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Investigational new drug ,orange book,understanding on 505(b) (2) applications

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INVESTIGATIONAL NEW DRUG , ORANGE BOOK, UNDERSTANDING ON 505(b) (2) APPLICATIONS prepared by s.susena,ssj college of pharmacy,hyderabad

INVESTIGATIONAL NEW DRUG , ORANGE BOOK, UNDERSTANDING ON 505(b) (2) APPLICATIONS prepared by s.susena,ssj college of pharmacy,hyderabad


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  • 1. INVESTIGATIONAL NEW DRUG ,ORANGE BOOK,UNDERSTANDING ON 505(b) (2)APPLICATIONSPrepared By: S.Susena( M. Pharm Sem-2)I.P.R . DepartmentGuided by: Y.MalyadriS. S. J. Pharmacy College1
  • 2. CONTENTSINVESTIGATIONAL NEW DRUG (IND)INTRODUCTIONPRE-IND MEETINGTHE CONTENT AND FORMAT OF AN INDAPPLICATIONORANGE BOOKUNDERSTANDING ON 505(b) (2)APPLICATIONSCONCLUSIONREFERENCES2
  • 3. 3New Drug Development Process.InitialSynthesisAnimalTestingINDAPPLICATIONPhaseIPhaseIIPhaseIIIPhaseIVAdverseReactionReportingSurveys/SamplingTestingInspectionsRange 1-3Yrs.Avg:18 Mos.FDATime30 DaySafety ReviewRange 2-10Yrs.Avg :5Yrs.NDASubmittedNDAApprovedRange 2 Mon –7Yrs.Avg:24 Mos.Average of Approximately 100 Months From Initial Synthesis to Approval of NDATreatment UsePreclinical Clinical Development NDA Review Post-Marketing
  • 4. IntroductionAn Investigational New Drug Application (IND) is asubmission to the Food and Drug Administrationrequesting permission to initiate a clinical study ofa new drug product.The Federal Food, Drug, and Cosmetic Act requiresthat all drugs have an approved marketingapplication (NDA, BLA, ANDA) before they can beshipped in interstate commerce.
  • 5. The IND application allows a company toinitiate and conduct clinical studies of theirnew drug product.The IND application provides the FDA withthe data necessary to decide whether thenew drug and the proposed clinical trialpose a reasonable risk to the humansubjects participating in the study.
  • 6. When Do I Need an IND?An IND is required any time you want toconduct a clinical trial of an unapproveddrugThe Act further defines a new drug, in part,as “any drug the composition of which issuch that such drug is not generallyrecognized as safe and effective for useunder the conditions prescribed,recommended, or suggested in the labeling
  • 7. When You Don’t Need an IND? An IND is not required to conduct a study ifthe drug:Is not intended for human subjects, but isintended for in vivo testing or laboratoryresearch animals (non clinical studies)Is an approved drug and the study is within itsapproved indication for use.7
  • 8. Pre-IND Meeting A meeting between the sponsor andthe FDA frequently is useful inresolving questions and issues raisedduring the preparation for an IND. The FDA encourages such meetingsto the extent that1.They aid in the solution ofscientific problems and2. To the extent that the FDA hasavailable resources. 8
  • 9. The Content and Format of an INDApplicationThe content and format of an initial IND is laid outin 21 CFR Part 312Cover Sheet —312.23(a)(1)FDA Form 1571Table of Contents —313.23(a)(2)Introductory Statement and GeneralInvestigational Plan —312.23(a)(3)Investigator’s Brochure —312.23(a)(5)Clinical Protocol —312.23(a)(6)Chemistry Manufacturing and ControlsInformation —312.23(a)(7) 9
  • 10. Pharmacology and Toxicology Information —312.23(a)(8)Previous Human Experience —312.23 (a)(9)Additional Information —312.23(a)(10)Relevant Information —312.23(a)(11)Other Important Information about the Format,Content and Submission of an INDThe FDA Review of the IND10
  • 11. IND review flow chart11
  • 12. Additional Information —312.23(a)(10) :This section is used to present information on specialtopics.Drug dependence and abuse potential.Radioactive drugs.Pediatric studies. Any plans the sponsor has for assessingthe safety and effectiveness of the drug in the pediatricpopulation.Other information. Any other relevant information thatmight aid in the evaluation of the proposed clinicalinvestigations.12
  • 13. Relevant Information —312.23(a)(11) :Any information specifically requested bythe FDA that is needed to review the INDapplication.13
  • 14. Other Important Information about theFormat, Content and Submission of an IND :For clinical studies that will be submitted as part of an NDAor BLA, IND sponsors must collect financial disclosureinformation from each investigator or sub investigator whois directly involved in the treatment or evaluation of clinicaltrial subjects.The sponsor may also reference a drug master file (DMF) inthe IND application that contains important informationnecessary to complete review of the IND.Reports or journal articles in a foreign language must beaccompanied by a complete and accurate Englishtranslation. Each IND submission must include a four-digitserial number.14
  • 15. IND Annual Reports :The IND regulations require IND sponsors to submit anannual report that provides the FDA with a brief update onthe progress of all investigations included in the IND.The annual report must contain the following information:Individual study information ,Summary Information ,Thegeneral investigational plan for the coming year.If the investigator brochure was modified during the year, alist of the changes along with a copy of the new brochureA listing of any significant foreign marketing developmentswith the drug, e.g., approval in another country orwithdrawal or suspension of marketing approval.15
  • 16. CLASSIFICATION of INDsINDs can be classified on four dimensions:Commercial / Noncommercial,Standard / Emergency,Paper / Electronic,Original / 505(b)(2).16
  • 17. Orange bookIts official title is Approved Drug Products withTherapeutic Equivalence Evaluations .Commonly known as the Orange Book due to theorange cover of the original print version, it is the Foodand Drug Administrations list of all drugs approved inthe United States as safe and effective.In addition to listing all approved drugs, the OrangeBook is also the authoritative source of information onthe therapeutic equivalence of drug products.17
  • 18. THE GREEN BOOK:the Green Book had some additional and advantageousfeatures. For example, it listed drugs for which “authorizedgenerics” were available, information which the Orange bookdoes not containTHE BLUE BOOK:The FDA publication Requirement of Laws and RegulationsEnforced by the U.S. Food and Drug Administration. It hasbeen discontinued as of October 2002. In its place there is aWealth Of Compliance Information on the FDA18
  • 19. The Orange Book consists of five mainsections:an introduction, a “how to use” section,the drug product lists,appendices, anda patentexclusivity information addendum.19
  • 20. TE CodesTE codes are divided into two categories, A and B‘A’ Drugs are those which the FDA considers to betherapeutically equivalent and, therefore, substitutablewhere permitted by the prescriber. They are furtherdivided as follows:‘B’ Drugs are those which the FDA considers NOT to betherapeutically equivalent due to actual or potentialbioequivalence problems which have not been resolved. B-rated drugs are not legally substitutable20
  • 21. CODE A product that FDA considersAA: Products in conventional dosage form.AB, AB1, AB2, AB3: Products meeting necessary bio-equivalence requirementsAN: Solutions and powder for aerosolizationAO: Injectable oil solutionsAP: Injectable aqueous solutions and intra-venous non-aqueous solutionsAT: Topical productsAB: actual or potential bioequivalence problems havebeen resolved through adequate in vivo and/or in vitrotesting. 21
  • 22. BC Extended-release dosage forms (capsules, injectables andtablets)BD Active ingredients and dosage forms with documentedbioequivalence problemsBE Delayed-release oral dosage formsBN Products in aerosol-nebulizer drug delivery systemsBP Active ingredients and dosage forms with potentialbioequivalence problemsBR Suppositories or enemas that deliver drugs for systemicabsorptionBS Products having drug standard deficienciesBT Topical products with bioequivalence issuesBX Drug products for which the data are insufficient to determinetherapeutic equivalence22
  • 23. UNDERSTANDING ON 505(b) (2)APPLICATIONSThe 505(b)(2) New Drug Application – ARapid Approval RouteThe 505(b)(2) application is one of threeestablished types of new drug application(NDA), and it is a pathway to approval thatcan potentially save pharmaceuticalsponsors both time and money23
  • 24. Basics of the 505(b)(2)Considered a full NDAMust be the same active product (API)Reporting requirements Previously reported safety and efficacy Information from studies not conducted by applicant Relying on FDA’s prior conclusions on safety and/orefficacy from Non-clinical or Clinical Information where applicant lacks the right of referenceNew studies to support change24
  • 25. NDA 505(b)(2)Products allowed under 505(b)(2):Changes to previously approved drugsDosage regimenAPI change (salt, ester, complex, chelate,)New indicationRx/OTC switchBioinequivalent to, but not inferior bioavailabilitycompared to the Reference Listed Drug (RLD)Formulation changes outside 505(j) limitsCan not be used for products eligible for ANDA
  • 26. NDA 505(b)(2)Products not allowed under 505(b)(2):• That are covered under Section 505(j)• For which the only difference is lowerextent of absorption than reference drug• For which the only difference is anunintended lower rate of absorption thanreference drug26
  • 27. 505(b)(2) NDA ExamplesRoute of AdministrationIV to other parenteral routesActive IngredientChange in salt, racemate or enantiomerNew Molecular EntityProdrug of an approved drugActive metabolite of an approved drugNew combination productCombining actives previously approved individuallyFormulation changeExcipient not allowed under 505(j)27
  • 28. The 505(b)(2) ProcessMajor ElementsMeetings and MaterialsPre-INDEOP2Pre-NDA (pre-BLA)SubmissionsINDNDAFDA Interactions 28
  • 29. CONCLUSIONThe IND application allows a company to initiate andconduct clinical studies of their new drug product.The Orange Book is also the authoritative source ofinformation on the therapeutic equivalence of drugproducts.The 505(b)(2) pathway is potentially low risk and hasadvantages in regards to time and moneyand,perhaps,exclusivity. Can get early FDA feedback29
  • 30. Referenceswww.fda.gov/opacom/laws/lawtoc.htmwww.fda.gov/cder/guidance/index.htmwww.fda.gov/cber/guidelines.htmwww.fda.gov/cder/handbook/www.fda.gov/cder/mapp.htmwww.fda.gov/oc/gcp/default.htmwww.regsource.com/default.html30
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