CENTER FOR DRUG EVALUATION AND IZESEARCH
`
`Guidance for Industry
`
`The FDA published Good Guidance Practices in February 1997.
`This guidance was developed and issued prior to that date.
`
`Additional copies are available from:
`Office of Training and Communications
`Division of Communications Management
`Drug Information Branch, HFD-210
`5600 Fishers Lane
`Rockville, MD 20857
`
`(Tel) 301-827-4573
`(Internet) http://Www.fda.gov/cderlguidance/index.htm
`
`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, FOOD AND DRUG ADMINISTRATION
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0001
`
`
`
`Guidance for Industry
`
`The FDA published Good Guidance Practices in February 1997.
`This guidance was developed and issued prior to that date.
`
`Additional copies are available from:
`Office of Training and Communications
`Division of Communications Management
`Drug Information Branch, HFD-210
`5600 Fishers Lane
`Rockville, MD 20857
`
`(Tel) 301-827-4573
`(Internet) http://Www.fda.gov/cderlguidance/index.htm
`
`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES, FOOD AND DRUG ADMINISTRATION
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0001
`
`
`
`Center for Drugs and Biologics
`Food and Drug Administration
`Department of Health and Human Services
`
`GUIDELINE FOR THE FORMAT AND CONTENT
`OF THE HUMAN PHARMACOKINETICS AND BIOAVAILABILITY SECTION
`OF AN APPLICATION
`
`FEBRUARY 1987
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0002
`
`
`
`GUIDELINE FOR THE FORMAT AND CONTENT
`
`OF THE HUMAN PHARMACOKINETICS AND BIOAVAILABILITY SECTION
`
`OF AN APPLICATION
`
`I. INTRODUCTION
`
`Biopharmaceutic studies are required by Part 320, Title 21, and
`
`by the Waxman-Hatch Amendments to the Federal Food, Drug and
`
`Cosmetic Act (the act). These amendments define bioequivalence
`
`and require generic drugs to show bioequivalence to the
`
`previously approved dosage form. The regulations define
`
`important biopharmaceutic terms and establish acceptable
`
`procedures for determining the bioavailability of drug
`
`products. The new drug application (NDA) rewrite regulations
`
`require a separate biopharmaceutic review section in the NDA (21
`
`CFR 314). This guideline is intended to assist applicants to
`
`prepare the biopharmaceutics section of the NDA.
`
`The guideline is issued under 21 CFR 10.90. An applicant may,
`
`but is not required to, rely upon the guideline in preparing the
`
`biopharmaceutics section of an application. When a different
`
`approach is chosen, the applicant is encouraged to discuss the
`
`-1-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0003
`
`
`
`matter in advance with FDA to prevent the expenditure of money
`
`and effort on preparing a submission that may later be
`
`determined to be unacceptable.
`
`II. TYPES OF STUDIES
`
`The particular studies required for a specific drug will depend
`
`on many factors. If there is any question concerning the
`
`requirements, the Division of Biopharmaceutics should be
`
`consulted for NDAs and the Division of Bioequivalence should be
`
`consulted for abbreviated new drug applications (ANDAs).
`
`The studies included in the Biopharmaceutics Section are of five
`
`general types:
`
`A. Pilot or Background Studies
`
`Pilot studies are carried out in small numbers of
`
`subjects/patients to provide a preliminary assessment of the
`
`absorption, distribution, metabolism and/or elimination (ADME)
`
`of a drug as a guide to the design of early clinical trials and
`
`definitive kinetic studies. As analytical methodology for
`
`measuring blood levels of the drug and its metabolites is often
`
`incomplete at the time such studies are carried out,
`
`radioisotope techniques may be used.
`
`-2-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0004
`
`
`
`B. Bioavailability/Bioequivalence Studies
`
`Bioavailability studies are intended to measure the rate and
`
`extent to which an active drug ingredient or therapeutic moiety
`
`is absorbed from a drug product and becomes available at the
`
`site of drug action. Several types of studies fall under the
`
`classification of bioavailability studies including:
`
`1.
`
`Bioavailability studies to define the rate and extent of
`
`absorption relative to a reference dosage form (e.g., an
`
`intravenous injection, true solution, or suspension).
`
`2.
`
`Bioequivalence studies comparing pharmaceutical
`
`equivalents/alternatives for the purpose of establishing
`
`equivalent extents and (where necessary) equivalent rates
`
`of absorption.
`
`3.
`
`Dosage strength equivalence studies which show that
`
`equivalent doses of different dosage forms deliver the same
`
`amount of drug (e.g., 3 X 100 mg vs. 1 X 300 mg tablets).
`
`C. Pharmacokinetic Studies
`
`Pharmacokinetic studies are intended to define the time course
`
`of drug and, where appropriate, major metabolite concentrations
`
`-3-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0005
`
`
`
`in blood and other body compartments. In the studies provided
`
`to support an NDA, usually the most critical information is that
`
`showing (by measurement of plasma drug levels) the rate of drug
`
`absorption and delivery to the systemic circulation, and the
`
`rate of elimination by metabolic or excretory processes. Of
`
`particular interest are changes in kinetic parameters with dose
`
`(i.e., dose-dependent kinetics) within the recommended clinical
`
`dosing range. When appropriate, other information may include
`
`influences of demographic characteristics (age, sex, race),
`
`influences of certain disease states, influences of external
`
`factors, such as meals or other drugs (drug-drug pharmacokinetic
`
`interaction), drug binding to biological constituents (e.g.,
`
`plasma protein, red blood cell), studies performed in special
`
`patient populations and studies performed under conditions of
`
`therapeutic use.
`
`D. Other In Vivo Studies
`
`These are bioavailability studies employing pharmacological or
`
`clinical measurements/endpoints in humans or animals. In
`
`addition, chemical analysis of body fluids in animals may be
`
`used, when appropriate.
`
`- 4-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0006
`
`
`
`E. In Vitro Studies
`
`In vitro dissolution studies are intended to define the release
`
`rate of a drug substance from the dosage form. They are
`
`conducted to characterize a dosage form and assure consistent
`
`batch-to-batch behavior. Other in vitro studies may be
`
`conducted to characterize further the drug moiety,(e.g., protein
`
`binding).
`
`III. FORMAT AND CONTENT OF THE BIOPHARMACEUTICS SECTION OF AN APPLICATION
`
`The following format should be used to present biopharmaceutic
`
`data submitted in all types of NDAs. The submissions should be
`
`legible and should use only standard abbreviations. The tables
`
`and graphs should be well constructed, clearly identified, and
`
`captioned. Studies should be identified as interim or final
`
`reports, reports of published literature, etc., and the
`
`sponsor's contact person(s) should be identified.
`
`Format for Biopharmaceutic Submission for an NDA, Paper NDA and ANDA
`
`A. Summary of Studies
`
`An overall tabulated summary of all in vivo biopharmaceutic
`
`studies carried out on the drug grouped by type, in the format
`
`shown in attachment A, "Biopharmaceutics Study Summary," should
`
`-5-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0007
`
`
`
`be provided. Each type of study (pharmacokinetic,
`
`bioavailability, etc.) should be listed in descending order of
`
`importance.
`
`B.
`
`Summary of Data and Overall Conclusions
`
`There should be a summary of all the
`
`bioavailability/pharmacokinetic data and overall conclusions.
`
`The summary should include a table with the following
`
`information: pharmacokinetic parameters giving the values, as
`
`appropriate, for the major parameters (mean and %CV) such as the
`
`peak concentration (C max), area under the curve (AUC), time to
`
`reach peak concentration (t max), the elimination constant
`
`(Kel), distribution volume (Vd), plasma and renal clearance,
`
`urinary excretion, etc., derived from each in vivo study
`
`(Attachment B). Overall conclusions to be derived from the data
`
`should be discussed, and any unresolved problems should be
`
`identified.
`
`C.
`
`Drug Formulation
`
`A list of all formulations used in clinical trials and in vivo
`
`bioavailability/pharmacokinetic studies should be provided. The
`
`studies in which each formulation was used should also be
`
`identified. For those batches employed in the
`
`-6-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0008
`
`
`
`bioavailability/pharmacokinetic studies, significant
`
`manufacturing and formulation changes for the drug product over
`
`the course of its evaluation should be identified clearly
`
`( Attachment C ) .
`
`D.
`
`Analytical Methods
`
`A summary of the analytical method employed in each in vivo
`
`biopharmaceutic study should be provided in the format shown in
`
`Attachment D(In Vivo Analytical Methods Summary). Detailed
`
`information should be provided with the individual study. (See
`
`paragraph F below.)
`
`E.
`
`Dissolution
`
`Dissolution data on each strength and dosage form for which
`
`approval is sought should be provided, including a comparison
`
`dissolution study with the lot undergoing an in vivo
`
`biopharmaceutic study.
`
`1. A summary of the product's dissolution performance should
`
`be included (See Attachment E).
`
`-7-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0009
`
`
`
`2. A summary of the dissolution method and specification
`
`proposed for the candidate product for approval should be
`
`provided. (See Attachment F).
`
`F. Individual Study Reports Format and Other Considerations
`
`Each study report should contain the following information:
`
`objective, dosage form(s) studied, principal investigator,
`
`clinical facilities, facilities where collected samples were
`
`assayed, all individual data needed for conclusions, including
`
`demographic information, concomitant medication, if any,
`
`blood/urine levels, abnormal laboratory test values, and adverse
`
`reactions, all presented in coherent tables, with an analysis of
`
`the data and conclusions. In addition, documentation should be
`
`provided of the sensitivity, linearity, specificity, and
`
`reproducibility of the analytical method, including sample
`
`chromatographs, recovery studies, etc.
`
`The data analyses should include appropriate statistical
`
`analyses usually involving Analysis of Variance, calculations of
`
`power analysis, 95% confidence intervals, and ratio analysis
`
`:
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0010
`
`
`
`(75/75-125 Rule). The details of pharmacokinetic parameter
`
`calculations, including pharmacokinetic models and equations
`
`utilized, should be adequately described and referenced.
`
`A brief paragraph summarizing the pertinent conclusions of the
`
`study should be provided.
`
`- 9-
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0011
`
`
`
`Firm
`
`D rug
`NDA/ANDA
`
`BIOPHARMACEUTICS STUDY SUMMARY
`
`ATTACHMENT A
`
`Study Route Dosage Form(s) Dose Batch No. No. of Related Submission Applicant Previous Agency
`Number Study Designs Plant/Date Subjects IND or NDA Date Conclusion Responses on Study
`Manufactured Numbers or Protocol with
`Date of Correspondence
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0012
`
`
`
`F i rm
`Drug
`NDA/ANDA
`
`IN VIVO STUDY DATA SUMMARY
`- - - - - - - - - - - - -Parameters- - - - - - - - - - - - - - - - -
`
`ATTACHMENT B
`
`Route of
`Study Administration Urinary
`Number posage Form Dose Cmax Tmax Vd AUC T1/2 Excretion CLp CLr Comments
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0013
`
`
`
`F i rm
`Drug
`NDA/ANDA
`
`DRUG FORMULAT[ON DEVELOPMENT SUMMARY
`
`ATTACHMENT C
`
`Formulation or significant
`Study Dosage Form Manufacturing Change (if any) Effect of
`Number Lot No. and Strength Batch Size and reason for change Change
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0014
`
`
`
`Drug
`
`NDA/ANDA
`
`IN VIVO ANALYTICAL METHODS SUMMARY
`
`ATTACHMENT D
`
`
`Study Submission Type of Sensitivity
`
`Specificity
`
`Number Date Biol. Fluid Method of Method/Range
`
`(parent/metabolites)
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0015
`
`
`
`Firm
`
`D rug
`
`NDA/ANDA
`
`DRUG PRODUCT DISSOLUTION TESTING
`
`ATTACHMENT E
`
`Units Tested/
`Date of Dosage Form Lot Dissolution Media/ Speed of Collection Range/Mean %
`Test and Strength Number Apparatus Temperature Rotation/FLow Times Dissolved/% C.V.
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0016
`
`
`
`PROPOSED PRODUCT DISSOLUTION METHOD
`
`AND SPECIFICATION
`
`ATTACHMENT F
`
`Firm
`
`Drug
`
`NDA/ANDA
`
`(l) Dosage Form •
`
`(2)
`
`Stren9th(s) :
`
`(3)
`
`Apparatus Tyae •
`
`(4)
`
`Media :
`
`(5)
`
`Volume •
`
`(6)
`
`Speed of Rotation: (Rate of Flou for Flow-throuah Apparatus)
`
`(7)
`
`Samplin9 Time(s) :
`
`(8)
`
`Brief Descrintion of Dissotution Analvtical Method :
`
`(9)
`
`Recommended Dissolution Soecification :
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0017
`
`
`
`For further information regarding the guidelines please contact:
`
`Food and Drug Administration
`Center for Drugs and Biologics
`Division of Biopharmaceutics (HFN-220)
`5600 Fishers Lane
`Rockville, Maryland 20857
`(301) 443-4750
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1049-0018
`
`
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