`DRUG
`PRODUCTS
`
`WITH
`
`THERAPEUTIC
`EQUIV ALENCE
`EVALUATIONS
`33 rd EDITION
`
`THE PRODUCTS IN THIS LIST HAVE BEEN APPROVED UNDER
`SECTION 505 OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT.
`
`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE OF PHARMACEUTICAL SCIENCE
`OFFICE OF GENERIC DRUGS
`
`2013
`
`Apotex v. Abraxis - IPR20 18-00 153, Ex. 1025, p.O I of34
`
`
`
`APPROVED DRUG PRODUCTS
`with
`THERAPEUTIC EQUIVALENCE EVALUATIONS
`
`The products in this list have been approved under section 505 of the
`Federal Food, Drug, and Cosmetic Act. This volume is current through
`December 31, 2012.
`
`33rd EDITION
`
`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AN D DRUG ADMINISTRATI ON
`CENTER FOR DRUG EVALUATION AN D RESEARCH
`OFFICE OF PHARMACEUTICAL SCI ENCE
`OFFICE OF GENERIC DRUGS
`
`2013
`
`Apotex v. Abraxis - IPR201 8-0015 3, Ex. 1025, p.02 of3 4
`
`
`
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`APPROVED DRUG PRODUCTS
`with
`Therapeutic Equivalence Evaluations
`
`CONTENTS
`
`PREFACE TO THIRTY THIRD EDITION ...... .
`
`PAGE
`
`. ... .... .... .. iv
`
`1
`1.1
`1.2
`1.3
`1.4
`1.5
`1.6
`1.7
`1.8
`1.9
`1.10
`1.11
`1.12
`1.1 3
`
`.... ..... .... .... .. ... vi
`INTRODUCTION ... .... ..... .... .... .... ..... ................. .... ..... ... ..... .... .... .... .
`. .... ..... ... .. ... vi
`Content and Exclusion .... .... .... .... ... ... ..... ... ... ..... .. .. .... .... ..... .... ....
`Therapeutic Equivalence-Related Terms ...... .... .. ..... ..... .... .... ... .... .... ... ..... .... .... .... .... .... vi
`Statistical Criteria for Bioequivalence .. ..... .. .... ..... ... .... ..... .... .... .
`. .... ..... .... .. viii
`Reference Listed Drug ... ..... .... .... ...... ..... .. .... .... ... .. .... .... .... ..... ....
`. .... ..... ... .. .... x
`General Policies and Legal Status ............. .... ..... ... .... ..... .... .... .
`. .... ..... .... .... xi
`Practitioner/User Responsibilities .. ............. .... .... . ... .... .... ..... .... .
`. .... ..... .... .... .... . xi
`Therapeutic Equivalence Evaluations Codes
`...... .... .... .... ...
`. ..... .... .... .... .... . xiii
`Description of Special Situations ... .......... ... .... .... . ... .... .... ..... .... .... ...
`. ..... ... xx
`Therapeutic Equivalence Code Change for a Drug Entity ..... .... .. ..... ..... ..
`. .. .... .... .. xxii
`Change of the Therapeutic Equivalence Evaluation for a Single Product .. .... ... ..... .... . xxiii
`Discontinued Section ..... .... ..... .... ............. .... ..... .... .... ..... .... .... ..... ... .... ..... .. ..... ..... .... .. . xxiii
`. .... ..... .... xxiii
`Changes to the Orange Book ...... ..... ..... ... ... .... ... .. .... .... .... ..... ....
`Availability of the Edition ..... ..... .... .. ...... .. .. ..... .... .. .. .... ..... .... .... ....
`. ..... ..... ... xxiv
`
`2
`2.1
`2.2
`2.3
`
`HOW TO USE THE DRUG PRODUCTS LISTS
`Key Sections for Using the Drug Product Lists .. .. .. ... ... ... .... ..
`Drug Product Illustration ... ... ... ....... ... ... ... ......
`Therapeutic Equivalence Evaluations Illustration. .. ... ... .. ..... ..
`
`..... .... .... .... .... .. .2-1
`. ...... ... ... .... 2-1
`. ... ... ... ... .... . .. .... ... ... 2-3
`. .... .... ... ... . 2-4
`
`DRUG PRODUCT LISTS
`..3-1
`... .. .. ... ... .... .
`Prescription Drug Product List ..... .. ... ... ...... ... ... . .... ... .. ... .... ....
`OTC Drug Product List .. ... ... ..... ..
`. .. .... .. ... ...... ..... .. .. ... ... ... ... .... .... ... ... .. . A-1
`Drug Products with Approval under Section 505 of the Act Administered
`by the Center for Biologics Evaluation and Research List .... .. ... ... ... ... .. .... .... ... .... .... 5-1
`Discontinued Drug Product List
`.... ..... ... ... . ....... .. . .... .... .. ... ... ... ... ... .. .... ... . .. ... .. .... . 6-1
`Orphan Products Designations and Approvals List .... . .. ..... ..... .. .... .. ...... .. ..... ... ... ... ... ... ... 7-1
`Drug Products Which Must Demonstrate in vivo Bioavailability
`Only if Product Fails to Achieve Adequate Dissolution
`
`.8-1
`
`APPENDICES
`A. Product Name Index .. ... ..... .... .. .... ...... .. .... . ... ... ... .... ... . .. .
`B. Product Name Index Listed by Applicant .... .. .... .
`C. Uniform Terms .. ... ... .. . .. ... ...... ... ... ...... ... ... ..... ... .
`
`. ... ... . .. .. ... ... . A-1
`..... .. ...
`..B-1
`. .... ... ... .. .. .... ... ... ... . C-1
`
`. .. .... .... AD1
`... .. .. ...
`PATENT AND EXCLUSIVITY INFORMATION ADDENDUM ... ... .... .
`A. Patent and Exclusivity Lists
`.... .. .. ..... .. .. ... ...... .. .
`. ... .... .. ... ... ... . ADA 1
`B. Patent and Exclusivity Terms ... ... .... . .... ... .. .. ... .. ....
`. .. .. .. ..... ... . .. ... .. . ADB1
`
`Apotex v. Abraxis - IPR2018-00153 , Ex. 1025, p.03 of34
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`
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`APPROVED DRUG PRODUCTS
`with
`Therapeutic Equivalence Evaluations
`
`PREFACE TO THIRTY THIRD EDITION
`
`The publication , Approved Drug Products with Therapeutic Equivalence
`Evaluations (the List , commonly known as the Orange Book) , identifies drug
`products approved on the basis of safety and effectiveness by the Food and
`Drug Administration (FDA) under the Federal Food , Drug , and Cosmetic Act (the
`Act) . Drugs on the market approved only on the basis of safety (covered by
`the ongoing Drug Efficacy Study Implementation (DES I ] review [e . g . , Donnatal®
`Tablets and Librax® Capsules) or pre-1938 drugs [e . g . , Phenobarbital
`Tablets]) are not included in this publication . The main criterion for the
`inclusion of any product is that the product is the subject of an application
`with an effective approval that has not been withdrawn for safety or efficacy
`reasons .
`Inclusion of products on the List is independent of any current
`regulatory action through administrative or judicial means against a drug
`product .
`In addition ,
`the List contains therapeutic equivalence evaluations
`for approved multisource prescription drug products . These evaluations have
`been prepared to serve as public information and advice to state health
`agencies , prescribers , and pharmacists to promote public education in the area
`of drug product selection and to foster containment of health care costs .
`Therapeutic equivalence evaluations in this publication are not official FDA
`actions affecting the legal status of products under the Act .
`
`Background of the Publication. To contain drug costs , virtually every
`state has adopted laws and/or regulations that encourage the substitution of
`drug products . These state laws generally require either that substitution be
`limited to drugs on a specific list (the positive formulary approach) or that
`it be permitted for all drugs e x cept those prohibited by a particular list
`(the negative formulary approach) . Because of the number of requests in the
`late 1970s for FDA assistance in preparing both positive and negative
`formularies , it became apparent that FDA could not serve the needs of each
`state on an individual basis . The Agency also recognized that providing a
`single list based on common criteria would be preferable to evaluating drug
`products on the basis of differing definitions and criteria in various state
`laws . As a result , on May 31 , 1978 ,
`the Commissioner of the Food and Drug
`Administration sent a letter to officials of each state stating FDA ' s intent
`to provide a list of all prescription drug products that are approved by FDA
`for safety and effectiveness , along with therapeutic equivalence
`determinations for multisource prescription products .
`
`It included only
`The List was distributed as a proposal in January 1979 .
`currently marketed prescription drug products approved by FDA through new drug
`applications (NDAs) and abbreviated new drug applications (ANDAs) under the
`provisions of Section 505 of the Act .
`
`The therapeutic equivalence evaluations in the List reflect FDA ' s
`application of specific criteria to the multisource prescription drug products
`on the List approved under Section 505 of the Act . These evaluations are
`presented in the form of code letters that indicate the basis for the
`evaluation made . An explanation of the code appears in the Introduction .
`
`A complete discussion of the background and basis of FDA ' s therapeutic
`equivalence evaluation policy was published in the Federal Register on
`January 12 , 1979 (44 FR 2932) . The final rule , which includes FDA ' s responses
`to the public comments on the proposal , was published in the Federal Register
`iv
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`on October 31 , 1980 (45 FR 72582) . The first publication , October 1980 , of
`the final version of the List incorporated appropriate corrections and
`additions . Each subsequent edition has included the new approvals and made
`appropriate changes in data .
`
`On September 24 , 1 904 , the President signed into law the Drug Pr i ce
`competition and Patent Term Restoration Act (1984 Amendments) . The 1984
`Amendments reqUire that FDA , among other things , make publicly available a
`list of approved drug products with monthly supplements . The Approved Drug
`Products with Therapeutic Equivalence Evaluations publication and its monthly
`Cumulative Supplements satisfy this requirement . The Addendum to this
`publication identifies drugs that qualify under the 1984 Amendments for
`periods of exclusivity (during which ANDAs or applications described in
`Section 505(b) (2) of the Act for those drugs may not be submitted for a
`specified period of time and , if allowed to be submitted , would be tentatively
`approved) and provides patent information concerning the listed drugs which
`also may delay the approval of ANDAs or Section 505(b) (2) applications . The
`Addendum also provides additional information that may be helpful to those
`submitting a new drug application to the Agency .
`
`The Agency intends to use this publication to further its objective of
`obtaining input and comment on the publication itself and related Agency
`procedures . Therefore , if you have comments on how the publication can be
`imp r oved , please send them to the Director , Division of Labeling and Pr ogram
`Support , HFD-6l0 , Office of Generic Drugs , Center for Drug and Evaluation and
`Research , 7620 Standish Place , Rockville , MD 20855 . Comments received are
`publicly available to the extent allowable under the Freedom of Information
`regulations .
`
`v
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`Apotex v. Abraxis - IPR20 18-00 153, Ex. 1025, p.05 of34
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`
`1. INTRODUCTION
`
`1.1 Content and Exclusion
`
`(1) approved prescription drug
`The List is c omposed of four parts :
`products wi th therapeutic equivalence evalua tions ;
`( 2 ) approved
`over-the-counter (OTC) drug products for those drugs that may not be marketed
`without NDAs or ANDAs because they are not covered under existing OTe
`monographs ;
`(3 ) drug products with approval under Section 505 of the Act
`administered by the Center for Biologics Evaluation and Research ; and (4) a
`cumulative list of approved products that have never been marketed , are for
`exportation , are for military use , have been discontinued from marketing , or
`have had their approvals withdrawn for other than safety or efficacy reasons
`subsequent to being discontinued from marketing . l This publication also
`includes indices of prescription and OTC drug products by trade or established
`name (if no trade name e x ists) and by applicant name (holder of the approved
`application) . All established names for active ingredients generally conform
`to official compendial names or United States Adopted Names (USAN) as
`prescribed in (21 CFR 299 . 4(e)) . The latter list includes applicants ' names
`as abbreviated in this publication ; in addition , a list of uniform terms is
`provided .
`
`An Addendum contains drug patent and e xclusivity information for the
`Prescription , OTC , Discontinued Drug Product Lists , and for the Drug Products
`with Approval under Section 505 of the Act Administered by the Center for
`Biologics Evaluation and Research . The publication may include additional
`information that the Agency deems appropriate to disseminate .
`
`the publication had excluded OTC drug products
`Prior to the 6th Edition ,
`and drug products with approval under Section 505 of the Act administered by
`the Center for Biologics Evaluation and Research because the main purpose of
`the publication was to provide information to states rega r ding FDA ' s
`recommendation as to which generic prescription drug products were acceptable
`candidates tor drug product selection . The 1984 Amendments required the
`Agency to begin publishing an up-to-date list of all marketed drug products ,
`OTC as well as prescriptio n, that have been approved for safety and efficacy
`and for which new drug applications are required .
`
`Under the 1984 Amendments , some drug products are given tentative
`approvals . The Agency will not include drug products with tentative approval
`in the List . Tentative approval lists are available at ANDA (Generic) Drug
`Approvals . When the tentative approval becomes a full approval through a
`subsequent action letter to the application holder ,
`the Agency will list the
`drug product and the f inal approval date in the appropriate approved drug
`product list .
`
`Distributo r s or repackagers of products on the List a r e not i dent i fied .
`Because distributors or repackagers are not required to notify FDA when they
`shift their sources of supply from one approved manufactu r e r to another , it is
`not possible to maintain complete information linking product approval with
`the distributor or repackager handling the products .
`
`1.2 Therapeutic Equivalence-Related Terms
`
`Pharmaceutical Equivalents . Drug products are considered pharmaceutical
`equivalents if t hey contain the same active ingredient{s) , are of the same
`
`, Ne wl y approved p roducts are ad ded to parts 1 , 2 , Ot· 3 , of the Lis t , depending on t he dispensing
`r equirements (prescri.ption or OTC ) or app r oval aut ho r iL y , un l e:.;s t he Orange Boo k staff j:.;
`otherwise no t i f ied be f o r e publica tio n .
`
`vi
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`dosage form , route of administration and are identical in strength or
`concentration (e . g . , chlordiazepoxide hydrochloride , 5mg capsules) .
`Pharmaceutically equivalent drug products are formulated to contain the same
`amount of active ingredient in the same dosage form and to meet the same or
`compendial or other applicable standards (i . e ., strength , quality , purity , and
`identity) , but they may differ in characteristics such as shape , scoring
`configuration , release mechanisms , packaging , excipients (including colors ,
`flavors , preservatives) , expiration time , and , within certain limits ,
`labeling .
`
`Pharmaceutica~ A~ternatives. Drug products are considered pharmaceutical
`alternatives if they contain the same therapeutic moiety , but are different
`salts , esters , or complexes of that moiety , or are different dosage forms or
`strengths (e . g . , tetracycline hydrochloride , 250mg capsules vs . tetracycline
`phosphate complex , 250mg capsules ; quinidine sulfate , 200mg tablets vs .
`quinidine sulfate , 200mg capsules) . Data are generally not available for FDA
`to make the determination of tablet to capsule bioequivalence . Different
`dosage forms and strengths within a product line by a single manufacturer are
`thus pharmaceutical alternatives , as are extended-release products when
`compared with immediate-release or standard-release formulations of the same
`active ingredient .
`
`Therapeutic Equivalents. Drug products are considered to be therapeutic
`equivalents only if they are pharmaceutical equivalents and if they can be
`expected to have the same clinical effect and safety profile when administered
`to patients under the conditions specified in the labeling .
`
`FDA classifies as therapeutically equivalent those products that meet the
`following general criteria :
`(1) they are approved as safe and effective ;
`(2)
`they are pharmaceutical equivalents in that they (a) contain identical amounts
`of the same active drug ingredient in the same dosage form and route of
`administration , and (b) meet compendial or other applicable standards of
`strength , quality , purity , and identity ;
`(3) they are bioequivalent in that
`(a) they do not present a known or potential bioequivalence problem , and they
`meet an acceptable in vitro standard , or (b) if they do present such a known
`or potential problem , they are shown to meet an appropriate bioequivalence
`standard ;
`(4) they are adequately labeled ;
`(5) they are manufactured in
`compliance with Current Good Manufacturing Practice regulations .
`The concept
`of therapeutic equivalence , as used to develop the List , applies only to drug
`products containing the same active ingredient(s) and does not encompass a
`comparison of different therapeutic agents used for the same condition (e . g . ,
`propoxyphene hydrochloride vs . pentazocine hydrochloride for the treatment of
`pain) . Any drug product in the List repackaged and/or distributed by other
`than the application holder is considered to be therapeutically equivalent to
`the application holder ' s drug product even if the application holder ' s drug
`product is single source or coded as non-equivalent (e . g . , BN ) . Also ,
`distributors or repackagers of an application holder ' s drug product are
`considered to have the same code as the application holder . Therapeutic
`equivalence determi nations are not made for unapproved , off-labe l
`i ndicat i ons .
`
`FDA considers drug products to be therapeutically equivalent if they meet
`the criteria outlined above , even though they may differ in certain other
`characteristics such as shape , scoring configuration , release mechanisms ,
`packaging , excipients (including colors , flavors , preservatives) , expiration
`date/time and minor aspects of labeling (e . g ., the presence of specific
`pharmacokinetic information) and storage conditions . When such differences
`are important in the care of a particular patient , it may be appropriate for
`the prescribing physician to require that a particular brand be dispensed as a
`medical necessity . With this limitation , however , FDA believes that products
`classified as therapeutically equivalent can be substituted with the full
`expectation that the substituted product will produce the same clinical effect
`and safety profile as the prescribed product .
`
`Bioavai~ability . This term means the rate and extent to which the active
`ingredient or active moiety is absorbed from a drug product and becomes
`vii
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`available at the site of action . For drug products that are not intended to
`be absorbed into the bloodstream, bioavailability may be assessed by
`measurements intended to reflect the rate and extent to which the active
`ingredient or active moiety becomes available at the site of action .
`
`Bioequivalent Drug Producta. This term describes pharmaceutical equivalent
`or pharmaceutical alternative products that display comparable bioavailability
`when studied under similar experimental conditions. Section 505 (j) (8) (B) of
`the Act describes one set of conditions under which a test and reference
`listed drug (see Section 1 . 4) shall be considered bioequivalent :
`
`the rate and extent of absorption of the test drug do not show a
`significant difference from the rate and extent of absorption of the
`reference drug when administered at the same molar dose of the
`therapeutic ingredient under similar experimental conditions in either
`a single dose or multiple doses ; or
`
`the extent of absorption of the test drug does not show a significant
`difference from the extent of absorption of the reference drug when
`administered at the same molar dose of the therapeutic ingredient under
`similar experimental conditions in either a single dose or multiple
`doses and the difference from the reference drug in the rate of
`absorption of the drug is intentional , is reflected in its proposed
`labeling , is not essential to the attainment of effective body drug
`concentrations on chronic use , and is considered medically
`insignificant for the drug .
`
`Where these above methods are not applicable (e . g ., for drug products that
`are not intended to be absorbed into the bloodstream) , other in vivo or in
`vitro test methods to demonstrate bioequivalence may be appropriate .
`
`Bioequivalence may sometimes be demonstrated using an in vitro
`bioequivalence standard , especially when such an in vitro test has been
`In other situations ,
`correlated with human in vivo bioavailability data .
`bioequivalence may sometimes be demonstrated through comparative clinical
`trials or pharmacodynamic studies .
`
`1.3 Statistical Criteria for Bioequivalence
`
`Under the Drug Price Competition and Patent Term Restoration Act of 1984 ,
`manufacturers seeking approval to market a generic drug product must submit
`data demonstrating that the drug product is bioequivalent to the pioneer
`(innovator) drug product . A major premise underlying the 1984 law is that
`bioequivalent drug products are therapeutically equivalent , and therefore ,
`interchangeable .
`
`Bioavailability refers to the rate and extent to which the active
`ingredient or therapeutic ingredient is absorbed from a drug product and
`becomes available at the site of drug action (Federal Food , Drug and Cosmetic
`Act , section 505 (j) (8)) . Bioequivalence refers to equivalent release of the
`same drug substance from two or more drug products or formulations . This
`leads to an equivalent rate and extent of absorption from these formulations .
`underlying the concept of bioequivalence is the thesis that , if a drug product
`contains a drug substance that is chemically identical and is delivered to the
`site of action at the same rate and extent as another drug product, then it is
`equivalent and can be substituted for that drug product . Methods used to
`define bioequivalence can be found in 21 CFR 320 . 24 , and include (1)
`pharmacokinetic (PK) studies,
`(2) pharmacodynamic (PO) studies ,
`(3)
`comparative clinical trials , and (4) in-vitro studies . The choice of study
`used is based on the site of action of the drug and the ability of the study
`design to compare drug delivered to that site by the two products .
`
`The standard bioequivalence (PK) study is conducted using a two-treatment
`crossover study design in a limited number of volunteers , usually 24 to 36
`viii
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`adults . Alternately , a four-period , replicate design crossover study may also
`be used .
`Single doses of the test and reference drug products are
`administered and blood or plasma levels of the drug are measured over time .
`Pharmacokinetic parameters characterizing rate and extent of drug absorption
`are evaluated statistically . The PK parameters of interest are the resulting
`area under the plasma concentration-time curve (AUC) , calculated to the last
`measured concentration (AUC(o_t )) and extrapolated to infinity (AUC(O- inf) ) , for
`extent of absorption ; and the maximum or peak drug concentrations (Cmax) , for
`rate of absorption . Crossover studies may not be practical in drugs with a
`long half-life in the body , and a parallel study design may be used instead .
`Alternate study methods , such as in-vitro studies or equivalence studies with
`clinical or pharmacodynamic endpoints , are used for drug products where plasma
`concentrations are not useful to determine delivery of the drug substance to
`the site of activity (such as inhalers , nasal sprays and topical products
`applied to the skin) .
`
`The statistical methodology for analyzing these bioequivalence studies is
`called the two one-sided test procedure . Two situations are tested with this
`statistical methodology . The first of the two one-sided tests determines
`whether a generic product (test) , when substituted for a brand-name product
`(reference) is significantly less bioavailable . The second of the two one(cid:173)
`sided tests determines whether a brand-name product when substituted for a
`generic product is significantly less bioavailable . Based on the opinions of
`FDA medical experts , a difference of greater than 20 % for each of the above
`tests was determined to be significant , and therefore , undesirable for all
`drug products . Numerically , this is expressed as a limit of test-product
`average/reference-product average of 80 % for the first statistical test and a
`limit of reference-product average/test-product average of 80 % for the second
`statistical test . By convention , all data is expressed as a ratio of the
`average response
`(AUC and Cmax) for test/reference , so the limit expressed in
`the second statistical test is 125% (reciprocal of 80 %)
`
`For statistical reasons , all data is log-transformed prior to conducting
`statistical testing .
`In practice , these statistical tests are carried out
`using an analysis of variance procedure (ANOVA) and calculating a 90 %
`confidence interval for each pharrnacokinetic parameter (ernax and AUC ) . The
`confidence interval for both pharmacokinetic parameters , AUC and Cmax , must be
`entirely within t he 80 % to 125% boundaries cited above . Because the mean of
`the study data lies in the center of the 90 % confidence interval , the mean of
`the data is usually close to 100 % (a test/reference ratio of 1) . Different
`statistical criteria are sometimes used when bioequivalence is demonstrated
`through comparative clinical trials pharmacodynamic studies , or comparative
`in - vitro methodology .
`
`The bioequivalence methodology and criteria described above simultaneously
`control for both differences in the average response between test and
`reference , as well as the precision with which the average response in the
`population is es t imated . This precision depends on the within-subject (normal
`volunteer or patient) variability in the pharmacokinetic parameters (AUe and
`Cmax) of the two products and on the number of subjects in the study . The
`width of the 90 % confidence interval is a reflection in part of the within(cid:173)
`subject variability of the test and reference products in the bioequivalence
`study . A test product with no differences in the average response when
`compared to the refe r ence might st i ll fail to pass the bioequivalence c ri ter i a
`if the variabili t y of one or both products is high and the bioequivalence
`study has insufficient statistical power (i . e ., insufficient number of
`subjects) . Likewise , a test product with low variability may pass the
`bioequivalence criteria , when there are somewhat larger differences in the
`average response .
`
`This system of assessing bioequivalence of generic products assures that
`these SUbstitutable products do not deviate substantially in in-vivo
`performance from the reference product . The Office of Generic Drugs has
`conducted two surveys to quantify the differences between generic and brand
`name products . The first survey included 224 bioequivalence studies submitted
`
`ix
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`Apotex v. Abraxis - IPR20 18-00 153, Ex. 1025, p.09 of34
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`in approved applications during 1985 and 1986 . The observed average
`differences between reference and generic products for AUC was 3 . 5 % (JAMA ,
`Sept . 4 , 1987 , Vol . 258 , No . 9) . The second survey included 127
`bioequiva1ence studies submitted to the agency in 273 ANDAs approved in 1997 .
`The three measures reviewed include AUC j o _ t ), AUCjO_inf) , and Cmax . The observed
`average differences between the reference and generic products were + 3 . 47 %
`(SO 2 . 84) for AUCjO_t ), + 3 . 25 % (SO 2 . 97) for AUCjO_inf) , and + 4 . 29 % (SO 3 . 72)
`for Cmax
`(JAMA , Dec . 1 ;- 1999 , Vol. 282 , No . 21) .
`
`The primary concern from the regulatory point of view is the protection of
`the patient against approval of products that are not bioequiva1ent . The
`current practice of carrying out two one-sided tests at the 0 . 05 level of
`significance ensures that there is no more than a 5% chance that a generic
`product that is not truly equivalent to the reference will be approved .
`
`1.4 Reference listed Drug
`
`(21 CFR 314 . 94 (a) (3») means the listed drug
`A reference listed drug
`identified by FDA as the drug product upon which an applicant relies in
`seeking approval of its ANDA .
`
`FDA has identified in the Prescription Drug Product and OTC Drug Product
`Lists those reference listed drugs to which the in vivo bioequivalence
`(reference standard) and , in some instances , the in vitro bioequiva1ence of
`the appl i cant ' s p r oduct i s compa r ed . By des i gnating a s i ngle refe r ence li sted
`drug as the standard to which all generic versions must be shown to be
`bioequivalent , FDA hopes to avoid possible significant variations among
`generic drugs and their brand name counterpart . Such variations could result
`if generic drugs were compared to different reference listed drugs . However ,
`in some instances when listed drugs are approved for a single drug product , a
`product not designated as the reference listed drug and not shown to be
`bioequivalent to the reference listed drug may be shielded from generic
`competition . A firm wishing to market a generic version of a listed drug that
`is not designated as the reference listed drug may petition the Agency through
`the Ci tizen Petition procedure (see 21 CFR 10 . 25 (a) and CFR 10 . 30) When the
`Citizen Petition is approved , the second listed drug will be designated as an
`additional reference listed drug and the petitioner may submit an Abbreviated
`New Drug Application citing the designated reference listed drug . Section
`1 . 7 , Therapeutic Equivalence Evaluations Codes products meeting necessary
`bioequivalence requirements explains the (AB , ABl , AB2, AB3 .. coding system
`for multisource drug products listed under the same heading with two reference
`listed drugs .
`
`there are two situations in which two listed drugs that have
`In addition ,
`been shown to be bioequivalent to each other may both be designated as
`reference listed drugs . The first situation occurs when the in vivo
`determination of bioequivalence is self-evident and a waiver of the in vivo
`bioequivalence may be granted . The second situation occurs when the
`bioequivalence of two listed products may be determined through in vitro
`methodology . The refe r ence listed drug is identified by the symbol " +" in the
`Prescription and Over-the-Counter (OTC) Drug Product Lists . These identified
`reference listed drugs represent the best judgment of the Division of
`Bioequivalence at this time . The Prescription and OTe Drug Product Lists
`identify reference drugs for oral dosage forms , Injectables , ophthalmics ,
`otics , and topical products .
`It is recommended that a firm planning to
`conduct an in vivo bioequivalence study , or planning to manufacture a batch of
`a drug product for which an in vivo waiver of bioequiva l ence will be
`requested , contact the Division of Bioequivalence , Office of Generic Drugs , to
`confirm the appropriate reference listed drug .
`
`x
`
`Apotex v. Abraxis - IPR201 8-00153 , Ex. 1025, p. IO of34
`
`
`
`1.5 General Policies and Legal Status
`
`It does not mandate the
`The List contains public information and advice .
`drug products which is purchased , prescribed , dispensed , or substituted for
`one another , nor does it , conversely , mandate the products that should be
`avoided . To Lile ex Lent that the List sets for-th fDA ' s evaluations of the
`therapeutic equivalence of drug products that have been approved , it contains
`FDA ' s advice to the public ,
`to practitioners and to the states regarding drug
`product selection . These evaluations do not constitute determinat i ons that
`any product is in violation of the Act or that any product is preferable to
`any other . Therapeutic equivalence evaluations are a scientific judgment
`based upon evidence , while generic substitution may involve social and
`economic policy administered by the states ,
`intended to reduce the cost of
`drugs to consumers . To the extent that the List identifies drug products
`approved under Section 505 of the Act , it sets forth information that the
`Agency is required to publish and that the public is entitled to und