1. Dr. Ivana Knezevic - World Health Organization

Ivana Knezevic |1 |
IFPMA-AIPM Workshop
Biotherapeutic Medicines: Regulatory Challenges and
Current Practices
WHO Standards for Regulatory Evaluation of
Biotherapeutic Products including SBPs
Moscow, 15-16 May 2013
Dr Ivana Knezevic, WHO/HIS/EMP

Ivana Knezevic2 |
Outline
 WHO products and activities
- International Standards:
– written (eg, Guidelines, Recommendations)
– measurement (Int. Standards and Reference Preparations)
- Implementation workshops
- Technical assistance
 Challenges in evaluating SBPs
 WHO focus in 2012 and 2013
 Regulatory risk assessment of Biotherapeutic Products
 Points for discussion

Ivana Knezevic3 |
WHO norms and standards for biologicals
Global written standards Global measurement
standards
Scientific evidence
Measurement
standards:
essential elements for development, licensing
and lot release
1) Standardization of assays
2) Further development
and refinement of QC tests
3) Scientific basis for setting
specifications
Reference preparations for
vaccines and biotherapeutics

Ivana Knezevic4 |
16 Available WHO International standards or
Reference reagents for Biosimilars (1)
The list is available on the following links:
1) WHO web
http://www.who.int/bloodproducts/catalogue/CytoMarch11.pdf
2) NIBSC web
http://www.nibsc.ac.uk/products/biological_reference_material
s/product_catalogue.aspx
Recently published review article by Thorpe R, Wadhwa M,
Biologicals 2011.

Ivana Knezevic
2008 2009 2010 2011
Development of measurement standards
for biotherapeutics, 2008 - 2012
2012
1. Urinary follicle stimulating hormone and urinary luteinizing hormone (5th IS)
2. Erythropoetin, recombinant for bioassay (3rd IS)
3. High molecular weight urokinase (2nd IS)
4. IL 2 (1st RR)
5. IL 2 (2nd IS)
6. Anti human neutrophil antigen-3ª (1st RR)
1. Thyroid stimulating antibody (2nd IS)
2. Follicle stimulating hormone (2nd IS)
3. Sex hormone binding globulin (2nd IS)
4. G-CSF (2nd IS)
1. Chorionnic gonadotrophin (5th IS)
2. Parathyroid hormone, 1-84 (1st IS)
1. Insulin-like growth factor (2nd IS)
1. Dihydrostreptomycin (3rd IS)
2. TGF beta-3 (1st IS)

Ivana Knezevic6 |
WHO Guidelines on SBPs and other
publications
1. The final version of the Guidelines on evaluation of similar
biotherapeutic products (SBPs) is available on WHO Biologicals
website (http://www.who.int/biologicals/en/) since April 2010.
 The document was adopted by the 60th meeting of the WHO
Expert Committee on Biological Standardization, in October 2009.
2. Web pages related to biotherapeutics:
http://www.who.int/biologicals/vaccines/biotherapeutic-
products/en/index.html
3. Link to special issue in Biologicals (2011), 39 devoted to SBPs: 25
articles with WHO experience in working with regulators worldwide

Ivana Knezevic
WHO Written Standards for Biologicals
 Technical specifications that help define safe and efficacious products
 Intended to be scientific and advisory in nature
 Starting point for setting national requirements as well as a basis for
vaccine prequalification
 Guidance for NRAs and manufacturers on international regulatory
expectations for the production and quality assurance , stability, non-
clinical and clinical evaluation of biologicals
 Facilitating international harmonization of biologicals licensure
 Living documents revised in response to scientific advances
Evolving concept: from quality specifications to scientific principles for
the entire regulatory oversight

Ivana Knezevic |8 |
Concept of WHO Guidelines on SBPs
1) Provide key principles for evaluation of SBPs as a basis for setting national
requirements;
2) Leave space to NRAs to formulate additional/ more specific requirements;
3) Living document that will be developed further in line with the progress in
scientific knowledge and experience
4) Assist with the implementation of the guidelines into regulatory and
manufacturers practice through:
 Global, regional and national workshops involving regulators,
manufacturers and other relevant experts
 Trainings, advisory groups
5) Consider guidance issued by other bodies – intention to complement them,
not to create a conflict.

Ivana Knezevic |9 |
Scope and key definitions
 Scope: Guidelines applies to well-established and well-characterized
biotherapeutic products such as recombinant DNA-derived therapeutic proteins.
Vaccines and plasma derived products and their recombinant analogues are
excluded from the scope of this document. WHO recommendations and
regulatory guidance for these products are available elsewhere
(http://www.who.int/biologicals/areas/en/).
 SBP is a biotherapeutic product which is “similar” in terms of quality, safety and
efficacy (Q, S, E) to an already licensed reference biotherapeutic product (RBP).
 RBP is used as the comparator for head-to-head studies with SBP in order to
show similarity in terms of Q, S and E. Only an originator product that was
licensed on the basis of a full licensing dossier can serve as an RBP. It does not
refer to measurement standards such as international, pharmacopoeial or
national standards or reference preparations.

Ivana Knezevic |10 |
Key principles for the licensing of SBPs
 SBPs are not generic medicines and many characteristics associated with the
authorization process and marketed use of generic medicines generally do not
apply.
 Effective regulatory oversight: critical for assuring Q, S, E of SBPs
 Stepwise approach
- Demonstration of similarity of SBP to RBP in terms of quality is a prerequisite
for the reduction of the non-clinical and clinical data set required for licensure.
- If major differences are found in the quality, non-clinical and clinical studies,
the product should not be considered as "similar" and, therefore, other options
for its further development and licensing (eg, stand alone) should be considered.
Important to note that biotherapeutics which are not
shown to be similar to a RBP should not be described
as "similar", nor called a "SBP".

Licensure requirements–
amount of data and applicability
Full dossier
(Stand alone
approach)
Similar Biotherapeutic
Products (SBPs)
Applicable to all
biologicals
Existing knowledge,
full, comparative
characterization, plus
Comparative BUT
reduced
non-clinical,
clinical data
Applicable to well characterized
biologicals only
Generic
For
chemical
entities
only
Not applicable
to biologicals

Reference Biotherapeutic Product (RBP)
 RBPs should have been marketed for a suitable duration and
have a volume of marketed use
 RBPs should be licensed based on a full Q, S and E data set
 The same RBP used throughout the development of the SBP
 An SBP should not be considered as a choice for RBP
 The active substance of the RBP and the SBP must be shown to
be similar
 The dosage form and route of administration of the SBP should
be the same as that of the RBP
 NRAs may need to consider establishing additional criteria to
guide the acceptability of using a RBP licensed or resourced in
other countries

Quality
 Development of an SBP
– Thorough characterization of a number of representative lots of
the RBP
– Engineering a manufacturing process that will reproduce a product
that is highly similar to the RBP in all critical product quality
attributes
 The quality comparison showing molecular similarity between the SBP
and the RBP provides the underlying rationale for predicting that the
clinical safety and efficacy profile of the RBP should also apply to the
SBP
– So that the extent of the non-clinical and clinical data required
with the SBP can be reduced
 To evaluate comparability
– The manufacturer should carry out a comprehensive
physicochemical and biological characterization of the SBP in head-
to-head comparison with the RBP

Non-clinical evaluation
 General principles:
– Address pharmaco-toxicological assessment of SBP
– Should be conducted with the final formulation intended for clinical use
– Minimum: head-to-head comparative toxicology studies
– Additional NC data depend of the specificities of a product
 In vitro studies
– Methodology: Receptor-binding studies, cell-based assays, etc
– Purpose: Establish comparability of biol/pharmacodynamic activity of SBP and RBP
 In vivo studies
– General principles
• Comparative in nature
• Performed in relevant species
• Employ state of the art technology
– Endpoints
• Biological/pharmacodynamic activity relevant to the clinical application
• Non-clinical toxicity as determined in at least one repeat dose toxicity study
with a relevant species and including toxicokinetic measurements

Clinical evaluation
 Designed to demonstrate comparable safety and efficacy of the SBP to the RBP
 Clinical comparability exercise: stepwise procedure; PK and PD studies followed by the
pivotal clinical trials
 Efficacy studies
– No dose-finding studies
– Demonstrate in adequately powered, randomized, and parallel group clinical trial (ICH
E9 and E10)
– Equivalence or non-inferiority studies may be acceptable for the comparison of
efficacy and safety of the SBP with the RBP; equivalence/non-inferiority margins have
to be pre-specified and justified
 Safety
– Usually, safety data obtained from the efficacy trials will suffice
– Comparison with the RBP should include type, frequency and severity of AEs
 Extrapolation
– Prerequisites
• Similarity shown in a sensitive model
• Mechanism of action/receptor the same
• Safety and immunogenicity sufficiently characterized in the evaluated population

Pharmacovigilance
 Close monitoring of the clinical safety: focus on (rare) serious AEs in all approved
indications
 Identification of SBPs: 1) brand name; 2) INN; 3) lot number; 4) country of
origin
 PhV system should be in place at the time of marketing authorization
 Manufacturer should submit a safety specification and PhV plan at the time of
submission of the MA application
 PhV plan should describe planned activities and methods based on the safety
specification
 Risk minimization measures may enhance safe use of SBPs
 NRA should monitor compliance with the marketing commitments
 PM report: to be evaluated in a scientific manner including frequency and
causality of AEs

ICDRA Recommendations 2010 (to countries)
NRAs (Member States) should
 Regulate biosimilars as biologicals. Therefore, a generic medicines
("biogeneric") regulatory approach is not appropriate and should not
be used.
 Implement WHO Guidelines as a whole. This means that only
products licensed on the basis of the full comparability study (Q, NC,
C) should be considered, and named as SBPs (biosimilars).
 Strengthen clinical and statistical expertise to improve evaluation of
the data submitted by the manufacturers for licensing. Additional
efforts are needed to address specific issues related to
pharmacovigilance of biosimilars.

ICDRA Recommendations 2010 (to WHO)
WHO should
 Consider developing guidelines on risk management strategies for
copy products already licensed as "biogeneric".
 Develop a template for Member States to share information on the
scientific basis for licensing biosimilars.
 Supplement its guidance on evaluation of similar biotherapeutic
products by providing up-to-date Guidelines for evaluation of
biotherapeutic products in general.
 Conduct a review of existing international reference preparations
for assay of biotherapeuctics. Identify gaps and take action to fill
the gap.

Implementation of WHO guiding principles
into regulatory and manufacturing practices
 Well defined regulatory requirements/ guidelines are the basis for
licensing
 Initiative at the country level is critical – all stakeholders should be
involved
 Joint effort by regulators and manufacturers
 Regional and national networks for information sharing
- Implementation of WHO Guidelines
- without modifying principles
- with modifications
 Important to complete global picture with the update from India, China
and Russian speaking countries

20 | Ivana Knezevic
 Focused on the implementation of the Guidelines into the regulatory and
manufacturer practice at the global level, in particular, the principles of clinical
designs and interpretation of clinical data generated in comparability study
 Outcomes
– Situation in 12 countries (Brazil, Canada, China, Cuba, India, Iran, Japan,
Jordan, Korea, Malaysia, Singapore, and Thailand) was discussed
– Better understanding and consensus on the scientific basis for the clinical
evaluation
– Comprehensive overview of national requirements in 12 countries: special
issue: Biologicals (2011), 39
 Proposal from participants
– NRAs should make efforts to build their capacities for regulation of SBPs; in
particular, expertise for clinical evaluation is very much needed
– WHO should revise WHO Guidelines for assuring the quality of products
prepared by recombinant DNA technology (WHO TRS 814) and continue
monitoring progress with the implementation of the Guidelines on SBPs.
Implementation workshop for SBPs:
24-26 August 2010, Seoul, Korea

21 | Ivana Knezevic
 Challenges identified
– Most of the biotherapeutics that are currently subject of licensing
belong to the category of known biological entity that undergoes
through the stand alone pathway with reduced data package rather
than through biosimilar pathway.
• E.g. partial comparative data in Q, comparison with literature data in
C; partial comparative data in Q and N, comparative data in C;
comparative data in Q, N, C, non-comparative data in C for Mab.
 It was noted
– that biotherapeutics which are not shown to be similar to a RBP should not
be described as "similar", nor called a "SBP",
– and that generic approach is not suitable for development, evaluation and
licensing of SBPs; however,
– the terminology which has been used in developing countries showed
that the biosimilar pathway is not yet there.
24-26 August 2010, Seoul, Korea

22 | Ivana Knezevic
28-30 May 2012, Xiamen, China
 Objective: Address key issues in quality assessment
 Outcomes
– Similarity of the quality attributes is a key for SBP
development. Having the same amino acid sequences is the
bottom line of proving the similarity between SBP and RBP.
– SBP and RBP have their own lifecycle, so there is no
requirement for maintaining their similarities (comparability)
once an SBP has been licensed.
– The closer the specifications of the SBP are to those of the
RBP, more confidence regarding its expected clinical
performance.
– Based on the degree of similarities achieved at quality
assessment, clinical trial should be designed.
– The term "biogeneric" is confusing and should not be used.

23 | Ivana Knezevic
 Support requested by participants (examples)
– Support the strengthening of expertise of NRAs/NCLs
• Prepare Q&A
• Develop e-learning tool
• Provide training program (training curriculum)
• Prepare public assessment report (information sharing)
– Publish advocacy materials
• Progress of developing the regulations/guidelines
• Monitoring licensed SBPs
• Plan for collaborative studies to establish ISs/RPs
• Update country situation reports
28-30 May 2012, Xiamen, China

Ivana Knezevic24 |
Challenges
1. Regulatory framework for biotherapeutics: diversity of approaches
1. Most of the biotherapeutics in developing countries belong to the category of
known biological entity that undergoes through the stand alone pathway with
reduced data package rather than through SBP pathway.
2. Some countries have regulatory pathway for "non-innovative biotherapeutic
products" but requirements are not always clear.
2. Lack of expertise and capacity for evaluation of biotherapeutics at NRA
3. Comparability studies with RBP: concept not well understood and used in developing
countries
5. PhV system in many countries: need to be developed/ improved
6. Additional responsibilities of NRAs and other national authorities:
1. IP issues
2. Interchangeability and substitutability
3. Labelling and prescribing information

WHO focus in 2012 and 2013
– 2nd implementation workshop: 28-30 May 2012, Xiamen
– Guidelines for quality, safety, and efficacy of biologicals prepared by
recombinant DNA technology: public consultation and ECBS Oct 2013
– Regulatory Risk Assessment for biotherapeutic products licensed with
insufficient/ inappropriate data
- Coordination of the technical assistance from WHO CCs with the expertise in
the evaluation of biotherapeutics – subject of discussion with CCs and ROs
- Development of training curriculum/ training programme at WHO CCs
- E-learning tool
– Regular update on the establishment of national regulatory requirements and
the development of SBPs at the global level
– Assess need for new international reference preparations (ie, mabs)
– Standardization of the assays
– Survey in regions and countries – feedback from countries
– Technical support to regional activities (eg, PANDRH meeting in Sep 2013)

Regulatory Risk Assessment for biotherapeutic products
licensed with insufficient/ inappropriate data
Draft Guidelines in preparation, public consultation planned for Q4 2013.
Options for regulatory actions in the case of licensure with insufficient/
inappropriate data:
1. Leave on the market and strengthen PMS systems to identify possible
adverse events associated with their use
2. Withdraw from the market immediately
3. Withdraw a product from the market only when a safety or efficacy
problem has been identified This option depends on countries being able to
identify adverse events associated with a particular product in a timely way
4. Leave on the market for a specified period, such as four years, during which
time manufacturers would be required to submit appropriate quality,
nonclinical, and clinical data, and risk management plan for regulatory
evaluation to support the continuation of the license. Products from
manufacturers who did not submit appropriate data, or submitted data
which were considered insufficient to support licensing approval, would be
automatically removed from the market.

Points for discussion
 Regulatory requirements for biotherapeutic products in Russian speaking countries: current
status and way forward
– National Regulatory Requirements for Biotherapeutic Products
– Guidelines on SBPs
– SBPs licensed in Russian speaking countries
 Experience and Information sharing:
– Science based regulation – expertise and capacity building
– Information sharing regarding the product evaluation
• Examples of European Public Assessment Reports, Health Canada, TGA;
• a possibility for having such reports issued by NRAs in Russian speaking countries
- What is most needed in terms of technical assistance?

1. Dr. Ivana Knezevic - World Health Organization

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