From Bench to the Clinic: Regulatory and Clinical Drug Development Strategies

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Margaretha Oortgiesen, PhD, VP of Drug Development and Managing Director, CATO Research, discusses aspects for consideration when taking a medicinal product (drug, biologic, or drug/device combination …

Margaretha Oortgiesen, PhD, VP of Drug Development and Managing Director, CATO Research, discusses aspects for consideration when taking a medicinal product (drug, biologic, or drug/device combination product) from the discovery phase into the first exposure in the clinic.

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  • 1. From Bench to theClinic: Regulatory andClinical DrugDevelopmentStrategiesJ Margaretha Oortgiesen14 May 2013
  • 2. AgendaBACKGROUND Early discovery - Proof of concept Clinical Development US FDATACTICAL REGULATORYCONSIDERATIONS IND Applications Marketing ApplicationsSTRATEGIC CONSIDERATIONSRegulatory mechanismsWorking with the FDA
  • 3. Clinical Development From nonclinical discovery Towards clinical data Towards licensing or marketing Safety Early stage Marketing Pharmacokinetics Pharmacodynamics Proof of Concept Proof of Efficacy
  • 4. Clinical Development Phases Phase 1 - First in humans Healthy volunteers/patients Safety PK Phase 2 Safety PK/PD Proof of concept Exploratory Phase 3 (pivotal) Confirmation of efficacy Extended safety
  • 5. Clinical Strategies Clinical development plan with end inmind >> label Regulatory pathway Input from: KOLs Patient advocacy groups Previously approved products Products under development
  • 6. Regulated ClinicalDevelopmentHighly regulated FDA ICH Local ethics
  • 7. 8Food and Drug Administration US FDA Part of US Department of Health & HumanServices Website: www.fda.gov
  • 8. FDA Mission and ActivitiesMISSION: To promote and protect the public health (helpingsafe and effective products reach the market in atimely way). To monitor products for continued safety (post-authorization) To advance public health (helping to speedinnovations that make medicines more effective,safer and more affordable) To help the public receive accurate science-based information (to improve their health)ACTIVITIES: New Product Review - Review of Data Keeping Watch - Safe manufacturing, distributionand handling Keeping Watch – Monitoring for New Risks Standards and Regulations Research Enforcement: Actions to Protect Public Health
  • 9. 10Scope of Products RegulatedDrugs (Prescription and Over-The-Counter)Biologics Vaccines Blood products Biotechnology products, cell products, and genetherapyMedical DevicesFoodVeterinary productsConsumer and Medical Radiation ProductsCosmetics
  • 10. How does FDA achieve itsmission?• For prescription drug/biologicsproducts:IND regulatory processNDA/BLA regulatory processPostmarketing surveillance of drugsafety
  • 11. 12FDA Organization andCentersEight Centers/Offices:• Center for Biologics Evaluation and Research(CBER)• Center for Drug Evaluation and Research (CDER)• Center for Devices and Radiological Health(CDRH)• Office of the Commissioner (OC)• Office of Regulatory Affairs (ORA)• Center for Food Safety and Applied Nutrition(CFSAN)• Center for Veterinary Medicine (CVM)• National Center for Toxicological Research(NCTR)
  • 12. 13Center for Drug Evaluationand Research (CDER)CENTER DIRECTOR: Janet Woodcock,M.D. (DBNA)Offices:• OFFICE OF REGULATORY POLICY• OFFICE OF MANAGEMENT• OFFICE OF COMMUNICATIONS• OFFICE OF COMPLIANCE• OFFICE OF MEDICAL POLICY• OFFICE OF TRANSLATIONAL SCIENCES• OFFICE OF EXECUTIVE PROGRAMS• OFFICE OF COUNTER-TERRORISM AND EMERGENCY COORDINATION• OFFICE OF SURVEILLANCE AND EPIDEMIOLOGY• OFFICE OF NEW DRUGS• OFFICE OF PHARMACEUTICAL SCIENCE• OFFICE OF PLANNING AND INFORMATICS
  • 13. 14Center for Biologics Evaluationand Research (CBER)CENTER DIRECTOR: Karen Midthun, M.D.Offices:• OFFICE OF MANAGEMENT• OFFICE OF COMPLIANCE AND BIOLOGICS QUALITY• OFFICE OF BLOOD RESEARCH AND REVIEW• OFFICE OF CELLULAR, TISSUE, AND GENE THERAPIES• OFFICE OF VACCINES RESEARCH AND REVIEW• OFFICE OF COMMUNICATION, OUTREACH AND DEVELOPMENT• OFFICE OF BIOSTATISTICS AND EPIDEMIOLOGY
  • 14. 15Center for Devices andRadiological Health (CDRH) Devices: primary intended purposesnot through chemical action within oron the body Classification (I – II – III) 510K PMAs Radioactive products Diagnostics Companion diagnostics Combination products Drug-device combination products Biologics-device combination products
  • 15. Food Product Categories• Food• Foods for Special Dietary Uses Infant formulas, weight loss products• Medical Foods Specific dietary management of a disease Nutritionally complete products, oralrehydration formulas• Dietary Supplements Vitamins, minerals, botanicals• Nutraceuticals*• Functional Foods**These terms are widely used in the marketplace. Such foods are regulated by FDAunder the authority of the FD&C Act, even though they are not specificallydefined by law.
  • 16. 17FDA Regulations & Guidances• Food, Drug, and Cosmetic (FD&C) Act Federal Law; sets broad legal requirements• Regulations (21 CFR) Prescribes specific legal requirements; codified inCode of Federal Regulations. The CFR presents theofficial and complete text of the Agency‟sregulations into an organized publication– IND (Title 21 CFR 312)– NDA/BLA (Title 21 CFR 314/601)– ANDA (Title 21 CFR 320)– 505(b)(2) (Title 21 CFR 314.107)– PMA (Title 21 CFR 814)• Guidances Represent FDA‟s current thinking on a given subject
  • 17. 18TACTICALCONSIDERATIONS
  • 18. 19IND  Clinical Trial/ProgramInitiationInvestigational New Drug (IND) Application• An IND to test the diagnostic or therapeutic potential of aninvestigational new drug/biological in a clinical investigation New Chemical Entity (NCE) Approved Drug• New indication• Unapproved doses• New dosage form• Change in route of administration• Change in dose regimen• IND: Described in 21 CFR Part 312 (Investigational New DrugApplication)• Pre- IND Meeting: Opportunity to have early discussion with FDA onyour product, the preliminary development plan and any issuesyou would like to obtain guidance/advice – Nonclin, CMC, Clin,Reg
  • 19. What is an IND?• Document through which the drug sponsoralerts the FDA of its intention to conductclinical studies with an investigational drug. Summation of data to support clinical exposure fordrug not previously authorized for marketing in the U.S. Promise of compliance and to do no harm• In legal terms, the IND is a request for anexemption from the federal statue thatprohibits an unapproved drug from beingshipped in interstate commerce
  • 20. 21IND  Clinical Trial/ProgramInitiationTypes of INDs Sponsor (Company/Corporate) IND Investigator (Research) IND (named investigator is Sponsor) Emergency Use IND (named patient/compassionateuse, bypasses IRB) Treatment IND (multiple patients for an indication beingstudied under „regular‟ IND) Exploratory IND (micro-dosing in Phase 0)Initiation of Clinical Trials Sponsor (company) may begin trials 30 days after filingIND, unless otherwise notified by FDA During development, maintain ongoing communication withFDA to help guide the program (e.g., EOP 1/2 meetings)
  • 21. 22IND Application IND Content Paper or electronic CTD or 21 CFR 312 format Form FDA 1571 Contains the signature of the Sponsor or the Sponsor‟sauthorized representative
  • 22. Typical IND for a NCE:~ 2,800 – 3,200 pagesIND: Scientific Technical SectionsChemistry,Manufacturing &ControlsMicrobiologyHumanPharmacokineticsand BioavailabilityStatisticsClinicalPharmacology &ToxicologyDrug RegulatoryApplication
  • 23. eCTD Structure Overview
  • 24. 25Sponsor Obligations• Sponsor Person who takes responsibility for an IND to initiate aclinical investigation Signed off on Form FDA 1571• General Sponsor Responsibilities: Select qualified investigators; provide them withinformation they need to conduct investigationproperly Ensure proper monitoring of the investigation(s) Ensure that the investigation(s) is conducted inaccordance with the general investigational plan andprotocols contained in the IND Maintain an effective IND Comply with safety reporting requirements
  • 25. IND Review Process Summary• FDA does not approve INDs• IND is “in effect” after 30 days (unless placed onclinical hold) Based on calendar – no holidays allowed! Clock begins when submission is logged into FDA DocumentControl Room• Clinical hold may occur at any point in the life ofthe IND and may affect a single study or the entireIND• FDA Communication May occur at any time during the course of the IND review Clarifications are usually sought during the review process withthe goal of avoiding clinical hold Comments are advisory unless accompanied by a clinicalhold order
  • 26. Maintaining the IND• Must be updated continually Safety Information Ongoing clinical trials• Types of modifications to IND Protocol Amendments• Change in previously submitted protocol• Add new protocol to original IND• IRB approval required prior to implementation
  • 27. Maintaining the IND (2)• Types of modifications to IND - continued Information Amendments• IB updates• New information about study drug– CMC information, nonclinical studies, final clinical study report• Report new information not ordinarily included in protocol or IND safetyreport submissions– Changes/updates to contact information– FDA Form 1572s– Letter of cross reference IND Safety Reports• Serious and unexpected Adverse Events (AEs)• Inform FDA and all participating investigators Annual Reports• Yearly submission• Within 60 days of “effective IND” anniversary date• Includes enrollment, demographic and conduct status information foreach study• AE summaries (safety reports, deaths, dropouts)• Preclinical study status
  • 28. Marketing Applications• New Drug Application (NDA)• Biologics Licensing Application (BLA)• Premarket Approval Application (PMA)
  • 29. 30Marketing Application - FDAReview  When to file NDA: File atcompletion of all 3 phases (withexception of acceleratedapproval) 21 CFR Part 314(Application for FDAApproval to Market a NewDrug) 21 CFR Part 601 (Licensing) FDA has 60 days to accept orrefuse to file. FDA assembles the ReviewTeam Role of an Advisory Committee– To provide Independentadvice that will contribute tothe quality of the agency‟sregulatory decision-making andlend credibility to the productreview process. Do the benefits outweigh therisks?
  • 30. 31NDA/BLA Review Actions► Refusal to File <60 days after submission►Not Approvable letter List deficiencies in application why product can not beapproved based on current submission►Approvable letter Signals that product ultimately can be approved. Lists minoroutstanding deficiencies (i.e., label, Phase 4 commitments►Approval letter
  • 31. 32STRATEGICCONSIDERATIONS
  • 32. 33Approval/Review Pathways►Type of approval „Regular‟ Approval Accelerated Approval►Filing/review type Fast Track Designation Priority Review Standard Review
  • 33. 34„Regular‟ ApprovalOn completion of Phase 3clinical studiesFull data packageApplication with sufficient data todemonstrateSafety and EfficacyClinical Benefit
  • 34. 35Accelerated Approval► Intended to make promising products for lifethreatening diseases available on the basis ofpreliminary evidence prior to formal demonstration ofpatient benefit Under Subpart H (21CFR314.510) & 21CFR 601.41► Approval based on a surrogate endpoint or on aneffect on a clinical endpoint other than survival orirreversible morbidity A measurement that is considered likely to predict patientbenefit► Considered provisional approval with a writtencommitment to complete clinical studies that formallydemonstrate patient benefit If studies don‟t confirm the initial results, the FDA canwithdraw approval Post-marketing studies should be underway. Sponsorneeds to show diligence in completing studies in a timelymanner. Status update may be requested to report atAdvisory meeting If confirmatory study shows clinical benefit, FDA will grant„regular‟ approval
  • 35. 36Fast Track► Fast Track is a process designed to facilitate thedevelopment and expedite the review of newdrugs that are intended to treat serious or lifethreatening conditions fill an unmet medical need► Applies to the product and the indication► May be requested at any time duringdevelopment. An applicant must submit a request( 60 days review)► Emphasizes the close and early communicationbetween the FDA and sponsor to improve theefficiency of product development► Benefits include “Rolling submission" for a marketing application More frequent meetings with FDA to discussdevelopment plans and ensure collection ofappropriate data needed to support approval The option of requesting evaluation of studies usingsurrogate endpoints (Accelerated Approval)
  • 36. 37Priority Review► Priority Review designation is given to drugs thatoffer major advances in treatment or provide atreatment where no adequate therapy exists► The goal for completing a priority review is 6months (versus standard review period of 10months)► A request for priority review is made by theSponsor at the time of the NDA filing, and theFDA will determine within 60 days whether apriority or standard review designation will beassigned
  • 37. 38Other considerations:Orphan DrugsTo treat a rare disease or condition whichaffects fewer than 200,000 people nationwide(e.g., cystic fibrosis, Lou Gehrig‟s, Tourette‟ssyndrome, certain cancers)Congress passed the Orphan Drug Act (ODA)in 1983 Applies to drugs and biologics Provides financial incentives, including tax creditsfor cost of clinical research Seven years exclusivity if approved first (fromapproval of NDA/BLA) FDA Assistance with Protocol DevelopmentApplication for Orphan Drug Designation canbe filed at anytime during the drugdevelopment process (60 days review)May receive Priority Review
  • 38. Other Considerations: AnimalRule►Human clinical trials are not ethicalor feasible, approval based onnonclinical evidence of efficacyBiodefensePoisoning antidotes►A type of surrogate endpointRequires postmarketing studies toconfirm efficacy observed in animals
  • 39. Target Product Profile (TTP) Development tool to strategize towards productlabel Tracking document containing Development steps towards an approved product Requirements towards with the proposed label (packageinsert) Presented in annotated, key sections of label Dynamic document during development May be shared with FDA
  • 40. 41WORKING WITH THEFDA
  • 41. 42FDA Project Manager► Main contact at FDA – important to establishan open communication and a goodworking relationship with your key contact atthe Agency (email, telephone)► FDA Project Managers assigned for IND - byclass of drug or based on project workload► Role: Logs submissions and distributes for review;coordinates formal FDA meetings; generatesFDA official minutes Handles Compassionate Use IND, Research IND Addresses questions/queries from sponsors
  • 42. CDER Office of New Drugs- Office of Antimicrobial Products (OAP)- Office of Drug Evaluation IDivision of Cardiovascular and Renal Products (DCaRP)Division of Neurology Products (DNP)Division of Psychiatry Products (DPP)- Office of Drug Evaluation IIDivision of Anesthesia, Analgesia, and Addiction Products (DAAAP)Division of Metabolism and Endocrinology Products (DMEP)Division of Pulmonary, Allergy, and Rheumatology Products (DPARP)- Office of Drug Evaluation IIIDivision of Dermatology and Dental ProductsDivision of Gastroenterology and Inborn Errors ProductsDivision of Reproductive and Urologic Products- Office of Drug Evaluation IVDivision of Medical Imaging ProductsRadioactive Drug Research Committee (RDRC) Program- Office of Hematology and Oncology Drug ProductsWhere to submit IND?
  • 43. 44Types of FDA Meetings► Type A: A critical path meeting (eg. Clinical Hold issue) Scheduled to occur within 30 days of FDA‟s receipt of request► Type B: Pre-IND meetings, certain End of Phase 1, meetings, End ofPhase 2 / pre-Phase 3 meetings, and pre-NDA / BLAmeetings. Should be scheduled to occur within 60 days of FDA‟s receiptof request► Type C: Any meetings other than a Type A or Type B meeting. Scheduled to occur within 75 days of FDA‟s receipt of requestNote: no charge to FDA
  • 44. 45FDA Meeting Process► Give careful consideration to your selectionof the proposed date(s) to optimize yourchoice► Consider the merits of Face-to-Face meetingversus Teleconference► Attendees fromcompany/advisors/experts/KoLs► Meetings are allocated 1 to 1.5 hoursmaximum Use allocated time effectively with carefulpreparations/rehearsals Summarize clearly the agreements and actions toavoid misunderstanding later► FDA‟s minutes are official and binding version Sponsor may submit minutes
  • 45. 46Advisory Committees► Public meetings to review: New NDAs, BLAs, new indications forapproved products New guidelines relating to therapeutic areas Development issues during INDs (closedsession if proprietary information discussed)► Non-FDA Members generallyacademic, mainly MDs plus statisticiansand consumer representatives
  • 46. 47FDA: General Principles -1► FDA is scientific and very data driven► Pre-plan interaction(s) to increase efficiency. Bespecific in your requests or issues Advice from FDA is only as good as the backgroundinformation provided► Work with FDA in partnership Early discussions to guide the development program► Company drug experts – FDA‟s extendedknowledge (i.e., access to a lot of data on alarge number of drugs)► FDA Terminology – advise, recommend, suggest,should = must► Document interactions with FDA to ensureunderstanding and for appropriate follow-up, asneeded
  • 47. 48FDA: General Principles - 2► Start discussions with FDA early in yourdevelopment program. Effective use of FDA meetings, e.g. Pre-IND, EOP 1and EOP 2 Use various FDA review process to obtainguidance (e.g., Request for SPA)► Regulatory advice normally given in astructured way, in a structured process andgenerally, within a definitive timeframe► FDA has a large number of opinion leaders;seek expert advice to refine your program(particularly important at AdCom time)► US is an important market – impact of globalclimate
  • 48. Thank YouQuestions:Marga OortgiesenEmail: marga.Oortgiesen@gmail.com49
  • 49. 50FDAWEBSITES/REFERENCES
  • 50. 51FDA Homepagehttp://www.fda.gov/default.htmAbout the FDAhttp://www.fda.gov/opacom/hpview.htmlOverview of the FDA: Choose Short Course-A Tour of the FDAhttp://www.fda.gov/opacom/hpview.html
  • 51. 52FDA Internet AddressCDER Home Pagehttp://www.fda.gov/cderCBER Home Pagehttp://www.fda.gov/cberCDRH Home Pagehttp://www.fda.gov/cdrhCode of Federal Regulationshttp://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfsearch.cfmFederal Register Noticeshttp://www.accessdata.fda.gov/scripts/oc/ohrms/index.cfmCDER Guidelineswww.fda.gov/cder/guidance/index.htm
  • 52. 53FDA Internet Addresses(contd)CBER Guidelineswww.fda.gov/cber/guidelines.htmFreedom of Informationhttp://www.fda.gov/foi/fola2.htmEnforcement ReportsGuide to InspectionsInvestigators Operations ManualRegulatory Procedure ManualWarning Letters, etcAdvisory Committee Meeting Transcriptshttp://www.fda.gov/oc/advisory/default.htm