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The IND Process

The IND Process. David A. Lepay, M.D., Ph.D. Senior Advisor for Clinical Science Office of the Commissioner, US FDA Johns Hopkins Program December 10, 2001. FDA’s Mission. FDA has a broad public protection mission

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The IND Process

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  1. The IND Process David A. Lepay, M.D., Ph.D. Senior Advisor for Clinical Science Office of the Commissioner, US FDA Johns Hopkins Program December 10, 2001

  2. FDA’s Mission • FDA has a broad public protection mission • Ensure the safe use of regulated products that are themselves safe and efficacious • Underlying this mission is FDA decision-making on product applications and labeling • Based on complete and accurate information from well-designed, ethically-conducted, and well-monitored clinical research

  3. FDA’s Mission in Clinical Research • Ensure Implementation of Good Clinical Practice Standards • Embodied in FDA regulation and guidance since the 1960’s and ‘70’s • International Standard (ICH E6) since 1996 • Enforced through FDA’s review process and in its program of on-site inspections • U.S. Clinical Investigator inspections from 1962 • Ethics Committee (IRB) inspections from 1978 • International CI inspections from 1980

  4. GCP is Comprehensive • International ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects • GCP embraces trial objectives, trial design, study oversight, data collection and quality assurance, study analysis, as well as human subject protection in studies that support product applications

  5. Good Clinical Practice • GCP is most fundamentally a System of Shared Responsibilities • Clinical Investigators • Institutions/Institutional Review Boards • Industry (Sponsors/Monitors) • Government Regulators

  6. FDA’s Authority to Regulate • Federal Food Drug and Cosmetic Act • Requires that an FDA approved marketing or research permit be obtained before certain commodities (such as human drugs, medical devices, veterinary drugs, food additives, etc.) may move across state lines

  7. Pharmaceuticals may move across state lines during two stages of human use • Research prior to “approval” • Requires research permit: e.g, Investigational New Drug Exemption (IND) • Marketing after “approval” • Requires marketing permit: e.g., New Drug Application (NDA)

  8. What is an IND/IDE ? • An exemption from the law which otherwise requires that a drug (biologic, device) be approved before it can be transported across state lines • The standard for approval is evidence of safety and efficacy • The IND exemption is granted for purposes of clinical investigation (research)

  9. Importance of the IND • Affirms a body of knowledge about the manufacturing, pharmacology, and toxicology of the drug to support its use in human testing • Requires that the clinical investigation(s) be performed in accordance with Good Clinical Practice (GCP) • Provides an additional level of protection through FDA oversight

  10. The FD&C Act Defines “Drug” Very Broadly • Any of: • Article recognized in the U.S. Pharmacopeia, official Homeopathic Pharmacopeia of the US, or official National Formulary, or any supplement • Article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals

  11. The FD&C Act Defines “Drug” Very Broadly • Any of: • Article (other than food) intended to affect the structure or any function of the body of man or other animals • Article intended for use as a component of any article specified in clauses above Section 201(g) of the FD&C Act

  12. “Clinical Investigation” is also Defined Broadly • Any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice 21 CFR 312.3

  13. So When Is an IND Required ? • In general: An IND is required when an unapproved drug (or biologic) is used in a clinical investigation

  14. What About Approved Products • No IND is needed when an approved product is used in the course of medical practice (even for an indication different from the approved indication) • But an IND may be required when an approved products is used in a clinical investigation

  15. What About Approved Products • An IND is needed if: • The clinical investigation is intended to be reported to FDA as a well-controlled study in support of a new indication or a significant change in the labeling of the drug • The clinical investigation is intended to support a significant change in advertising for the product

  16. What About Approved Products • With the above caveats, clinical investigation of an approved product may be exempt from IND requirements if: • The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases risks AND • The investigation is conducted in accordance with IRB and informed consent requirements

  17. What About Approved Products • FDA has generally allowed the IRB to assess whether risk of an approved product is increased for a given protocol • But FDA retains final authority for such determinations

  18. What About Approved Products • It is also important to note that shelf chemicals which bear the same “name” as an approved product are not considered as “lawfully marketed” equivalents of the approved product • Approval is specific to dose, formulation, and applicant

  19. Need for an IND/IDE:Who to Contact with Questions • Drugs (CDER) • Drug Information Branch: (301) 827-4573 • Biological Products (CBER) • (301) 827-0373 • Medical Devices (CDRH) • IDE Staff: (301) 594-1190 • Food Safety (CFSAN): (202) 418-3126

  20. Related Information • GCP Regulations • IND/IDE Regulations: 21 CFR Part 312/812 • IRB Regulations: 21 CFR Part 56 • Informed Consent Regs: 21 CFR Part 50 • All are accessible at: • www.fda.gov/oc/gcp

  21. Related Information • IND Forms • Available on-line through: www.fda.gov/cder/regulatory/applications/

  22. IND: What is Required -1- • General Investigation Plan • Investigator’s Brochure • Protocol(s): Later protocols submitted as amendments • Chemistry, manufacturing and control information • Animal pharmacology and toxicology information

  23. IND: What is Required -2- • Previous human experience • Additional information • Dependence and abuse potential • Plans for pediatric studies • Amount of information required in each section depends on novelty of the drug, extent studied, and known or suspected safety concerns

  24. The FDA Form “1572” • IND sponsors are required to obtain a signed FDA Form “1572” from each clinical investigator, containing: • Name and address of CI • Name and code number of any protocol(s) • Name and address of research facility and any clinical labs • Name and address of responsible IRB • Names of subinvestigators • Signed commitment by the investigator

  25. Clinical Investigator Responsibilities* • Personally conduct or supervise investigations • Ensure all persons assisting in conduct of studies are informed of their obligations • Ensure informed consent (21 CFR 50) and IRB review, approval , and reporting (21 CFR 56) requirements are met *(Form FDA 1572: #9. Commitments)

  26. Clinical Investigator Responsibilities* • Conduct studies according to relevant, current protocol • Make changes in a protocol only after notifying the sponsor • Maintain adequate and accurate records • Make records available for inspection • Agree to comply with all other requirements in 21 CFR 312 *(Form FDA 1572: #9. Commitments)

  27. Review of IND Application • FDA also has responsibilities under GCP • The focus of FDA’s IND Review is on safety for human research subjects and ensuring that the studies will produce useful information to assess safety and efficacy of the test product

  28. Reviews are Conducted by Teams of Specialists • Medical Officer • Consumer Safety Officer/Project Manager • Statistician • Chemist • Pharmacologist • Human Biopharmaceutics • (Microbiologist)

  29. Review of IND Application • Review team has 30 days to review • Focus of review is always on safety/ human subject protection • No News = Good News

  30. IND Application: If Problems.. • “Clinical Hold” • Legal order to delay or stop the study in the U.S. • Subjects may not be given the investigational drug • May be imposed if: • Exposure of subjects to unreasonable risk (includes manufacturing problems) • Investigator brochure is misleading, erroneous, or materially incomplete • Investigator is not qualified

  31. Drug Development Under an IND • Review Team Monitors • New Protocols (IND amendments) • Safety reports • Annual reports • Additional chemistry, animal toxicology, microbiology data • Review team is available to consult/meet with sponsors: advise on protocol design, advise on drug development plan

  32. IND and Non-US Studies • Studies performed outside of the U.S. may be conducted with or without IND • With an IND: • Test article can be exported from the U.S. • Study must conform to U.S. IND regulations (including U.S. IRB and informed consent rules)

  33. IND and Non-US Studies • Studies performed outside of the U.S. may be conducted with or without IND • Without an IND • May be acceptable for FDA review in support of a marketing application • Export of the test article from the U.S. must conform to FDA regulations

  34. Export of an Investigational Drug • Mechanisms (21 CFR 312.110) • FDA authorization of a written request from the person that seeks to export • Adequate information; investigational purposes only; can be legally used in the importing country for investigation; specifies quantity/frequency of shipment • FDA authorization of a formal request from the government of the receiving country

  35. Export of an Investigational Drug • 1996 law also allows drug export for investigational use without prior FDA approval if intended for use in one of 25 countries • Australia; Canada; Israel; Japan, New Zealand; Switzerland; European Union Member States (15), Iceland, Norway, and Liechtenstein

  36. Center for Drugs ODE I Cardio-Renal (110) 301-594-5300 Neuropharm (120) 301-594-2850 Oncology (150) 301-594-2473 Center for Drugs ODE II Anesthetic, Critical Care & Addiction (170) 301-827-7410 Metabolic/Endocrine (510) 301-827-6430 Pulmonary (570) 301-827-1050 IND Content/Submission:Who to Contact with Questions

  37. Center for Drugs ODE III Medical Imaging & Radiopharm (160) 301-827-7510 GI & Coagulation (180) 301-827-7310 Repro/Urologic (580) 301-827-4260 Center for Drugs ODE IV Anti-Infective (520) 301-827-2120 Antiviral (530) 301-827-2330 Special Pathogens & Immunologic (590) 301-827-2336 IND Content/Submission:Who to Contact with Questions

  38. Center for Drugs ODE V Derm/Dental (540) 301-827-2021 Anti-Inflammatory, Analgesic & Ophthalmic (550) 301-827-2040 Over-the-Counter (OTC) (560) 301-827-2222 IND Content/Submission:Who to Contact with Questions

  39. IND Content/Submission:Who to Contact with Questions • Center for Biologics (CBER) • Office of Vaccines Research and Review • (301) 827-0654 • Office of Blood Research and Review • (301) 827-3524 • Office of Therapeutics Research and Review • (301) 827-5099

  40. Office of Generic DrugsWho to Contact with Questions • OGD Regulatory Support Branch • (301) 827-5862

  41. IDE Content/Submission:Who to Contact with Questions • Center for Devices and Radiological Health (CDRH) • General, Restorative, and Neurological Devices: (301) 594-1184 • Clinical Laboratory Devices: (301) 594-3084 • Cardiovascular and Respiratory Devices: (301) 443-8320

  42. IDE Content/Submission:Who to Contact with Questions • Center for Devices and Radiological Health (CDRH) • Ophthalmic and ENT Devices: (301) 594-2205 • Reproductive, Abdominal, and Radiological Devices: (301) 594-5072 • Dental, Infection Control, and General Hospital Devices: (301) 443-8879

  43. Sponsor Responsibilities • Selecting Qualified Investigators • Providing investigators with information they need to conduct an investigation properly. • Ensuring proper monitoring of the investigation(s) • Conduct per protocol • Ethical considerations • Control of investigational product(s) • Safety reporting

  44. Sponsor Responsibilities • Review Ongoing Investigations • A sponsor who discovers that an investigator is not complying with the signed 1572, general investigation plan, or regulations shall promptly either: • secure compliance or • end the investigator’s participation in the investigation (discontinue shipment and require return/disposal of drug; notify FDA).

  45. Sponsor-Investigators • FDA regulations allow an individual to be both study sponsor and clinical investigator • The Dilemma: • Many sponsor-investigators believe that the lack of external monitoring and oversight means that they can perform to a lower standard

  46. Sponsor-Investigators • The Dilemma -2- • Where a sponsor and an investigator are the same, the number of GCP control points is reduced from four to three • A sponsor-investigator therefore needs to be more (not less) informed of responsibilities and more attentive to standards of study conduct and subject protection

  47. Subject Education • Subject Education is an often neglected facet of GCP; yet, an educated, fully informed, and inquiring subject may be the best resource for ensuring ethical and quality performance in a clinical trial • The IRB and institution should pay particular attention to informing subjects where to go with questions or complaints

  48. Reporting to FDA • Sponsors are required to report serious non-compliance • But anyone can report complaints in FDA-regulated clinical trials to FDA • FDA’s GCP website (www.fda.gov/oc/gcp) highlights where to report complaints in clinical trials

  49. New At FDA • FDA has recently established a new Office for Good Clinical Practice to coordinate GCP across FDA and beyond...

  50. OGCP: Structure • Small Office • Strategically located • Office of the Commissioner and its Office of Science Coordination and Communication • Key Positions • David A. Lepay, MD PhD: Senior Advisor for Clinical Science and Director • Stan W. Woollen: Associate Director for Bioresearch Monitoring • Bonnie Lee: Associate Director for Human Subject Protection Policy

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