; Dr Y. Choi, Ministry of 27
Food and Drug Safety, Osong, Republic of Korea; Dr J. Gangakhedkar, Central Drugs Standard 28
Control Organization, New Delhi, India; Dr K. Gao, National Institutes for Food and Drug 29
Control, Beijing, China; Ms C. Gongora Torres on behalf of the Ministry of Health of Colombia, 30
Bogota, Colombia; Dr T. Guo, National Institutes for Food and Drug Control, Beijing, China; Dr 31
H. Hamedifar, CinnaGen Co., Tehran, Iran; Dr H-K. Heim, Bundesinstitut für Arzneimittel und 32
Medizinprodukte (BfArM), Bonn, Germany; Dr J. Joung, Ministry of Food and Drug Safety, 33
Osong, Republic of Korea; Dr B. Kim, Ministry of Food and Drug Safety, Osong, Republic of 34
Korea; Dr Y. Kishioka, Pharmaceutical and Medical Devices Agency, Tokyo, Japan; Mrs S. Kox 35
on behalf of the European Generic Medicines Association; Dr P. Kurki, Finnish Medicines 36
Agency, Helsinki, Finland; Dr C. Liang, National Institutes for Food and Drug Control, Beijing, 37
China; Dr N. Lyoko, Zambia Medicines Regulatory Authority, Lusaka, Zambia; Mr R. 38
Mezzasalma, on behalf of the European Association for BioIndustries, Brussels, Belgium; Dr R. 39
WHO/BS/2015.2251
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Mody, United States Pharmacopeia - India, India; Mr F. Montes de Oca, on behalf of Argentine 1
Association of Industrial Pharmacy and Biochemistry, Buenos Aires, Argentina; Dr V. Murthy, 2
Apotex Inc., Toronto, Canada; Dr C. Njue, Health Canada, Ottawa. Canada; Dr D. Pathankar, 3
United States Pharmacopeia - India, India; Dr Z. Sauna, Food and Drug Administration, USA; 4
Dr T. Schreitmueller, on behalf of La Federación Latinoamericana de la Industria Farmacéutica, 5
Mexico City, Mexico; Dr M. Seigelchifer, United States Pharmacopeia - India, India; Ms J. Shim, 6
on behalf of Korea Biomedicine Industry Association, Seoul, Republic of Korea; Dr J. Southern 7
(Developing Country Vaccine Regulators’ Network representative), South Africa; Dr S. Suh, , 8
Ministry of Food and Drug Safety, Osong, Republic of Korea; Dr M. Wadhwa, National Institute 9
for Biological Standards and Control, Potters Bar, United Kingdom; Dr J. Wang, Health Canada, 10
Ottowa, Canada. 11
Also taken into consideration were comments and advice provided in the WHO informal 12
consultation for regulatory risk assesment for biotherapeutic products held 2930 April 2015 in 13
Geneva, Switzerland, attended by the following participants: 14
Mrs A. Abas, Ministry of Health Malaysia, Selangor, Malaysia; Dr A. Abdelaziz, Jordan Food 15
and Drug Administration, Amman Jordan; Dr K. Bangarurajan, Central Drug Standards Control 16
Organization, New Delhi, India; Mrs J. Bernat, on behalf of the International Federation of 17
Pharmaceutical Manufacturers and Associations, Geneva, Switzerland; Dr B. Boonyapiwat, 18
Ministry of Public Health, Nonthaburi, Thailand; Ms J. Dahlan, National Agency of Drug and 19
Food Control, Jakarta, Indonesia; Mrs D. Darko, Food and Drug Authority, Accra, Ghana; Mr D. 20
Goryachev, Ministry of Health, Moscow, Russia; Dr E. Griffiths, Consultant, Kingston-upon-21
Thames, United Kingdom; Dr K. Guo, World Health Organization, Geneva, Switzerland; Dr K. 22
Heidenreich, Novartis International AG, Switzerland, on behalf of the International Federation of 23
Pharmaceutical Manufacturers and Associations; Dr H-K. Heim, Federal Institute for Drugs and 24
Medical Devices, Bonn, Germany; Dr C. Ilonze, National Agency for Food and Drug 25
Administration and Control, Abuja, Nigeria; Mr R. Ivanov, Biocad, Saint Petersburg, Russia; 26
Mrs W. Jariyapan, Ministry of Public Health, Nonthaburi, Thailand; Dr J. Joung, Ministry of 27
Food and Drug Safety, Seoul, Republic of Korea; Dr H-N. Kang, World Health Organization, 28
Geneva, Switzerland; Dr D. Khokal, Health Sciences Authority, Singapore; Dr I. Knezevic, 29
World Health Organization, Geneva, Switzerland; Dr P. Kurki, Finnish Medicines Agency, 30
Helsinki, Finland, on behalf of the European Medicines Agency Biosimilar Medicinal Products 31
Working Party; Mrs S. Kox, on behalf of the European Generic Medicines Association, Brussels, 32
Belgium; Ms I. Lyadova, Ministry of Health, Moscow, Russia; Ms S. Marlina, National Agency 33
of Drug and Food Control, Jakarta, Indonesia; Dr J. Meriakol, Ministry of Health, Nairobi, 34
Kenya; Mr K. Nam, Ministry of Food and Drug Safety, Osong, Republic of Korea; Dr C. Njue, 35
Health Canada, Ottawa, Canada; Mrs Y. Nunez, Centro para el Control Estatal de la Calidad de 36
los Medicamentos, Habana, Cuba; Ms H. Pedersen, World Health Organization Regional Office 37
for Europe, Copenhagen, Denmark; Dr M. Pombo, Pan American Health Organization, 38
Washington (DC), USA; Dr A. Qu, Shanghai Institute of Biological Products Co. Ltd., Shanghai, 39
WHO/BS/2015.2251
Page 15
China, on behalf of the Developing Countries Vaccine Manufacturers Network; Dr S. Ramanan, 1
Amgen Inc., Thousand Oaks (CA), USA, on behalf of the International Federation of 2
Pharmaceutical Manufacturers and Associations; Dr M. Schiestl, Sandoz GmbH, Kundl, Austria, 3
on behalf of the European Generic Medicines Association; Dr E. Spitzer. On behalf of the Latin 4
American Association of Pharmaceutical Industries, Buenos Aires, Argentina; Ms I. Susanti, Bio 5
Farma, Bandung, Indonesia, on behalf of the Developing Countries Vaccine Manufacturers 6
Network; Dr R. Thorpe, Consultant, Welwyn, United Kingdom; Dr C. Vaca Gonzalez, Ministry 7
of Health, Bogota, Colombia; Ms B. Valente, National Health Surveillance Agency (Agência 8
Nacional de Vigilância Sanitária), Brasilia, Brazil; Ms N. Vergel, National Institute of Drugs and 9
Food Surveillance (Nacional de Vigilancia de Medicamentos y Alimentos), Bogota, Colombia; 10
Dr M. Wadhwa, National Institute for Biological Standards and Control, Potters Bar, United 11
Kingdom; Dr J. Wang, Health Canada, Ottawa, Canada;Dr J. Wang, National Institutes for 12
Food and Drug Control, Beijing, China; Dr L. Wang, National Institutes for Food and Drug 13
Control, Beijing, China; Dr K. Watson, AbbVie Ltd., Maidenhead, United Kingdom, on behalf 14
of the International Federation of Pharmaceutical Manufacturers and Associations; Dr C. 15
Webster, Baxter Healthcare Corporation, Newbury, United Kingdom, on behalf of the European 16
Generic Medicines Association; Dr S. Xie, China Food and Drug Administration, Beijing, China; 17
Dr T. Yamaguchi, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan; Dr A. Zhang, 18
China National Biotec Group Co. Ltd., Beijing, China, on behalf of the Developing Countries 19
Vaccine Manufacturers Network. 20
21
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