Contains Nonbinding Recommendations
Draft Guidance on Beclomethasone Dipropionate
This draft guidance, when finalized, will reprent the current thinking of the Food and Drug Administration (FDA, or the Agency) on this topic. It does not establish any rights for any person
and is not binding on FDA or the public. You can u an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact
the Office of Generic Drugs.
Active Ingredient: Beclomethasone dipropionate
Dosage Form; Route: Aerosol; metered; inhalation
Strength: 0.04 mg/INH
0.08 mg/INH
Recommended Studies: In vitro and in vivo studies
FDA recommends the following in vitro and in vivo studies to establish bioequivalence (BE) of the test (T) and reference (R) metered do inhalers (MDIs) containing beclomethasone dipropionate.
_____________________________________________________________________________________ In Vitro Studies
U at least three batches1 each of T and R products, with no fewer than 10 units from each batch.
1.Type of study: Single actuation content (SAC)
Design: The SAC test should be performed at the beginning (B), middle (M), and end (E) lifestages2 of the product, using a flow rate of 28.3 L/min. U.S. Pharmacopeia (USP)
<601> Apparatus A or another appropriate apparatus may be ud to determine the SAC using a validated assay. The number of actuations per determination should be one.
Equivalence bad on: Population bioequivalence (PBE) analysis of SAC. Plea refer
to the draft Budesonide Inhalation Suspension BE Guidance for additional information
regarding PBE.3
2.Type of study: Aerodynamic particle size distribution (APSD)
Design: The APSD test should be performed at the B and E lifestages of the product
using a flow rate of 28.3 L/min or 30 L/min. The USP <601> Apparatus 1, Apparatus 6, or another appropriate method may be ud to determine APSD using a validated assay.
1 A single batch of solution can be split-filled into three equal size sub-lots of product. The sub-lots should be prepared from three different batches of the same device (metering valve and actuator) components.
2Bad on the labeled number of actuations, the terms, B lifestage, M lifestage, and E lifestage reprent the first actuation(s) following the labeled number of priming actuations, the actuation(s) corresponding to 50 percent of the labeled number of actuations, and the actuation(s) corresponding to the labeled number of actuations, respectively.
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The APSD determination of each unit should be performed with a minimum number of
inhalations justified by the nsitivity of the validated assay.
Additional comments: Drug deposition on individual sites, including the mouthpiece
adapter, the induction port, each stage of the cascade impactor (CI), and the filter, is
requested. Mass balance accountability should be reported bad on the sum of all
deposition sites. For electronic submission of the individual CI data for the T and R
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products, plea provide a table using the format in the appendix, and nd them as part of the abbreviated new drug application (ANDA) submission for BE evaluation.
Equivalence bad on: PBE analysis of impactor-sized mass (ISM).4 The CI profiles
reprenting drug deposition on the individual stages of the CI along with the mass
median aerodynamic diameter (MMAD), geometric standard deviation (GSD) and fine
particle mass (FPM) should be submitted as supportive evidence for equivalent APSD.
3.Type of study: Spray pattern
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Design: The spray pattern test should be performed at the B lifestage of the product and at two different distances from the actuator orifice. The lected distances should be at
least 3 cm apart and bad on the range of 3 to 7 cm from the R actuator mouthpiece.5
Impaction (thin-layer chromatography plate impaction), non-impaction (lar light sheet technology), or other suitable method may be ud to determine the spray pattern.
Additional comments: Spray pattern should be measured quantitatively in terms of
ovality ratio and area within the perimeter of the true shape (to include a high proportion,
<, 95 % of the total pattern) for the automated analysis or ovality ratio and D max for the
manual analysis. Ovality ratio is defined as the ratio of D max to D min. D max and D min are
the longest and shortest diameters, respectively, that pass through the center of mass or
the center of gravity, as appropriate. The number of sprays per spray pattern would
preferably be one.
Equivalence bad on: At two lected distances, (i) qualitative comparison of spray
shape, and (ii) PBE analysis of ovality ratio and area within the perimeter of the true
shape or ovality ratio and D max.
4.Type of study: Plume geometry
Design: The plume geometry test should be performed at B lifestage of the product. The time quence sound-triggered flash photography method, lar light sheet technology, or other suitable method may be ud to determine the plume geometry at the appropriate
post-actuation delay time.
Additional comments: Plume geometry measurements should be reported at a single
delay time while the fully developed plume is still in contact with the actuator
mouthpiece. Plume geometry should be measured quantitatively in terms of plume angle and width. The plume angle is bad on the conical region of the plume extending from a vertex that occurs at
or near the actuator mouthpiece. The plume width is measured at a 4ISM is defined as a sum of the drug mass on all stages of the CI plus the terminal filter, but excluding the top CI stage becau of its lack of a specified upper cutoff size limit.
5The distance between the actuator orifice and point of spray pattern measurement should be same for T and R.
distance equal to the greater of the two distances lected for characterization of the spray pattern.
Equivalence bad on: Ratio of the geometric mean of the three batches of T to that of
the three batches of R (bad on log transformed data) for plume angle and width, which should fall within 90 - 111%.
5.Type of study: Priming and repriming
Design: Priming and repriming tests should be bad on the emitted do (ex-actuator) of
a single actuation immediately following the specified number of priming or repriming
actuations specified in the R product labeling. The repriming test should be performed
following storage for the specified period of non-u after initial u and/or other
conditions (e.g., dropping), if the R product labeling provides such repriming
information.
Additional comments: For BE evaluation, the priming and repriming tests should be
bad on products stored in the valve upright position, with the exception of MDIs for输出设备
which the R labeling recommends storage in the valve down position. The priming data
can be bad on the SAC data at the B lifestage.
Equivalence bad on: PBE analysis of the emitted do of a single actuation
immediately following the specified number of priming or repriming actuations specified in the R product labeling.
______________________________________________________________________________ Pharmacokinetic (PK) BE Study
FDA recommends that applicants conduct the following pharmacokinetic (PK) BE study for both strengths of the T and R products.
6.Type of Study: Fasting
硼Design: Single-do, two-way crossover
Do: Minimum number of inhalations that is sufficient to characterize a PK profile by
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Subjects: Normal healthy males and non-pregnant females, general population
Additional comments: Subjects enrolled for in vivo studies should be trained in the u of the inhalation aerosols in a standard fashion, prior to each treatment ssion, to assure a
relatively consistent inspiratory flow rate and inspiratory duration. The subjects should
adhere to labeling as follows: “Rin your mouth with water after each do.” A Bio-IND is required prior to conduct of the PK study if the do exceeds the maximum labeled
single do.
Analyte(s) to measure (in appropriate biological fluid): Beclomethasone dipropionate and Beclomethasone 17-monopropionate (active metabolite) in plasma
Equivalence bad on: AUC and C max for Beclomethasone 17-monopropionate. The
90% confidence intervals for the geometric mean T/R ratios of AUC and C max should fall within the limits of 80.00 - 125.00%.
______________________________________________________________________________ Clinical Pharmacodynamic BE Study
FDA recommends that applicants conduct the following clinical pharmacodynamic study for the lowest strength of the T and R products.
7. Type of Study: BE study
Design: A randomized multiple-do, placebo-controlled, parallel group design, at
minimum consisting of a 2-week run-in period followed by a 4-week treatment period of the placebo, T or R product
Strength: 0.04 mg/INH
Do: 0.04 mg/INH; one inhalation twice daily
Additional comments:
Inclusion criteria should, at minimum, include:
a)Adult male or female subjects of non-childbearing or of childbearing potential
committing to consistent and correct u of an acceptable method of birth control.
b)Diagnosis of asthma as defined by the National Asthma Education and Prevention
Program6 at least 12 months prior to screening.
c)Pre-bronchodilator FEV1 of >45% and <85% of predicted value during the
screening visit and on the first day of treatment.
d)>15% and >0.20 L reversibility of FEV1 within 30 minutes following 360 mcg of
albuterol inhalation (pMDI).
e)Patients should be stable on their chronic asthma treatment regimen for at least four
weeks prior to enrollment.
f)Currently non-smoking; had not ud tobacco products (i.e., cigarettes, cigars, pipe
tobacco) within the past year, and having had <10 pack-years of historical u.
g)Ability to replace current short-acting β agonist (SABAs) with salbutamol/albuterol
inhaler for u as needed for the duration of the study. Subjects should be able to
withhold all inhaled SABAs for at least six hours prior to lung function asssments
on study visits.
h)Ability to discontinue their asthma medications (inhaled corticosteroids and long-
acting β agonists) during the run-in period and for remainder of the study.
i)Willingness to give their written informed connt to participate in the study.
Exclusion criteria should, at minimum, include:
a)Life-threatening asthma, defined as a history of asthma episodes(s) requiring
intubation, and/or associated with hypercapnia, respiratory arrest or hypoxic
izures, asthma related syncopal episode(s), or hospitalizations within the past year
prior to the screening or during the run-in period.
b)Significant respiratory dia other than asthma (COPD, interstitial lung dia,
etc.)
6Guidelines for the Diagnosis and Management of Asthma: Expert Panel Report 3. National Education and Prevention Program; National Institute of Health; National Heart, Lunt, and Blood Institute. 2007, Publication No. 07-4051
c)Evidence or history of clinically significant dia or abnormality including
congestive heart failure, uncontrolled hypertension, uncontrolled coronary artery
dia, myocardial infarction, or cardiac dysrhythmia. In addition, historical or
current evidence of significant hematologic, hepatic, neurologic, psychiatric, renal,
or other dias that, in the opinion of the investigator, would put the patient at risk through study participation, or would affect the study analys if the dia
exacerbates during the study.
d)Viral or bacterial, upper or lower respiratory tract infection, or sinus, or middle ear
infection within four weeks prior to the screening, during the run-in period, or on
the day of treatment.
e)Hypernsitivity to any sympathomimetic drug (e.g., albuterol) or any inhaled,
intranasal, or systemic corticosteroid therapy.
f)Patients receiving β2-blockers, anti-arrhythmics, anti-depressants, and monoamine
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oxida inhibitors within 4 weeks prior to the screening.
g)Patients who required systemic corticosteroids (for any reason) within the past 2
months.
•The study may enroll all asthma patients who meet the inclusion and exclusion criteria, or may be enriched by using a subpopulation of patients predicted to respond well to the study treatment (appropriate justification should be included for the population chon for study).
•Subjects who discontinue from the study early should be identified, and the protocol should clearly prospectively state how missing data will be handled in the statistical
analys and provide appropriate justification for the method chon. The protocol should also include subject retention strategies and other plans to minimize missing data.
•All spirometry should be conducted in accordance with American Thoracic Society Standards.
•The study should begin with a placebo run-in period at least two weeks in duration, to wash out any pre-study corticosteroids/long-acting bronchodilators and to establish FEV1 baline values.
•The study protocol should include pre-specified definitions of asthma exacerbation, as well as pre-specified and appropriate escape criteria with consideration to patient safety. •The study protocol should provide a definition of compliant subjects (e.g., ud at least 75% and no more than 125% of study drug dos) and specify how compliance will be verified (e.g., by the u of subject diaries).
•To ensure study nsitivity, the T and R products should both be statistically superior to placebo (p<0.05) with regard to the BE study primary endpoint.
•It is the sponsor’s responsibility to enroll a sufficient number of subjects for the study to demonstrate BE of the T to the R product.
•The start and stop date of concomitant medication u during the study should be provided in the data t in addition to the reason for the medication u. The sponsor should clearly explain whether the medication was ud prior to baline visit, during the study or both.
•All adver events (AEs) should be reported, whether or not they are considered to be related to the treatment. The report of each AE should include the date of ont,
description of AE, verity, relation to study medication, action taken, outcome, and date
