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: kangh@who.int. 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 bookorders@who.int). 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: permissions@who.int). 38

mailto:kangh@who.intmailto:bookorders@who.int

WHO/BS/2015.2251

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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

Page 12

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

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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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