Preparing An IND Application: CBER Breakout Session
Preparing an IND Application:CBER Breakout SessionDonald W. Fink, Jr., Ph.D.Division of Cellular and Gene TherapiesOffice of Tissue and Advanced TherapiesCenter for Biologics Evaluation and ResearchFood and Drug AdministrationFDA Clinical Investigator Training CourseNovember 15, 2018
Products Regulated by CBEROBRROVRRBlood Derivatives andAllergenic ExtractsRecombinant AnaloguesPREVENTATIVE/TherapeuticVaccines: Infectious DiseasesBlood ComponentsWhole BloodDiagnostic Skin TestsProbioticsDevicesTherapeutic VaccinesSomatic Cellular &Gene TherapiesDevices / TissuesXenotransplantationOTAT2
Cellular Therapies: Applying TissueRegulations – 21 CFR §127121 CFR 1271.3(d)- Articles consisting of / derived from humancells or tissues intended for implantation, transplantation,infusion, or transfer, into a human recipient regulated as humancells, tissues and cellular and tissue-based products (HCT/Ps)HCT/Ps may be eligible for regulation as tissues solely underSection 361 of the PHS Act and 21CFR § 12713
HCT/P Regulation Solely Under Section 361and 21 CFR 1271ONLY when ALL FOUR of the following are met: Minimally Manipulated: Relevant biologic characteristic(s) are not alteredby processing Homologous Use Only: The HCT/P performs the same basic function orfunctions in the recipient as in the donor. Production of the HCT/P does not involve combination of cells withanother article: (limited exceptions and on the condition that addition ofthe excepted article does not raise new clinical safety concerns). No systemic effect, not dependent upon the metabolic activity of livingcells for primary function: exceptions for (a) autologous use, (b) first- orsecond-degree blood relatives, or (c) reproductive use.4
NoMinimallymanipulated?Yes Homologous use?(normal function)NoYes Combined with drugor device?No YesNo351BiologicYesSystemic effect ordependent onmetabolic activity ofthe cells?YesNoTissueIs it a sterilizing, preserving, or storageagent with no new clinical safetyconcerns?YesAutologous use?ORAllogeneic use in firstor second degreerelative?ORReproductive use?NoEXCEPTION(compliance with 21 CFR 1271regulationsnotrequiredwhencells/tissues removed from andreturned to the patient during thesame surgical procedure: 21 CFR1271.15[b])5
Key Elements of the IND SubmissionClinical ProtocolRachel Witten, armacology/ToxicologyAllen Wensky, Ph.D.6
21 CFR 312.20 Subpart B: IND Application Form FDA 157121 CFR 312.23(a)(1) Table of Contents21 CFR 312.23(a)(2) Introductory statement and general investigationalplan21 CFR 312.23(a)(3) Investigator’s brochure21 CFR 312.23(a)(5) Protocols21 CFR 312.23(a)(6) Chemistry, manufacturing, and control data(including environmental assessment21 CFR 312.23(a)(7) Pharmacology and toxicology data21 CFR 312.23(a)(8) Previous human experience21 CFR 312.23(a)(9) Additional information21 CFR 312.23(a)(10) Biosimilar User Fee Cover SheetForm FDA 3792 Clinical Trials Certification of ComplianceForm FDA 36747
Information Provided in CMC Section ShouldDemonstrate Ability to consistently and reproducibly manufacture yourinvestigational cellular product using: Well-controlled manufacturing process that relies on practices andprocedures executed according to standardized written procedures. Qualification program for source materials, reagents, ingredients,excipients and components used throughout the manufacturingprocess. In-process and final product release testing that demonstrates overallproduct quality and safety/sterility.8
Harnessing the Manufacturing ProcessChemistry,Manufacturing,Controls9
Helpful Reference: Preparing CMCSection for Cell-based Product INDGuidance for FDA Reviewers and Sponsors: Content andReview of Chemistry, Manufacturing, and Control (CMC)Information for Human Somatic Cell Therapy Investigational New Drug Applications (April dances/Xenotransplantation/ucm092705.pdf10
CMC Guidance: Information to Include in INDSubmissionI. PRODUCT MANUFACTURING/CHARACTERIZATION Components and Materials Cells: Autologous or Allogeneic, cell source/type (stem/progenitor or functionallyspecialized), description of characteristic attributes Reagents/Materials/Excipients: List of all used during manufacturing process,indicate whether clinical grade. Describe qualification program for acceptance Manufacturing Procedures Provide an outline of the manufacturing process for the cellular product includingtiming for specific steps and overall duration Describe facility where manufacturing takes place, list equipment used, provideinformation about the qualifications of persons responsible for performingmanufacturing Indicate final formulation, unit dosage, total number of units produced permanufacturing run, and method of storage if product not given fresh11
CMC Guidance: Information to Include in INDSubmission (cont.)II.PRODUCT RELEASE TESTING/RESULTS Microbiological Testing Sterility Testing (Bacterial/Fungal): Performed in accordance with requirements outlined in21 CFR 610.12. Sterility test appropriate to material being tested, does not interfere or hinder the test. Test must be validated to demonstrate capability to reliably and consistently detectpresence of viable, contaminating microorganisms. Mycoplasma: Performed when manufacturing process involves extended periods of cellculture. May use recommended culture based assay, or PCR / other alternative test method(demonstrate adequate sensitivity/specificity). Test sample composition important Adventitious Agents For cells recovered from allogeneic, unrelated donors: perform donor eligibility determinationfor communicable diseases Cell Banks (Master and Working): In vivo and in vitro test methods for viral adventitiousagents as appropriate12
CMC Guidance: Information to Include in INDSubmission (cont.)II. PRODUCT RELEASE TESTING/RESULTS (2) Identity: assay that is specific for the cellular product, able to uniquelyidentify product from others that may be manufactured in the same facility Purity: testing performed to demonstrate the final product is free fromundesired extraneous materials introduced during the manufacturingprocess. Residual Contaminants: Assays to detect the presence of residual substancesincluding cytokines, growth factors, antibodies, magnetic beads and serum usedduring manufacturing process and purification. Pyrogenicity/Endotoxin (manufacturing process impurities)13
CMC Guidance: Information to Include in INDSubmission (cont.)II. PRODUCT RELEASE TESTING/RESULTS (3) Potency: Tests for potency shall consist of either in vitro or in vivo tests, or both,which have been specifically designed for each product so as to indicate itspotency Potency is interpreted to mean the specific ability or capacity of the product, asindicated by appropriate laboratory tests .to effect a given result. Biological Activity is “the specific ability or capacity of a product to achieve a definedbiological effect.” A measure of potency. Potency assay(s) provides quantitative measurement of a relevant biological activityidentified on the basis of preclinical testing and product characterization that isindicative of a cellular product’s capacity to elicit a clinical effect.14
CMC Guidance: Information to Include in INDSubmission (cont.)III. FINAL PRODUCT RELEASE TESTING: ACCEPTANCE CRITERIA (Drug Substance Drug Product) Release testing is performed on the final formulated product for each lot manufactured(could be N 1) Specifications/acceptance criteria, test methods for safety (sterility), purity, identity, andpotency described in the IND. Results from final product release testing should be available prior to patient administration. If finalized test results will not be available prior to product/lot release, should include inIND reporting notification process in event acceptance criteria are not met. Perform pilot manufacturing runs that demonstrate ability to manufacture cellular productthat meets release test specifications/acceptance criteria.15
CMC Guidance: Information to Include in INDSubmission (cont.)IV. FINAL PRODUCT STABILITY IND should include description of stability testing programdeveloped to demonstrate cellular product is sufficiently stable foruse throughout the time period covered by a clinical study. Stability test panel should include assays to monitor productsterility, identity, purity, quality, and potency. Test results shouldmeet specifications established prospectively. For each assay included in the stability test panel, you shouldprovide a description of the test method, indicate sampling timepoints, and specify composition of the test article.16
CMC Guidance: Information to Include in INDSubmission (cont.)V. OTHER ISSUES Product Tracking/Segregation: You should include in IND submission information about adequate system to identifyproduct from time of collection until patient administration Include description of procedures developed to ensure segregation from other productsmanufactured in the same facility, preventing inadvertent cross-contamination Labeling: Describe labeling used throughout manufacturing process and provide sample of labelaffixed to the final cellular product Label for investigational product must contain the statement: “CAUTION: New Drug –Limited by Federal law to Investigational Use” Additional labeling necessary if donor eligibility testing is incomplete or not performed17(e.g. cells for autologous use)
CMC Guidance: Information to Include in INDSubmission (cont.)V. OTHER ISSUES (2) Processing/Manufacturing at Multiple Sites:When cell processing/manufacturing is performed at several participating clinical sites,you should include in your IND a description of the plan used for qualifying manufacturingperformed at each site. Shipping From Single Manufacturing Location to Multiple Clinical Sites.Your IND submission should include a summary of testing performed to qualify productshipping procedures. Product Delivery DeviceIf you will be using a novel device for product administration, or standard syringes andneedles not developed for injection of a cellular product, you need to supply informationin your IND demonstrating biocompatibility and uniform delivery of viable cell dose.18
CMC Guidance: Information to Include in INDSubmission (cont.)V. OTHER ISSUES (3) Lot-to-Lot Comparability Relevant when the quantity of initial source material or output of asingle manufacturing run may be insufficient to generate the totalnumber of doses necessary to complete a clinical study Describe in your IND in vitro and/or in vivo preclinical testing that willbe conducted to demonstrate product comparability for: Separate manufactured lots produced from the same starting materialOR Separate manufactured lots produced from different starting material19
Stages of Product DevelopmentIND SubmissionBenchTestingPreclinicalPhase IPhase IIPhase IIIBLAProduct characterizationQualification & Validation studiesPotencySafetyStage of product development serves to determine key review issues, with safety being a primaryfocus during all stages of development/clinical testing.20
CMC Issues Typically Resulting in Placing an INDGoing on Clinical Hold21
Opportunities for FDA InteractionPre-IND rketingApplication PhasePhaseIND Review PhasePreClinicalINDReviewPre-INDMeetingCLINICAL TRIALSPh 1Ph 2Ph 3End of Ph 1MeetingPre-BLAMeetingEnd of Ph 2Meeting30-day Review ClockBLAReviewPostMarketingSafetyMeetingsPost BLAMeetingProduct development is an iterative process that may involvemultiple FDA and sponsor interactions2222
Early Interaction with FDA INTERACT (Initial Targeted Engagement for Regulagory Advice on CBERProducts): Informal, Non-Binding Discussion: Generally CMC and PreclinicalTopics, No Minutes dVaccines/ResourcesforYou/Industry/ucm611501.htm Pre-IND / Type B: –Formal Meeting, Minutes Generated, Non-BindingRecommendations Sponsors and CBER/FDA staff discuss product development activities prior tosubmission of an Investigational New Drug application (IND): may touch on CMC,Preclinical and Clinical topics Represents a key juncture in the regulatory process Rule of Thumb: Generally grant one Type B / pre-IND meeting prior to the submissionof an IND: Exceptions do occur when circumstances dictate. Follow-upcommunication/ interaction is not uncommon23
“Right Time” to Request a Pre-IND Meeting:CMC Perspective Determined by the maturity of your cellular product developmentefforts Should have developed standard procedures that allow forreproducible product manufacturing: adequate cellular productcharacterization24
Take-Home Messages The CMC section of your IND submission should include sufficientinformation regarding product manufacturing, release testing andcharacterization to permit assessment of the potential risks to subjectsposed by the proposed clinical studies A summary of the information expected in the CMC section of an INDfor an investigational cellular product may be found in availablepublished guidance. Early interaction with FDA is encouraged during development tofacilitate preparation of the IND submission, especially for particularlyinnovative products.25
Contact InformationDonald W. Fink, PhD Donald.Fink@fda.hhs.govRegulatory Questions: OTAT Main Line: 240-402-8190Email: OTATRPMS@fda.hhs.gov andLori.Tull@fda.hhs.govOCTGT/OTAT Learn Webinar Series:FDA HeadquartersFederal Research Center at White Oak10903 New Hampshire AvenueSilver Spring, MD s/NewsEvents/ucm232821.htm CBER website: www.fda.gov/BiologicsBloodVaccines/default.htm Phone: 1-800-835-4709 or 240-402-8010Consumer Affairs Branch: ocod@fda.hhs.govManufacturers Assistance and Technical Training Branch:industry.biologics@fda.govFollow us on Twitter: https://www.twitter.com/fdacber www.fda.gov26
Putting Together Your IND Submission(CBER): Preclinical ConsiderationsAllen Wensky, Ph.D.Center for Biologics Evaluation and Research (CBER)Office of Tissues and Advanced Therapies (OTAT)Division of Clinical Evaluation and Pharmacology/Toxicology (DCEPT)Pharmacology/Toxicology Branch (PTB)allen.wensky@fda.hhs.govCLINICAL INVESTIGATOR TRAINING COURSE (CITC): SESSION 7: INDs AND IDEs FROM START TO FINISHNovember 15, 2018
Overview Preclinical Regulatory Review Principles Potential Pitfalls / Regulatory Issues Early Interactions Resources28
Product Lifecycle for Biologics:Focus on the Preclinical nical TrialsPreclinicalPhase 1Phase 2IND submissionPhase 3BLAPost-marketingPostmarketingBLA submission2929
What Regulations Govern Preclinical Testing?Pharmacology & Toxicology Studies“ adequate information about the pharmacological and toxicologicalstudies on the basis of which the sponsor has concluded that it isreasonably safe to conduct the proposed clinical investigations. The kind,duration, and scope of animal and other tests required varies with theduration and nature of the proposed clinical investigations.”IND Regulations [21 CFR 312.23 (a)(8) - Pharmacology and Toxicology]30
Final Guidance Current thinking of the Agency on this topicFirst comprehensive FDA guidance on preclinicalassessment of cell and gene therapy (CGT)ProductsExplicitly incorporates 3 R’s: recommendations toreduce, refine, and replace animal use in apreclinical program31
Expectations from Preclinical Data To support a rationale for the first-in-human clinical trial– For cell and gene therapy products, the trial is usually conducted in the diseasepopulation, not in healthy volunteers To make recommendations regarding the proposed clinical trial– Initial safe starting dose, dose-escalation scheme, dosing schedule, organ toxicity,eligibility criteria, clinical monitoring To meet regulatory requirements– 21 CFR 312.23 (a)(8)– 21 CFR 58 (Good Laboratory Practice (GLP) compliance)32
CBER Review: Product-Based No “one size fits all” regulatory approach Data necessary to support development depends on thecharacteristics of the product Preclinical studies are designed to support use of a specific productfor a specific clinical indication. Review approach is based on balancing risk and benefit.33
Sources of Data to Support an IND GLP-compliant toxicology studies conducted by a certified testing facility Well-controlled studies conducted in house Published data in peer-reviewed journals Cross-reference to similar products in previously submitted files to FDA Detailed clinical study reports from clinical trials34
Preclinical Expectations for Early Phase Clinical Trials Potential mechanism of action (e.g., targeted killing, antitumor, tolerance induction) Establish pharmacologically effective dose(s) Optimize route of administration (ROA) / dosing regimen Establish rationale for species / model selection35
Preclinical Expectations for Early Phase Clinical Trials Establish a dosing scheme Potential target tissue(s) of toxicity / activity Parameters to monitor clinically Eligible patient population36
Preclinical Study Design(s) Assess pharmacology / proof-of-concept (POC) / vector distribution /cell fate in relevant animal model(s) of disease / injury, as feasible Assess safety / toxicology (T) / vector distribution / cell fate in healthyanimals Hybrid pharmacology-toxicology study design– POC T product fate – incorporate activity and safety endpoints in an animalmodel of disease / injury– Local microenvironment and pathophysiology status of the model may impactthe safety / bioactivity of the product37
Considerations for Appropriate Animal Species / Model There is no ‘default’ to the use of nonhuman primates There is no ‘default’ to the use of both a rodent and a non-rodentspecies There is no ‘default’ to the use of multiple species Understand the limitations of the species / model(s) used Scientific justification should be provided for the animal species/ model(s) used38
Opportunities for Interaction Preclinical ApplicationClinical TrialsPreclinicalPre-INDMeetingPhase 1Phase 2End of Ph 2MeetingEnd of Ph 1MeetingPhase LAMeetingPDUFA VMeetingsIND submission3939
Early Communication with OTAT: INTERACT* INitial Targeted Engagement for Regulatory Advice on CBER producTs (previously knownas pre-pre-IND interactions) Goal: To obtain early feedback on a product development program for a novelinvestigational agent Purpose––––A mechanism for early communication with OTATNon-binding, informal scientific discussions with CBER/OTAT review disciplinesInitial targeted discussion of specific issuesPrimary contact: 501.htm4040
Pre-IND Meeting: Preclinical Preclinical– A comprehensive summary of all completed preclinical studies (in vitro and invivo studies, animal species/models, study designs, product manufacturing andformulation, resulting data and interpretation)– Discussion of the planned preclinical program (e.g., animal species/models,product manufacturing and formulation, study designs, ‘Animal Rule’ issues,etc.)www.fda.gov41
Do’s for INTERACT andPre-IND Meetings [Preclinical Perspective] Do read and understand FDA/ICH Guidances, regulations, etc. beforemeeting with FDA Do include the preclinical development plan Do specify similarities and differences between the preclinical andclinical products Do specify similarities and differences between the preclinical andclinical delivery devices/procedures Do include the design of your
Nov 15, 2018 · CMC Guidance: Information to Include in IND Submission (cont.) 19 . Pre-IND Phase. IND Review Phase. Marketing . Application Phase. Post-marketing . Phase. Product development is an iterative process that may involve mult
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Freyja Williams, CBER, FDA, Silver Spring, MD USA 09:30 – 09:55 Definition of Analytical Control Strategy for Robust Vaccine Development Christina Campa, GlaxoSmithKline Vaccines, Siena, Italy 09:55 – 10:10 Panel Discussion - Questions and Answers 10:10 – 11:00 AM Break - Visi
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