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WHO/RRA BT_DRAFT/10 December 2014 2

ENGLISH ONLY 3

4

Guidance on scientific principles for regulatory risk 5

assessment of biotherapeutic products 6

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NOTE: 9

This document has been prepared for the purpose of inviting comments and 10 suggestions on the proposals contained therein, which will then be considered by the 11 Expert Committee on Biological Standardization. Publication of this early draft is to 12

provide information about the proposed WHO guidance on scientific principles for 13 Regulatory Risk Assessment of Biotherapeutic Products to a broad audience and to 14 improve transparency of the consultation process. 15

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The text in its present form does not necessarily represent an agreed formulation 17 of the Expert Committee. Written comments proposing modifications to this text 18

MUST be received by 30 January 2015 in the Comment Form available separately 19 and should be addressed to the World Health Organization, 1211 Geneva 27, 20 Switzerland, attention: Department of Essential Medicines and Health Products (EMP). 21

Comments may also be submitted electronically to the Responsible Officer: Dr Hye-Na 22 Kang at email: kangh@who.int. 23

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The outcome of the deliberations of the Expert Committee will be published in the 25

WHO Technical Report Series. The final agreed formulation of the document will be 26

edited to be in conformity with the "WHO style guide" (WHO/IMD/PUB/04.1). 27

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30 © World Health Organization 2014 31

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, 32 World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: 33 +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate WHO 34 publications – whether for sale or for non-commercial distribution – should be addressed to WHO Press, 35 at the above address (fax: +41 22 791 4806; e-mail: permissions@who.int). 36 The designations employed and the presentation of the material in this publication do not imply the 37 expression of any opinion whatsoever on the part of the World Health Organization concerning the legal 38 status of any country, territory, city or area or of its authorities, or concerning the delimitation of its 39 frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may 40 not yet be full agreement. 41 42

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The mention of specific companies or of certain manufacturers’ products does not imply that they are 1 endorsed or recommended by the World Health Organization in preference to others of a similar nature 2 that are not mentioned. Errors and omissions excepted, the names of proprietary products are 3 distinguished by initial capital letters. 4 5 All reasonable precautions have been taken by the World Health Organization to verify the information 6 contained in this publication. However, the published material is being distributed without warranty of 7 any kind, either expressed or implied. The responsibility for the interpretation and use of the material 8 lies with the reader. In no event shall the World Health Organization be liable for damages arising from 9 its use. 10

11 The named authors [or editors as appropriate] alone are responsible for the views expressed in this 12 publication. 13 14 15

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This guidance document published by WHO is intended to be scientific and advisory in

nature.

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Contents 2

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1. Background and Scope ··················································································· 4 4

2. Regulatory Expectations for Biotherapeutic Products ··········································· 5 5

3. Regulatory Expectations for Similar and Other Copy Biotherapeutic Products ··········· 6 6

4. Regulatory Situation regarding Copy Products ··················································· 7 7

5. Risk Assessment Considerations ······································································ 9 8

6. Points to Consider in a Stepwise Risk Based Assessment ······································ 10 9

7. Conclusions ······························································································ 13 10

8. Glossary (alphabetical order) ········································································ 15 11

Authors and Acknowledgements ········································································ 18 12

References ··································································································· 20 13

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1. Background and Scope 1

This document sets out scientific principles to be considered by national regulatory 2

authorities (NRAs) and manufacturers in the process of licensing biotherapeutic 3

products used in human medicine. It covers the regulatory expectations for innovative 4

biotherapeutic products, and for so called copy products including similar 5

biotherapeutic products (also call biosimilars) (see the section of Glossary). The 6

document also considers the regulatory risk assessment needed for dealing with 7

situations where, for various historical reasons, products were licensed using a 8

pathway which did not follow globally agreed and relevant regulatory expectations for 9

these biologicals as set out in this document and for which there may be concerns of 10

safety and efficacy, e.g. biotherapeutic products licensed through a generic 11

approach/pathway with little or no clinical data (1). The International Conference of 12

Drug Regulatory Authorities (ICDRA) discussed such situations at its meeting in 13

Singapore in 2010 (2) and requested the WHO to assist in developing approaches to 14

evaluating these already licensed products according to WHO guidelines thus 15

enabling them to remain on the market or for phasing them out in a reasonable period 16

of time. More recently, the World Health Assembly adopted two resolutions, one on 17

the critical needs in the biotherapeutics area, that is to promote access to these 18

products as well as to ensure their quality, safety and efficacy (3), and the other on 19

regulatory systems strengthening, where WHO is requested to provide guidance on 20

strengthening regulatory systems, especially those dealing with increasingly complex 21

biological products (4). 22

23

The scope of products covered by this WHO guidance note includes: 24

All biologically active protein products used in the treatment of human 25

diseases and which are prepared by rDNA technology; 26

Protein product used for in vivo diagnosis, such as monoclonal antibody 27

products used for imaging and products used for ex vivo treatment; 28

Protein products intentionally modified by e.g. pegylation, conjugation with a 29

cytotoxic drug or modification of rDNA sequences. 30

Although the document deals primarily with biotherapeutic protein products, some 31

aspects are also relevant to polysaccharide based medicines, such as heparins. 32

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1

2. Regulatory Expectations for Biotherapeutic Products 2

Special considerations apply to the production and control of biological medicines, 3

including biotherapeutics, which do not apply to chemical drugs. This is because of 4

the biological nature of the starting materials, the manufacturing processes and the test 5

methods needed to characterize batches of the product. For example, production of 6

many biotherapeutics involves the culture of cells and microorganisms. Others, such 7

as heparins, are isolated directly from biological materials. Also, biologicals are 8

highly complex products in molecular terms. Even with the great progress made in the 9

ability to purify and characterize biologically active macromolecules with respect to 10

their protein and post-translational components, such as lipid and oligosaccharides, it 11

is still not possible to fully predict their biological properties and clinical performance 12

from their physicochemical characteristics alone. Changes, such as deamidation, 13

oxidation or N-and C-terminal differences, can also occur in the polypeptide chain. 14

Details vary depending on the production process and may or may not affect clinical 15

performance. Nonclinical and clinical evaluation are therefore key components of the 16

regulatory assessment of all biotherapeutics. 17

Furthermore, biological systems are known to be inherently variable, a feature which 18

has important consequences for the safety and efficacy of the resulting product (5). 19

Although comprehensive analytical characterization of the drug substance and/or drug 20

product is expected, considerable emphasis must also be given to the manufacturing 21

process, including process validation and in-process control. Understanding the 22

production process and monitoring consistency of production are, therefore, critical 23

since even slight variations in the manufacturing process can impact the clinical safety 24

and efficacy of the product and occasionally lead to major adverse effects, such as 25

immunogenicity, with potentially serious safety implications. The demonstration that 26

batches of product do not differ in clinically relevant quality attributes from those of 27

lots shown to be safe and effective in clinical studies is a crucial component not only 28

of product evaluation and licensing but also of on-going regulatory oversight. 29

Regulatory expectations for biotherapeutic protein products can be found in the WHO 30

Guidelines on the Quality, Safety and Efficacy of Biotherapeutic Protein Products 31

Prepared by Recombinant DNA Technology which were adopted by the WHO Expert 32

Committee on Biological Standardization (ECBS) at its meeting in October 2013 (2). 33

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These extensive guidelines provide NRAs and manufacturers with guidance on the 1

quality, safety and efficacy of biotherapeutic protein products prepared by 2

recombinant DNA technology and intended for use in humans. They are based on 3

over three decades of experience in this technically demanding field and replace 4

“WHO Guidelines for assuring the quality of pharmaceutical and biological products 5

prepared by recombinant DNA technology” (6). They are the result of several reviews 6

and consultations during the period 2012-2013 and are considered to be a replacement 7

and not a revision of the original WHO guidelines. This is because they contain new 8

sections on nonclinical and clinical evaluation of rDNA-derived protein 9

biotherapeutics which were lacking in the original document. In addition, a section on 10

issues related to manufacturing changes both during development and once the 11

product is on the market also has been briefly introduced. WHO guidelines on 12

evaluating the impact of manufacturing and other changes on marketed vaccines were 13

adopted by the WHO ECBS at its meeting in October 2014 (7). The general principles 14

set out in this document could also apply to biotherapeutic products. 15

16

3. Regulatory Expectations for Similar and Other Copy 17

Biotherapeutic Products 18

Following considerable international consultations at the global level since 2004, 19

WHO Guidelines on evaluation of similar biotherapeutic products were adopted by 20

the WHO ECBS in 2009 (8). These emphasize the need for a head to head 21

demonstration of the “similarity” of a copy biological product’s characteristics, with 22

respect to both physicochemical, immunochemical and biological properties to a 23

defined and already licensed reference product in order to justify a reduced non-24

clinical and clinical package for licensing a candidate product. This is expected to 25

reduce overall development costs and time to marketing authorization. Only an 26

originator product that was licensed on the basis of a full registration dossier can serve 27

as a reference product, as defined in the WHO Guidelines (8). Critically, the head to 28

head comparability exercise involves not only evaluation of quality attributes but also 29

of non-clinical and clinical aspects with the same reference biological product 30

throughout. Clinical studies should be designed so as to specifically demonstrate 31

comparable safety, efficacy and immunogenicity between the products in sensitive 32

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populations in order for the candidate product to be called a similar biotherapeutic 1

product (SBP). 2

3

These WHO Guidelines are intended to provide a globally acceptable set of basic 4

principles regarding the evaluation of similar biotherapeutics although it was 5

recognized that, by themselves, they will not resolve all issues. Several countries or 6

jurisdictions have now developed their own guidelines but there are some differences 7

in detail between them. Furthermore, other regulatory pathways, such as a stand-alone 8

approach based on a full registration dossier as described in the WHO Guidelines (5), 9

may also be appropriate for licensing copy biologicals (9). However, it was reaffirmed 10

at a WHO Consultation in Seoul (9, 10) in 2010 that only copy biotherapeutic 11

products licensed on the basis of a full comparability package involving head to head 12

comparative evaluation of quality, nonclinical and clinical aspects with one defined 13

reference product should be called SBPs, i.e. biosimilars. It was suggested that copy 14

products appropriately licensed by other pathways might be called “non-innovative 15

biological products” (9) but this has not yet been universally accepted and several 16

names are being considered. Nevertheless, there is full agreement that the approach to 17

licensing small - molecule generic medicines, involving only product analysis and the 18

demonstration of bioequivalence to a reference product, is not appropriate for the 19

development, evaluation and authorization of copy biological products. As already 20

mentioned above, clinical performance of biologicals is highly dependent on the 21

manufacturing process and slight changes can lead to adverse clinical effects. Beside 22

the comprehensive comparison at the quality level, appropriately designed clinical 23

studies with sufficient statistical power are therefore essential to demonstrate the 24

safety and efficacy of copy biological products since it is currently not possible to 25

predict all aspects of the clinical performance from measurable and detectable 26

physicochemical characteristics alone. Consistency of production is also critical since 27

unintentional changes during production may impact product performance. 28

29

4. Regulatory Situation regarding Copy Products 30

As patents and data protection measures for innovative biotherapeutic products expire, 31

or near expiration, there has been considerable interest in producing copies of these 32

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highly successful medicinal products. Indeed, copies of biotherapeutic protein 1

products have been produced in some developing countries even before patents had 2

expired globally. For example, under trade-related aspects of the Intellectual Property 3

Rights (TRIPS) Agreement of the World Trade Organization, the pre-1995 product 4

patents did not apply in India and this left copies of many biological products that 5

were patented before 1995 marketable in India. Moreover, due to regulatory gaps at 6

the time, some copy biotherapeutic products may have been approved for marketing 7

without undergoing adequate regulatory evaluation consistent with WHO Guidelines 8

(5, 8). Furthermore, innovators have not sought patent protection for some drugs in 9

India thereby creating an opportunity for Indian companies to influence the domestic 10

market and to supply other countries where these products had not been patented (11). 11

The emphasis of many Indian pharmaceutical manufacturers has been directed more 12

toward the development of copies rather than original molecules because of much 13

lower development costs including reduced time to market (12). 14

15

Much of the interest in this pharmaceutical area has been driven by the possibility that 16

copy products would be more affordable than the innovative ones and thus potentially 17

improve access to much needed biotherapeutic medicines globally. The major 18

question that arose was how copies of the innovator products should be licensed, and 19

whether there could be a reduction in the nonclinical and clinical package submitted, 20

bearing in mind that these medicines are highly complex products, manufactured by 21

equally complex and sophisticated processes, a situation compounded by the 22

challenges of dealing with biological variability. It was recognized that copying 23

biologicals would be much more complex than copying small molecules. Quite 24

clearly some clinical data are required for licensing such copy biological products, 25

and quite clearly too, a traditional generic pathway as used for small molecule drugs is 26

not appropriate (1, 13). The concept of “similar but not necessarily identical 27

biological products”, with a designated comparative regulatory pathway as described 28

in the section 3, was developed by the WHO (8) and other countries, following the 29

lead of the European Medicines Agency (14). Accordingly any new product 30

referencing an innovator product and using the designation SBP (or equivalent) 31

should be developed and licensed in accordance with the WHO standards (8). Copy 32

products not meeting these criteria can be evaluated by other regulatory pathways, 33

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such as a stand-alone approach based on a full registration dossier as described in the 1

WHO Guidelines (5). These should not be referred to as SBPs. 2

3

5. Risk Assessment Considerations 4

A serious problem has been identified in some countries where, for historical reasons, 5

biotherapeutic products have been licensed on data which did not meet present 6

regulatory expectations as agreed on a global level regarding quality, nonclinical and 7

clinical data (1). Sometimes, copy products have been licensed as simple generics. 8

Often, little is known about the safety and efficacy of the individual products, since in 9

many cases pharmacovigilance in the countries concerned is weak and sometimes 10

non-existent. In addition, the nomenclature for these products is confusing and 11

traceability poor (13, 15). In some countries, the coexistence on the market at the 12

same time of copy products licensed inappropriately by a generic pathway, or without 13

sufficient nonclinical and clinical data, and true biosimilars is a matter of concern. 14

The lack of terminology for products developed as copy products with only partial or 15

no comparability to a reference product has compounded the problem and led to a 16

great diversity in evaluating as well as naming these products (10) 17

Slight differences between the biotherapeutic product of one manufacturer and that of 18

another, or between an innovator and copy biotherapeutic product, could have 19

unintentional effects on their clinical performance and safety and need to be handled 20

carefully from a regulatory perspective. NRAs should undertake a regulatory risk 21

assessment of biotherapeutic products already on the market but known to have been 22

licensed with data which do not meet globally agreed and relevant regulatory 23

expectations. A risk based approach to dealing with this problem would allow 24

licensed biotherapeutic products to remain on the market for a specified period during 25

which time manufacturers would be required to submit first a risk management plan 26

for regulatory approval and subsequently appropriate quality, nonclinical and clinical 27

data, as necessary, for regulatory evaluation to support the continuation of the license. 28

This plan should consist of an analysis of available and missing data in accordance 29

with WHO guidelines on SBPs (8) as well as a description of measures intended to fill 30

the identified data gaps. 31

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The timeline for completing such a review exercise would depend on the risk 1

assessment of each individual product on the market (see the section of Points to 2

Consider in a Stepwise Risk Based Assessment). Products from manufacturers who 3

did not submit a risk management plan or appropriate data, or submitted data which 4

were considered insufficient to support continued licensing, would be automatically 5

removed from the market. 6

In adopting a risk based approach, product supply would not be compromised and 7

authorization would be regularized after the defined time period when all products 8

would have undergone further regulatory evaluation and found to meet internationally 9

accepted standards of quality, safety and efficacy. Should a problem be identified with 10

a particular product before the end of the specified time period, the implicated 11

product’s license could be withdrawn immediately or the labelling modified as 12

appropriate. A product claimed to be a SBP but failing to meet WHO Guidelines (8) 13

could be given the opportunity to be re-submitted as a stand-alone product on the 14

basis of a full registration dossier as described in the WHO rDNA Guidelines (5) or be 15

withdrawn from the market in a period as defined by the local risk-based assessment. 16

In the third implementation workshop on WHO SBP guidelines held in Seoul in 2014, 17

it was stated that some NRAs require manufacturers to submit reports to re-evaluate 18

and continue regulatory approval 3-5 years following licensing (e.g. Brazil, Europe, 19

Egypt, India, Indonesia, Iran, Japan, Korea, Peru, Russia, Singapore). Some of the 20

considerations for a stepwise risk based assessment described below maybe helpful in 21

such reviews. 22

Traceability is a key element in monitoring the performance of biotherapeutic 23

products since some problems maybe product specific (e.g. product specific safety 24

issues) and/or batch related. An adequate nomenclature system is essential to ensure 25

specific identification. This should include all important indicators such as brand 26

(proprietary) name, manufacturer’s name, country of origin and, critically, the lot 27

number. 28

29

6. Points to Consider in a Stepwise Risk Based Assessment 30

A stepwise risk-benefit and prioritization assessment, based on product-specific 31

considerations, should be carried out in order to decide the appropriate action and the 32

time a particular inappropriately licensed product should be allowed to remain on the 33

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market prior to finalization of the review. Initially, this will depend upon the time 1

needed to generate and provide the missing information, the risk associated with 2

removing the product from the market and the risk of keeping the product on the 3

market, and could be between say 6 months and 4 years. However, manufacturers 4

should first be required to submit a risk management plan to the NRA within a short 5

time period detailing their proposals for dealing with the situation including the 6

generation and provision of quality, non-clinical and clinical data as appropriate. An 7

example of a risk based plan for dealing with a particular regulatory situation can be 8

found in the actions of Health Canada. In 2009, Health Canada initiated a risk based 9

plan of action to deal with changes in the regulatory oversight of heparins to reflect 10

the fact that in future they would be regulated in Canada as biologicals (biologics) and 11

not pharmaceutical drugs. While both unfractionated heparins and low molecular 12

weight heparins are administratively controlled as drugs in some administrations, they 13

are essentially biologicals and the importance of their biological origin is increasingly 14

recognized by the global regulatory community. Health Canada set a 12 month 15

transition period to allow manufacturers to update their files to reflect data required 16

for biological drugs. Manufacturers were also required to identify immediately after 17

the official date of transfer of regulatory authority how much of their licensed product 18

was sold in Canada per year. In addition Health Canada announced that any biosimilar 19

heparin submissions should follow Health Canada’s regulatory framework for 20

subsequent entry biologics and not the generic pathway used for small molecule drugs 21

(16). 22

23

Consideration should be given to the following in deciding appropriate actions: 24

a) The number of products on the market which have been licensed using 25

inappropriate regulatory pathways and whether there are any therapeutic 26

alternatives on the market which have been licensed also by an experienced 27

NRA meeting the standards of the relevant WHO Guidelines (see b, below). 28

b) Whether the product in question is manufactured and licensed in a country 29

with a jurisdiction which has and follows well established regulatory 30

frameworks including all principles for SBPs according WHO (8), as well as 31

considerable experience in the evaluation of biotherapeutic products, SBPs, 32

and post marketing surveillance activities. If a product is manufactured and 33

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licensed in such a country, then this provides confidence regarding its quality, 1

safety and efficacy. However, it would be important to ascertain whether the 2

actual product on the market in the country with limited regulatory experience 3

is identical, including site of manufacture (process validation and in-process 4

control), and conditions of use especially the labelling to that licensed, 5

supplied and used in the manufacturing country with the more experienced 6

jurisdiction; 7

c) The extent to which the registration dossier of the biotherapeutic product 8

meets the recommendations of the WHO Guidelines on the Quality, Safety and 9

Efficacy of Biotherapeutic Protein Products Prepared by Recombinant DNA 10

Technology and the WHO Guidelines on evaluation of similar biotherapeutic 11

products (5, 8). Attention should be paid to any important differences between 12

national requirements and WHO Guidelines, such as mandatory requirement 13

for viral validation and human immunogenicity studies and data needed to 14

allow extrapolation of biosimilars to other indications (12). In this case, the 15

NRA should recommend critical data set for re-registration of such products; 16

d) The level of actual use of the biotherapeutic product (market share or number 17

of patients impacted); 18

e) Whether the product is essential for treating certain patients. This assessment 19

should cover: What is the disease being treated?; Is the condition life-20

threatening?; What are the consequences of treating or not treating or stopping 21

treatment in patients already under the product? What is the risk of switching 22

between therapeutic alternatives?; What is the nature of the affected patient 23

population (paediatric, adult, senior/elderly); 24

f) The likelihood and the potential consequences, if any, of supply problems on 25

clinical outcomes should the product be taken off the market; 26

g) The seriousness of a potential lack of efficacy, as well as possible safety 27

issues that may result from the continued use of the product under review. 28

This should include an assessment of the severity of the potential impact on a 29

patient of an immunogenic effect arising from the use of the product (e.g. 17); 30

h) The ability of the pharmacovigilance system in place in the country to monitor 31

and determine adverse reactions and / or efficacy problems, such as reduced 32

clinical effectiveness, associated with the biotherapeutic product, should they 33

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exist. With poor pharmacovigilance systems in many countries, as well as 1

nomenclature difficulties, it may be impossible to obtain sufficient data to 2

demonstrate that a particular product was the cause of an adverse reaction or 3

that patients may be at risk from the use of clinically inadequate products. 4

Traceability is a key element in monitoring the safety performance of 5

biologicals by enabling pharmacovigilance measures. 6

i) As already mentioned, the expertise and capacity of regulators responsible for 7

licensing biotherapeutic products is critically important for the appropriate 8

evaluation of these products. Capacity building will be needed where 9

resources and expertise is considered inadequate. Where the number and 10

experience of persons available to undertake an overall review is limited, 11

consideration could be given to the possible mentoring, through the WHO, of 12

the NRA needing support by an experienced authority that has established and 13

follows guidelines according to WHO SBP guidelines. Work sharing 14

agreements with other NRAs including joint reviews should also be explored. 15

j) Consideration should be given to transparency with respect to informing 16

healthcare professionals, pharmacists and patients of the review process and 17

its time lines. This could be done through website posting, as in Canada (16), 18

or via a symbol and some text in the product information and referring to the 19

need to align the licensing process with current international expectations. 20

21

7. Conclusions 22

Although discussions on how best to license copy biotherapeutics on the basis of a 23

reduced nonclinical and clinical data package continues, there is increasing alignment 24

between jurisdictions on key issues (see 18). Since the publication of the WHO 25

Guidelines on evaluation of similar biotherapeutic products (8), several activities 26

such as implementation workshops (10), development of case studies (19-21), and 27

other publications (18) have been undertaken by the WHO at both global and regional 28

levels. It has become clear that much investment in the development of biosimilar and 29

copy biotherapeutic products is taking place worldwide, including in countries with 30

emerging economies. It is also becoming clear that the regulatory agencies of many 31

countries need to be strengthened with respect to their regulatory oversight of 32

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biotherapeutic products in general and biosimilars and copy products in particular. 1

The expertise and continuous training of regulators responsible for licensing is 2

critically important for the appropriate evaluation of these sophisticated products 3

which should be understood to be biologicals and which may include proteins, 4

polysaccharides and DNA molecules. These issues are reflected in the already 5

mentioned World Health Assembly resolution in 2014 which calls for the 6

strengthening of national regulatory authorities with respect to regulating increasingly 7

complex biological products (4). Regional initiatives to improve the awareness of 8

countries concerning these issues are already well underway in some areas, for 9

example in PAHO (22, 23), but needs may differ from region to region. It is expected 10

that this guidance document will contribute to these initiatives. 11

12

13

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8. Glossary (alphabetical order) 1

The definitions given below apply to the terms as used in this document. They may 2 have different meanings in other contexts. 3 4

Biological medicine 5 A medicinal product used in the treatment, prevention or diagnosis of disease, the 6

production of which involves biological starting materials and manufacturing 7 processes, as well as the use of biological test methods to characterize the product. It 8 includes rDNA-derived medicines. In addition, biologicals are highly complex 9 products in molecular terms and their clinical performance cannot be fully defined by 10 physicochemical means alone. In some countries, biologicals are defined in 11

regulations as vaccines, biotherapeutics, blood and blood products, genetic therapy 12

products, cells, tissues and organs. 13

14

Biotherapeutic product 15 A biological medicinal product used in treating human diseases. 16 17

Comparability exercise 18 In the case of changes to an already licensed product, the activities – including study 19

design, conduct of studies, and evaluation of data – that are designed to investigate 20 whether a pre-change product and a post-change product are highly similar. In the 21

case of a similar biotherapeutic product, the activities designed to compare the quality, 22

safety and efficacy of a candidate biosimilar with the properties of a reference 23

biotherapeutic product (RBP). 24

25

Copy product 26 A copy version of a previously licensed originator or innovative medicinal product. A 27 copy biotherapeutic product may be licensed through a biosimilar regulatory pathway 28

or as a stand-alone product on the basis of a full registration dossier. 29 30

Generic pathway 31 A regulatory pathway established for small molecule and chemically derived 32 medicines. A generic medicine contains the same active pharmaceutical ingredient as, 33

and is bioequivalent to, an originator (comparator) medicine. Since generic medicines 34

are identical in the active pharmaceutical substance, dose, strength, route of 35

administration, safety, efficacy and intended use, they can be substituted for the 36 originator product. Biological products cannot be licensed through this pathway nor 37 called ‘generic biologicals’ or ‘biogenerics’. 38

39

Head-to-head comparison 40 Direct comparison of the properties of the similar biotherapeutic product with the 41 reference biotherapeutic product in the same study. 42

43

Noninnovative product 44 A copy biological medicinal product developed on its own and licensed through a 45 stand-alone regulatory pathway possibly designed for abbreviated application, and not 46

directly compared and analysed in a head to head comparability study of quality, 47

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safety and efficacy against a licensed reference product. It may or may not have been 1 compared clinically, however, extrapolation of clinical indications is not acceptable in 2

any case, since quality or clinical comparison alone is not sensitive enough to justify 3 differences of potential relevance (13). 4 5

Originator product/innovator product 6 A medicine that has been licensed by a national regulatory authority on the basis of a 7

full registration dossier; i.e. the approved indication(s) for use were granted on the 8 basis of full quality, efficacy and safety data. 9 10

rDNA-derived biotherapeutics 11 Biotherapeutics prepared by recombinant DNA technology and developed as 12 described in the WHO Guidelines (5), i.e. all biologically active protein products 13 which are used in the treatment of human diseases and which are prepared by rDNA 14

technology. 15 16

Reference biotherapeutic product (RBP) 17 A reference biotherapeutic product is used as the comparator for head-to-head 18

comparability studies with the similar biotherapeutic product in order to show 19 similarity in terms of quality, safety and efficacy. Only an originator product that was 20

licensed on the basis of a full registration dossier can serve as an RBP. The selection 21 of the RBP is usually made at the national level by the national regulatory authority. 22 The term does not refer to measurement standards such as international, 23

pharmacopoeial or national reference standards. 24

25

Recombinant DNA technology 26 Technology that joins together (i.e. recombines) and possibly alters the sequence of 27

DNA segments from two or more different DNA molecules that are inserted into a 28 host organism to produce new genetic combinations. It is also referred to as gene 29

manipulation or genetic engineering because the original gene is artificially altered 30 and changed. These new genes, when inserted into the expression system, form the 31 basis for the production of rDNA-derived protein(s). 32

33

Regulatory risk evaluation 34 A systematic approach to evaluating information to support a benefit-risk decision 35

within a regulatory review and evaluation framework. It consists of an independent 36 evaluation of the risk assessment performed by the manufacturer, taking into 37

consideration all relevant and available information and data. 38 39

Risk 40 The combination of the probability of occurrence of harm and the severity of that 41 harm. In the context of pharmaceutical quality it is the probability and severity of any 42

kind of negative impact (hazard) on the quality of the product which may impact its 43 clinical performance. 44

45

Risk assessment 46 A systematic process of organizing information to support a risk decision to be made 47

within a risk management process. It consists of the identification of hazards and the 48 analysis and evaluation of risks associated with exposure to those hazards. 49

WHO/RRA BT_DRAFT/10 December 2014

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1

Risk evaluation 2 The comparison of the estimated risk to given risk criteria, using a quantitative or 3 qualitative scale to determine the significance of the risk. 4 5

Risk management 6 A systematic approach to the assessment, control, communication and review of risks. 7 Risk management in the context of pharmaceutical quality is often referred to as 8 quality risk management – a systematic process for the assessment, control, 9 communication and review of risks to the quality of the medicinal product across the 10

product’s life cycle. A model for quality risk management is outlined in the WHO 11 (24) and International Conference on Harmonisation guidelines (25). 12

13

Risk management plan 14 A detailed description of the activities that continuously ensure patients’ safety and 15 their benefit from a medicinal ingredient. A risk management plan includes 16 pharmacovigilance and many other elements. 17

18 Risk reduction strategy 19 A plan or method for decreasing the probability of occurrence of harm and/or the 20 severity of that harm. 21

22 Similar biotherapeutic product (SBP) 23 Biotherapeutic product identified by its similarity in all characteristics to a chosen 24

reference product in terms of quality, safety and efficacy demonstrated through a 25

head-to-head comparability exercise, as described in the WHO Guidelines (8). It is 26 licensed through a specific regulatory pathway. Any differences between biosimilar 27 candidate and its reference product should be shown to be of no clinical relevance, 28

and extrapolation of clinical indications may only be acceptable if scientifically 29 justified. A similar biotherapeutic product is also called a ‘biosimilar’ and in some 30

countries, a ‘subsequent entry biologic’. 31

32 Stepwise risk based assessment 33 A stepwise approach to the risk-benefit assessment based on product-specific 34 considerations. It should start with initial assessment, addressing the question whether 35

the risks of a product clearly outweigh the benefits or vice versa. Depending on a risk 36

management plan submitted by manufacturers, the risk associated with removing the 37

product from the market and the risk of keeping the product on the market can be 38 estimated. Then it continues to decide the appropriate action and the time needed to 39 generate and provide the missing information. 40

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Authors and Acknowledgement 1

The first draft of this document was prepared by Dr Elwyn Griffiths, WHO 2 consultant, Kingston-upon-Thames, UK; Dr Hye-Na Kang, TSN/EMP/HIS, WHO, 3 Geneva, Switzerland; and Dr Ivana Knezevic, World Health Organization, Geneva, 4 Switzerland. 5

6

Comments were recieved from the following reviewers: 7

Mrs Arpah Abas, Ministry of Health Malaysia, Selangor, Malaysia; Dr Wesal Salem 8 Alhaqaish, Jordan Food and Drug Administration, Amman, Jordan; Nestor Annibali, 9 ALIFAR, Argentina; Mrs Janis Bernat on behalf of the International Federation of 10

Pharmaceutical Manufacturers and Associations (IFPMA), Geneva, Switzerland; Dr 11 Boontarika Boonyapiwat, Ministry of Public Health, Nonthaburi, Thailand; Gioconda 12 Castillero, Ministerio de Salud, Panama; José Manuel Cousiño, FIFARMA, Chile; 13 Fabiola Muñoz Espinoza, Agencia Nacional de Medicamentos Instituto Nacional de 14

Salud – Chile; María Teresa Ibarz, INH “RR”, Caracas, Venezuela; Dr Agnes Klein, 15 Health Canada, Ottawa, Canada; Dr Catherine Njue, Health Canada, Ottawa, 16 Canada; Dunia Pérez, INH “RR”, Caracas, Venezuela; Dr G. R. Soni, National 17 Institute of Biologics, Ministry of Health and Family Welfare, Government of India, 18

Noida, India; Mr Hans Vásquez, DIGEMID, Lima, Perú. 19

20

The second draft was prepared by Dr Elwyn Griffiths, WHO consultant, Kingston-21 upon-Thames, UK; and Dr Hye-Na Kang, TSN/EMP/HIS, WHO, Geneva, 22

Switzerland; taking into considerations of comments recieved from above reviewers 23 as well as the discussion at the 2nd WHO Implementation Workshop on Quality 24

Assessment of Similar Biotherapeutic Products held in Xiamen, China, on 28 May – 25 30 May 2012, attended by: 26

27

Mrs Arpah Abas, Ministry of Health Malaysia, Selangor, Malaysia; Dr Wesal Salem 28 Alhaqaish, Jordan Food and Drug Administration, Amman, Jordan; Ms Jennifer 29

Archer, Hospira, Thebarton, Australia, representative of the International Generic 30 Pharmaceutical Alliance (IGPA); Dr Boontarika Boonyapiwat, Ministry of Public 31

Health, Nonthaburi, Thailand; Dr Laura Gomes Castanheira, ANVISA, Brasilia, 32 Brazil; Dr Weihong Chang, State Food and Drug Administration (SFDA), Beijing, 33

China; Dr Ranjan Chakrabarti, United States Pharmacopeia-India, Shameerpet, India, 34 representative of the United State Pharmacopoeial Convention; Mr Dusheng Cheng, 35 Beijing Four Rings Bio-Pharmaceutical Co., Ltd., Beijing, China; Dr Liang 36 Chenggang, National Institutes for Food and Drug Control (NIFDC), Beijing, China; 37 Dr Youngju Choi, Korea Food and Drug Administration (KFDA), Osong, Korea; Ms 38

Juliati Dahlan, National Agency of Drug and Food Control, Jakarta, Indonesia; Mr 39 Geoffrey Eich, Amgen Inc. Corporate Services / Global Regulatory Affairs & Safety, 40 Thousand Oaks, USA, representative of IFPMA; Dr Martin Howell Friede, IER/IEA, 41 WHO, Geneva, Switzerland; Dr Kai Gao, NIFDC, Beijing, China; Mr Thomas Go, 42 Health Sciences Authority (HSA), Helios, Singapore; Dr Elwyn Griffiths, Kingston-43

upon-Thames, UK; Dr Lawrence Gu, Shenyang Sunshine Pharmacetical Co. LTD., 44 Shenyang, China; Dr Zhongping Guo, Chinese Pharmacopoeia Commission, Beijing, 45

China, representative of the Chinese Pharmacopoeia; Dr Nazila Hassannia, Biological 46

WHO/RRA BT_DRAFT/10 December 2014

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Office Food and Drug Organization, Tehran, Iran; Dr Kowid Ho, ANSM, France; Dr 1 Simon Hufton, National Institute for Biological Standards and Control, Potters Bar, 2 UK; Mrs Wichuda Jariyapan, Ministry of Public Health, Nonthaburi, Thailand; Mr 3 Ren Jian, HSA, Helios, Singapore; Dr Jeewon Joung, KFDA, Osong, Korea; Dr Hye-4 Na Kang, TSN/EMP/HIS, WHO, Geneva, Switzerland; Dr Yasuhiro Kishioka, 5

Pharmaceutical and Medical Devices Agency (PMDA), Tokyo, Japan, representative 6 of the Japanese Pharmacopoeia; Dr Ivana Knezevic, TSN/EMP/HIS, WHO, Geneva, 7 Switzerland; Mr James Leong, HSA, Helios, Singapore; Dr Jing Li, Shanghai CP-8 Guojian Pharmaceutical Co., Ltd., Shanghai, China; Dr Jianhui Luo, SFDA, Beijing, 9 China; Mrs Vivian Madrigal, Recepta Biopharma, Sao Paulo, Brazil; Dr Catherine 10

Njue, Health Canada, Ottawa, Canada; Mrs Yanet Hechavarria Nunez, Centro para 11 el Control Estatal de la Calidad de los Medicamentos (CECMED), Habana, Cuba; Dr 12

Pan Huirong Pan, Innovax BIOTECH CO. Ltd., Xiamen, China, representative of the 13 Developing Country Vaccine Manufacturing Network (DCVMN); Dr Rolando Perez, 14 Biotech Pharmaceutical Co., Ltd., Beijing, China; Dr Stefanie Pluschkell, Pfizer Inc., 15 Groton, USA, representative of the IFPMA; Prof Chunming Rao, NIFDC, Beijing, 16 China; Dr Martin Schiestl, Sandoz GmbH, Kundl/Tirol, Austria, representative of 17

IGPA; Dr Thomas Schreitmueller, F. Hoffmann-La Roche, Ltd. Basel, Switzerland, 18 representative of IFPMA; Dr Satyapal Shani, Ministry of Health and Social Welfare, 19

Government of India, New Delhi, India; Dr Qi Shen, NIFDC Beijing, China; Dr 20 Xinliang Shen, China Bio-Tech Group, Beijing,China; Dr G. R. Soni, National 21

Institute of Biologics, Ministry of Health and Family Welfare, Government of India, 22 Noida, India; Dr Li Sun, Xiamen Amoytop Biotech Co., LTD., Xiamen, China; Dr 23 Robin Thorpe, NIBSC, Potters Bar, UK; Mrs Cornelia Ulm, Mylan GmbH, Zurich, 24

Switzerland, representative of the European Generic medicines Association (EGA); 25

Dr Antonio Vallin, Centre of Molecular Immunology, Habana, Cuba; Dr Jian Wang, 26 Health Canada, Ottawa, Canada; Dr Junzhi Wang, NIFDC, Beijing, China; Dr Miao 27 Xu, NIFDC, Beijing, China; Dr Shumin Zhang, SFDA, Beijing, China. 28

29

The draft document was posted on the WHO Biologicals web site for the first round 30

of public consultation from 11 February to 12 March 2014. The draft was also 31 discussed at the 1st WHO Implementation Workshop on Evaluation of Biotherapeutic 32 Products held in Seoul, Republic of Korea, on 13 – 14 May 2014. 33

34

The third draft was prepared by Dr Elwyn Griffiths, WHO consultant, Kingston-35

upon-Thames, UK; and Dr Hye-Na Kang, TSN/EMP/HIS, WHO, Geneva, 36

Switzerland, taking into account comments received from following reviewers: 37

38

Mrs Arpah Abas, Ministry of Health Malaysia, Selangor, Malaysia; Asociación 39 Latinoamericana de Industrias Farmacéuticas (ALIFAR), Buenos Aires, Argentina; 40

Mrs Janis Bernat on behalf of the International Federation of Pharmaceutical 41 Manufacturers and Associations (IFPMA), Geneva, Switzerland; Dr Boontarika 42

Boonyapiwat, Ministry of Public Health, Nonthaburi, Thailand; Dr Youngju Choi, 43 Ministry of Food and Drug Safety, Osong, Korea; Dr Fabiola Munoz Espinoza, 44 Instituto de Salud Publica de Chile, Santiago, Chile; Dr Hans-Karl Heim, 45

Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), Bonn, Germany; Dr 46

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Jeewon Joung, Ministry of Food and Drug Safety, Osong, Korea; Dr Yasuhiro 1 Kishioka, Pharmaceutical and Medical Devices Agency (PMDA), Tokyo, Japan; Dr 2

Agnes Klein, Health Canada, Ottawa, Canada; Dr Suzette Kox on behalf of the 3 European generic Medicines Association, Brussels, Belgium; Dr Pekka Kurki, 4 Finnish Medicines Agency, Helsinki, Finland; Mrs Vivian Madrigal, Recepta 5 Biopharma, Sao Paulo, Brazil; Dr Catherine Njue, Health Canada, Ottawa, Canada; 6 Mrs Yanet Hechavarria Nunez, Centro para el Control Estatal de la Calidad de los 7

Medicamentos (CECMED), Habana, Cuba; Dr Jinho Shin, WPRO/WHO, Manila, 8 Philippines; Dr Woody Tan, Genzume Singapore, Singapore; Dr Robin Thorpe, WHO 9 consultant, Welwyn, UK; Dr Jian Wang, Health Canada, Ottawa, Canada; Dr 10 Martina Weise, BfArM, Bonn, Germany; Dr Songmei Xie, Center for Drug 11

Evaluation, China Food and Drug Administration, Beijing, People’s Republic of 12 China. 13

14

The draft document is posted on the WHO Biologicals web site for the second round 15 of public consultation from 16 December 2014 to 30 January 2015. 16

17

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