Draft Guidance on Iron Sucrose
REDBOOK译稿word精品文档45页
铸钢件冒口和补缩指导美国铸钢工作者协会2019年索引1 前言 (3)2 浇冒口的基础知识和术语 (5)3 浇冒口程序 (11)4 冒口和端部区域的铸件致密性 (14)4.1 顶部浇冒口的铸件节段在模具中终止 (16)4.2 顶部浇冒口铸件节段的横向补缩 (19)4.3 侧部浇冒口的铸件节段 (23)5 补缩距离的计算 (25)5.1 具备端部效应的顶部冒口 (25)5.2 横向补缩（在顶部冒口之间补缩） (28)5.3 带端部效应的侧部冒口 (30)5.4 冷铁 (33)5.5 锥形 (36)5.6 其它铸造条件 (38)6 冒口尺寸计算 (41)7 参考 (44)附录 (45)1 前言1973年，美国铸钢工作者协会（SFSA）出版了《钢铸件浇冒口方案》 [1]，编制该铸造手册的目的是为钢铁铸造厂提供浇冒口指导。
《钢铸件浇冒口方案》中包括的指导方针以铸造实验以及计算机模拟为基础。
该指导手册为钢铁铸造行业带来了福音。
遵循指导手册开展铸造作业获得的铸造件通常都是无疵铸件。
但是，在过去二十五年中出现的情况表明，《钢铸件浇冒口方案》中规定的冒口补缩距离规则在某些情况下显得太过保守，当利用规定的冒口补缩距离规则推断结果时，情况就更是如此。
因为补缩距离规则相对保守，导致出现铸造件冒口浪费情形，而这种情形进而降低了铸件产量。
为制订一套新的浇冒口指导原则[2、3]，从二十世纪九十年代中期开始，开展了大量研究工作。
研究工作以一组广泛的低合金钢板铸造实验为基础，实验在北美洲的多家铸造厂进行。
在实验中使用了多种钢板尺度，生产出了各种规格的铸造件，从影像学角度来讲的无疵铸件以及ASTM收缩X射线5级（ASTM shrinkage x-ray level 5）铸件均在其列。
各铸造厂分别记录了每个钢板铸件的铸造条件（合金成分、模具材料、过热、浇注时间等），后来借助现代铸造模拟软件，利用这些信息对各钢板的铸造进行了数值模拟。
FDA_Draft Guidance_Budesonide Suspension for Inhalation
Contains Nonbinding RecommendationsDraft Guidance on BudesonideThis draft guidance, once finalized, will represent the Food and Drug Administration's (FDA's)current thinking on this topic. It does not create or confer any rights for or on any person and doesnot operate to bind FDA or the public. You can use an alternative approach if the approach satisfiesthe requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the Office of Generic Drugs.Active ingredient: BudesonideForm/Route: Suspension/InhalationRecommended studies:1. Testing Requirements for the Highest Strength (1 mg/2 mL) Product:The generic budesonide suspension/inhalation product must be qualitatively (Q1) and quantitatively (Q2) the same as the reference listed drug product (RLD).Option A. In Vitro Bioequivalence Studies Alone:The following in vitro comparative tests are recommended. Pari LC Plus Nebulizer/Pari Master compressor system is recommended for those tests requiring nebulization. The tests include:1)2) Sameness of shape (crystalline habit) of the drug substance.3) Comparative Unit Dose Content (UDC) of drug in the ampules.4) Comparative Mean Nebulization Time (MNT) and Mean Delivered Dose (MDD): The test should be conducted at the mouthpiece (% nominal dose) at the labeled flow rate of 5.5 L/min through such time that mist is no longer coming out of the mouthpiece.5) Comparative drug particle and agglomerate Particle Size Distribution (PSD) in the suspension (in the ampoule): The PSD determination should be based on a validated method. Validation should demonstrate method sensitivity to drug particle size over the expected size range in the suspension.6) Comparative drug particle and agglomerate PSD in the nebulized aerosol: Recommended method for this test is the aerodynamic particle size distribution (APSD) of the nebulized aerosol based on Apparatus 5 (USP <601>) at a flow rate of 15 L/min through theApparatus. We recommend the study be conducted based on USP <1601> using the Pari LC Plus Nebulizer/Pari Master compressor system. The amount of drug deposited on the induction port, the seven stages of the cascade impactor, and the sum of the back-up filter and micro-orifice collector (MOC) should be submitted.7) Comparative aqueous droplet size distribution of the nebulized aerosol by a Laserdiffraction method.Option B. Combination of In Vitro and In Vivo Bioequivalence Studies:1) Tests should include all described above in 1. Option A, with the exception ofcomparative drug particle and agglomerate PSD in the nebulized aerosol referred in 1. Option A. 6)2) A clinical endpoint bioequivalence study, with demonstration of acceptable dose-response for test and reference products to assure study sensitivity. At this time, the Agency has no recommendations regarding the clinical bioequivalence study design.3) A systemic exposure (pharmacokinetic) bioequivalence study.2.Testing Requirements for the Two Lower Strengths (0.5 mg/2 mL or 0.25mg/2 mL) Products:If the micronized budesonide (bulk drug) used in the lower strength product is the same as that used in the higher strength product, i.e., same particle size, PSD, polymorphic form, and shape, and the respective lower strength test and reference formulations are Q1 and Q2 the same, the Division of Bioequivalence (DB) recommends that the firm conduct the following tests for the lower strengths of the test product:Option A. I n Vitro Bioequivalence Studies Alone:If the comparative drug particle and agglomerate PSD in the nebulized aerosol between the test and reference products for both the higher and lower strengths can be determined, the following in vitro testing should be sufficient to demonstrate the equivalence of the lower strengths:1) Documentation of bioequivalence of the higher strength product based onacceptable comparative in vitro data outlined above.2) Comparative drug particle and agglomerate PSD in the suspension (in theampoule) between the respective lower strengths of the test and referenceproducts: The PSD determination should be based on a validated method.Validation should demonstrate method sensitivity to drug particle size over the expected size range in the suspension.3) Comparative drug particle and agglomerate PSD in the nebulized aerosol betweenthe respective lower strengths of the test and reference products: Recommended method for this test is the aerodynamic particle size distribution (APSD) of thenebulized aerosol based on Apparatus 5 (USP <601>) at a flow rate of 15 L/minthrough the Apparatus.We recommend the study be conducted based on USP<1601> using the Pari LC Plus Nebulizer/Pari Master compressor system. Theamount of drug deposited on the induction port, the seven stages of the cascadeimpactor, and the sum of the back-up filter and micro-orifice collector (MOC)should be submitted.4) Comparative Unit Dose Content (UDC) of drug between the respective lowerstrengths of the test and reference products.5) Comparative Mean Nebulization Time (MNT) and Mean Delivered Dose (MDD):The test should be conducted at the mouthpiece (% nominal dose) at the labeledflow rate of 5.5 L/min through such time that mist is no longer coming out of the mouthpiece, between the respective lower strengths of the test and referenceproducts.6) The Mean Delivered Dose (MDD) ratio of the higher to lower strength of the testproduct should be similar to that of the reference product.Option B. Combination of In Vitro and In Vivo Bioequivalence Studies:If the drug particle and agglomerate PSD in the nebulized aerosols of the higher and lower strengths of the test and reference products cannot be determined as described above, the following testing should be sufficient to demonstrate the equivalence of the lower strengths:1) Documentation of bioequivalence of the higher strength product based onacceptable comparative in-vivo and in-vitro data outlined in 1, option B.2) Comparative Unit Dose Content (UDC) of drug between the respective lowerstrengths of the test and reference products.3) Comparative Mean Nebulization Time (MNT) and Mean Delivered Dose (MDD)at the mouthpiece (% nominal dose) at the labeled flow rate of 5.5 L/min through such time that mist is no longer coming out of the mouthpiece, between therespective lower strengths of the test and reference products.4) The Mean Delivered Dose (MDD) ratio of the higher to lower strength of the testproduct should be similar to that of the reference product.3. Recommendations Related to the Batch Size Recommendation for In Vitro BEStudies:1) In vitro BE studies for Budesonide Inhalation Suspension should generally beperformed on samples from each of three or more batches of the test product and three or more batches of the reference listed drug.2) The number of units per batch to be studied should not be fewer than 30 for eachstrength of the test and reference products (i.e., no fewer than 10 from each ofthree batches).4. Recommendations Related to the Number of Retention Samples of Test Article from the In Vivo and In Vitro BE Studies:According to 21 CFR 320.63, the applicant and the contract research organization “shall retain reserved samples for any test article and reference standard used in conducting an in vivo or in vitro bioequivalence study required for approval of the abbreviated application or supplemental application.”A. If the BE studies are conducted at one site, the number of BE retention samples forBudesonide Inhalation Suspension drug product is recommended as follows: At least 50 units for each batch of test and reference products, including placebos (if applicable), must be retained for BE studies for Budesonide InhalationSuspension drug product, in line with the FDA draft Guidance for Industry“Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (April 2003), for multi-unit nasal aerosols and nasal spraysdelivering 30 or more actuations per canister or bottle.B. If the BE studies are conducted at multiple sites, the number of BE retentionsamples for Budesonide Inhalation Suspension drug product is recommended asfollows:At least 50 units for each batch of test and reference products, including placebos (if applicable), with not less than 10 units per each batch per site, be retained forthe BE studies. For instance, if a BE study is conducted at 6 sites, using 1 batch of the test and reference products, the total number of reserve samples to be retained for the test and reference products must be at least 60, with at least 10 units pereach batch per site (10 units/batch/site X 1 batch/product X 6 sites = at least 60units/product).5. Recommendation Related to the Population Bioequivalence (PBE) Statistical Analysis Procedure Used in Bioequivalence Determination of Budesonide Suspension Inhalation Product:A. Step-wise Procedure of the PBE Computation:Step 1. Establish population BE criterion: Population BE criterion:()()θσσσμμ≤−+−2222R R T R T or ()()θσσσμμ≤−+−20222T RT R TLinerarized Criteria:()()022221<•−−+−=R p R T R T σθσσμμη for 0T R σσ>()()0202222<•−−+−=T p R T R T σθσσμμη for 0T R σσ≤Where,R T μμ−: Mean difference of T (log scale) and R (log scale) products22,R T σσ:Total variance of T and R productsσTO : Regulatory constant (σTO = 0.1)θp: Regulatory constant (θp = 2.0891) calculated as following:089.21.001.0)]11.1[ln(22=+Estimating the Linerarized Criteria:mMSW m m MSB m MSW m m MSB R p R p TT )1()1()1()1(ˆ21−+−+−−++Δ=θθη) for 0T R σσ>2022)1()1(ˆT p R R T T mMSW m m MSB m MSW m m MSB σθη−−−−−++Δ=) for 0T R σσ≤Where, ⋅⋅⋅⋅⋅⋅−=ΔR T X X )m: number of life stagesMSW T : within-bottle variability for test productMSW R : within-bottle variability for reference product(MSB T -MSW T )/m : between-bottle variability for test product(MSB R – MSW R )/m : between-bottle variability for reference productStep 2. Calculate MSB and MSW:Calculation for MSW T , MSW R , MSB T and MSB R can be conducted as follows.1)(112−⋅−⋅=∑∑==⋅⋅⋅⋅k k j n i k ijk k n X X m MSB kkl l k refers to either test or reference product)1()(1112−⋅⋅−=∑∑∑===⋅m n X XMSW k k j n i ms ijk ijksk kkl lmXX ms ijksijk ∑=⋅=1; kk i n j ijk k n XX kkl l ⋅=∑∑==⋅⋅⋅⋅11R T n n , : Number of canisters or bottles per batch, for T and R productsR T l l ,: Number of batches of T and R productsX ijks is the i th bottle in batch # j at life stage s for test or reference product;⋅ijk X is the average m life stages for i th bottle in batch # j;⋅k X ..is the population mean for the reference or test products.Step 3. Calculate σR and σT1) σR can be conducted as follow:σR = mMSW m m MSB R R )1(−+a. If σR > σTO (regulatory constant, 0.1), using the reference-scaled procedure to determine BE for the measured parameter(s)b. If σR ≤ σT0 (regulatory constant, 0.1), using the constant-scaled procedure to determine BE for the measured parameter(s)2) σT can be conducted as follow:σT =mMSW m m MSB TT )1(−+Step 4. Calculate linearized point estimate and 95% upper confidence bound:1) Reference-scaled Criterion (1η∧): Use α=0.05 for a 95% upper confidence bound:Equation for Linearized Point Estimate:Eq = E D + E1+ E2+ E3s+ E4s95% upper confidence bound (H η1):H η1 = (E D + E1+ E2+ E3s+ E4s) + (U D + U1+ U2+U3s+U4s)½Following are the equations to compute each component:E q = Point Estimate H q = Confidence BoundU q =(H q - E q )22D E ∧=Δ22/12,1ˆ⎟⎟⎠⎞⎜⎜⎝⎛⎟⎟⎠⎞⎜⎜⎝⎛⋅⋅+⋅⋅+Δ=−⋅+⋅−m n MSB m n MSB t H R R R T T T n n D R R T T l l l l α D UmMSB E T=1 2,11)1(1αχ−⋅⋅−⋅=TTnT T E n H l l1UmMSW m E T⋅−=)1(22),1(2)1(2αχ−⋅⋅⋅−⋅⋅=m nT T T TE m n H l l2UmMSB s E Rp )1(3θ+−= 21,13)1(3αχ−−⋅⋅−⋅=R R n R R sE n s H l ls U 3mMSW m s E Rp )1()1(4−+−=θ21),1(4)1(4αχ−−⋅⋅⋅−⋅⋅=m n R R R R sE m n s H l ls U 4Where is from the cumulative distribution function of the chi-square distribution with degrees of freedom, i.e. 2,1αχ−⋅T T n l 1−⋅T T n l αχχα=≤−⋅−⋅)Pr(2,121T T T T n n l lFor data collected on one life stage (m=1), ignore E2 and E4s and their corresponding H and U terms in the calculation. For data collected on more than one stage (m ≥2), use the equations listed above.2) Constant-scaled Criterion (2η∧): Use α=0.05 for a 95% upper confidence bound:Equation for Linearized Point Estimate:E q = E D + E1+ E2+ E3c+ E4c- θp σT0295% upper confidence bound (H η2):H η2= (E D + E1+ E2+ E3c+ E4c - θp σT02) + (U D + U1+ U2+U3c+U4c)½Following are the equations to compute each component:E q = Point Estimate H q = Confidence BoundU q =(H q - E q )22D E ∧=Δ22/12,1ˆ⎟⎟⎠⎞⎜⎜⎝⎛⎟⎟⎠⎞⎜⎜⎝⎛⋅⋅+⋅⋅+Δ=−⋅+⋅−m n MSB m n MSB t H R R R T T T n n D R R T T l l l l α D UmMSB E T=1 2,11)1(1αχ−⋅⋅−⋅=TTnT T E n H l l1UmMSW m E T⋅−=)1(22),1(2)1(2αχ−⋅⋅⋅−⋅⋅=m nT T T TE m n H l l2UmMSB c E R−=3 21,13)1(3αχ−−⋅⋅−⋅=R R n R R cE n c H l lc U 3mMSW m c E R)1(4−−=21),1(4)1(4αχ−−⋅⋅⋅−⋅⋅=m n R R RR rcE m n c H l lc U 4For data collected on one life stage (m=1), ignore E2 and E4c and their corresponding H and U terms in the calculation. For data collected on more than one stage (m ≥2), use the equations listed above.The method of obtaining the upper confidence bound is based on two FDA guidances: 1) Statistical Information from the June 1999 Draft Guidance and Statistical Information for In Vitro Bioequivalence Posted on August 18, 1999, accompanying to Draft Guidance for Industry: Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (April 2003); and 2) Guidance for Industry: StatisticalApproaches to Establishing Bioequivalence (Jan. 2001). The concept is adapted from the method for the two-sequence, four-period study design using T-distribution.Step 5. For the test product to be bioequivalent to the reference product, the following condition must be satisfied:The 95% upper confidence bound for linearlized criteria H η must be ≤ 0.B. An Example of PBE Computation:Study Design:The data given in this example are simulated. A parallel design with two products (test or reference) including 3 batches and 10 bottles/containers per batch foreach product with three life stages (beginning, middle and end).Batches Container Stage Product In vitro measurement1 31 BREF 5.957211REF 5.9618021 31 MREF 5.9671781 31 EREF 6.0102511 32 BREF 6.0047111 32 MREF 6.0047971 32 EREF 5.8841611 33 BREF 5.8940851 33 MREF 5.8959771 33 EREF 5.6247051 34 BREF 5.6329911 34 MREF 5.6144281 34 EREF 5.9573291 35 BREF 5.9660591 35 MREF 5.9681431 35 EREF 5.0742981 36 B1 36 MREF 5.063063REF 5.0585191 36 EREF 5.4185871 37 BREF 5.4205911 37 MREF 5.4181781 37 EREF 6.3251781 38 BREF 6.3219541 38 MREF 6.3031481 38 EREF 5.6562861 39 BREF 5.680251 39 MREF 5.6750361 39 E1 40 BREF 5.792299REF 5.7751611 40 MREF 5.7930831 40 EREF 5.6010332 41 BREF 5.6112232 41 MREF 5.6011422 41 EREF 5.615532 42 BREF 5.5874122 42 MREF 5.5910042 42 EREF 5.6824662 43 BREF 5.6764722 43 M2 43 EREF 5.671434REF 5.8443362 44 B2 44 MREF 5.855172REF 5.862329 2 44 EREF 5.898151 2 45 BREF 5.883657 2 45 MREF 5.878956 2 45 EREF 6.100662 2 46 B2 46 MREF 6.105463REF 6.108098 2 46 EREF 6.294753 2 47 B2 47 MREF 6.28534REF 6.302333 2 47 EREF 5.638072 2 48 BREF 5.627372 2 48 MREF 5.623516 2 48 EREF 5.113562 2 49 B2 49 MREF 5.122454REF 5.109271 2 49 EREF 5.932752 2 50 B2 50 MREF 5.913438REF 5.912427 2 50 EREF 5.961947 3 51 BREF 5.955332 3 51 MREF 5.943721 3 51 EREF 6.2334 3 52 B3 52 MREF 6.250689REF 6.219668 3 52 EREF 6.041431 3 53 B3 53 MREF 6.038234REF 6.080464 3 53 EREF 6.049713 3 54 BREF 6.039759 3 54 MREF 6.054218 3 54 EREF 6.834563 3 55 B3 55 MREF 6.85264REF 6.857395 3 55 EREF 4.864966 3 56 B3 56 MREF 4.907521REF 4.891049 3 56 EREF 5.895176 3 57 BREF 5.885851 3 57 MREF 5.874895 3 57 EREF 6.45826 3 58 B3 58 MREF 6.443113REF 6.435882 3 58 EREF 6.090533 3 59 B3 59 MREF 6.102835REF 6.077606 3 59 E3 60 BREF 5.886724REF 5.920949 3 60 MREF 5.915749 3 60 ETEST 6.894594 4 1 BTEST 6.913011 4 1 MTEST 6.895764 4 1 E4 2 BTEST 5.832334TEST 5.846562 4 2 MTEST 5.832269 4 2 E4 3 BTEST 6.235755TEST 6.26231 4 3 MTEST 6.245095 4 3 ETEST 5.646185 4 4 BTEST 5.635887 4 4 MTEST 5.63034 4 4 E4 5 BTEST 5.960711TEST 5.962902 4 5 MTEST 5.961959 4 5 E4 6 BTEST 5.500354TEST 5.508444 4 6 MTEST 5.513115 4 6 ETEST 6.663099 4 7 BTEST 6.64733 4 7 MTEST 6.651215 4 7 E4 8 BTEST 5.724774TEST 5.72086 4 8 MTEST 5.71411 4 8 E4 9 BTEST 6.183375TEST 6.186433 4 9 MTEST 6.182109 4 9 ETEST 5.64053 4 10 BTEST 5.648589 4 10 MTEST 5.6263954 10 E5 11 BTEST 6.69764TEST 6.71128 5 11 MTEST 6.699829 5 11 E5 12 BTEST 6.555609TEST 6.549935 5 12 MTEST 6.551611 5 12 ETEST 5.009683 5 13 BTEST 5.013969 5 13 MTEST 5.010928 5 13 E5 14 BTEST 5.440976TEST 5.42057 5 14 MTEST 5.447687 5 14 E5 15 BTEST 6.477609TEST 6.456082 5 15 MTEST 6.448981 5 15 ETEST 6.442601 5 16 BTEST 6.426217 5 16 MTEST 6.436262 5 16 ETEST 5.640496 5 17 BTEST 5.63846 5 17 MTEST 5.640755 5 17 ETEST 6.597718 5 18 B5 18 MTEST 6.599232TEST 6.609437 5 18 ETEST 6.007241 5 19 BTEST 5.990695 5 19 MTEST 5.984292 5 19 ETEST 6.781806 5 20 B5 20 MTEST 6.774386TEST 6.784001 5 20 ETEST 5.993852 6 21 B6 21 MTEST 5.994287TEST 5.993541 6 21 ETEST 6.012322 6 22 B6 22 MTEST 6.006182TEST 6.017961 6 22 ETEST 5.965969 6 23 BTEST 5.97125 6 23 MTEST 5.967839 6 23 ETEST 5.592609 6 24 B6 24 MTEST 5.581154TEST 5.588877 6 24 ETEST 6.002182 6 25 B6 25 MTEST 6.011583TEST 6.018746 6 25 ETEST 5.267014 6 26 BTEST 5.272291 6 26 MTEST 5.265213 6 26 ETEST 5.766104 6 27 B6 27 MTEST 5.786727TEST 5.773194 6 27 ETEST 6.054975 6 28 BTEST 6.05232 6 28 MTEST 6.061088 6 28 ETEST 5.838689 6 29 B6 29 MTEST 5.837566TEST 5.842508 6 29 ETEST 5.784255 6 30 B6 30 MTEST 5.789891TEST 5.788662 6 30 EFollowing the step-wise PBE computation procedure outlined above, the following components can be determined:Reference-scaled:Eq related intermediate parametersHq related intermediate parametersU q related intermediate parametersH η= Eq + (Uq)½E D = 0.022094106 H D = 0.113976896 U D = 0.008442447 E1= 0.219742944 H1= 0.359860715 U1= 0.01963299 E2= 3.9108E-05 H2= 5.43319E-05 U2= 2.31765E-10 E3s= -0.505515326 H3s= -0.344478125 U3= 0.02593298 E4s= -0.000256672 H4s= -0.000194739 U4= 3.83572E-09Eq (linearized point estimate) =-0.26389584U q = (H q - E q )2 = 0.054008421H η = -0.031498721Constant-scaled:Eq related intermediate parametersHq related intermediate parametersU q related intermediateparameters H η= Eq + (Uq)½E D = 0.022094106 H D = 0.113976896 U D = 0.008442447 E1= 0.219742944 H1= 0.359860715 U1= 0.01963299 E2=3.9108E-05 H2= 5.43319E-05 U2= 2.31765E-10 E3c= -0.163644789 H3c= -0.111514028 U3= 0.002717616 E4c= -8.30895E-05 H4c= -6.30405E-05U4= 4.0196E-10Eq (linearized point estimate) =0.057257267U q = (H q - E q )2 = 0.030793054H η = 0.232736764Calculate σR:σR = mMSW m m MSB R R )1(−+= 163727878.0= 0.4046 > 0.1 (regulatory constant),therefore, reference-scaled procedure applies.Since the 95% upper confidence bound for linearized criteria of reference-scaled procedure is negative (-0.031498721), bioequivalence can be concluded.C. Electronic Table Templates for BE Study DataThe following table templates have been developed in a concise format consistent with the Common Technical Document (CTD). For electronic submission of the individual data and summary data from the BE studies, please provide complete tables using theformats indicated below, and send them as a part of the ANDA bioequivalencesubmission. Submission of these electronic summary tables is necessary for improving the efficiency of the review process.Table 1. Individual Data of In Vitro Tests Using SAS Transport FormatBatches Container Stage ProductIn vitro measurement(original data)1 1 Beginning Reference 1 1 Middle Reference 1 1 End Reference2 2 Beginning Test 2 2 Middle Test 2 2 End TestTable 2. Summary Tables of PBE Results Using Word and/or PDF FormatGeometric MeanStandard Deviation VariableTest Reference Geometric Mean RatioSigmaTSigmaRSigmaT/SigmaRRatioScaledLinearized Point Estimate 95% UpperConfidence BoundPass or Fail PBEReference-scaled Constant-scaled。
FDA药物临床前指南-Guidance for Industry Unmarketed Investigational Drugs
Codevelopment of Two or More Unmarketed Investigational Drugs for Use in CombinationDRAFT GUIDANCEThis guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.For questions regarding this draft document contact (CDER) Colleen Locicero 301-796-1114.U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)December 2010Clinical MedicalCodevelopment of Two or More Unmarketed Investigational Drugs for Use in CombinationAdditional copies are available from:Office of CommunicationsDivision of Drug Information, WO51, Room 220110903 New Hampshire Ave.Silver Spring, MD 20993Phone: 301-796-3400; Fax: 301-847-8714druginfo@/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)December 2010Clinical MedicalTable of Contents 1234 5 6 7 8 910111213141516171819202122 I.INTRODUCTION (1)II.BACKGROUND (2)III.DETERMINING WHETHER CODEVELOPMENT IS AN APPROPRIATEDEVELOPMENTOPTION (2)IV.NONCLINICAL CODEVELOPMENT (3)A.Demonstrating the Biological Rationale for the Combination (3)B.Nonclinical Safety Characterization (3)V.CLINICAL CODEVELOPMENT (4)A.Early Human Studies (Phase 1) (4)1.Safety of the Individual Components (4)2.Safety and Dosing of the Combination (5)B.Clinical Pharmacology (5)C.Proof of Concept Studies (Phase 2) (6)D. Confirmatory Studies (Phase 3) (8)VI.REGULATORY PROCESS ISSUES IN CODEVELOPMENT (8)A. Early Interaction with FDA (8)B. IND Submissions and Marketing Applications (9)beling Issues (9)D.Pharmacovigilance (9)232425262728Guidance for Industry1Codevelopment of Two or More Unmarketed Investigational Drugsfor Use in Combination2930 This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current31 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to32 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of33 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA34 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call35 the appropriate number listed on the title page of this guidance.36373839404142434445464748495051525354555657 I. INTRODUCTIONThis guidance is intended to assist sponsors in the codevelopment2 of two or more novel (not previously marketed) drugs to be used in combination to treat a disease or condition. The guidance provides recommendations and advice on how to address certain scientific and regulatory issues that will arise during codevelopment. It is not intended to apply to development of fixed-dose combinations of already marketed drugs or to development of a single new investigational drug to be used in combination with an approved drug or drugs. The guidance is also not intended to apply to vaccines, gene or cellular therapies, blood products, or medical devices.3FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.2Codevelopment herein refers to the concurrent development of two or more drug products with the intent that the products be used in combination to treat a disease or condition.3 For purposes of this guidance, the term drug includes therapeutic biological products that are regulated by CDER. Consult the Therapeutic Biologics web page for further information on the types of biological products to which this guidance applies:/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/T herapeuticBiologicApplications/default.htmII. BACKGROUND585960616263646566676869707172737475767778798081828384858687888990919293949596979899 100 101 102 103 Combination therapy is an important treatment modality in many disease settings, including cancer, cardio-vascular disease, and infectious diseases. Recent scientific advances have increased our understanding of the pathophysiological processes that underlie these and other complex diseases. This increased understanding has provided further impetus for new therapeutic approaches using combinations of drugs directed at multiple therapeutic targets to improve treatment response or minimize development of resistance. In settings in which combination therapy provides significant therapeutic advantages, there is growing interest in the development of combinations of investigational drugs not previously developed for any purpose.Because the existing developmental and regulatory paradigm focuses primarily on assessment of the effectiveness and safety of a single new investigational drug acting alone, or in combination with an approved drug, FDA believes guidance is needed to assist sponsors in the codevelopment of two or more unmarketed drugs. Although interest in codevelopment has been most prominent in oncology and infectious disease settings, codevelopment also has potential application in other therapeutic settings. Therefore, this guidance is intended to describe a high-level, generally applicable approach to codevelopment of two or more unmarketed drugs. It describes the criteria for determining when codevelopment is an appropriate option, makes recommendations about nonclinical and clinical development strategies, and addresses certain regulatory process issues. III. DETERMININGWHETHERCODEVELOPMENT IS AN APPROPRIATE DEVELOPMENT OPTIONConcurrent development of two or more novel drugs for use in combination generally will provide less information about the safety and effectiveness of the individual drugs than would be obtained if the individual drugs were developed alone. How much less will vary depending on a variety of factors, including the stage of development at which the individual drug components cease to be studied independently. For example, in codevelopment scenarios in which rapid development of resistance to monotherapy is a major concern, it may not be possible or appropriate to obtain clinical data for the individual components of the combination beyond phase 1 testing. Because codevelopment will generally provide less information about the safety and effectiveness of the individual drugs, it will present greater risk compared to development of an individual drug. Therefore, FDA believes that codevelopment should ordinarily be reserved for situations that meet the following criteria:•The combination is intended to treat a serious disease or condition.•There is a compelling biological rationale for use of the combination (e.g., the agents inhibit distinct targets in the same molecular pathway, provide inhibition of both aprimary and compensatory pathway, or inhibit the same target at different binding sites to decrease resistance or allow use of lower doses to minimize toxicity).• A preclinical model (in vivo or in vitro) or short-term clinical study on an established biomarker suggests that the combination has substantial activity and provides greater thanadditive activity or a more durable response (e.g., delayed resistance) compared to the individual agents alone. 104105106107108109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138139140141142143144145146 • There is a compelling reason for why the agents cannot be developed individually (e.g., monotherapy for the disease of interest leads to resistance and/or one or both of the agents would be expected to have very limited activity when used as monotherapy). FDA recommends that sponsors consult with FDA on the appropriateness of codevelopment before initiation of clinical development of the combination. IV. NONCLINICAL CODEVELOPMENT A. Demonstrating the Biological Rationale for the Combination The biology of the disease, pathogen, or tumor type should be sufficiently understood to provide a plausible biological rationale for the use of combination therapy to treat the disease or condition. For example, in an oncology setting the biological rationale may be to intervene at different steps in the cell proliferation pathway. The biological rationale for a combination anti-infective therapy may be to target different metabolic pathways or different steps in the replication cycle of the pathogen to reduce the chance of developing resistance to the therapy or increase efficacy in treating disease caused by resistant organisms (e.g., multidrug-resistant atypical tuberculosis). Sponsors should develop evidence to support the biological rationale for the combination in an in vivo (preferable) or in vitro model. The model should compare the activity of the combination to the activity of the individual components. Ordinarily, the model should demonstrate that, compared to the individual components, the combination has substantial activity and provides greater than additive activity or a more durable response in a pathophysiological process considered pertinent to the drug’s intended use in humans. An animal model of activity generally would not be necessary. However, if there is an animal model relevant to the human disease, valuable activity data, as well as information about the relative doses of the drugs, might be obtained from evaluating the combination in that model. B. Nonclinical Safety Characterization For detailed recommendations regarding nonclinical safety characterization for two or more investigational drugs to be used in combination, sponsors should consult the recently revised International Conference on Harmonisation (ICH) Guidance on Nonclinical Safety Studies.4 Section XVII of that guidance (Combination Drug Toxicity Testing) includes a discussion of nonclinical safety studies appropriate in a combination drug development setting involving two early stage entities. The ICH guidance defines early stage entities as compounds with limited clinical experience (i.e., phase 2 studies or less), so the discussion is specifically applicable to the4 Guidance for Industry: M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials andMarketing Authorization, January 2010 (this guidance is a revision of 1997 ICH guidance M3: Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals).147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 type of development described in this guidance. In situations in which it is possible to obtain only limited clinical data for the individual drugs, additional nonclinical data for the individual drugs or combination may be needed before beginning human studies with the combination. (e.g., see section V.A.1).V. CLINICAL CODEVELOPMENTThis section provides a general roadmap and guiding principles for concurrent clinical development of two or more investigational drugs to be used in combination. It includes recommendations for characterizing the clinical safety and effectiveness of the combination and, to the extent needed or possible, the individual components of the combination.Note: The appropriate review division should always be consulted on the specifics of a given clinical development program.A. Early Human Studies (Phase 1)The main objectives of early studies in humans are to characterize the safety and pharmacokinetics of the individual components and then the combination and to provide data to support appropriate dosing for the combination in phase 2 testing.1. Safety of the Individual ComponentsWhenever possible, the safety profile of each individual drug should be characterized in phase 1 studies in healthy volunteers in the same manner as would be done fordevelopment of a single drug, including determination of the maximum tolerated dose(MTD), the nature of the dose limiting toxicity (DLT), and pharmacokinetic parameters.If there is a useful measure (e.g., biomarker) of pharmacologic activity, it will also beimportant to determine dose-response for that measure. If testing in healthy volunteers is not possible (e.g., if nonclinical data suggest a drug may be genotoxic or otherwiseunacceptable for studies in healthy volunteers), the safety profile of the individual drugs should be evaluated in patients with the disease of interest. These safety data will guide decisions in later studies about starting doses, dose escalation increments, and final dose selection.If it is not possible to characterize the safety of the individual drugs in humans (e.g.,where drug toxicity prevents use of healthy volunteers and monotherapy would beunethical in patients with the disease of interest), the sponsor should conduct nonclinical studies of the combination to support initial dosing of the combination in humans.The nonclinical data for the combination should include pharmacokinetic (absorption,distribution, metabolism, and excretion) and toxicokinetic data and appropriatebiomarker/target inhibition, if relevant.2. Safety and Dosing of the Combination 193194195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237For initial human effectiveness studies of the combination, the combination starting dose, dosing escalation intervals, and doses to be used in dose-response studies should bedetermined based on phase 1 safety data for the individual components, if available. Ifphase 1 safety data for the components are unavailable, nonclinical data for thecombination will be needed to determine the initial combination dose in humans (seeprevious paragraph). Phase 1 safety studies of the combination could also be conducted — for example, sequential testing in which subjects get drug A, then drug B, then AB — to support dosing in subsequent studies.B. ClinicalPharmacologyThe sponsor should conduct the same clinical pharmacology studies for each of the individual drugs in the combination as would be done if the drugs were being developed separately. In general, such studies include the assessment of bioavailability, characterization of pharmacokinetics, mass balance, the evaluation of effects of intrinsic (such as renal impairment and hepatic impairment) and extrinsic (such as food effect and drug interactions) factors on pharmacokinetics or pharmacodynamics, and exposure-response. Studies to address intrinsic and extrinsic factors could be conducted with the combination instead of the individual drugs.The evaluation of drug interaction potential follows the same sequence as in other development programs; results of in vitro drug metabolism and drug transporter studies inform the need for in vivo drug interaction studies. The role of pharmacogenomics should be investigated and incorporated into the combination drug development plan to identify potential sources of pharmacokinetic or pharmacodynamic variability.Dose-response should be evaluated for each drug of the combination. The results of such studies should be used to determine doses to further explore for the combination. If the drug products cannot be administered alone, various doses of each drug administered as the combination should be assessed.If one drug has no activity or minimal activity by itself, dose-response should be assessed when the drug products are administered in combination using a number of doses of the active drug and the inactive drug. The same approach should be used in evaluating dose-response for the combination of drugs where each drug has minimal activity when used alone.In addition to evaluating dose-response, response should be evaluated with respect to systemic drug concentration to provide insight into efficacy and safety as a function of drug exposure. Concentration-response assessments should be done in both phase 2 and phase 3 trials. To increase exposure ranges in phase 3 and to further assess dose-response, the incorporation of more than one dose of each of the drugs used in the combination in the phase 3 trials should be considered.C. Proof of Concept Studies (Phase 2) 238239240 241 242 243 244 245 246247 248 249 250 251 252 253 254 255 256 257 258 In general, phase 2 testing should accomplish the following to the extent needed for a given combination (e.g., to the extent not sufficiently established by existing data): •Demonstrate the contribution of each component of the combination to the extent possible and needed (given available nonclinical and pharmacologic data);•Provide evidence of the effectiveness of the combination; and•Optimize the dose or doses of the combination for phase 3 trials.The amount and types of clinical data needed and appropriate study designs will vary depending on the nature of the combination being developed, the disease, and other factors. For the types of combinations contemplated by this guidance, it will often be inappropriate to use monotherapy treatment arms in studies of the disease of interest, or it will be possible to administer the components of the combination as monotherapy only for short durations. In these circumstances, the study design typically employed to determine the contributions of the components to the combination — a four-arm factorial design comparing the combination to individual components and placebo or standard of care (SOC) therapy (AB v. A. v. B v. placebo or SOC) — will have limited utility. The following scenarios illustrate possible phase 2 study designs for combinations of two investigational drugs in different situations.Scenario 1: The components of the combination cannot be administered individually259 260261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278If in vivo or in vitro models, or phase 1 or other early clinical studies make clear that the components of the combination cannot be administered individually in clinical trials inthe disease of interest (e.g., because such testing would involve administering treatment known to be ineffective as monotherapy), or can’t be administered as monotherapy forthe duration needed to evaluate effectiveness (e.g., because of rapid development ofresistance), proof-of-concept evidence for the combination ordinarily should come froma study directly comparing the combination (AB) to SOC. Alternatively, if SOC isknown to be an effective therapy (not solely palliative), an add-on design could be used comparing the combination plus SOC to SOC alone.In some resistance scenarios, it may be possible to administer the individual drugs in acombination as monotherapy for a short duration, but long enough to establish proof ofconcept in humans. For example, direct-acting antivirals (DAAs) to treat chronichepatitis C virus infection can be administered as monotherapy for three days to establish antiviral activity and for initial dose exploration. For DAA studies of longer duration, the combination should be used or the individual components should be added to an activecontrol.55 See draft guidance for industry: Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Agents for Treatment (section III. 4. b. – Phase 1b (proof-of-concept) trials) or consult the Division of Antiviral Drug Products in CDER for more specific recommendations.279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 Scenario 2: Each drug alone has activity and can be administered individuallyIf in vivo or in vitro models, or phase 1 or other early clinical studies indicate that each drug has some activity, but the combination appears to have greater than additive activity, and rapid development of resistance is not a concern, a four-arm, phase 2 trial comparing the combination to each drug alone and to placebo or SOC (AB v. A v. B v. SOC or placebo6) should be used to demonstrate the contribution of the components to the combination and proof of concept. As noted above, if SOC is a known effective therapy, a study design in which each of the arms is added to SOC could be used (AB + SOC v. A + SOC v. B + SOC v. placebo + SOC).An adaptive trial design with the same four treatment arms might also be used where appropriate, initially using the treatment arms described above. The single-drug arms could be terminated early if it became clear that they had much less activity than the combination. These designs could demonstrate the activity of each component of (i.e., the contribution of each component to the combination) without exposing the large numbers of patients typically required for phase 3 trials to therapeutic products with inadequate activity. For these trials, it may not be necessary to use a clinical endpoint as a primary efficacy measurement. A credible pharmacodynamic or other biomarker, such as tumor response, may be adequate.300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 Scenario 3: One drug is active alone and one is inactiveIf in vivo or in vitro models, or phase 1 or other early clinical studies suggest that one of the drugs is inactive or minimally active and one drug is modestly active, but the combination has substantial activity, the more active drug generally will require greater scrutiny and should ordinarily be studied as a single drug in a phase 2 study. The minimally active drug generally would not require study as a single drug beyond initial phase 1 safety studies. In this scenario, proof of concept and the contribution of each component could be demonstrated using a three-arm comparison of the active drug alone, SOC, and the combination (AB v. A v. SOC), or the combination and the individual drug added to SOC where SOC is a known effective therapy (AB + SOC v. A + SOC v. SOC). If the inactive drug in a combination is a pharmacokinetic or metabolic enhancer that contributes to the activity of the combination only by increasing the therapeutic concentrations of the active drug, human pharmacokinetic data may provide adequate evidence to support the enhanced activity of the combination and demonstrate the contribution of the inactive drug. A confirmatory study of the combination would usually be needed to provide evidence of effectiveness for the combination (see section V.D). Dose Finding319 320321 322Dose-finding studies could be very important to refine the combination dose or doses and select doses for phase 3 trials. Depending on the role of each component, it may be6 Note that the placebo arm is intended to show the effect size compared to non-treatment, not to show the contribution of each component.323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367useful to test multiple doses of both components to establish a best dose in terms of risks and benefits. If one component in a two-drug combination is more active than the other, it may be more important to study multiple doses of the more active drug (as part of thecombination). For the same reason, it may be more important to study multiple doses ofa drug that is significantly more toxic than the other component of the combination.Other study designs and types of studies also may be appropriate.D. Confirmatory Studies (Phase 3)If findings from in vivo or in vitro models and/or phase 2 trials adequately demonstrate the contribution of each component to the combination, phase 3 trials comparing the combination to SOC or placebo generally will be sufficient to establish effectiveness. If the contribution of the individual components is not clear and it is ethically feasible to use a component or components of the combination as monotherapy in a study arm, it may be necessary to demonstrate the contribution of the components in phase 3 studies (e.g., by use of a factorial design). For example, if phase 2 data do not provide sufficient evidence of the contribution of each component of a two drug combination, but provide strong evidence that the combination is superior to one of the components, a phase 3 trial comparing the combination to the more active component alone and SOC may be needed to demonstrate that the less active component contributes to the activity of the combination. In this and other situations, it will often be useful to study more than one dose of the more active drug in phase 3 studies.Unexpected toxicity (e.g., serious adverse events observed at higher than expected rates) in phase 2 trials is a potential complication for development of a combination and progressing to phase 3 trials. If the toxicity can be attributed to one component of the combination, it may be possible to conduct phase 3 trials with the combination using a lower dose or doses of the more toxic component. If the toxicity cannot be attributed to an individual component of the combination, additional studies may be needed to identify the more toxic component and appropriate dosing for the combination before initiating phase 3 trials. The specifics of any phase 3 design should be discussed with the appropriate FDA review division at an End-of-Phase 2 meeting.VI. REGULATORY PROCESS ISSUES IN CODEVELOPMENTSponsors should consider a number of regulatory issues when planning the codevelopment of two or more novel drugs for use in combination. Key issues are outlined below.A. Early Interaction with FDASponsors are encouraged to communicate as early as possible (e.g., pre-IND meeting) with the appropriate FDA review division when considering codevelopment of innovative combination therapy. Sponsors also are encouraged to consult FDA frequently throughout the development process. We believe such communication will help facilitate development of the combination therapy.368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398B. IND Submissions and Marketing ApplicationsDecisions about the type of IND submission(s) and marketing application(s) needed (e.g., individual component submissions, combination submission) will depend on the sponsor's overall codevelopment and marketing strategy. Until FDA has more experience with codevelopment, FDA recommends that these decisions be made on a case-by-case basis in consultation with the appropriate review division.C. Labeling IssuesFDA also anticipates that the content of labeling for the combination and/or the components will be case specific, depending on the nature of the combination, the intended uses of the individual components, the marketing strategy, and other factors. Therefore, FDA does not believe it can provide generally applicable labeling guidance at this time. Again, we recommend consultation with the appropriate review division.D. PharmacovigilanceApplicants should develop a pharmacovigilance plan that takes into account the additional postmarket risks presented by initial marketing of two or more previously unapproved drugs for use in combination (compared to risks associated with marketing of a single drug). Risk will vary, depending on the nature of the combination and how the combination is marketed. The risk assessment should consider, among other things:•Potential for use of each drug individually;•Potential for use of any of the components of the combination in combinations with other drugs; and•Drugs likely to be co-administered with the combination.Applicants should discuss their pharmacovigilance plans with the appropriate review division and the Office of Surveillance and Epidemiology.。
Draft Guidance for Industry and Food and Drug Administration Staff
Draft Guidance for Industry and 1 Food and Drug Administration2 Staff3 45 eCopy Program for Medical Device6 Submissions78 DRAFT GUIDANCE910 This guidance document is being distributed for comment purposes only.11 Document issued on: [use release date of FR Notice]1213 You should submit comments and suggestions regarding this draft document within 30 days of 14 publication in the Federal Register of the notice announcing the availability of the draft guidance. 15 Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug 16 Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic17 comments to . Identify all comments with the docket number listed in 18 the notice of availability that publishes in the Federal Register . 1920 For questions regarding this document, contact the Premarket Notification (510(k)) Section or 21 the Premarket Approval Section of CDRH at 301-796-5640 or CBER’s Office of 22 Communication, Outreach and Development at 1-800-835-4709 or 301-827-1800. 23 2425262728U.S. Department of Health and Human Services 29 Food and Drug Administration 30 Center for Devices and Radiological Health 31 Center for Biologics Evaluation and Research32Preface3334Additional Copies3536Additional copies are available from the Internet. You may also send an e-mail request to37dsmica@ to receive an electronic copy of the guidance or send a fax request to 301-38827-8149 to receive a hard copy. Please use the document number (1797) to identify the39guidance you are requesting.4041Additional copies of this guidance document are also available from the Center for Biologics42Evaluation and Research (CBER), Office of Communication, Training and Manufacturers43Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by44calling 1-800-835-4709 or 301-827-1800, or from the Internet at45/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/defau 46lt.htm.4748Table of Contents491.Introduction (1)502.What is an eCopy? (2)513.Are differences between the contents of an eCopy and paper submission acceptable? 2 524.For what submission types would an eCopy be required? (3)535.What submission types would FDA consider exempt from submission of an eCopy? .4 546.What submission types or applicants should be eligible for an eCopy waiver? (4)557.How many copies of a submission would be needed? (4)568.What are the processing steps for an eCopy? (5)57a. What are the standards for an eCopy? (5)58b. How do I know if my eCopy meets FDA’s standards for acceptance?? (6)59c. What if there is another processing party involved? (6)60d. How do you submit an eCopy to FDA? (6)61e. How does FDA process an eCopy? (7)629.What if your device is regulated by CBER? (7)63a. Will the new eCopy Program apply? (7)64b. Can you submit an electronic submission instead? (7)65c. How do you prepare and submit an electronic submission to CBER? (8)66Attachment 1 –Standards for eCopies (7)67A. Cover Letter that accompanies an eCopy (10)68B. Volume versus non-volume structure (11)69C. Folder naming convention for volume-based submissions that house PDF files (13)70D. Adobe Acrobat PDF file format (14)71E. Non-PDF file formats (15)72F. PDF file naming convention (16)73G. PDF file size limit (17)74H. Creating a PDF version from the source document (17)75I. Bookmarks and hypertext links within PDFs (20)76J. PDFs created from scanning paper documents (21)77K. Common mistakes in creating an eCopy (22)7879Guidance for Industry and Food and Drug 80Administration Staff8182eCopy Program for Medical Device83Submissions84851.Introduction86The purpose of this guidance is to explain the new electronic copy (eCopy) Program for medical 87device submissions. At this time, submission of an eCopy of a medical device submission is88voluntary. However, section 745A(b) of the Federal Food, Drug, and Cosmetic Act (FD&C89Act), added by section 1136 of the Food and Drug Administration Safety and Innovation Act90(FDASIA) (Pub. L. 112-144), requires the submission of eCopies after this guidance is finalized.91This draft guidance describes how the Food and Drug Administration (FDA) plans to implement 92the eCopy Program under section 745A(b) of the FD&C Act. The inclusion of an eCopy is93expected to improve the efficiency of the review process by allowing for the immediate94availability of an electronic version for review rather than relying solely on the paper version.9596This draft guidance provides, among other things, the standards for a valid eCopy under section 97745A(b)(2)(A) of the FD&C Act. In accordance with section 745A(b), following the issuance of98a final guidance on this topic, submission types identified in the final guidance must include an99eCopy in accordance with the standards provided by this guidance for the submission to be100processed and accepted for review by FDA. Submissions submitted without an eCopy and101eCopy submissions that do not meet the standards provided in this guidance will be placed on 102hold until a valid eCopy is submitted to FDA and verified to meet the standards, unless a waiver 103or exemption has been granted. While the submission is on hold, the review clock will not104begin.105106In Section 745A(b), Congress granted explicit statutory authorization to FDA to implement the 107statutory eCopy requirement by providing standards, criteria for waivers, and exemptions in108guidance. Accordingly, to the extent that this document provides such requirements under109section 745A(b) of the FD&C Act (i.e., standards, criteria for waivers, and exemptions),110indicated by the use of the words must or required,this document is not subject to the usual111restrictions in FDA’s good guidance practice (GGP) regulations, such as the requirement that 112guidances not establish legally enforceable responsibilities. See 21 CFR 10.115(d).113114However, this document also provides guidance on FDA’s interpretation of the statutory eCopy 115requirement and the Agency’s current thinking on the best means for implementing other aspects 116of the eCopy program. Therefore, to the extent that this document includes provisions that are 117not “standards,” “criteria for waivers,” or “exemptions” under section 745A(b)(2), this document 118does not create or confer any rights for or on any person and does not operate to bind FDA or the 119public, but will represent the Agency’s current thinking on this topic when finalized. The use of 120the word should in such parts of this guidance means that something is suggested or121recommended, but not required. You can use an alternative approach if the approach satisfies 122Draft – Not for Implementationthe requirements of the applicable statutes and regulations. If you want to discuss an alternative 123approach, contact the FDA staff responsible for implementing this guidance. If you cannot124identify the appropriate FDA staff, call the appropriate number listed on the title page of this125guidance.126127To comply with the GGP regulations and make sure that regulated entities and the public128understand that guidance documents are nonbinding, FDA guidances ordinarily contain standard 129language explaining that guidances should be viewed only as recommendations unless specific 130regulatory or statutory requirements are cited. FDA is not including this standard language in 131this draft guidance because it is not an accurate description of all of the effects of this guidance, 132when finalized. This guidance, when finalized, will contain both binding and nonbinding133provisions. Insofar as this guidance, when finalized, provides “standards,” “criteria for waivers,” 134and “exemptions” pursuant to section 745A(b) of the FD&C Act, it will have binding effect. For 135these reasons, FDA is not including the standard guidance language in this draft guidance.136137The eCopy Program is not intended to impact (reduce or increase) the type or amount of data the 138applicant1 includes in a submission to support clearance or approval. Please refer to other FDA 139device or program-specific guidance documents from CDRH140(/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/defau 141lt.htm) and CBER142/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida 143nces/General/ucm214106.htm) for the appropriate contents for submissions.1441452.What is an eCopy?146An electronic copy (eCopy) is defined as an exact duplicate of the paper submission, created and 147submitted on a compact disc (CD), digital video disc (DVD), or in another electronic media148format that FDA has agreed to accept, accompanied by a copy of the signed cover letter and the 149complete original paper submission.21501513.Are differences between the contents of an eCopy and152paper submission acceptable?153While an eCopy is defined as an exact duplicate of the paper copy, there are limited cases in154which differences between the eCopy and the paper copy may be justified because a paper copy 155is not practical or appropriate for analysis purposes (e.g., raw data and statistical analysis156programs,3 data line listings to facilitate a bioresearch monitoring review) or is not feasible (e.g., 157videos, x-rays). The critical attribute of an eCopy is that it must include in electronic form all 1581 For the purposes of this guidance, applicant includes “submitter,” “sponsor,” or “holder.”2 An eCopy is not considered to be an electronic submission. For information on eSubmissions, refer to “FDAeSubmitter” (/ForIndustry/FDAeSubmitter/default.htm) and “Regulatory Submissions inElectronic Format for Biologic Products”(/BiologicsBloodVaccines/DevelopmentApprovalProcess/ucm163685.htm).3 For information on electronically submitted data, refer to “Clinical Data for Premarket Submissions”(/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissi ons/ucm136377.htm).Draft – Not for Implementationdata required for that submission type.4 In other words, the eCopy must include all of the159required information for FDA review, whereas the paper copy can include a page cross-160referencing the location of certain information in the eCopy.161162The cover letter must contain the eCopy statement described in Attachment 1 and describe any 163differences between the paper version and the eCopy. The paper version must also have a164placeholder (e.g., a piece of paper printed with the appropriate section title or a divider165appropriately cross-labeled to the table of contents) that cross-references the eCopy to indicate 166that there are additional data/information in the eCopy and where in the eCopy that information 167is located.168169FDA will consider the eCopy loaded into the appropriate Center’s official document repository 170to be the official record. Any undisclosed differences between the eCopy and the paper version 171may need to be rectified and could delay the review of the submission.1721734. For what submission types is an eCopy required?174Once FDA finalizes this guidance, section 745A(b) of the FD&C Act, as added by section 1136 175of FDASIA, will require an eCopy for the following submission types5:176•Premarket notification submissions (510(k)s), including third party 510(k)s;177•Evaluation of automatic class III designation petitions (de novos);178•Premarket approval applications (PMAs)6;179•Modular PMAs;180•Transitional PMAs;181•Product development protocols (PDPs);182•Investigational device exemptions (IDEs);183•Humanitarian device exemptions (HDEs), including Humanitarian Use Device184designation requests (HUDs);185•Certain investigational new drug applications (INDs)7;186•Certain biologics license applications (BLAs)8; and187•Pre-Submissions9.1884 For example, the content requirements for a 510(k) submission are found in 21 CFR 870.87 and 807.92; those fororiginal PMA submissions are found in 21 CFR 814.20.5 Although not subject to the eCopy legislation, FDA accepts and strongly encourages eCopies for Master AccessFiles (“MAF” submissions), 513(g) Requests for Classification (“C” submissions), and Clinical LaboratoryImprovement Act (CLIA) Categorization – Exempt Device submissions (“X” submissions). If you choose to submit an eCopy, it must meet the standards outlined in Attachment 1.6 This includes all PMA submission types, including, but not limited to, original PMAs, panel-track supplements,180-day supplements, manufacturing site change supplements, and post-approval study supplements.7 Applicable only to those devices regulated by CBER that are also biologics under section 351 of the Public HealthService (PHS) Act and that also require submission of an IND prior to submission of a BLA. Such devices aregenerally those intended for use in screening donated blood for transfusion transmissible diseases.8 Applicable only to those devices regulated by CBER that are also biologics under Section 351 of the PHS Act,including those that do not require submission of an IND prior to the submission of the BLA. Such devicesgenerally include those reagents used in determining donor/recipient compatibility in transfusion medicine inaddition to those for use in screening blood for transfusion transmissible diseases.9 Refer to the draft guidance entitled, “Medical Devices: The Pre-Submission Program and Meetings with FDAStaff” (/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm310375.htm).Draft – Not for Implementation189eCopies for all subsequent submissions to an original submission, including amendments,190supplements, and reports10 to the submission types identified above would also be required even 191if the original was submitted to FDA prior to implementation of the eCopy requirement.1921935.What submission types does FDA consider exempt from 194submission of an eCopy?195Due to the potential urgent nature of the following types of submissions, FDA considers these to 196be exempt from the requirement for an eCopy:197•Compassionate use IDE submissions;198•Emergency use IDE submissions11; and199•Emergency Use Authorizations (EUAs)12.200201However, we encourage you to submit eCopies of these submissions, when feasible, in order to 202facilitate the review process. In addition, this exemption would not preclude you from sending 203in pertinent electronic information, such as imaging data, as supporting information for these 204submission types when an eCopy is not submitted.2052066.What submission types or applicants are eligible for an207eCopy waiver?208FDA believes that, given the widespread availability of software to enable the creation of an209acceptable eCopy at little to no cost, all applicants should have the ability to provide an eCopy. 210Therefore, at this time, FDA does not anticipate the need for waivers, except as described in211Section 9.2122137.How many copies of a submission are needed?214The eCopy Program would not change the overall number of copies to submit to FDA. Upon 215finalization of this guidance document, an eCopy (with a signed cover letter) will serve as one of 216the required number of copies for the various submission types. (See Table 1 below.) FDA will 217accept additional eCopies (each with a signed cover letter) in lieu of additional paper copies as 218long as at least one paper copy is submitted along with the eCopy and the total number of219required copies remains the same.22022110 Reports include all reports submitted to an applicable submission type, including annual/periodic and post-approval reports. Section 745A(b) of the FD&C Act does not apply to Medical Device Reports submitted under 21 CFR Part 803 .11 Please refer to CDRH’s device advice page entitled “IDE Early/Expanded Access”(/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDevi ceExemptionIDE/ucm051345.htm#compassionateuse) and FDA’s “Guidance on IDE Policies and Procedures”(/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080202.htm) for additional details on compassionate and emergency use IDE submissions.12 Refer to the guidance entitled, “Emergency Use Authorization of Medical Products”(/RegulatoryInformation/Guidances/ucm125127.htm) for more information on EUAs.Draft – Not for ImplementationFor submission types for which only two copies are required to be submitted, one must be an 222eCopy and the other must be a paper copy. For submission types requiring more than two223copies, this policy would allow additional flexibility in how the application is submitted. For 224example, for an original PMA, you would submit: (1) one eCopy and five paper copies; (2) five 225eCopies and one paper copy; or (3) any other combination that results in six total copies as long 226as there is at least one eCopy and one paper copy.227228Table 1, provides the total number of copies to be submitted to FDA. As explained above, you 229must submit at least one eCopy and one paper submission. The format for the remaining copies 230(i.e., eCopy or paper) is your choice.231232Table 1 – Number of Copies for Submission233Submission Type Total Number ofCopies510(k)s 213Third Party 510(k)s 213Original PMAs and Panel-Track Supplements 614Other PMA supplement types 315PMA reports 2Modular PMAs 3HDEs Same as PMAs,16except for HUDdesignationrequests, whichrequire two.17PDPs Same as PMAsIDEs 318INDs 319BLAs 3Pre-Submissions 32348.What are the processing steps for an eCopy?235Below are the processing steps for the submission and acceptance of an eCopy.236237a.What are the standards for an eCopy?238With regard to the standards for an eCopy submitted to FDA, please refer to Attachment 2391. Because an eCopy cannot be accepted by our eCopy loading system if it does not meet 240the standards, you should carefully review this information.24124213 See 21 CFR 807.90(a)(3)(c).14 See 21 CFR 814.20(b)(2).15 See 21 CFR 814.39(c).16 See 21 CFR 814.104(b)(4).17 See 21 CFR 814.102(d).18 See 21 CFR 812.20(a)(3).19 See 21 CFR 312.23(d).b.How do I know before submission whether my eCopy meets FDA’s243standards for acceptance?244To confirm that your eCopy will meet FDA’s standards, we strongly encourage you to 245use the new free eSubmitter-eCopies tool available on FDA’s website at246/ForIndustry/FDAeSubmitter/ucm317334.htm. One of the benefits of 247utilizing the eSubmitter-eCopies tool is that it creates an eCopy in real-time that is248consistent with the standards. Use of the eSubmitter-eCopies tool is intended to prevent 249delays in review of your submission due to the need to resolve technical issues.250Although it is highly encouraged, you will not be required to utilize the eSubmitter-251eCopies tool and may choose to skip the eSubmitter step.252253Should you have any technical questions when generating your eCopy, please contact 254cdrhesub@ prior to submission of the eCopy to FDA.255256c.What if there is another processing party involved?257In the case that another party (e.g., law firm, consultant) submits a submission on behalf 258of an applicant, the eCopy must still meet the standards for an eCopy in order to be259successfully processed whether accomplished by you (the applicant) or the submitting 260party. While the applicant may or may not include their own cover letter as part of the 261eCopy, our standards require that the submitting party include a signed cover letter with 262an eCopy statement, as described in Attachment 1.263264In the case of Third Party 510(k)s, two separate CDs comprise the eCopy. The first CD 265includes the applicant’s submission and should be clearly marked as such. The contents 266of the CD must include a cover letter with an eCopy statement, as described in267Attachment 1, that the applicant has provided. The second CD includes the Accredited 268Person’s review records and should be clearly marked as such. The Accredited Person is 269responsible for ensuring that the CDs meet the standards in Attachment 1 for an eCopy. 270In addition, the Accredited Person is responsible for providing a signed cover letter that 271includes an eCopy statement, as described in Attachment 1, that speaks to both: (1) the 272Accredited Person’s portion of the eCopy and (2) the presence of the eCopy statement 273provided by the applicant. It is not sufficient for the Accredited Person to address only 274one of these two eCopy statement issues in their cover letter.275276d.How do you submit an eCopy to FDA?277An eCopy is submitted simultaneously with the paper submission(s). First, attach the 278signed cover letter with the eCopy statement to your eCopy. Then attach this eCopy279package to the paper submission(s) and send them to CDRH’s or CBER’s Document280Control Center20 (DCC). An eCopy that is sent to the DCC without a cover letter and 281accompanying paper submission(s) will be placed on hold.282283If more than one eCopy is to be submitted, then you must attach a signed cover letter as 284described above to each additional eCopy.28528620 Refer to 21 CFR 807.90 for the DCC addresses for CDRH and CBER.e.How does FDA process an eCopy?287If an eCopy passes the validation check, the cover letter and eCopy contents will be288loaded into the appropriate Center’s official submission repository.289290If an eCopy fails the validation check (i.e., is rejected), we will notify you in writing291(e.g., by email or fax) of the reason(s). The notification will describe the logistics for 292submitting a replacement eCopy, including how to properly mark it as a replacement293eCopy, the address to which to send it, and the submission number to write on it. It is 294important that you follow these directions to avoid delays in processing the replacement 295eCopy. The submission will be placed on hold until a valid replacement eCopy is296submitted to FDA and verified to meet the standards.2972989.What if your device is regulated by CBER?299a.Will the new eCopy Requirement apply?300Yes, unless your submission is an entirely electronic submission exempted under this 301guidance, as described below. Upon implementation of the statutory requirement, all 302medical device submission types listed in Section 4 must be accompanied by an eCopy 303regardless of the Center in FDA in which the submission will be reviewed unless the304requirement is waived or exempted. Accordingly, submissions for devices subject to 305review under the FD&C Act and submitted by filing paper copies with CBER’s DCC 306must be accompanied by an eCopy, except where exempted as described below.307308While many submissions made to CBER are still in paper format and require submission 309of multiple copies, CBER is also currently able to receive and manage submissions that 310are entirely electronic.311312Submissions for devices that are subject to licensure under the Public Health Service313(PHS) Act, including biologics license applications and supplements, investigational new 314drug applications, and EUAs and pre-submissions for these devices, may be submitted as 315entirely electronic submissions as detailed in sections 9b and 9c below. FDA will316exempt such entirely electronic submissions from the eCopy requirement.317318FDA additionally waives the eCopy requirement to submit paper copies of any entirely 319electronic submission made to CBER. Accordingly, entirely electronic submissions that 320comply with CBER guidance identified in Section 9.c. below do not need to be321accompanied by paper copies.322323b.Can you submit an electronic submission instead?324Yes, and there are several advantages for both industry and for CBER staff when you 325choose to make submissions electronically.326327The main advantage to you is in the financial savings that will likely result. The costs 328associated with printing, binding, labeling, and shipping multiple paper copies can be 329significant, especially for submissions that contain a great deal of supporting330Draft – Not for Implementationdocumentation. Likewise, we anticipate that FDA will recognize financial savings in that 331FDA avoids the costs associated with tracking, routing, and storing large amounts of332paper when you choose to submit electronically.333334Another advantage with the use of the electronic submission process is that all parties 335involved in the submission and review are referencing the same document – the336electronic one. There is no question about whether the paper copy is an exact copy of the 337eCopy. Electronic submissions may also reduce the need for reviewers to request re-338submission of previously submitted information due to an inability to read or interpret the 339information on the paper copy, as sometimes occurs when documents are photocopied. 340341c.How do you prepare and submit an electronic submission to CBER?342CBER has several resources available to applicants who choose to submit electronic343submissions as outlined in the document “Regulatory Submissions in Electronic Format 344for Biologic Products.”345(/BiologicsBloodVaccines/DevelopmentApprovalProcess/ucm163685 346.htm). Thus, specific details are available in the cited references and will not be repeated 347in this guidance.348349For devices that are regulated under the PHS Act and require the submission of a BLA, 350consult the guidance document entitled “Providing Regulatory Submissions to the Center 351for Biologics Evaluation and Research (CBER) in Electronic Format - Biologics352Marketing Applications”353(/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator 354yInformation/Guidances/General/UCM192413.pdf) for details on preparing your355electronic submission. Note that certain sections of this guidance, for example, those on 356pharmacology and toxicology, are generally not pertinent to licensed devices.357358For guidance on preparing electronic submissions for other device submissions (e.g.,359510(k)s, PMAs) sent to CBER, please see “Guidance for Industry: Providing Regulatory 360Submissions in Electronic Format - General Considerations”361(/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances 362/UCM072390.pdf) and “CBER SOPP 8110: Submission of Paper Regulatory363Applications to CBER”364(/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformati 365on/ProceduresSOPPs/ucm079467.htm), which includes information about providing366electronic copies to CBER.367368We are currently developing additional, updated guidance for other electronic369submissions sent to CBER and have issued a revised, updated draft guidance document 370for comment entitled, “Draft Guidance for Industry: Providing Regulatory Submissions 371in Electronic Format-General Considerations”372(/RegulatoryInformation/Guidances/ucm124737.htm). When373finalized, this document will provide an additional resource for applicants preparing374electronic submissions.375376。
Guidance for industries stability testing of drug
Stability Testing of Drug Substances and Drug Products
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
II. STABILITY TESTING FOR NEW DRUG APPLICATIONS . . . . . . . . . . . . . . . . . . . . 3 A. Drug Substance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 B. Drug Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 C. New Dosage Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 D. Other NDAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
阿霉素
Contains Nonbinding RecommendationsDraft Guidance on Doxorubicin HydrochlorideThis draft guidance, once finalized, will represent the Food and Drug Administration's (FDA's)current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the Office of Generic Drugs.Active ingredient: Doxorubicin HydrochlorideForm/Route: Liposome injection/IntravenousRecommended studies: 2 StudiesWhen the test and reference pegylated liposome products•have the same drug product composition and•are manufactured by an active liposome loading process with an ammonium sulfate gradient and •have equivalent liposome characteristics including liposome composition, state of encapsulated drug, internal environment of liposome, liposome size distribution, number of lamellar, graftedPEG at the liposome surface, electrical surface potential or charge, and in vitro leakage rates.The following clinical and in vitro studies are recommended to demonstrate bioequivalence:Clinical Study:1.Type of study: Fasting*Design: Single-dose, two-way crossover in vivoStrength: 50 mg/vialDose: 50 mg/m2Subjects: Ovarian cancer patients whose disease has progressed or recurred after platinum-based chemotherapy.Additional Comments: Patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of Doxil should not be entered into the study.Females should not be pregnant or lactating. Other exclusion criteria include: total cumulativedose of doxorubicin HCl approaches 550 mg/m2; patient is < 18 years of age or > 75 years of age;active opportunistic infection with mycobacteria, cytomegalovirus, toxoplasma, P. carinii or other microorganism if under treatment with myelotoxic drugs; clinically significant cardiac, liver orkidney disease.* If the health conditions of patients prevent fasting, the sponsor can provide a non-high-fat diet during the proposed study. Alternatively, the treatment can be initiated 2 hours after a standard(non-high-fat) breakfast.Analytes to measure (in appropriate biological fluid): Free doxorubicin and liposomeencapsulated doxorubicin.Bioequivalence based on (90% CI): AUC and Cmax for free doxorubicin and liposomeencapsulated doxorubicin.Note: the pivotal bioequivalence study should be conducted using test product produced by theproposed commercial scale manufacturing process.Note: as doxorubicin is a cytotoxic drug, a Bio-IND is required for bioequivalence studies ofdoxorubicin liposome injection to ensure that proposed generic products are safe for use in human test subjects and do not expose them to undue risk.In Vitro Study:2.Type of study: Liposome Size DistributionDesign: in vitro bioequivalence study on at least three lots of both test and reference productsParameters to measure: D10, D50, D90Bioequivalence based on (95% CI): Population bioequivalence based on D50 and SPAN(D90-D10)/D50 or polydispersity index.Dissolution test method and sampling times:Please note that a Dissolution Methods Database is available to the public at the OGD website at/scripts/cder/dissolution/. Please find the dissolution information for this product at this website. Please conduct comparative dissolution testing on 12 dosage units each of all strengths of the test and reference products. Specifications will be determined upon review of the application.Additional information:Same drug product compositionBeing a parenteral drug product, a generic doxorubicin HCl liposome injection must be qualitatively and quantitatively the same as the RLD, except differences in buffers, preservatives and antioxidants provided that the applicant identifies and characterizes these differences and demonstrates that the differences do not impact the safety/efficacy profile of the drug product. Currently, FDA has no recommendations for the type of studies that would be needed to demonstrate that differences in buffers, preservatives and antioxidants do not impact the safety/efficacy profile of the drug product.Lipid excipients are critical in the liposome formulation. ANDA sponsors should obtain lipids from the same category of synthesis route (natural or synthetic) as found in the RLD. Information concerning the chemistry, manufacturing and control of the lipid components should be provided at the same level of detail expected for a drug substance as suggested in the liposome drug products draft guidance1. ANDA sponsors should have specification on lipid excipients that are similar to those used to produce the RLD. Additional comparative characterization (beyond meeting specifications) of lipid excipients including the distribution of the molecular species should be provided.Active liposome loading process with an ammonium sulfate gradientIn order to meet the compositional equivalence and other equivalence tests, an ANDA sponsor would be expected to use an active loading process with an ammonium sulfate gradient. The major steps include 1) formation of liposomes containing ammonium sulfate, 2) liposome size reduction, 3) creation of ammonium sulfate gradient, and 4) active drug loading. An active loading process uses an ammonium1 Draft guidance for industry: Liposome drug products chemistry, manufacturing, and controls; human pharmacokinetics and bioavailability; and labeling documentation, FDA (2002),/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070570.pdfsulfate concentration gradient between the liposome interior and the exterior environment to drive the diffusion of doxorubicin into the liposomes2,3.Sponsors should use a Quality by Design approach to identify critical material attributes and critical process parameters, and guide process optimization. It is recommended to identify the critical process parameters and critical material attributes by evaluating the sensitivity of liposome characteristics to changes in process parameters and attributes. The optimal values of critical process parameters should be selected based on comparison of resulting liposome characteristics to those of the RLD.Equivalent liposome characteristicsAs with other locally acting products with complex bioequivalence requirements (such as nasal sprays and inhalation products), in vitro liposome characterization should be conducted on at least three batches of the ANDA and RLD products (at least one ANDA batch should be produced by the commercial scale process and used in the in vivo bioequivalence study). Attributes that should be included in the characterization of ANDAs claiming equivalence to Doxil are:•Liposome compositionLiposome composition including lipid content, free and encapsulated drug, internal and total sulfate and ammonium concentration, histidine concentration, and sucrose concentration should be measured. The drug-to-lipid ratio and the percentage of drug encapsulation can be calculated from liposome composition values.•State of encapsulated drugThe doxorubicin in DOXIL is largely in the form of a doxorubicin sulfate precipitate inside the liposome. The generic doxorubicin HCl liposome must contain an equivalent doxorubicin precipitate inside the liposome.•Internal environment (volume, pH, sulfate and ammonium ion concentration)The internal environment of the liposome, including its volume, pH, sulfate and ammonium concentration, maintains the precipitated doxorubicin. The measurements of total and free concentrations of components (including sulfate ions) described in liposome composition section allow the inference of the internal concentration inside the liposome.•Liposome morphology and number of lamellaeLiposome morphology and lamellarity should be determined as drug loading, drug retention, and the rate of drug release from the liposomes are likely influenced by the degree of lamellarity.•Lipid bilayer phase transitionsEquivalence in lipid bilayer phase transitions will contribute to demonstrating equivalence in bilayer fluidity and uniformity. The phase transition profiles of the raw lipid excipients and liposomes should be comparable to those of RLD.•Liposome size distributionLiposome size distribution is critical to ensuring equivalent passive targeting. The ANDA sponsor should select the most appropriate particle size analysis method to determine the particle size distributions of both test and reference product. The number of liposome product vials to be studied should not be fewer 2 A. Gabizon, H. Sheemda, Y. Barenholz. Pharmacokinetics of pegylated liposome doxorubicin: review of animal and human studies. Clin Pharmcokinet 42(5): 419-436 (2003)3 F. Martin. Product evolution and influence of formulation on pharmaceutical properties and pharmacology, Advisory Committee for Pharmaceutical Science Presentation (Jul 2001),/ohrms/dockets/AC/01/slides/3763s2_08_martin.ppt.than 30 for each of the test and reference products (i.e., no fewer than 10 from each of three batches). See recommended study 2 (above) for details of the recommended statistical equivalence tests.•Grafted PEG at the liposome surfaceThe surface-bound methoxypolyethylene glycol (MPEG) polymer coating protects liposomes from clearance by the mononuclear phagocyte system (MPS) and increases blood circulation time. The PEG layer thickness is known to be thermodynamically limited and estimated to be in the order of several nanometers. The PEG layer thickness should be determined.•Electrical surface potential or chargeSurface charge on liposomes can affect the clearance, tissue distribution, and cellular uptake. Liposome surface charge should be measured.•In vitro leakage under multiple conditionsIn vitro drug leakage testing to characterize the physical state of the lipid bilayer and encapsulated doxorubicin should be investigated to support a lack of uncontrolled leakage under a range of physiological conditions and equivalent drug delivery to the tumor cells. Below are some examples of proposed conditions.Table 1. Examples of in vitro leakage conditions of doxorubicin liposomesIn Vitro DrugLeakage ConditionPurpose RationaleAt 37ºC in 50% human plasma for 24 hours Evaluate liposome stabilityin blood circulation.Plasma mostly mimics blood conditions.At 37ºC with pH values 5.5, 6.5, and 7.5 for 24 hours in buffer Mimic drug release innormal tissues, aroundcancer cells, or insidecancer cellsNormal tissues: pH 7.3Cancer tissues: pH 6.6Insider cancer cells (endosomes and lysosomes ):pH 5-6 (Endosome and lysosomes of cancer cellsmay be involved in liposome uptake and inducedrug release).At a range of temperatures (43ºC,47ºC, 52ºC, 57ºC) in pH 6.5 buffer for up to 12 hours or until complete release Evaluate the lipid bilayerintegrityThe phase transition temperature (Tm) of lipids isdetermined by lipid bilayer properties such asrigidity, stiffness and chemical composition.Differences in release as a function oftemperature (below or above Tm) will reflectsmall differences in lipid propertiesAt 37ºC under low-frequency (20 kHz) ultrasound for 2 hours or until complete release. Evaluate the state ofencapsulated drug in theliposome.Low-frequency ultrasound (20 kHz) disrupts thelipid bilayer via a transient introduction of pore-like defects and will render the release ofdoxorubicin controlled by the dissolution of thegel inside the liposome.Equivalent in vivo plasma pharmacokinetics of free and encapsulated drugA Bio-IND is required to conduct bioequivalence studies of doxorubicin liposome injection in humans since doxorubicin is a cytotoxic drug. We recommend single dose fasting two-way crossover bioequivalence studies in ovarian cancer patients at 50 mg/m2 dose. Sponsors should measure both liposome-encapsulated and free doxorubicin to demonstrate the same in vivo stability of generic liposome formulation and RLD. The studies may be conducted under either fasted or standard diet conditions depending on patient needs. See recommended study 1 (above) for details of the recommended statistical equivalence tests.。
大马士革刀类英文广告文案
大马士革刀类英文广告文案In the realm of culinary arts, the Damascus knife stands as a paragon of craftsmanship and tradition. Forged from layers of steel folded upon themselves, it is a testament to the artistry and skill of ancient blacksmiths. The distinctive patterns, reminiscent of flowing water, are not merely decorative but are indicative of the strength and sharpness that these knives possess.The Damascus knife is not just a tool; it is a piece of history, a slice of tradition, and a beacon of the blacksmith's art. Each blade, unique in its swirls and contours, tells a story of its creation. The process begins with the selection of high-quality steel, which is then heated to a high temperature and folded repeatedly. This labor-intensive process, which can involve hundreds of folds, results in a blade with unparalleled durability and a cutting edge that remains sharp through the rigors of kitchen use.Chefs and culinary enthusiasts treasure Damascus knives for their balance and precision. The weight of the knife is distributed evenly, allowing for effortless cutting and slicing. The sharpness of the blade makes it ideal for delicate tasks such as filleting fish or slicing vegetables thinly. Moreover, the robustness of the knife means it can handle more demanding jobs like cutting through tough meat or disjointing poultry.Owning a Damascus knife is an experience that transcends the mere act of cooking. It is an invitation to partake in a legacy of excellence, to hold in one's hand the result of centuries of perfected technique. It is a call to create, to transform ingredients into art, and to do so with a tool that is as beautiful as it is functional.Caring for a Damascus knife is part of the ritual of its use. The blade should be hand-washed and dried immediately to maintain its integrity. Honing the knife regularly ensures that it remains at peak sharpness, and storing it properly protects its edge. With proper care, a Damascus knife can be a lifelong companion in the kitchen, an heirloom to be passed down through generations.In conclusion, the Damascus knife is more than a mere implement; it is a symbol of the enduring quest for perfection. It embodies the fusion of form and function, a harmonious blend of beauty and utility. For those who seek the finest tools in their culinary pursuits, the Damascus knife is the quintessential choice, a blade that upholds the highest standards of quality and elegance. 。
俗话说打铁还要本身硬绣花要得手绵巧英语作文
俗话说打铁还要本身硬绣花要得手绵巧英语作文The saying goes that one must have a strong body to forge iron and a skillful hand to embroider. This proverb emphasizes the importance of having both physical strength and craftsmanship in achieving success. Just as a blacksmith needs a strong body to strike the iron and shape it into useful tools, an embroiderer needs delicate and skillful hands to create beautiful and intricate designs. The underlying message is that success often requires a combination of physical prowess and mental dexterity.In today's world, the same principle applies. Whetherit's in sports, academics, or the workplace, individuals need to have both physical and mental capabilities to excel. Athletes train their bodies to be strong and agile, but they also need to develop their mental toughness to overcomechallenges and perform under pressure. Similarly, students need to have a solid grasp of academic knowledge, but they also need to cultivate critical thinking and problem-solving skills to succeed in their studies and future careers. In the workplace, employees need to be physically fit to handle the demands of their jobs, but they also need to have the creativity and adaptability to thrive in a fast-changing environment.Furthermore, the proverb also highlights the idea that success requires dedication and hard work. Forging iron and embroidering flowers both demand patience, practice, and perseverance. The blacksmith must repeatedly heat and hammer the iron to shape it into the desired form, while the embroiderer spends hours carefully stitching to create a beautiful pattern. Similarly, achieving success in any endeavor often involves countless hours of effort and determination. Whether it's mastering a new skill, building abusiness, or pursuing a personal goal, individuals need toput in the time and effort to see results.Moreover, the proverb underscores the value of honingone's craft. Both the blacksmith and the embroiderer need to continually improve their skills to produce high-quality work. They need to learn new techniques, refine their abilities,and stay up-to-date with the latest trends. This idea applies to any pursuit, whether it's professional development,creative endeavors, or personal growth. Continuous learning and improvement are essential for reaching higher levels of achievement.In conclusion, the proverb "打铁还要本身硬绣花要得手绵巧" encapsulates timeless wisdom about the keys to success. It reminds us that achieving success often requires acombination of physical strength and mental skill, dedication and hard work, and continual improvement. By embracing theseprinciples, individuals can strive towards their goals with confidence and determination.。
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Contains Nonbinding Recommendations
Draft Guidance on Iron Sucrose
This draft guidance, once finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does
not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the Office of Generic Drugs.
Active ingredient: Iron Sucrose
Form/Route: Injectable; Intravenous
Recommended studies: 2 studies
1.Type of study: Fasting
Design: Single-dose, randomized, parallel in vivo study
Strength: 100mg/5mL (Dose 100 mg)
Subjects: Healthy males and females, general population
Additional Comments: The products should be administered undiluted as a slow
intravenous injection dose of 100 mg over 5 minutes.
Analytes to measure (in appropriate biological fluid): Measure each of the following:
1. [Total Iron] in serum
2. [Transferrin-bound Iron] in serum
Bioequivalence based on (90% CI):
•Maximum value of the difference in concentration between Total Iron and Transferrin-bound Iron over all time points measured; and
•Difference in AUC between Total Iron and Transferrin-bound Iron* *AUC of Total Iron and AUC of Transferrin-bound Iron should be calculated separately to maximize the number of data points used in cases of missing data in the transferrin-bound iron and total iron concentration-time profiles. In addition, there is no need to perform baseline correction of Total Iron and Transferrin-bound Iron.
2.Type of study: Particle size distribution
Design: In vitro testing on at least three lots of both test and reference products
Parameters to measure: D10, D50, D90
Bioequivalence based on: D50 and SPAN [i.e. (D90-D10)/D50] or polydispersity index using the population bioequivalence statistical approach.
Recommended Mar 2012; Revised Nov 2013
Waiver request of in vivo testing: 50mg/2.5mL, 65mg/3.25mL, and 200mg/10mL, based on (i) acceptable bioequivalence studies on the 100mg/5mL strength; and (ii) proportional similarity of the formulations across all strengths.
Dissolution test method and sampling times: Not Applicable.
Special Considerations:
1.The proposed parenteral drug product should be qualitatively (Q1) and quantitatively (Q2)
the same as the RLD. Equivalence in the stoichiometric ratios of iron, sucrose, and other relevant components need to be established.
2.Sameness in physicochemical properties needs to be established. These in vitro
characterizations should be conducted on at least three batches of the ANDA and RLD.
Attributes that should be included in the characterization are:
•Iron core characterizations including but not limited to core size determination, iron oxide crystalline structure and iron environment.
•Composition of carbohydrate shell and surface properties.
•Particle morphology.
•Labile iron determination under physiologically relevant conditions. The tests can be performed with in vitro haemodialysis system 1, the catalytic bleomycin assay of
spiked human serum samples 1,2, the spectrophotometric measurement of Fe
reduction, or other methods that are validated for accuracy and precision.
3.For additional information regarding statistical analysis of in vitro data, please refer
to Bioequivalence Recommendations for Specific Products: Budesonide Suspension (Draft).
1 Balakrishnan VS, et al. Physicochemical properties of ferumoxytol, a new intravenous iron preparation. Eur J Clin Invest. 2009 Jun;39(6):489-96.
2 Burkitt MJ, et al. A simple, highly sensitive and improved method for the measurement of bleomycin-detectable iron: the 'catalytic iron index' and its value in the assessment of iron status in haemochromatosis. Clin Sci (Lond). 2001 Mar;100(3):239-47.
Recommended Mar 2012; Revised Nov 2013 2。