WHO Guideline for Abbreviated Licensing Pathways for Certain Biological Therapeutic Products

Elwyn Griffiths On behalf of the WHO Drafting Group

Biotechnology Derived Biotechnology Derived MedicinesMedicines

On the market since the early 1980s (rDNA derived products / products from novel cell lines)Regulatory oversight (guidelines) put in place early on during their development-maximized their safety and efficacyThey are best characterized biological medicines

Biotechnology Derived Biotechnology Derived MedicinesMedicines

Increasing number of patents/data protection expiring Biologicals “similar” to the originals (innovator) coming to the market Licensing relying in part on data from approved innovator product Clear that these products here to stay

DriversDrivers

Alternatives to innovator products expected more affordable – may contribute to increased accessGlobal markets for biologicals growing and attractive - so considerable global interestDifficult and contentious issuesKey question is how to handle the licensing of these products

Nomenclature DifficultiesNomenclature Difficulties

Different NAMES given by different jurisdictions Follow-on Biologics/protein products(USA, Japan)Biosimilar Products (EU)Subsequent-entry Biologics (Canada) Biogeneric products (India)

Request to WHO for ActionRequest to WHO for Action

International Conference of Drug Regulatory Authorities , Seoul, 2006WHO requested to develop global regulatoryconsensus and guidanceWHO Consultations on Nomenclature (INNs) for Biosimilars, 2006, 2007WHO consultations on regulatory evaluation of therapeutic biological medicines, April 2007, 2008WHO Expert Committee on Biological Standardization (2006, 2007)

WHO Consultations WHO Consultations outcomesoutcomes

Understanding of current directions and challenges in the regulatory evaluation of the quality, safety and efficacy of biosimilarsExchange of information between regulators, the identification of key issues and gaps, and recommendations on the next stepsWide range of regulatory preparedness Clear need for global road mapDecision on INNs WHO Guideline Drafting Group established

Not GenericsNot Generics

Agreed – biologicals do not meet criteria for true GENERICS - should not be regulated under generic pharmaceuticals regulations Biologicals, by definition, are not “identical” Biologicals are highly complex in nature and production

Biological Product Biological Product Characteristics Characteristics

Very sensitive to production parametersNature of cell substrate and growth conditions / downstream processingMinor changes can have major effects on biological activityImpact potential immunogenicityCannot be predictedCan happen with innovator productCan be a safety issue

Key Consensus Points Key Consensus Points

Possibility of licensing a new biological product on basis of “similarity” with a well established licensed product agreedExtensive product characterizationAbridged non clinical and clinical data package (case by case) Head to head direct comparison with a reference product at different stages of the study depending on regulatory pathway chosen

Regulatory directionsRegulatory directions

Some authorities already established regulatory pathway (Europe)Others close to doing so Yet others do not have a regulatory framework for such productsSometimes legal framework problemGenerally same issues highlighted

Issues Issues

Definitions and terminologyType of regulatory pathwayScope of products – only rDNA proteins ? Polysaccharides (Heparins)?Degree of “similarity” – potentialimmunogenicityDemonstration of “similarity” Defined comparator / reference productExtrapolation of indications from originalInterchangeability / substitutability

WHO Guideline refers toWHO Guideline refers to33 Regulatory PathwaysRegulatory Pathways

Full license application : no reliance on data from clinical use of already licensed product (stand alone approach)Focus-two abbreviated licensing pathways: reliance on “similarity” of product with innovator and knowledge of safety and efficacy profiles of that product to justify reduction in non-clinical and clinical packages

Abbreviated pathway 1 Abbreviated pathway 1 BiosimilarBiosimilar approachapproach

Reliance on head to headdemonstration of “similarity” of product characteristics (physico chemical / biological activity ) to a chosen reference productReduced non-clinical and clinical data based on head to head comparisonwith the same reference product

BiosimilarBiosimilar Approach Approach Choice of Reference ProductChoice of Reference ProductReference must be a licensed productObject of comparability studies is to demonstrate product “similarity” and clinical equivalenceSame reference throughout studiesIntention to assign all of the indications of the Reference Product to the biosimilar on basis of one clinical study

BiosimilarBiosimilar Approach Approach Choice of Reference ProductChoice of Reference Product

Unavailability of reference drug substance, only formulated productNeed to extract from formulated productVerification that extraction does not affect drug substance propertiesFull characterization of product essentialAdditionally, head to head comparison with reference product

Abbreviated pathway 2 Abbreviated pathway 2 Clinical comparability approachClinical comparability approach

Reliance on “similarity” to product class without head to head comparison with a reference product -Full quality dossierReduced non-clinical data packageReduced clinical data based head to head comparison with reference product

Abbreviated pathway 2 Abbreviated pathway 2 Clinical comparability approachClinical comparability approach

Expect FULL quality dossierSame gene / same sequence /same primary sequenceGlycosylation to be fully characterizedImpurity profile fully characterized Biological activity calibrated using a reference product Significant differences in glycosylation means additional dose finding studies

Clinical comparability approachClinical comparability approachReference ProductReference Product

Only required for head to head clinical studiesNo need to extract drug substance since formulated product used in clinical studiesComparator should be well established product Distinguish from WHO International Biological Standard used for calibration of biological activity

Ivana Knezevic | 11 June 200820 |

Regulatory approaches for biotherapeuticsfollowing licensing of the originator

Stand aloneproduct

Biosimilar product Clinically comparable product

Full licensing application

Abbreviated licensing pathways

Biosimilar approach1) Full quality dossier

with a comparability exercise

2) Reduced non-clinical and clinical data (comparative)

Clinical comparability approach

1) Full Quality dossier 2) Reduced nonclinical data3) Clinical data (head to

head comparison with reference product)

Full dossier (no data reduction)

Extrapolation of indication(s) No extrapolation of indication(s)

WHO GuidelineWHO Guideline

Developed by WHO Drafting Group-Germany, UK, USA, Canada, South Korea Consultation, Seoul, May 2008, public consultation/comment on going, Draft will be presented to WHO Expert Committee on Biological Standardization , October 2008

WHO GuidelineWHO Guideline

Globally acceptable set of principles for abbreviated licensing pathways for biological therapeutic productsWill not resolve all issues Need for implementation strategyNeed for transition period

ImplementationImplementation

Consultations with NRAs and manufacturers in different RegionsAdditional consultation with other stakeholders (relevant government representatives, physicians, patients groups)– adoption by drug formularies – Interchangeability and substitutability – Post-market surveillance issues which are an

important component of the draft guideline

Nomenclature implicationsNomenclature implications

Important in prescribing and distinguishing biologicals in useINNs widely used for pharmaceuticals but limited value in distinguishing subtle differences between biologicalsWHO Consultations in INNs for biologicals considered “similar” products

WHO RecommendationsWHO Recommendations

No distinctive INN designation to indicate a “similar” biologicalNaming of biosimilars should be handled in same way as stand alone biologicalsAssignment of INNs should be independentof the regulatory processTerm “similar” biological is a regulatory and legal, not scientific, conceptNeed to explain clearly to stakeholders

limitations of INNs for biologicals

Limitations of Limitations of INNs INNs for for biologicals biologicals

Decisions on interchangeability or substitutability should be based on appropriate scientific and clinical data (not available to INN Committee), not on INNsFor pharmacovigilance purposes INN is onlyone component of biological productidentificationFor a biological, additional identification needed (Lot Number, product identifier) Discussions on nomenclature on going

Final conclusionsFinal conclusions

Regulatory oversight of “similar” biologicals evolving rapidlyNo question that they will become a future major player on the world marketExpectation this will open up global accessNeed to move forward BUT carefully

Questions for discussion 1Questions for discussion 1

What are main obstacles to development and regulation of similar biotherapeutics in developing countries?

- Lack of legal frameworks- Limited access to technology and

assessment tools- Lack of pharmacovigilance

Questions for discussion 2 Questions for discussion 2

1) What guidance do regulators expect from WHO?

- What should guidelines provide ?- What further assistance might be

helpful - in additional to written guidelines?

Questions for discussion 3Questions for discussion 3

What should be done at the national level?What might be done at the regional level?Role of regulators?Role of other stakeholders?