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1、Bioavailability and Bioequivalence Study in Generic and new Drug Applications生物利用度和生物等效性在仿制药和新药申请中的法规要求魏晓雄 Jim Wei, MD, PhDAAPS/CPA Workshop Shanghai, June 28-29, 2010Agenda议程General BA/BE生物利用度和生物等效性内容概述Biowaiver 生物等效性试验豁免Regulatory requirements for BE supplies, sample storage and data analysis 生物等效
2、性试验的法规要求BE and 505(b)(2) NDA 生物等效性和505(b)(2) 类新药上市申报申请 Bioavailability defined生物利用度定义“Bioavailability is the fraction (F) of an administered dose that actually reaches systemic circulation when compared to a solution (SLN), suspension (SUSP), or intravenous (IV) dosage form.” - 21 CFR 320.25(d)(2)&(
3、3) -absolute: test drug vs. IV reference -BA of an IV drug is assumed to be 100%, or F = 1.00amount reaching circulation = F x Doserelative: test drug vs. SLN or SUSP reference Plasma Concentration Profile血药浓度时间曲线Points to Consider BA生物利用度PK指标For bioavailability studies, our primary “metric” of inte
4、rest is:area under the concentration-time curve (AUC)AUC is a derived parameter, it is not observedTypes:AUCt = to the last detectable concentrationAUC = from zero to infinity (single dose)AUC = between dosing intervals at steady-stateApproaches to Determining Bioequivalence (21 CFR 320.24)检测生物等效性试验
5、的各种方法In vivo measurement of active moiety or moieties in biologic fluidIn vivo pharmacodynamic comparisonIn vivo limited clinical comparisonIn vitro comparisonAny other approach deemed appropriate by FDAFeV1 AlbuterolBlanching StudyTopical CorticosteroidTopicals Nasal SuspensionsQuestran - Binding S
6、tudiesNasal Solutions-Sprayer EvaluationPropofol - Droplet SizeSingle-dose, two-way crossover, fastedSingle-dose, two-way crossover, fedAlternativesSingle-dose, parallel, fastedLong Half-Life (wash-out): Amiodarone, EtidronateSingle-dose, replicate designHighly Variable DrugsMultiple-dose, two-way c
7、rossover, fastedLess Sensitive: Clozapine (Patient Trials); Chemotherapy TrialsClinical endpoint studyTopicals: Nasal SuspensionsBE Study Designs生物等效性试验的设计BE Statistical Analysis生物等效性试验的统计分析Bioequivalence criteriaTwo one-sided tests procedureTest (T) is not significantly less than referenceReference
8、 (R) is not significantly less than testSignificant difference is 20% ( = 0.05 significance level)T/R = 80/100 = 80%R/T = 80% (all data expressed as T/R so this becomes 100/80 = 125%)Biopharmaceutics Classification System (BCS)生物药剂学分类体系The BCS is a scientific framework for classifying drugs based on
9、 their aqueous solubility and intestinal permeabilityApplies to drug substance with high solubility and high permeability (BCS Class 1)Waivers of In Vivo BE studies for BCS Class 1 drugs in immediate release solid oral dosage forms that exhibit rapid dissolutionWaiver of in vivo BE studies based on
10、a Biopharmaceutics Classification System (BCS)生物药剂学分类体系和生物等效性试验豁免Recommended for a solid oral Test product that exhibits rapid (85% in 30 min) and similar in vitro dissolution under specified conditions to an approved Reference product when the following conditions are satisfied:Products are pharmac
11、eutical equivalentsDrug substance is highly soluble and highly permeable and is not considered have a narrow therapeutic rangeExcipients used are not likely to effect drug absorptionHighly Variable Drugs (HVD)高变异药物DefinitionUse ANOVA Root Mean Square Error (RMSE) to estimate within-subject or intra-
12、subject variability:Drug is classified as highly variable if RMSE 0.3 or 30%Two main types or sources of variabilityHighly variable PK (inherent drug characteristic)Highly variable formulation Standard BE study approach may need more than 100 subjectsRef-1Ref-2Ref-1Ref-266661313131327272727777716161
13、61620202020CmaxAUClastReasons for Inconsistent Variability in BE Studies生物等效性试验中不一致变异的原因Differences in formulationsImproperly handling of Bioanalytical assaysSubjects with irregular plasma concentrationsNumber of study subjectsUncontrolled food status90%CIs & BE Limits90%可信区间和生物等效性试验界线GreenLow WSV (
14、15%)Narrow 90%CIPassesRedHigh WSV (35%)Wide 90%CILower bound 80%Fails125%100%80%GMR & the # of subjectsare the same in both casesBE Studies in Highly Variable Drugs (HVD)高变异药物的生物等效性试验FDA Study to Characterize Highly Variable Drugs in BE Studies: Collected data from 1127 acceptable BE studies, submit
15、ted524 ANDAs from 2003-2005 (3 years)Most sponsors used 2-way crossover studiesUsed ANOVA Root Mean Square Error to estimate within-subject varianceDrug was classified as highly variable if RMSE 0.3 or 30%BE studies of HVD enrolled more study subjects than studies of drugs with low variabilityAverag
16、e N in studies of HVD = 47Average N in studies of drugs with lower variability = 33Range 18 73 subjects10% of studies evaluated were HVDScaled Average BE for HVD高变异药物的増宽平均生物等效性试验Three-period, partial replicate designReference product (R) is administered twiceTest product (T) is administered onceSequ
17、ences = RTR, TRR, RRTSample size: Determined by sponsor (adequate power)minimum is 24 subjectsBE criteria scaled to reference variability (Cmax & AUC)The point estimate (test/reference geometric mean ratio) must fall within 0.80-1.25Both conditions must be passed by the test product to conclude BE t
18、o the reference product Advantages of Scaled BE増宽的生物等效性试验的优点 (Reference Scaled)Test product will benefit if:T variability R variabilityWhat if high variability results from formulations problems or poor study conduct?If T variability R variability, no benefit in using scaled approachThe burden is on
19、 the applicant to convince FDA that product is a HVD21 CFR 320.36 Requirements for maintenance of records of bioequivalence testing生物等效性试验记录保存的法规要求All records of in vivo or in vitro tests shall be maintained by the manufacturer for at least 2 years after the expiration date of the batch and submitte
20、d to the Food and Drug Administration on request.Any person who contracts with another party to conduct a bioequivalence study from which the data are intended to be submitted to FDA as part of an application submitted under part 314 of this chapter shall obtain from the person conducting the study
21、sufficient accurate financial information to allow the submission of complete and accurate financial certifications or disclosure statements required under part 54 of this chapter and shall maintain that information and all records relating to the compensation given for that study and all other fina
22、ncial interest information required under part 54 of this chapter for 2 years after the date of approval of the application. The person maintaining these records shall, upon request for any properly authorized officer or employee of the Food and Drug Administration, at reasonable time, permit such o
23、fficer or employee to have access to and copy and verify these records.21 CFR -320.38 Retention of bioavailability samples生物等效性试验样品保存的法规要求Each reserve sample shall be stored under conditions consistent with product labeling and in an area segregated from the area where testing is conducted and with
24、access limited to authorized personnel. Each reserve sample shall be retained for a period of at least 5 years following the date on which the application or supplemental application is approved, or, if such application or supplemental application is not approved, at least 5 years following the date
25、 of completion of the bioavailability study in which the sample from which the reserve sample was obtained was used.BE Sample Retention生物等效性试验样品保存The guidance highlights how the test article and reference standard for BA and BE studies should be distributed to the testing facilitieshow testing facil
26、ities should randomly select samples for testing and material to maintain as reserve sampleshow the reserve samples should be retained. FDA/DSI Inspection on BE Studies FDA对生物等效性试验的监察A frequent finding from these inspections is the absence of reserve samples at the testing facilities where the studi
27、es are conducted:In many cases, DSI finds that testing facilities return reserve samples to the study sponsors and/or drug manufacturers,In other cases, study sponsors and/or drug manufacturers, SMOs, or contract packaging facilities designate the study test article and reference standard for each s
28、ubject, and preclude the testing facilities from randomly selecting representative reserve samples from the supplies. The study sponsor and/or drug manufacturer should send to the testing facility batches of the test article and reference standard packaged in such a way that the testing facility can
29、 randomly select samples for bioequivalence testing and samples to maintain as reserve samples.FDA/DSI Inspection on BE Studies contd FDA对生物等效性试验的监察Quantity of Reserve Samples Sufficient to perform five times all of the release tests required in the application or supplemental applicationFor solid o
30、ral dosage forms (e.g., tablets, capsules), an upper limit of 300 units each for the test article and reference standardEach site is asked to retain a reasonable amount of test article and reference standard a minimum limit (e.g., 5 dose units) for each of the test articles and reference standardsIn
31、-House Studies Conducted by a Study Sponsor and/or Drug ManufacturerIf a study sponsor and/or drug manufacturer conducts such a study, manufacturing reserve samples (21 CFR 211.170) and BE study reserve samples (21 CFR 320.38 and 320.63) should be separated.Type 1: New Molecular Entity(NME)505 (b) (
32、2)Type 2:New ester, new salt, or other non-covalent derivativeType 3:New formulationType 4:New combinationType 5:New manufacturerType 6:New indicationType 7:Drug already marketed but without an approved NDA505 (b) (1)NDA Types & Chemistry Classification新药类型和化学分类新药类型和化学分类Summary of DifferencesFDA三大类药
33、物申请差异总结Types of 505(b)(2) NDAs505(b)(2) 新药类型New Chemical Entity (rarely)Changes to a previously approved drugNew dosage form, dosing regimen, strength, or route of administrationNew indicationNew active ingredient New inactive ingredient that requires studies beyond limited confirmatory studiesRx OT
34、C switch (Claritin)Duplicates of approved drugs that cannot be approved under an ANDA Features of 505(b)(2) Product?505(b)(2) 新药特点Not a completely new product,Not a generic,A product with some differences from a previously approved product.Approval requires clinical data, but the studies may have be
35、en conducted by others.The applicant and FDA may rely on prior FDA safety and efficacy determinations, based on studies conducted by someone else even though the applicant does not have a right of reference to the data. 21 U.S.C. 355(b)(2)Safety and efficacy can also be supported by published report
36、sPatent and Exclusivity Issues 505(b)(2) 新药专利A 505(b)(2) product may itself qualify for 3 or 5 years of new drug exclusivity3-year exclusivity requires:New clinical studies (other than BE studies)Conducted by the applicantEssential to the approval of the application5-year exclusivity for New Chemical EntitiesNCEs can be old drugs (i.e., ingredient never approved under an NDA)CONTACT INFORMATIONJIM WEI513-763-9770E-MAIL: WEIJIMYAHOO.COMThank you!谢谢谢谢
