上海CMC培訓(xùn) 生物利用度和生物等效性在仿制藥和新藥申請(qǐng)中的法規(guī)要求ppt課件

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藥和新藥申請(qǐng)中的法規(guī)要求魏曉雄 Jim Wei, MD, PhDAAPS/CPA Workshop Shanghai, June 28-29, 2010Agenda議程General BA/BE生物利用度和生物等效性內(nèi)容概述Biowaiver 生物等效性試驗(yàn)豁免Regulatory requirements for BE supplies, sample storage and data analysis 生物等效

2、性試驗(yàn)的法規(guī)要求BE and 505(b)(2) NDA 生物等效性和505(b)(2) 類新藥上市申報(bào)申請(qǐng) Bioavailability defined生物利用度定義“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)&a

3、mp;(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血藥濃度時(shí)間曲線Points to Consider BA生物利用度PK指標(biāo)For bioavailability studies, our primary “metric” of

4、interest is: area under the concentration-time curve (AUC) AUC is a derived parameter, it is not observedTypes: AUCt = to the last detectable concentration AUC = from zero to infinity (single dose) AUC = between dosing intervals at steady-stateApproaches to Determining Bioequivalence (21 CFR 320.24)

5、檢測(cè)生物等效性試驗(yàn)的各種方法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 -

6、Binding StudiesNasal Solutions-Sprayer EvaluationPropofol - Droplet SizeSingle-dose, two-way crossover, fastedSingle-dose, two-way crossover, fedAlternativesSingle-dose, parallel, fasted Long Half-Life (wash-out): Amiodarone, EtidronateSingle-dose, replicate designHighly Variable DrugsMultiple-dose,

7、 two-way crossover, fasted Less Sensitive: Clozapine (Patient Trials); Chemotherapy TrialsClinical endpoint study Topicals: Nasal SuspensionsBE Study Designs生物等效性試驗(yàn)的設(shè)計(jì)BE Statistical Analysis生物等效性試驗(yàn)的統(tǒng)計(jì)分析Bioequivalence criteria Two one-sided tests procedureTest (T) is not significantly less than refer

8、enceReference (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)生物藥劑學(xué)分類體系The BCS is a scientific framework for classifying d

9、rugs based on 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 stud

10、ies based on a Biopharmaceutics Classification System (BCS)生物藥劑學(xué)分類體系和生物等效性試驗(yàn)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: Produc

11、ts are pharmaceutical equivalents Drug substance is highly soluble and highly permeable and is not considered have a narrow therapeutic range Excipients used are not likely to effect drug absorptionHighly Variable Drugs (HVD)高變異藥物Definition Use ANOVA Root Mean Square Error (RMSE) to estimate within-

12、subject or intra-subject variability: Drug is classified as highly variable if RMSE 0.3 or 30%Two main types or sources of variability Highly variable PK (inherent drug characteristic) Highly variable formulation Standard BE study approach may need more than 100 subjectsRef-1Ref-2Ref-1Ref-2666613131

13、3132727272777771616161620202020CmaxAUClastReasons for Inconsistent Variability in BE Studies生物等效性試驗(yàn)中不一致變異的原因Differences in formulationsImproperly handling of Bioanalytical assaysSubjects with irregular plasma concentrationsNumber of study subjectsUncontrolled food status90%CIs & BE Limits90%可信區(qū)間

14、和生物等效性試驗(yàn)界線GreenLow WSV (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)高變異藥物的生物等效性試驗(yàn)FDA Study to Characterize Highly Variable Drugs in BE Studies: Collected data from 1127 a

15、cceptable BE studies, submitted 524 ANDAs from 2003-2005 (3 years) Most sponsors used 2-way crossover studies Used ANOVA Root Mean Square Error to estimate within-subject variance Drug was classified as highly variable if RMSE 0.3 or 30% BE studies of HVD enrolled more study subjects than studies of

16、 drugs with low variability Average N in studies of HVD = 47 Average N in studies of drugs with lower variability = 33 Range 18 73 subjects 10% of studies evaluated were HVDScaled Average BE for HVD高變異藥物的増寬平均生物等效性試驗(yàn)Three-period, partial replicate design Reference product (R) is administered twice Te

17、st product (T) is administered once Sequences = 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 b

18、e passed by the test product to conclude BE to the reference product wrw00.223EXP lower upper, limits, BE1.01.11.21.31.41.51.61.7Geometric Mean Ratio020406080100Percent of Studies PassingAverage vs. Scaled Average BioequivalenceCV% = 60, Simulations = 106, N = 36 vs. 24, w0=0.25Scaled ABE + Point Es

19、timate (N = 24)Average BE (N = 24)Scaled ABE + Point Estimate (N = 36)Average BE (N = 36)Advantages of Scaled BE増寬的生物等效性試驗(yàn)的優(yōu)點(diǎn) (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

20、 R variability, no benefit in using scaled approach The burden is on the applicant to convince FDA that product is a HVD21 CFR 320.36 Requirements for maintenance of records of bioequivalence testing生物等效性試驗(yàn)記錄保存的法規(guī)要求All records of in vivo or in vitro tests shall be maintained by the manufacturer for

21、at least 2 years after the expiration date of the batch and submitted 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 31

22、4 of this chapter shall obtain from the person conducting the study 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

23、relating to the compensation given for that study and all other financial 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

24、 the Food and Drug Administration, at reasonable time, permit such officer or employee to have access to and copy and verify these records.21 CFR -320.38 Retention of bioavailability samples生物等效性試驗(yàn)樣品保存的法規(guī)要求Each reserve sample shall be stored under conditions consistent with product labeling and in a

25、n area segregated from the area where testing is conducted and with 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 supplemen

26、tal application is not approved, at least 5 years following the date of completion of the bioavailability study in which the sample from which the reserve sample was obtained was used.BE Sample Retention生物等效性試驗(yàn)樣品保存The guidance highlights how the test article and reference standard for BA and BE stud

27、ies should be distributed to the testing facilities how testing facilities should randomly select samples for testing and material to maintain as reserve samples how the reserve samples should be retained. FDA/DSI Inspection on BE Studies FDA對(duì)生物等效性試驗(yàn)的監(jiān)察A frequent finding from these inspections is th

28、e absence of reserve samples at the testing facilities where the studies 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 facil

29、ities designate the study test article and reference standard for each subject, 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

30、 reference standard packaged in such a way that the testing facility can randomly select samples for bioequivalence testing and samples to maintain as reserve samples.FDA/DSI Inspection on BE Studies contd FDA對(duì)生物等效性試驗(yàn)的監(jiān)察Quantity of Reserve Samples Sufficient to perform five times all of the release

31、tests required in the application or supplemental application For solid oral 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.

32、g., 5 dose units) for each of the test articles and reference standardsIn-House Studies Conducted by a Study Sponsor and/or Drug Manufacturer If 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

33、and 320.63) should be separated.Type 1: New Molecular Entity(NME)505 (b) (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

34、 & Chemistry Classification新藥類型和化學(xué)分類新藥類型和化學(xué)分類Summary of DifferencesFDA三大類藥物申請(qǐng)差異總結(jié)Types of 505(b)(2) NDAs505(b)(2) 新藥類型New Chemical Entity (rarely)Changes to a previously approved drug New dosage form, dosing regimen, strength, or route of administration New indication New active ingredient New inactiv