INDs: When Required and Contents


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An introduction intended for professionals who are not familiar with Investigational New Drug applications.

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INDs: When Required and Contents

  1. 1. Louise Johnson, M.S. INVESTIGATIONAL NEW DRUG APPLICATION (IND) Requirements for Filing and Contents of Submission The Bio2Device Group May 18, 2010
  2. 2. What is an IND, its benefits, & your responsibilities as a sponsor? <ul><li>The law - an open Investigational New Drug application allows the interstate transport of investigational products and all the components used to manufacture them </li></ul><ul><li>With an open IND, the sponsor can conduct clinical trials of the investigational product in the US </li></ul><ul><li>The sponsor is required to closely monitor and report important safety information and provide annual reports to FDA </li></ul>
  3. 3. When an IND is Required <ul><li>New drug or biologic product </li></ul><ul><li>New use of an approved drug or biologic </li></ul><ul><li>New use of a combination of an approved drugs or biologics </li></ul><ul><li>Combination products in which the components are physically, chemically or otherwise combined and the primary mode of action is due to the drug or biologic </li></ul>
  4. 4. When an IND is Not Required <ul><li>Drugs and biologics </li></ul><ul><ul><li>Study of placebo </li></ul></ul><ul><ul><li>Study of approved drug or biologic used under the approved label </li></ul></ul>
  5. 5. Examples <ul><li>New product is an approved drug used with an IV infusion device </li></ul><ul><ul><li>Approved use is for IV administration </li></ul></ul><ul><ul><li>IND is not required </li></ul></ul><ul><li>New product is an approved drug used in an implantable device </li></ul><ul><ul><li>Approved use is for oral administration </li></ul></ul><ul><ul><li>IND is required </li></ul></ul><ul><ul><li>A study of only the diluent for the drug does not require an IND </li></ul></ul>
  6. 6. Pharmaceutical-Specific Terminology <ul><li>New drug </li></ul><ul><ul><li>A new molecule, drug combination, dosage, or route of administration, used in diagnosing, curing, mitigating, treating, or preventing a disease, or to affect a structure or function of the body, even though such drug is not a new drug when used in another disease or to affect another structure or function of the body </li></ul></ul><ul><ul><ul><li>Note that this definition includes biologics </li></ul></ul></ul>
  7. 7. Pharmaceutical-Specific Terminology <ul><li>Effectiveness (to support approval) </li></ul><ul><ul><li>The desired measure of a drug’s influence on a disease condition as proved by substantial evidence from adequate and well-controlled investigations </li></ul></ul>
  8. 8. Pharmaceutical-Specific Terminology <ul><li>GMP – Good Manufacturing Practice </li></ul><ul><ul><li>A standard for the production and testing of a pharmaceutical or device to ensure product quality </li></ul></ul><ul><li>GLP – Good Laboratory Practice </li></ul><ul><ul><li>A standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of animal studies </li></ul></ul><ul><li>GCP – Good Clinical Practice </li></ul><ul><ul><li>A standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical studies </li></ul></ul>
  9. 9. Pharmaceutical-Specific Terminology <ul><li>IRB – Institutional Review Board </li></ul><ul><ul><li>Independent body constituted of medical, scientific, and non-scientific members, whose responsibility it is to ensure the protection of the rights, safety, and well-being of human subjects involved in a clinical study </li></ul></ul><ul><li>Nonclinical studies </li></ul><ul><ul><li>In vitro or in vivo studies conducted in animals </li></ul></ul><ul><ul><li>Studies conducted both before clinical studies and concurrently with clinical studies </li></ul></ul>
  10. 10. Pharmaceutical-Specific Terminology <ul><li>CMC – Chemistry, Manufacturing, and Control </li></ul><ul><ul><li>Information to assure the proper identification, quality, purity, and strength of the investigational drug </li></ul></ul><ul><li>DMF – Drug Master File </li></ul><ul><ul><li>A submission to the FDA used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs </li></ul></ul>
  11. 11. Pharmaceutical-Specific Terminology <ul><li>Drug substance – Active Pharmaceutical Ingredient (API) </li></ul><ul><ul><li>Intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body </li></ul></ul><ul><li>Drug product </li></ul><ul><ul><li>Finished dosage form that contains one or more APIs generally, but not necessarily, in association with inactive ingredients. The term also includes a finished dosage form which does not contain an API but is intended to be used as a placebo </li></ul></ul>
  12. 12. Pharmaceutical-Specific Terminology <ul><li>Pre-IND Meeting </li></ul><ul><ul><li>Purpose can be to review and agree on the design of animal studies to initiate human testing, the scope and design of Phase 1 study, and/or the best approach for presentation and formatting of data in the IND </li></ul></ul><ul><ul><li>Useful if your questions are not fully answered by guidance and other information provided by FDA </li></ul></ul><ul><ul><li>Early interactions with FDA can help to prevent clinical hold issues and can start a good reputation for your company at FDA </li></ul></ul><ul><ul><ul><li>However, some Divisions currently reply via FAX most often </li></ul></ul></ul>
  13. 13. Pharmaceutical-Specific Terminology <ul><li>Clinical Hold </li></ul><ul><ul><li>Mechanism FDA uses when it does not believe, or cannot confirm, that the study can be conducted without unreasonable risk to subjects </li></ul></ul><ul><ul><ul><li>Subjects would be exposed to unreasonable and significant risk of illness or injury </li></ul></ul></ul><ul><ul><ul><li>Clinical investigator unqualified to conduct the clinical study </li></ul></ul></ul><ul><ul><ul><li>Investigator’s brochure is misleading, erroneous, or materially incomplete </li></ul></ul></ul><ul><ul><ul><li>IND does not contain sufficient information to assess risks to subjects in the proposed study </li></ul></ul></ul><ul><ul><ul><li>Product is intended to treat a serious or life-threatening disease and subjects with reproductive potential are excluded </li></ul></ul></ul>
  14. 14. Pharmaceutical-Specific Terminology <ul><li>ICH – International Conference on Harmonization </li></ul><ul><li>CTD – Common Technical Document </li></ul><ul><ul><li>A standard format for pharmaceutical registration submissions </li></ul></ul><ul><ul><li>FDA recommends for INDs as well, although many INDs are still filed in the traditional format </li></ul></ul><ul><li>eCTD – electronic CTD </li></ul><ul><ul><li>XML, FDA electronic submissions gateway </li></ul></ul>
  15. 15. Typical Development Timeline <ul><li>Time </li></ul>
  16. 16. An IND Supports 3 Phases of Clinical Development <ul><li>Phase 1 : Initial introduction of a new drug into humans </li></ul><ul><li>Phase 2 : Controlled clinical studies to evaluate the efficacy of the drug </li></ul><ul><li>Phase 3 : Expanded controlled and uncontrolled clinical studies for additional information on effectiveness and safety to evaluate the benefit-risk of the drug </li></ul>
  17. 17. Phase 1 <ul><li>Conducted with normal, healthy volunteer subjects (20-80 patients) </li></ul><ul><li>Designed to determine the metabolism and pharmacological actions of the drug in humans </li></ul><ul><li>Determine side effects associated with increasing doses </li></ul><ul><li>Gain early evidence on effectiveness, if possible </li></ul>
  18. 18. Phase 1 (continued) <ul><li>Includes studies of drug metabolism structure-activity relationships and mechanism of action in humans </li></ul><ul><li>Studies also used as research tools to explore biological phenomena or disease processes </li></ul><ul><li>Sufficient information about the drug’s pharmacokinetics and pharmacological effects should be obtained before designing a Phase 2 study </li></ul>
  19. 19. Phase 2 <ul><li>Purpose is to evaluate the efficacy of the drug </li></ul><ul><li>Well controlled and closely monitored </li></ul><ul><li>Relatively small number of subjects, usually involving no more than several hundred subjects </li></ul>
  20. 20. Phase 3 <ul><li>Expanded controlled and uncontrolled studies </li></ul><ul><li>Involves several hundred to thousands of subjects </li></ul><ul><li>Intended to gather additional information about effectiveness and safety </li></ul><ul><li>Evaluate the benefit-risk relationship </li></ul><ul><li>Provide adequate basis for labeling </li></ul>
  21. 21. IND Regulations and Guidance <ul><li>21 CFR 312.23 IND Content and Format </li></ul><ul><li>Guidance for Industry: INDs for Phase 1 Studies (Nov. 1995) </li></ul><ul><li>Guidance for Industry: CGMP for Phase 1 Investigational Drugs </li></ul><ul><li>Guidance for Industry: INDs for Phase 2 and 3 Studies of Drugs; CMC Content and Format (May 2003) </li></ul><ul><li>Guidance for Industry: Current Good Manufacturing Practice for Combination Products ( Draft Sep 2004 ) </li></ul>
  22. 22. IND Content <ul><li>Investigational New Drug Application </li></ul><ul><ul><li>Cover sheet (Form FDA-1571) </li></ul></ul><ul><ul><li>Table of Contents </li></ul></ul><ul><ul><li>Introductory statement and general investigational plan </li></ul></ul><ul><ul><li>Investigator’s brochure </li></ul></ul><ul><ul><li>Protocol(s) </li></ul></ul><ul><ul><li>Clinical Investigator Information </li></ul></ul><ul><ul><ul><li>CV, Form FDA-1572 </li></ul></ul></ul>
  23. 23. IND Content (continued) <ul><li>Investigational New Drug Application </li></ul><ul><ul><li>CMC Information </li></ul></ul><ul><ul><li>Pharmacology and toxicology information </li></ul></ul><ul><ul><li>Previous human experience with the drug </li></ul></ul><ul><ul><li>Additional information: </li></ul></ul><ul><ul><ul><li>i.e. Drug dependence, radioactive drug </li></ul></ul></ul><ul><ul><li>Other relevant information </li></ul></ul><ul><ul><li>FDA Form 3674 Clinical study registration </li></ul></ul><ul><ul><ul><li>Only for Phase 2 and Phase 3 studies </li></ul></ul></ul>
  24. 24. Individual IND Sections
  25. 25. Cover Sheet - Form 1571 <ul><li>Sponsor name, address, phone number </li></ul><ul><li>Commitment not to begin clinical studies until an IND is in effect </li></ul><ul><li>Commitment that an IRB complies with requirements, will review and approve each of the clinical studies and investigator will report any changes to the IRB </li></ul><ul><li>Includes a warning – A willfully false statement is a criminal offense. </li></ul>
  26. 26. Cover Sheet - Form 1571 (Cont.) <ul><li>Name and title of person responsible for monitoring the conduct and progress of the clinical studies </li></ul><ul><li>Name and title of person responsible for review of safety information relative to the investigative drug </li></ul><ul><li>Transfer of obligations to a CRO (if applicable) </li></ul><ul><li>Sponsor signature or authorized representative </li></ul>
  27. 27. IND Table of Contents <ul><li>List of all the sections of the IND submission, including any appendices, tables, etc. </li></ul><ul><li>Should have sufficient detail to provide location of each individual document </li></ul><ul><li>Should follow CTD format or the format described in 21CFR312.23 </li></ul>
  28. 28. Introductory Statement and General Investigational Plan (1) <ul><li>Brief introductory statement and plan </li></ul><ul><ul><li>Name of product </li></ul></ul><ul><ul><li>active ingredient(s) </li></ul></ul><ul><ul><li>pharmacological class </li></ul></ul><ul><ul><li>structural formula </li></ul></ul><ul><ul><li>formulation </li></ul></ul><ul><ul><li>route of administration </li></ul></ul><ul><ul><li>objectives of the proposed study(ies) </li></ul></ul>
  29. 29. Introductory Statement and General Investigational Plan (2) <ul><li>Brief summary of previous human experience with reference to other INDs or experience in other countries relevant to safety </li></ul><ul><li>Information regarding any withdrawal from investigation or marketing in any country for any reasons related to safety or effectiveness </li></ul>
  30. 30. Introductory Statement and General Investigational Plan (3) <ul><li>Brief description of the overall plan </li></ul><ul><ul><li>Rationale for the drug or research </li></ul></ul><ul><ul><li>Proposed indication </li></ul></ul><ul><ul><li>General approach </li></ul></ul><ul><ul><li>Type of clinical studies to be conducted in the first year </li></ul></ul><ul><ul><li>Estimated number of patients </li></ul></ul><ul><ul><li>Any anticipated risks </li></ul></ul><ul><ul><li>Defined at 21 CFR 312.23(3) </li></ul></ul>
  31. 31. Investigator’s Brochure <ul><li>A brief description of the drug substance, formulation, including the structural formula, if known </li></ul><ul><li>Summary of pharmacological and toxicological effects in animals (humans, if known) </li></ul><ul><li>Summary of the pharmacokinetics and biological disposition of the drug in animals (humans, if known) </li></ul>
  32. 32. Investigator’s Brochure <ul><li>Summary information relating to safety and effectiveness in humans from prior clinical studies </li></ul><ul><li>Description of possible risks and side effects to be anticipated </li></ul><ul><li>Content and format defined in ICH E6: Good Clinical Practice </li></ul>
  33. 33. Clinical Protocols <ul><li>Content and format defined in ICH E6: Good Clinical Practice and 21CFR312.23(6)(iii) </li></ul><ul><li>Statement of the objectives and purpose of the study </li></ul><ul><li>Name, address, CV of Investigator, names of subinvestigators, IRB information (usually just use Form FDA 1572) </li></ul><ul><li>Criteria for patient selection, estimated number of patients </li></ul>
  34. 34. Clinical Protocols (continued) <ul><li>Description of the study design, methods to be used to minimize bias </li></ul><ul><li>Method to determining the dose to be administered, maximum dose, and duration of subject exposure to drug </li></ul><ul><li>Description of observations and measurements to be made </li></ul>
  35. 35. Clinical Protocols (Continued) <ul><li>Description of clinical procedures, laboratory tests, or other measures </li></ul><ul><li>Phase 1 protocols are expected to be less detailed and more flexible than Phase 2 and 3 protocols </li></ul><ul><li>Phase 1 protocols are reviewed primarily for safety, FDA does not expect to see efficacy endpoints </li></ul>
  36. 36. Clinical Investigator Information <ul><li>Form FDA 1572 </li></ul><ul><li>CV </li></ul><ul><li>Statement that no investigator is disbarred/ disqualified </li></ul><ul><li>Medical license (not submitted) </li></ul><ul><li>Financial disclosure (not submitted in IND) </li></ul><ul><ul><li>Only if study will be used to establish effectiveness </li></ul></ul>
  37. 37. Form FDA 1572 <ul><ul><li>Clinical investigator’s commitment to conduct study in compliance with protocol, relevant regulations, and human subject protection </li></ul></ul><ul><ul><li>Includes specifics about study site, laboratory, IRB </li></ul></ul><ul><ul><li>Legally binding </li></ul></ul>
  38. 38. Chemistry, Manufacturing, and Control (CMC) <ul><li>Phase 1 submission emphasis placed on safety </li></ul><ul><li>Amount of information depends on the scope of the proposed clinical study </li></ul><ul><li>Submit sufficient information to assure the proper identification, quality, purity, and strength of the drug </li></ul>
  39. 39. CMC (Continued) <ul><li>Drug Substance </li></ul><ul><ul><li>Structure & physicochemical properties </li></ul></ul><ul><ul><li>Manufacturer – name and address </li></ul></ul><ul><ul><li>Method of manufacture </li></ul></ul><ul><ul><li>Characterization </li></ul></ul><ul><ul><li>Container Closure System </li></ul></ul><ul><ul><li>Stability Data </li></ul></ul><ul><ul><li>Can refer to a DMF from a contract manufacturer </li></ul></ul>
  40. 40. CMC (Continued) <ul><li>Drug Product </li></ul><ul><ul><li>Description & composition </li></ul></ul><ul><ul><li>Manufacturer name & address </li></ul></ul><ul><ul><li>Method of manufacture </li></ul></ul><ul><ul><li>Control of excipients </li></ul></ul><ul><ul><li>Control of drug product </li></ul></ul><ul><ul><li>Container Closure System </li></ul></ul><ul><ul><li>Stability Data </li></ul></ul><ul><ul><li>Can refer to a DMF from a contract manufacturer </li></ul></ul>
  41. 41. CMC (Continued) <ul><li>Composition, manufacture, and control of any placebo used in a controlled study </li></ul><ul><li>A copy of all labels and labeling to be provided to each investigator </li></ul><ul><li>Environmental analysis: claim for categorical exclusion under § 25.30 or 25.31 or an environmental assessment under § 25.40 </li></ul>
  42. 42. CMC (Continued) <ul><li>Stability data required for all phases; the amount of data correlates with the planned clinical studies ( i.e., if very short-term tests are proposed, the supporting stability data can be limited) </li></ul><ul><li>As drug development progresses, amendments to the IND adding CMC information should be submitted </li></ul>
  43. 43. Nonclinical Information <ul><li>Adequate information about pharmacological and toxicological studies of the drug involving laboratory animals or in vitro, on the basis of which the sponsor has concluded it is reasonably safe to conduct the proposed clinical study </li></ul>
  44. 44. Nonclinical Information (continued) <ul><li>Pharmacology – Primary and secondary pharmacodynamics </li></ul><ul><li>ADME information, including summaries of bioanalytical methods </li></ul><ul><li>Toxicology </li></ul>
  45. 45. Toxicology <ul><li>An integrated summary of the toxicological effects of the drug in animals and in vitro </li></ul><ul><ul><li>Single dose toxicology studies </li></ul></ul><ul><ul><li>Multiple dose toxicology studies </li></ul></ul><ul><ul><li>Toxicokinetics to support clinical dose selection </li></ul></ul><ul><ul><li>Genotoxicity </li></ul></ul><ul><ul><li>Local tolerance, if applicable </li></ul></ul>
  46. 46. Toxicology (continued) <ul><li>For each toxicology study that is intended primarily to support the safety of the proposed clinical investigation, a full tabulation of data suitable for detailed review </li></ul><ul><ul><li>FDA accepts audited draft reports in the original IND submission </li></ul></ul>
  47. 47. Previous Human Experience <ul><li>Summary of any previous human experience </li></ul><ul><li>If marketed elsewhere, details of clinical studies, any published material relevant to safety </li></ul><ul><li>List of countries where marketing, including any countries where drug has been withdrawn from marketing </li></ul>
  48. 48. Additional Information <ul><li>Drug dependence and abuse potential </li></ul><ul><ul><li>Describe any relevant clinical studies and experience and studies in test animals </li></ul></ul><ul><li>Radioactive drugs </li></ul><ul><ul><li>Sufficient data from animal or human studies to calculate the radiation-absorbed dose to the whole body and critical organs upon administration to a human subject </li></ul></ul>
  49. 49. Additional Information <ul><li>Pediatric studies </li></ul><ul><ul><li>Plans for assessing pediatric safety and effectiveness </li></ul></ul><ul><li>Any other information that would aid in evaluating the safety or design of the proposed clinical study </li></ul>
  50. 50. Other Considerations <ul><li>CTD format encouraged, but not required </li></ul><ul><li>Information previously submitted may be referenced rather than resubmitted </li></ul><ul><li>Material in foreign language must be submitted with complete, certified English translation </li></ul><ul><li>Original foreign language publication to be submitted </li></ul>
  51. 51. Other Considerations (Continued) <ul><li>Paper submission: original + 2 copies </li></ul><ul><ul><li>Also applies to all amendments </li></ul></ul><ul><li>CBER SOPP 8007: DCC Binding Procedures for Regulatory Documents </li></ul><ul><li>Numbering of IND submissions: using a single, four digit serial number; initial is required to be 0000; each subsequent submission is sequentially numbered </li></ul><ul><li>Electronic Submission Gateway </li></ul>
  52. 52. FDA Review of an IND <ul><li>30 calendar day review, required by law </li></ul><ul><li>Review division assigns a review team </li></ul><ul><ul><li>Clinician </li></ul></ul><ul><ul><li>Pharm/tox reviewer </li></ul></ul><ul><ul><li>CMC manufacturing reviewer </li></ul></ul><ul><ul><li>Supervisors </li></ul></ul><ul><ul><li>Project manager </li></ul></ul><ul><li>For Phase 1 clinical studies, each reviewer focuses on the safety of the proposed study </li></ul>
  53. 53. FDA Review of an IND (continued) <ul><li>If all reviewers agree it is safe to conduct the study, the IND is deemed to be “open” </li></ul><ul><ul><li>INDs are not formally approved </li></ul></ul><ul><li>FDA may inform the sponsor that the IND is open or may be silent </li></ul><ul><ul><li>If 30 days have passed with no comment from FDA, the IND is open </li></ul></ul>
  54. 54. FDA Review of an IND (continued) <ul><li>If reviewers conclude it is not safe to conduct the study, they contact the sponsor </li></ul><ul><ul><li>Usually request a teleconference </li></ul></ul><ul><ul><li>If protocol can be modified to address safety concerns or requested information can be provided promptly, the IND can be considered open </li></ul></ul><ul><ul><li>Otherwise, the IND is placed on clinical hold </li></ul></ul><ul><ul><ul><li>Clinical hold and the reasons for it are confirmed in writing within 30 days </li></ul></ul></ul>
  55. 55. Clinical Hold <ul><li>Sponsor must address all FDA concerns for the clinical hold to be lifted </li></ul><ul><li>FDA to respond to request to lift the hold within 30 days </li></ul><ul><li>Can occur at any stage of development </li></ul>
  56. 56. IND Success <ul><li>The investigational product gets to the patient! </li></ul>
  57. 57. Useful URLs <ul><li>FDA’s IND Page </li></ul><ul><li>FDA Guidance </li></ul><ul><li>IND Forms </li></ul><ul><li>Good Clinical Practice </li></ul><ul><li>CTD Mapping v1.2.pdf </li></ul><ul><li>eCTD Basics http:// </li></ul><ul><li>Electronic Submission Gateway </li></ul><ul><li>Drug Development and Review Definitions </li></ul><ul><li> </li></ul><ul><li>International Conference on Harmonisation </li></ul><ul><li> </li></ul>
  58. 58. <ul><li>Louise C. Johnson, M.S. </li></ul><ul><li>[email_address] </li></ul><ul><li> </li></ul><ul><li> </li></ul><ul><li>Louise_Johnson </li></ul><ul><li>On Twitter </li></ul>Thank you!