中美仿制药研发和申报流程--涂家生PPT资料.ppt

1、申报、基于问题的美国仿制药：申报、基于问题的审评和研发对策审评和研发对策展望展望1 12 23 34 4药物经济学催生美国仿制药制度药物经济学催生美国仿制药制度美国社会安全制度导致政府赤字严重美国社会安全制度导致政府赤字严重SSA已经破产：如何破局？已经破产：降低医疗费用成为必然降低医疗费用成为必然Hatch-Waxman法案出台法案出台美国美国FDA药品注册申请：新药（两类）、仿制药和药品注册申请：新药（两类）、仿制药和非处方药申请非处方药申请3Ceryak1984年后年后New Drug Applications（NDAs）Abbreviated New Drug Applications

2、（ANDAs）“Full Reports”of Safety and Efficacy Investigations Applicant has right of reference to essential investigations?Duplicate of an already approved product No safety/efficacy data permitted（only bioequivalence）YESNO505（b）（1）505（b）（2）505（j）NDA的研发和申报的研发和申报505（b）（1）新药申报资料内容新药申报资料内容1.Index2.Summary

3、3.Chemistry,Manufacturing and Control4.Samples,Methods Validation Package and Labeling5.Nonclinical Pharmacology and Toxicology6.Human Pharmacokinetics and Bioavailability7.Microbiology（for anti-microbial drugs only）8.Clinical Data9.Safety Update report（typically submitted 120 days after the NDAs su

4、bmission）10.Statistical11.Case Report Tabulations12.Case Report Forms13.Patent Information14.Patent Certification505（b）（2）:历史过程历史过程vHatch Waxman法案：法案：1984vParkman LetterPhantom ANDAvFDA Draft Guidance for Industry（1999）vFDA Response to Citizens Petition（2003）v可以降低研发的费用和审评力量的浪费可以降低研发的费用和审评力量的浪费505（b）

5、（2）的关键的关键:可靠性可靠性vWhat is“Reliance”By whom?On what?vReliance and ExclusivityMarket vs.Data ExclusivitySafety/Efficacy Data vs.CM&C datavFDA Process for Determining RelianceWho,when and how?505（b）（2）的意义的意义v介于全创新药物和仿制药之间介于全创新药物和仿制药之间v具有专利保护，且不存在产权纠纷具有专利保护，且不存在产权纠纷v和仿制药不同，无替换的要求和仿制药不同，无替换的要求 v应有突破应有突破50

6、5（b）（2）范围范围vNew Chemical Entity（rarely）：我：我国国1.1-1.3vNew dosage form：我国：我国5类类vNew dosing regimen：我国补充申：我国补充申请请vNew strength：我国补充申请：我国补充申请vNew route of administration：我国国2类类vNew indication：我国1.6505（b）（2）情形情形vNew active ingredient（different salt,ester,complex,chelate,clathrate,racemate,or enantiomer o

7、f active moiety）vNew inactive ingredient that requires more than limited confirmatory studiesvRx OTC switchvNew Combination Productsv“Generic biologics”505（b）（2）排他性排他性Exclusivities available for 505（b）（2）productsNCE Exclusivity（5 years）New Product Exclusivity（3 years）Orphan Drug Exclusivity（7 years）

8、Pediatric exclusivity extensions（6 months）Patent Issues505（b）（2）drugs can have Orange Book-listed patents,and enjoy 30-month stay protection against generic competitorsBut,505（b）（2）NDAs may also be blocked by patents on Reference Drugs505（b）（2）新药的成功例子新药的成功例子vNCEThalomid（thalidomide）（1998）vMarketed u

9、napproved drugsLevothyroxine（2000）Guaifenesin extended release（2002）Quinine sulfate（2005）vNew Dosage FormTramadol orally disintegrating tablets（2005）Ondansetron oral spray（filed 2006）505（b）（2）新药的例子新药的例子vNew Dosing RegimenTramadol extended release tablets（2005）vNew Strength/FormulationAntara（microniz

10、ed fenofibrate caps）（2004）（130 mg is BE to Tricor 200 mg）vNew Formulation/Inactive IngredientAvita（tretinoin gel）（new emollient）（1998）Abraxane（cremaphor-free paclitaxel）（2005）Oxy-ADF（oxycodone formulated to reduce drug abuse）（in development）505（b）（2）新药的例子新药的例子vNew Active IngredientPexeva（paroxetine

11、mesylate）（new salt）（2003）vNew Route of AdministrationEmezine（prochlorperazine）（new buccal/transmucosal delivery）（NDA pending）Oral amphotericin-B（pre-clinical）vRxOTC SwitchAlavert（loratadine）（2002）505（b）（2）新药的例子新药的例子v“Generic Biologics”Omnitrope（rHGH）（2006）Glucagen（glucagon recombinant）（1998）Hyaluron

12、idase（various approvals 2004-05）Fortical（calcitonin salmon recombinant）（2005）*Examples based on publicly available informationFDA NDA 审评审评过程过程FDA 可以使用已有数据用于审评可以使用已有数据用于审评NDA吗？吗？vHatch-Waxman之前之前,国会限制国会限制 FDA在审评在审评 NDA X时应时应用用 NDA Y的数据：的数据：“No data in an NDA can be utilized to support another NDA wit

13、hout express permission of the original NDA holder.”FDA“Finkel Memorandum”（1978,1981）vHatch-Waxman 解除只适合解除只适合 ANDAs：ANDA process allows“generic producer of the fully tested drug to rely on the safety and efficacy data of a prior applicant.”v505（b）（2）does not authorize such data relianceMerely sets c

14、onditions for certain NDAsRequires“full reports of investigations”establishing safety and effectiveness 21 USC 355（b）（1）（A）,（d）（1）美国仿制药 A generic drug product is one that is comparable to an innovator drug product（also known as the reference listed drug（RLD）product as identified in the FDAs list of

15、Approved Drug Products with Therapeutic Equivalence Evaluations）in dosage form,strength,route of administration,quality,performance characteristics and intended use.Generic drug applications are termed“abbreviated”in that they are generally not required to include preclinical（animal）and clinical（hum

16、an）data to establish safety and effectiveness.These parameters were established upon the approval of the innovator drug product,which is the first version of the drug product approved by the FDA.FDA审评仿制药程序二、美国仿制药的申报、审评和研发对策二、美国仿制药的申报、审评和研发对策v由由FDA的的OGD审评审评v审评方式采用审评方式采用QbRv申报资料采用申报资料采用CTDv资料内容也针对问题资料内容也针对问题Office of Generic Drugs如何保证审评质量和效率？如何保证审评质量和效率？