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  3. REGULATORY COURSE • Sponsor Activities: • Preclinical Investigations: • Identify potential effects of the drug or biologic in the body using laboratory and animal testing • Pharmacology, Toxicology • Gather facts on the potential new drug or biologic to determine if safe to proceed with trials in humans • Prior notice of these tests to FDA not required

  4. REGULATORY COURSE • Preclinical Investigations (Cont’d): • In-vitro and in-vivo testing, and facilities used, subject to Good Laboratory Practices Regulations (GLPs) 21 CFR 58 • Unapproved new drugs and biologics can be shipped without prior FDA approval or notification if properly labeled • Need to keep records and available for inspection

  5. REGULATORY COURSE • Preclinical Investigations (Cont’d) • Testing facility is responsible for the adherence to Good Laboratory Practices (GLP) and the these regulations create reasons for the involvement of the sponsor, to oversee, by virtue of impact on the application.

  6. REGULATORY COURSE • Clinical Investigations: • Gather facts about the safe and effective use of the product in humans to support approval. • Requirements for an Investigational New Drug Application (IND) detailed under 21 CFR 312


  8. REGULATORY COURSE • Investigational New Drug Application: • Formal notice to the FDA of impending studies • Received at least 30 days before start of first trial in the U.S. • If no objection, IND becomes “Effective” • Trials can start or Agency can initiate a “Clinical Hold”

  9. REGULATORY COURSE • IND (Cont’d) • Contents of an IND • Information on Drug Substance • Information on Drug Product • Information on proposed clinical program • Information on proposed study (Protocol) • Principal Investigator (1572)

  10. REGULATORY COURSE • IND (Cont’d) • Information on the Informed Consent to be signed by each subject to ensure that patients enter the Trial voluntarily and knowingly (21CFR 50) • IRB - local committee that is required by regulation 21 CFR 56, to give oversight to the clinical investigation to ensure patients are adequately protected and that scientific and medical standards are met.

  11. REGULATORY COURSE • IND (Cont’d) • Meetings allowed during IND Phase: • Pre-IND Meeting • Post-IND Submission Meeting • End of Phase II Meeting (EOPII) • Pre-NDA Meeting

  12. REGULATORY COURSE • IND (Cont’d) • Phases of Clinical Study • Phase I - initial exposure in less than 100 healthy subjects or patients to evaluate • Safety and tolerance, single and multiple rising dose, adverse reactions • Metabolism - handled in the body • Pharmacological - PK/PD

  13. REGULATORY COURSE • IND (Cont’d) • Phases of Clinical Study • Types of acceptable, clinical trials: • Historical Control • Open labeled (No treatment concurrent control) • Dose Comparison • Placebo Control • Active Treatment Control

  14. REGULATORY COURSE • Phases of Clinical Study (Cont’d) • Phase II - Usually adequate, well-controlled trials in small numbers of patients, approximately 200 or so. Evaluate efficacy and safety of the dose. Sometimes used to define optimal dosing. • Phase III - Required to be adequate, well-controlled trials in larger numbers of patients, maybe several thousand, at various locations (global). Considered the pivotal studies on which to base a determination of “safe and effective.” “Approval”


  16. NDA Summary Section Labeling Patent Information Pharmacokinetics and Bioavailability Statistical Section Clinical Data Section New Drug Applications (NDA) Requirements Non-Clinical Pharmacology and Toxicology Chemistry, Manufacturing and Controls Safety Information

  17. C. T. D.Modules I Not part of CTD Module I Regional Administrative Information IIA Overall Summaries Quality, Nonclinical and Clinical Module II IIB IIC Nonclinical Summaries Clinical Summaries CTD IIC1 Written Summaries IIC2 Tabulated Summaries IIB1 Written Summaries IIB2 Tabulated Summaries V III IV Quality Data Report Nonclinical Data Study Reports Clinical Data Study Reports Raw Data

  18. REGULATORY COURSE • New Drug Application (NDA) • Contents as defined in 21 CFR 314 • Information on (in great detail): • Drug substance, i.e. how to, stability, impurities, etc. • Drug Product, same as substance, plus • Pharmacological and Toxicological findings • Clinical Information, and “labeling” • “Any and all” information known about the drug or drug product.

  19. REGULATORY COURSE • NDA (Cont’d) • Submitted to Center for Drugs Evaluation and Review (CDER) • Division within Office of New Drugs which is responsible for the review of that therapy area • Use Form 356H as transmittal form

  20. REGULATORY COURSE • FDA Activities: • Actions which can be taken by FDA • Refusal to file- • NDA is incomplete • Improper form ? • Omission of critical data • Fails to make required certifications

  21. REGULATORY COURSE • FDA Activities (Cont’d) • Actions to be taken by FDA • Review application • Drug must be safe & effective • Risk vs. benefit • Substantial evidence • evidence from adequate, well-controlled trials • usually replicate trials, • FDAMA allows for one with confirmatory evidence

  22. REGULATORY COURSE • FDA Activities (Cont’d) • Safe and effective: • Need adequate tests to showdrug is safe & effective for use, under conditions prescribed in labeling • Benefit vs Risk • FDA evaluates drug’s effective against risks associated with use of drug determine if benefit outweighs risks (seriousness of disease, unmet medical need, etc.)

  23. REGULATORY COURSE • FDA Activities (Cont’d) • Adequacy of manufacturing and controls • Pre-approval Inspection (PAI) - compliance with cGMP • Labeling review, usually last step. • Advisory Committee - Optional, but usually for NCEs. FDAMA requires decision within 90 days.

  24. REGULATORY COURSE • FDA Activities (Cont’d) • Discipline review letters: • Action Letters: • Non-approval - major issues of safety or efficacy • Approvable - addressable deficiencies • Approval - all issues resolved

  25. REGULATORY COURSE • FDA Activities (Cont’d) • Timeframes: • Prescription Drug User Fee Act (PDUFA) • More reviewers to meet demand of submissions • Established timelines • Priority Review - 6 months • Standard Review - 10 months • Faster review times

  26. REGULATORY COURSE • FDA Activities (Cont’d) • Other Reviews • Fast Track • Joint program with FDA, quick, rolling review and approval • Accelerated Approval • Approval granted for limited indication until additional Clinical trials are completed. If unsuccessful, the product is quickly withdrawn. Other restrictions enforced.

  27. REGULATORY COURSE • Market Exclusivity • Five Year Exclusivity • Available only to drug products with new chemical entities. Excludes esterified forms, salts, chelates, complexes or clathrates of the molecule. Example: a compound, other than an ester, that requires metabolic conversion to produce an already approved active moiety is considered a new chemical entity and entitled to 5 yrs. exclusivity

  28. REGULATORY COURSE • Market Exclusivity • Three Year Exclusivity • Available to drug products for which the application or supplement contains new clinical investigations conducted by the sponsor deemed essential for approval.

  29. REGULATORY COURSE • NDA Postapproval Requirements • Annual Reports • Manufacturing Info • Stability Info • Production Info • Study Info • Safety Reports • Alert reports • Periodic Reports


  31. REGULATORY COURSE • HISTORICAL BACKGROUND: • Smallpox Vaccine - Variolation • Counterfeit products • Tetanus outbreaks for smallpox and diphtheria vaccines • Biologics Act of 1902, reenacted in 1944 as part of the Public Health Services Act, USC 351

  32. REGULATORY COURSE • HISTORICAL BACKGROUND (Cont’d): • FDA’s oversight of Biologicals via Bureau of Biologics until 1982. • Bureau of Drugs and Biologics until 1988 • Center for Biologics Evaluation and Research

  33. REGULATORY COURSE • DEFINITION:(21 CFR 600.3) • “…means any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment or cure of diseases or injuries in man.”

  34. REGULATORY COURSE • DEFINITION: (PHS Act) • “…any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or its derivatives (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of diseases, or injuries in man…”

  35. REGULATORY COURSE • CBER Oversight Of Biologics: • Development and Investigation of Biologicals: • 21 CFR 312 • Biologics License Applications • 21 CFR 600

  36. REGULATORY COURSE • Comparison of Biologics and Drugs • Products are plant specific • Prior to BLA, required two separate applications • Product License Application • Establishment License Application • Biologicals are more difficult to characterize and identify • May require clinical testing to confirm sameness

  37. REGULATORY COURSE • Comparison of Biologics and Drugs: • Intercenter Agreements • Vaccines • in vivo diagnostic allergenic extracts and allergens for hyposensitization • immunoglobulin products • proteins made in the body • animal venom

  38. REGULATORY COURSE • Comparison of Biologics and Drugs: • Stages of Development • IND - Same as for drugs • Preclinical - watch for immune responses • Clinical - watch for antibody activity (neutralizing) • Submission - BLA vs. NDA • Review - Prior to PDUFA, no timelines • Post approval requirements - Same as for Drugs


  40. REGULATORY COURSE • BIOLOGICALS - • Agents or products as defined in the law and the regulations • BIOTECHNOLOGY - • A Process!!!!


  42. REGULATORY COURSE Labeling 21 CFR 201 Very Important part of the NDA Format and Content General requirements……. 21 CFR 201.56 Specific requirements……. 21 CFR 201.57

  43. REGULATORY COURSE Labeling (Cont’d) Format and Content Description: Names Therapy class Clinical Pharmacology Indications and Usage Used as basis of review

  44. REGULATORY COURSE Labeling (Cont’d) Format and Content Contraindications hypersensitivity, age, sex, concom meds. Warnings Serious AEs, potential safety hazards Precautions Special Care for safe use, i.e. labs, carcinogenesis, pregnancy, etc.

  45. REGULATORY COURSE Labeling (Cont’d) Format and Content Common adverse reactions Drug abuse and dependence Overdose Dosage & administration How supplied Animal pharmacology (optional)


  47. NDA Summary Section Labeling Patent Information Pharmacokinetics and Bioavailability Statistical Section Clinical Data Section New Drug Applications (NDA) Requirements Non-Clinical Pharmacology and Toxicology Chemistry, Manufacturing and Controls Safety Information

  48. Bioequivalence Data/Waiver Labeling Abbreviated New Drug Applications - Core Contents - Patent Certifications Chemistry, Manufacturing, Controls

  49. REGULATORY COURSE • CMC: BULK ACTIVE • Typically, bulk active is obtained from a supplier. • ANDA applicant references supplier’s DMF. • Specifications and analytical methods for the active can be found in USP, BP, EP if compendial • For non-compendial items, supplier can recommend/provide methods to applicant • No bulk stability data required in ANDA

  50. REGULATORY COURSE • CMC: FINISHED PRODUCT • Similar requirements to NDA (21 CFR 314.50(d)(1)), • Example: • - Components/composition • - Specifications and analytical methods • - in-process controls • - executed batch records