2009.11.27 서수경 첨단제제과 / 바이오생약국 식품의약품안전청
I. 바이오시밀러의평가 II. 국제바이오시밀러규제동향 III. 바이오시밀러평가시고려사항및 향후심사방향
동등생물의약품의정의 이미제조판매 수입품목허가를받은품목과 품질및비임상 임상적비교동등성이입증된 생물의약품
바이오시밀러에대한평가 제네릭의개념을적용할수없음 과학적근거에기초하여기존의의약품규제및심사에적용하는원칙을적용 대조약과의철저한비교분석시험을통한비교동등성인정 품질의비교동등성시험결과를바탕으로비임상시험 / 임상시험자료축소가능 품질의비교동등성평가를한후순차적으로비임상 / 임상시험수행 동등성의결정은품질, 비임상, 임상시험결과를종합적으로판단하여최종결정
가이드라인의적용범위 모든생물학적제제 주성분으로서특성분석이잘된단백질을포함한제제에적용
대조약의선정 국내허가되어시판되고있는의약품으로서, 신약또는신약에준하는자료를제출하여허가된품목 대조약과제형, 용량, 투여경로가동일하여야함 품질, 안전성, 유효성분야에서동일대조약사용 동등생물의약품은대조약으로사용될수없음 국내허가되어있으나구매가불가능하거나, 외국에서구매하고자하는경우 국내에허가되어있는생물의약품과동일한제품인지입증필요 ( 제조소및제조방법포함 )
제조공정 제조공정상일관성이유지되어품질이확보된 제품을생산가능한상세화된제조공정 GMP 에적합한제조공정및품질관리
품질평가 동등생물의약품에대한품질평가자료제출 비교동등성시험자료포함 원료의약품과완제의약품수준에서평가 최신의분석기술을이용하여검증된분석방법사용 허용기준은대표적인로트에서얻은자료들을기초로확립되고, 기준설정의타당성제시필요 대조약으로부터주성분을추출하는경우주성분의특성이변화되지않았음을입증
품질평가 - 특성분석시험 비교동등성시험 동등생물의약품과대조약을직접비교 특성분석시험의범위 물리화학적성질 생물학적성질 면역화학적성질 순도및유연물질
품질평가 특성분석시험시고려사항 물리화학적성질 조성, 물리학적성질, 1차및고차구조, 단백질수식후변형구조체규명 생물학적성질 관련된여러가지생물학적활성법등을사용하여생물학적활성전반을평가 활성단위는국제또는국가표준품에대하여보정된단위로표시 순도 가속및분해조건, 단백질수식후변형가능성고려 불순물 ( 공정관련, 제품관련불순물 ) 비교확인규명필요
분석방법 원료의약품 ( 주성분 ) 및제품수준에서최신기술을이용한광범위한특성분석필요 분석방법에서고려할사항 물리화학적및생물학적성질을충분히규명하기위해서는한가지품질항목에대하여한가지이상의분석방법을사용 특성분석에사용되는시험법은검증된시험법을사용할필요 역가시험법은과학적으로타당하고신뢰성있는결과도출
기준규격 기준규격에포함될항목의선정은제품에특이적이어야하며, 관련규정에적합하여야함 각항목의허용기준은대표적인로트에서얻은자료들을기초로자체적으로설정 비임상 / 임상시험자료, 제조공정의일관성을증명하기위해사용된롯트의시험자료, 안정성시험자료, 관련제품개발시수행자료와품질, 안정성, 유효성에대한비교동등성시험자료 허용기준의범위를결정한타당성제시필요
안정성시험 유효기간과저장조건을설정하기위한자체적인장기보존안정성시험수행 대조약과의비교한시험은반드시요구되지는않음 대조약과의불순물및분해산물에대한동등성비교를위한가속또는가혹시험필요
비임상평가 시험관내 (in vitro) 시험 수용체결합평가또는세포수준평가 ( 세포증식시험등 ) 생체내 (in vivo) 시험 약력학적활성시험 ( 효력시험자료 ) 단회투여독성시험 반복투여독성시험 독성동태, 항체반응 / 특성분석측정포함 국소내성시험포함가능 ( 투여경로에따라 ) 필요시, 기타독성시험수행고려
비임상평가시고려사항 임상에사용될최종제형 (formulation) 사용 적절한동물종사용 장기투여에따른항체생성고려 대조약과의차이를관찰할수있도록디자인 동등생물의약품의특성에따라반복투여독성시험기간설정 품질평가및임상평가시의대조약과동일한대조약사용
임상평가 약동학시험 모든적용투여경로, 치료용량범위내의용량 민감하고동질한시험군대상 : 건강한자원자 평가항목 : 흡수 / 생체이용률, 청소율 / 제거반감기 동등성허용기준은사전에정의 내인성단백질에의한영향최소화 약력학시험 일반적으로약동학 / 약력학이결합된형태로연구 용량 / 체내노출과효과사이의관계확인 임상적효과와의상관성에근거한약력학변수설정 유효성시험 동등성시험설계권고 동등성한계사전정의
임상평가 확증적약동력학시험 다음의조건을모두만족하는경우 대조약의약동학과약력학특성이잘특성화된경우 유효성을대변하는잘정립된약력학대리변수가하나이상있는경우 대조약에서용량-노출관계, 관련성이정립된약력학변수, 반응- 유효성간의관계가확립된경우
임상평가 - 안전성 대조약과비교 : 이상반응의종류, 빈도, 증증도 허가전임상시험으로부터얻어진안전성자료제출 시판후단계에서의면밀한임상적안전성모니터링필요
임상평가 면역원성 항체의발생빈도와형태, 면역반응으로인한임상적영향비교 ( 중화항체포함 ) 면역반응에영향을미치는인자고려필요 유연물질, 첨가제, 투여경로, 투여방법 ( 용량 ), 환자 / 질병요인등 임상시험에참여한모든피험자를대상으로수행 밸리데이션된항체분석방법사용 ( 중화항체포함 ) 만성투여약물등필요시추적자료추가제출 ( 시판후 )
임상평가 적응증외삽 다음의조건을모두만족하는경우 동등생물의약품과대조약사이의잠재적차이점을발견할수있는민감한시험모델이사용된경우 적응증간의작용기전에관련된수용체가동일한경우 안전성, 면역원성에대한특성이충분히알려진경우 대조약의재심사중인적응증은외삽불가능
바이오시밀러가이드라인국제동향 유럽 2005. 10. 일본 2009. 4. 말레이시아 2008. 7. 대한민국 2009. 7. 터키 2008. 8. WHO 2009. 10. 호주 2008. 8. 캐나다 2009.? 대만 2008. 11. 미국?
Nomenclature of Biosimilar Similar Biologic Medicinal Product (Biosimilar) a medicine which is similar to a biological medicine that has already been authorised Follow-on Protein Products Protein and peptide products that are intended to be sufficiently similar to a product already approved Follow-on Protein Products A biotechnological product developed by a company to be comparable to an approved product of a different company Subsequent Entry Biologics A biologic product that would enter the market subsequent to, and similar to, an innovator product authorized for sale in Canada Similar Biopharmaceutical Product A biological medicinal product developed to be similar in terms of quality, safety and efficacy to an already licensed, well established product
유럽의현황 Similar Biologic Medicinal Product (Biosimilar) a medicine which is similar to a biological medicine that has already been authorised 허가현황 연번 성분명 품목수 개발사 허가 1 somatropin 2 Sandoz, Biopartners 2006 2 Epoetin alfa 3 Sandoz, Haxal, Medice 2007 Epoetin zeta 2 Hospira, Stada 2007 3 Figrastim 6 Ratiopham 외 5개사 2008/2009
EU Biosimilar Guideline Overarching guideline: EMEA/CHMP/437/04 Guideline on Quality Issues: EMEA/CHMP/BWP/49348/05 Guideline on Non-clinical & Clinical Issues: EMEA/CHMP/42832/05 Product-class specific annexes Insulin EMEA/CHMP/ 32775/05 HGH EMEA/CHMP/94528/05 GCSF EMEA/CHMP/31329/05 EPO EMEA/CHMP/94526/05 α-ifn (draft) LMW Heparin (draft)
일본의현황 Follow-on Protein Products A biotechnological products developed by a company to be comparable to an approved product of a different company 허가현황 연번성분명품목수개발사허가 1 somatropin 1 Sandoz 2009. 6
캐나다의현황 Subsequent Entry Biologics A biologic product that would enter the market subsequent to, and similar to, an innovator product authrized for sale in Canada 가이드라인진행현황 2008. 1. : 1 st Draft guideline 2009. 3. : revised draft 2009. 5. : public comments Information and Submission Requirements for Subsequent Entry Biologics (SEBs)
WHO 가이드라인현황 Similar Biopharmaceutical Product A biological medicinal product developed to be similar in terms of quality, safety and efficacy to an already licensed, well established product 가이드라인진행현황 2007.4 : WHO Drafting group 회의 2008.5 : KFDA/WHO Joint Symposium 및 WHO DG 회의 2008.10 : ECBS 상정부결 2009.2~7 : WHO Drafting group 회의 2009. 10: ECBS 채택
미국의현황 Follow-on Protein Products Protein and peptide products that are intened to be sufficiently similar to a product already approved 허가현황 연번성분명품목수개발사허가 1 somatropin 3 Sandoz, LG, Cangene 2006/07/08
주요국의가이드라인비교 적용범위 유럽 : 모든생물학적제제 일본 : 재조합단백질, 폴리펩티드제제및그유도체로서고도의정제, 특성분석이잘된단백질 대조약선정 유럽, 일본 : 자국내허가, 판매되는생물의약품 캐나다 : 자국시판품원칙, 아닌경우시판품과동등성입증시가능
Peptide backbone Amino acid sequence Substitution Oxidation Deamination Truncation N&C term heterogeneity High Order Structure Conformation Aggregates Disulfide scrambling Dissociation Post-translational Modifications Glycosylation Methylation, Acetylation, Acylation Phospholyation, sulfatation
The demonstration of comparability does not necessarily mean that the quality attributes of the two products will be identical, but they are highly similar with two consequences Minor structural differences such as variability in posttranslational modifications may be acceptable but must be justified Differences in impurity profiles should be justified The impact of observed differences in the quality attributes should be assessed and then non-clinical and clinical studies should be designed and conducted on the basis of the results
Naming Traceability Immunogenicity Interchangeability Substitution
Biopharmaceuticals are different from small molecule chemical drug Generic drug approval approach is not appropriate Establishing a high degree of similarity in quality between the biosimilar product and the original product is a crucial key in the regulatory approval process Development of the biosimilar products involves a stepwise approach of comparability exercise beginning with quality studies and followed by non-clinical and clinical studies The development of the biosimilar products is complex and there is a need for a consistent and efficient global approach, in order to expand global access to safe and effective biological medicines
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