1. Dr. Ivana Knezevic - World Health Organization

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“WHO Standards for Regulatory Evaluation of Biotherapeutic Products including SBPs”


Provides an overview of the WHO activities & standards setting for biotherapeutic medicines & similar biotherapeutic product

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1. Dr. Ivana Knezevic - World Health Organization

  1. 1. Ivana Knezevic |1 |IFPMA-AIPM WorkshopBiotherapeutic Medicines: Regulatory Challenges andCurrent PracticesWHO Standards for Regulatory Evaluation ofBiotherapeutic Products including SBPsMoscow, 15-16 May 2013Dr Ivana Knezevic, WHO/HIS/EMP
  2. 2. 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
  3. 3. Ivana Knezevic3 |WHO norms and standards for biologicalsGlobal written standards Global measurementstandardsScientific evidenceMeasurementstandards:essential elements for development, licensingand lot release1) Standardization of assays2) Further developmentand refinement of QC tests3) Scientific basis for settingspecificationsReference preparations forvaccines and biotherapeutics
  4. 4. Ivana Knezevic4 |16 Available WHO International standards orReference reagents for Biosimilars (1)The list is available on the following links:1) WHO webhttp://www.who.int/bloodproducts/catalogue/CytoMarch11.pdf2) NIBSC webhttp://www.nibsc.ac.uk/products/biological_reference_materials/product_catalogue.aspxRecently published review article by Thorpe R, Wadhwa M,Biologicals 2011.
  5. 5. Ivana Knezevic2008 2009 2010 2011Development of measurement standardsfor biotherapeutics, 2008 - 201220121. 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)
  6. 6. Ivana Knezevic6 |WHO Guidelines on SBPs and otherpublications1. The final version of the Guidelines on evaluation of similarbiotherapeutic products (SBPs) is available on WHO Biologicalswebsite (http://www.who.int/biologicals/en/) since April 2010. The document was adopted by the 60th meeting of the WHOExpert Committee on Biological Standardization, in October 2009.2. Web pages related to biotherapeutics:http://www.who.int/biologicals/vaccines/biotherapeutic-products/en/index.html3. Link to special issue in Biologicals (2011), 39 devoted to SBPs: 25articles with WHO experience in working with regulators worldwide
  7. 7. Ivana KnezevicWHO 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 forvaccine prequalification Guidance for NRAs and manufacturers on international regulatoryexpectations 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 advancesEvolving concept: from quality specifications to scientific principles forthe entire regulatory oversight
  8. 8. Ivana Knezevic |8 |Concept of WHO Guidelines on SBPs1) Provide key principles for evaluation of SBPs as a basis for setting nationalrequirements;2) Leave space to NRAs to formulate additional/ more specific requirements;3) Living document that will be developed further in line with the progress inscientific knowledge and experience4) Assist with the implementation of the guidelines into regulatory andmanufacturers practice through: Global, regional and national workshops involving regulators,manufacturers and other relevant experts Trainings, advisory groups5) Consider guidance issued by other bodies – intention to complement them,not to create a conflict.
  9. 9. Ivana Knezevic |9 |Scope and key definitions Scope: Guidelines applies to well-established and well-characterizedbiotherapeutic products such as recombinant DNA-derived therapeutic proteins.Vaccines and plasma derived products and their recombinant analogues areexcluded from the scope of this document. WHO recommendations andregulatory 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 andefficacy (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 toshow similarity in terms of Q, S and E. Only an originator product that waslicensed on the basis of a full licensing dossier can serve as an RBP. It does notrefer to measurement standards such as international, pharmacopoeial ornational standards or reference preparations.
  10. 10. Ivana Knezevic |10 |Key principles for the licensing of SBPs SBPs are not generic medicines and many characteristics associated with theauthorization process and marketed use of generic medicines generally do notapply. 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 prerequisitefor 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 optionsfor its further development and licensing (eg, stand alone) should be considered.Important to note that biotherapeutics which are notshown to be similar to a RBP should not be describedas "similar", nor called a "SBP".
  11. 11. Ivana Knezevic |11 |Licensure requirements–amount of data and applicabilityFull dossier(Stand aloneapproach)Similar BiotherapeuticProducts (SBPs)Applicable to allbiologicalsExisting knowledge,full, comparativecharacterization, plusComparative BUTreducednon-clinical,clinical dataApplicable to well characterizedbiologicals onlyGenericForchemicalentitiesonlyNot applicableto biologicals
  12. 12. Ivana Knezevic |12 |Reference Biotherapeutic Product (RBP) RBPs should have been marketed for a suitable duration andhave 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 tobe similar The dosage form and route of administration of the SBP shouldbe the same as that of the RBP NRAs may need to consider establishing additional criteria toguide the acceptability of using a RBP licensed or resourced inother countries
  13. 13. Ivana Knezevic |13 |Quality Development of an SBP– Thorough characterization of a number of representative lots ofthe RBP– Engineering a manufacturing process that will reproduce a productthat is highly similar to the RBP in all critical product qualityattributes The quality comparison showing molecular similarity between the SBPand the RBP provides the underlying rationale for predicting that theclinical safety and efficacy profile of the RBP should also apply to theSBP– So that the extent of the non-clinical and clinical data requiredwith the SBP can be reduced To evaluate comparability– The manufacturer should carry out a comprehensivephysicochemical and biological characterization of the SBP in head-to-head comparison with the RBP
  14. 14. Ivana Knezevic |14 |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 studywith a relevant species and including toxicokinetic measurements
  15. 15. Ivana Knezevic |15 |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 thepivotal clinical trials Efficacy studies– No dose-finding studies– Demonstrate in adequately powered, randomized, and parallel group clinical trial (ICHE9 and E10)– Equivalence or non-inferiority studies may be acceptable for the comparison ofefficacy and safety of the SBP with the RBP; equivalence/non-inferiority margins haveto 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
  16. 16. Ivana Knezevic |16 |Pharmacovigilance Close monitoring of the clinical safety: focus on (rare) serious AEs in all approvedindications Identification of SBPs: 1) brand name; 2) INN; 3) lot number; 4) country oforigin PhV system should be in place at the time of marketing authorization Manufacturer should submit a safety specification and PhV plan at the time ofsubmission of the MA application PhV plan should describe planned activities and methods based on the safetyspecification 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 andcausality of AEs
  17. 17. Ivana Knezevic |17 |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 notbe used. Implement WHO Guidelines as a whole. This means that onlyproducts 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 ofthe data submitted by the manufacturers for licensing. Additionalefforts are needed to address specific issues related topharmacovigilance of biosimilars.
  18. 18. Ivana Knezevic |18 |ICDRA Recommendations 2010 (to WHO)WHO should Consider developing guidelines on risk management strategies forcopy products already licensed as "biogeneric". Develop a template for Member States to share information on thescientific basis for licensing biosimilars. Supplement its guidance on evaluation of similar biotherapeuticproducts by providing up-to-date Guidelines for evaluation ofbiotherapeutic products in general. Conduct a review of existing international reference preparationsfor assay of biotherapeuctics. Identify gaps and take action to fillthe gap.
  19. 19. Ivana Knezevic |19 |Implementation of WHO guiding principlesinto regulatory and manufacturing practices Well defined regulatory requirements/ guidelines are the basis forlicensing Initiative at the country level is critical – all stakeholders should beinvolved 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, Chinaand Russian speaking countries
  20. 20. 20 | Ivana Knezevic Focused on the implementation of the Guidelines into the regulatory andmanufacturer practice at the global level, in particular, the principles of clinicaldesigns 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 clinicalevaluation– Comprehensive overview of national requirements in 12 countries: specialissue: Biologicals (2011), 39 Proposal from participants– NRAs should make efforts to build their capacities for regulation of SBPs; inparticular, expertise for clinical evaluation is very much needed– WHO should revise WHO Guidelines for assuring the quality of productsprepared by recombinant DNA technology (WHO TRS 814) and continuemonitoring progress with the implementation of the Guidelines on SBPs.Implementation workshop for SBPs:24-26 August 2010, Seoul, Korea
  21. 21. 21 | Ivana Knezevic Challenges identified– Most of the biotherapeutics that are currently subject of licensingbelong to the category of known biological entity that undergoesthrough the stand alone pathway with reduced data package ratherthan through biosimilar pathway.• E.g. partial comparative data in Q, comparison with literature data inC; 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 notbe described as "similar", nor called a "SBP",– and that generic approach is not suitable for development, evaluation andlicensing of SBPs; however,– the terminology which has been used in developing countries showedthat the biosimilar pathway is not yet there.Implementation workshop for SBPs:24-26 August 2010, Seoul, Korea
  22. 22. 22 | Ivana KnezevicImplementation 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 SBPdevelopment. Having the same amino acid sequences is thebottom line of proving the similarity between SBP and RBP.– SBP and RBP have their own lifecycle, so there is norequirement for maintaining their similarities (comparability)once an SBP has been licensed.– The closer the specifications of the SBP are to those of theRBP, more confidence regarding its expected clinicalperformance.– Based on the degree of similarities achieved at qualityassessment, clinical trial should be designed.– The term "biogeneric" is confusing and should not be used.
  23. 23. 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 reportsImplementation workshop for SBPs:28-30 May 2012, Xiamen, China
  24. 24. Ivana Knezevic24 |Challenges1. Regulatory framework for biotherapeutics: diversity of approaches1. Most of the biotherapeutics in developing countries belong to the category ofknown biological entity that undergoes through the stand alone pathway withreduced data package rather than through SBP pathway.2. Some countries have regulatory pathway for "non-innovative biotherapeuticproducts" but requirements are not always clear.2. Lack of expertise and capacity for evaluation of biotherapeutics at NRA3. Comparability studies with RBP: concept not well understood and used in developingcountries5. PhV system in many countries: need to be developed/ improved6. Additional responsibilities of NRAs and other national authorities:1. IP issues2. Interchangeability and substitutability3. Labelling and prescribing information
  25. 25. Ivana Knezevic |25 |WHO focus in 2012 and 2013– 2nd implementation workshop: 28-30 May 2012, Xiamen– Guidelines for quality, safety, and efficacy of biologicals prepared byrecombinant DNA technology: public consultation and ECBS Oct 2013– Regulatory Risk Assessment for biotherapeutic products licensed withinsufficient/ inappropriate data- Coordination of the technical assistance from WHO CCs with the expertise inthe 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 andthe 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)
  26. 26. Ivana Knezevic |26 |Regulatory Risk Assessment for biotherapeutic productslicensed 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 possibleadverse events associated with their use2. Withdraw from the market immediately3. Withdraw a product from the market only when a safety or efficacyproblem has been identified This option depends on countries being able toidentify adverse events associated with a particular product in a timely way4. Leave on the market for a specified period, such as four years, during whichtime manufacturers would be required to submit appropriate quality,nonclinical, and clinical data, and risk management plan for regulatoryevaluation to support the continuation of the license. Products frommanufacturers who did not submit appropriate data, or submitted datawhich were considered insufficient to support licensing approval, would beautomatically removed from the market.
  27. 27. Ivana Knezevic |27 |Points for discussion Regulatory requirements for biotherapeutic products in Russian speaking countries: currentstatus 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?

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