中美仿制药研发申报流程课件.ppt

中美仿制药研发和申报流程,涂家生， Ph. D.中国药科大学药剂学教授Tel: 025-83271305Email: 2011.11 郑州,我国仿制药申报、审评和研发对策,主要内容,中美关于原研药和仿制药的背景,美国仿制药：申报、基于问题的审评和研发对策,展望,1,2,3,4,Company Logo,3,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SSA已经破产：如何破局？降低医疗费用成为必然Hatch-Waxman法案出台美国FDA药品注册申请：新药（两类）、仿制药和非处方药申请,1984年后,New Drug Applications(NDAs),Abbreviated New Drug Applications (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),505(b)(1),505(b)(2),505(j),NDA的研发和申报,505(b)(1) 新药申报资料内容,IndexSummaryChemistry, Manufacturing and ControlSamples, Methods Validation Package and LabelingNonclinical Pharmacology and Toxicology,6. Human Pharmacokinetics and Bioavailability7. Microbiology ( for anti-microbial drugs only)8. Clinical Data9. Safety Update report ( typically submitted 120 days after the NDAs submission ),10. Statistical11. Case Report Tabulations12. Case Report Forms13. Patent Information14. Patent Certification,505(b)(2): 历史过程,Hatch Waxman法案：1984Parkman LetterPhantom ANDAFDA Draft Guidance for Industry (1999)FDA Response to Citizens Petition (2003)可以降低研发的费用和审评力量的浪费,505(b)(2)的关键: 可靠性,What is “Reliance”By whom?On what?Reliance and ExclusivityMarket vs. Data ExclusivitySafety/Efficacy Data vs. CM&C dataFDA Process for Determining RelianceWho, when and how?,505(b)(2)的意义,介于全创新药物和仿制药之间具有专利保护，且不存在产权纠纷和仿制药不同，无替换的要求 应有突破,505(b)(2)范围,New Chemical Entity (rarely)：我国1.1-1.3New dosage form：我国5类New dosing regimen：我国补充申请New strength：我国补充申请New route of administration：我国2类New indication：我国1.6,505(b)(2)情形,New active ingredient (different salt, ester, complex, chelate, clathrate, racemate, or enantiomer of active moiety)New inactive ingredient that requires more than limited confirmatory studiesRx OTC switchNew Combination Products“Generic biologics”,505(b)(2)排他性,Exclusivities available for 505(b)(2) productsNCE Exclusivity (5 years)New Product Exclusivity (3 years)Orphan Drug Exclusivity (7 years)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 Drugs,505(b)(2)新药的成功例子,NCEThalomid (thalidomide) (1998)Marketed unapproved drugsLevothyroxine (2000)Guaifenesin extended release (2002)Quinine sulfate (2005)New Dosage FormTramadol orally disintegrating tablets (2005)Ondansetron oral spray (filed 2006),505(b)(2)新药的例子,New Dosing RegimenTramadol extended release tablets (2005)New Strength/FormulationAntara (micronized fenofibrate caps) (2004) (130 mg is BE to Tricor 200 mg)New 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,New Active IngredientPexeva (paroxetine mesylate) (new salt) (2003)New Route of AdministrationEmezine (prochlorperazine) (new buccal/transmucosal delivery) (NDA pending)Oral amphotericin-B (pre-clinical)RxOTC SwitchAlavert (loratadine) (2002),505(b)(2)新药的例子,“Generic Biologics”Omnitrope (rHGH) (2006)Glucagen (glucagon recombinant) (1998)Hyaluronidase (various approvals 2004-05)Fortical (calcitonin salmon recombinant) (2005)* Examples based on publicly available information,FDA NDA 审评过程,FDA 可以使用已有数据用于审评NDA吗？,Hatch-Waxman之前,国会限制 FDA在审评 NDA X时应用 NDA Y的数据：“No data in an NDA can be utilized to support another NDA without express permission of the original NDA holder.”FDA “Finkel Memorandum” (1978, 1981)Hatch-Waxman 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 . . . .”505(b)(2) does not authorize such data relianceMerely sets conditions 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 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 (human) 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,由FDA的OGD审评审评方式采用QbR申报资料采用CTD资料内容也针对问题,Office of Generic Drugs,如何保证审评质量和效率？,Structured Product Labeling (SPL)Makes labeling available on Internet via National Library of Medicine (NLM)Review EfficienciesEarly DMF reviewCluster reviews product specialistsSupplement triaging at team leader levelDBE Truncated ReviewQuestion based Review (QbR) Will have a very positive impact,New resources developedDissolution DatabaseIndividual Product Bioequivalence InformationEncouraged the use of telephone in review processIncreased the number of 1st cycle approvalsDecreased the total number of review cyclesTotal time to approval did not increase in spite of increased workload,ben,This guidance contains an Internet link to a listing of drug products, each linked in turn to a corresponding bioequivalence recommendation. Clicking on a product name in that list will bring up the bioequivalence recommendations for that specific product. Recommendations have been developed for several drugs that are not yet eligible for generic competition (i.e., newly approved products) and some older products for which information has previously been provided. As additional recommendations are developed, those will be posted on the Web site. When this guidance is finalized, the listing will be available through the Agencys Web page.,QbR: 从提出到完善,1/2005 2/2005: Question-based Review Drafted3/2005 4/2005: Division Directors Discussion5/2005 6/2005: Team Leaders Discussion7/2005 8/2005: Reviewers Discussion9/2005 1/2006: Model Pharmaceutical Development Report and Quality Overall Summary2/2005 12/2005: Discussions with Stakeholders and Upper Management1/2005 12/2006: Gradual Implementation1/2007: Full Implementation,QbR的内涵,Question-based Review is a general framework for a science and risk-based assessment of product qualityQuestion-based Review contains the important scientific and regulatory review questions to关键制备工艺及其质控产品的工艺、处方是否有设计缺陷强调QbD,ANDAs Under QbR (Continued),Future Generic Applications generic sponsors submit generic applications based on the format of ICH CTD, preferably, electronicallyModule 1: Administrative InformationModule 2: Quality Overall Summary and Clinical SummaryModule 3: QualityPharmaceutical Development; Quality by DesignModule 4: NonclinicalModule 5: Clinical (Bioequivalence),新药申报（NDA） 和仿制药申报（ANDA）的比较,NDA requirements,ANDA requirements,美国仿制药申报,FDA仿制药部（OGD）鼓励申请人根据ICH对于人用药物的注册技术要求，即通用技术文件（CTD）的格式，提交ADNA。包括以下模块：,OGD QBR The question based review (QBR) serves as a general framework for the CMC assessment of ANDAs that focuses on critical pharmaceutical attributes of product quality. With justification, deviations or alternate approaches to this framework can be utilize, as necessary, to ensure the adequacy of the assessment of product qualityFor ease of discussion, a simple dosage form is defined as a solution or an immediate release (IR) solid oral dosage form.,QBR: Drug Substance,Description and CharacterizationWhat are the nomenclature, molecular structure, molecular formula, and molecular weight?What are the pKa, aqueous solubility (as function of pH), partition coefficient, polymorphism, hygroscopicity, and melting points?Control of Drug SubstanceAppearance and IdentificationAre the specifications for appearance and identification appropriate?AssayIs the proposed drug substance assay limit acceptable? Is the analytical method validated and stability-indicating?Impurities and Residual SolventsAre all the possible impurities accounted for? What is the justification for the impurity acceptance limits?Are the analytical methods validated and suitable for their intended function?Additional SpecificationsBased on the review of the drug product and manufacturing process are specification(s) required on particle size, solid state form, moisture content, or other properties of the drug substance and why? For each additional specification: What is the justification for the acceptance limit? Is it suitable for its intended function?,QBR: Drug Product,Description and Composition What are the components and composition of the final product? What is the function of each excipient?Do any excipients exceed IIG limits in the context of maximum daily dose and route of administration?If product is an NTI drug or a non-simple dosage formAre there significant differences between this formulation and the RLD that present potential concerns with respect to product performance? Control of ExcipientsWhat are the specifications for the inactive ingredients and are they appropriate per their intended function?,Simple Dosage Form: Either a solution or an IR solid oral dosage form,QBR: Drug Product (Continued),ManufactureFor all productsDoes the batch formula accurately reflect the drug product composition? If not, what are the differences and the justifications (e.g. potency adjustment, overage, excess coating solution, etc.)?If product is not a solution What are the key unit operations in the drug product manufacturing process?Are in-process tests identified by the sponsor appropriate? What is the difference in size between commercial scale and biobatch and do they use the same unit operations?If product is an NTI drug or a non-simple dosage formWhat are the critical steps in the manufacturing process?What are the in-process tests/controls that ensure each critical step is successful?In the proposed scale up process what operating conditions will be adjusted to ensure the product meets all in-process and final product specifications?Why do you believe the sponsor has demonstrated a reasonable plan to scale up the process?,QBR: Drug Product (Continued),Control of Drug ProductIdentityIs the specification for the identity of the drug product appropriate? Assay and UniformityAre the proposed drug assay limits acceptable?Is the assay method validated and stability-indicating?How is the content uniformity evaluated? Is it acceptable?Impurities/Degradation ProductsAre the degradation products and their origins adequately described?What is the justification for the acceptance limits on degradation products?Are the analytical methods validated and suitable for their intended function?Dissolution What are the dissolution methods and acceptance criteria and how were they selected? What is the significant role of dissolution testing for this product?Additional SpecificationsAre there additional specifications that are required to ensure the product will perform as labeled and why?For each additional specification: What is the justification for the acceptance limit? Are the analytical methods validated and suitable for their intended function?,QBR: Drug Product (Continued),Reference StandardAre there a qualification report and COA provided for the reference standard or is this material purchased from an appropriate source?Container/Closure System Has the container/closure system been used in a previously approved product or otherwise qualified for this dosage form?What specific container/closure attributes are necessary to ensure product performance?Drug Product StabilityDataWhat stability data has been submitted? Has the sponsor provided stability data for the drug product packaged in the proposed container/closure?Acceptance limitsAre all attributes that could change over time evaluated in the stability tests? What are the acceptable limits on these attributes? Shelf-life recommendationWhat is the justification of shelf life?Is the post-approval stability protocol acceptable?,QBR: Product Development Report for Complex Dosage Forms and NTI Drugs,Drug Substance Which properties or physical chemical characteristics of the drug substance affect drug product performance?Excipients Is there any evidence of incompatibility between the excipients and drug substance? Formulation What is the formulation intended to do?What mechanism does it use to accomplish this?Were any other formulation alternatives investigated and how did these perform?Were any formulation optimization or sensitivity studies carried out for variations in composition around the final formulation? Were these studies sufficient to establish a design space for formulation composition?Is the formulation design consistent with the dosage form classification in the label?Drug ProductWhat are the critical quality attributes that ensure the product will perform as labeled?,QBR: Process Development Report,Process DescriptionWhy was this manufacturing process selected for this drug product?Were alternative unit operations investigated by process development studies?Critical Steps and Scale UpHow were the critical steps in the process identified?What are the critical process parameters for each critical step and how were they identified, monitored and/or controlled?Were process development studies that varied starting materials or operating parameters conducted? Were these studies sufficient to establish a design space for process?In process testsWhy is each in process test required?How were the acceptance limits chosen? Why were the in-process tests identified as critical to product quality?What scale-up experience does the sponsor have with the unit operations in this process?,QBR: Risk Summary,NTI drugClassified as a non-NTI drug, risk score = + 0Classified as an NTI drug, risk score = +1Dosage FormSimple Dosage Form, risk score = + 0Other Dosage Forms and NTI drugs, risk score = + 1Development ReportIf the sponsor submits a development report that addresses the FDAs questions: Risk score = + 0Solution and IR Products: Product Development ReportOther Dosage Forms: Product and Process Development ReportsInsufficient or missing development report, risk score = + 1If the application is of high overall quality Less than or equal to 2 cycles, risk score = + 0. Greater than 2 cycles, risk score = + 1,QBR: Risk-Based Conclusion,Should the application be approved?What post-approval waivers/commitments are appropriate for this product?If the total risk score is less than or equal to 1CBE0 and CBE30 changes may be in annual reportsMany PAS to CBE 30If the total risk score is greater than 1All supplements should be submitted as usual,生物等效性豁免,生物等效性豁免是指基于体外数据审批的管理程序。固体制剂往往采用溶出度、释放度作为证据。,I、基于药物剂型的生物等效性豁免,只有供试品和参比制剂的原料及其含量一致，辅料一致、用量相当，且符合如下规定时，可生物等效性豁免：1、注射液；2、口服溶液，含量一致，且不含已知会影响胃肠道功能和主药稀释的辅料；3、气体；4、溶液散剂；5、耳用或眼用溶液；、6、外用溶液；7、采用同样装置使用的吸入剂或鼻喷剂。,II、基于剂型剂量比