1. Dr. Ivana Knezevic - World Health Organization

Ivana Knezevic | 1 |

IFPMA-AIPM WorkshopBiotherapeutic Medicines: Regulatory

Challenges and Current Practices

IFPMA-AIPM WorkshopBiotherapeutic 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 Knezevic 2 |

Outline 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 Knezevic 3 |

WHO norms and standards for biologicals

WHO norms and standards for biologicals

Global written standards

Global measurement standards

Scientific evidence

Measurementstandards: essential elements for development, licensing and lot release

1) Standardization of assays2) Further development and refinement of QC tests3) Scientific basis for settingspecifications

Reference preparations for vaccines and biotherapeuticswww.who.int/

biologicals

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16 Available WHO International standards or Reference reagents for

Biosimilars (1)

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_materials/product_catalogue.aspx

Recently published review article by Thorpe R, Wadhwa M, Biologicals 2011.

http://www.who.int/bloodproducts/catalogue/CytoMarch11.pdf



Ivana Knezevic

2008 2009 2010 2011

Development of measurement standards for biotherapeutics, 2008

- 2012

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)

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WHO Guidelines on SBPs and other publications

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

http://www.who.int/biologicals/en/

http://www.who.int/biologicals/vaccines/biotherapeutic-products/en/index.html



Ivana Knezevic

WHO Written Standards for Biologicals

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


Concept of WHO Guidelines on SBPs 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.


Scope and key definitionsScope 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.

http://www.who.int/biologicals/areas/en/


Key principles for the licensing of SBPs

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

Licensure requirements– amount of data and applicability

Full dossier

(Stand alone approach)

Similar BiotherapeuticProducts (SBPs)

Applicable to all

biologicals

Existing knowledge, full, comparative characterization,

plusComparative BUT

reducednon-clinical,clinical dataApplicable to well

characterized biologicals only

Generic

For chemical entities

only

Not applicable

to biologicals


Reference Biotherapeutic Product (RBP)

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


QualityQuality

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 evaluationNon-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 evaluationClinical 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 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)

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)

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

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.



22 | Ivana Knezevic

Implementation workshop for SBPs: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



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ChallengesChallenges

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:3. IP issues4. Interchangeability and substitutability5. Labelling and prescribing information


WHO focus in 2012 and 2013WHO 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

Regulatory Risk Assessment for biotherapeutic

products licensed with insufficient/ inappropriate

dataDraft 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 discussionPoints 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

Health & Medicine

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evaluation of sbps

licensing of sbps sbps