1. (Investigational New Drug) IND

6. New drug,

7. The proposed trial, and the

10. A new chemical entity Not approved for the indication under investigation In a new dosage form.

11. Being administered at a new dosage level.

12. In combination with another drug and the combination is not approved. All clinical studies where a new drug is administered to human subjects, regardless of whether the drug will be commercially developed, require an IND.

13. When You Don’t Need an IND? An IND is not required to conduct a study if the drug: Is not intended for human subjects, but is intended for in vivo testing or laboratory research animals (non clinical studies) Is an approved drug and the study is within its approved indication for use.

14. Pre-IND Meeting A meeting between the sponsor and the FDA frequently is useful in resolving questions and issues raised during the preparation for an IND. The FDA encourages such meetings to the extent that They aid in the solution of scientific problems and To the extent that the FDA has available resources.

15. Pre-IND Meeting A pre-IND meeting is considered a Type B meeting. It is a “formal” meeting requiring a written request that includes, A list of specific objectives. Expected outcomes. List of specific questions, grouped by discipline.

16. Pre-IND Meeting Most issues and questions are usually related to the Design of animal studies needed to initiate clinical trials also The scope and design of the initial study in humans. Type B meetings should be scheduled to occur within 60 days of the FDA’s receipt of the written request for the meeting.

18. The briefing document should provide

19. summary information relevant to the product and

20. supplementary information that the FDA can use to provide responses to the questions that have been identified by the sponsor for the IND submission.

22. FDA personnel in clinical pharmacology/toxicology,

23. Bio pharmaceutics,

24. Chemistry,

25. Statistics,

26. Microbiology, and

28. The Content and Format of an IND Application The content and format of an initial IND is laid out in 21 CFR Part 312 Cover Sheet —312.23(a)(1)FDA Form 1571 Table of Contents —313.23(a)(2) Introductory Statement and General Investigational Plan —312.23(a)(3) Investigator’s Brochure —312.23(a)(5) Clinical Protocol —312.23(a)(6) Chemistry Manufacturing and Controls Information —312.23(a)(7)

29. The Content and Format of an IND Application Pharmacology and Toxicology Information —312.23(a)(8) Previous Human Experience —312.23 (a)(9) Additional Information —312.23(a)(10) Relevant Information —312.23(a)(11)

30. The Content and Format of an IND Application The form 1571 is a required part of the initial IND and every subsequent submission related to the IND application. The 1571 serves as a cover sheet for IND submissions and provides the FDA Basic information about the submission: Name of the sponsor. IND number. Name of the drug. Type of submission. Serial number, and The contents of the application.

31. The Content and Format of an IND Application It is important to note that the FDA expects every submission, even the most routine correspondence, to be submitted with a completed form 1571 and have a serial number. The FDA tracks all IND submissions based on serial numbers and will file them according to the serial number when received.

32. The Content and Format of an IND Application The 1571 form provides a section for the sponsor to state whether a contract research organization (CRO) will conduct any parts of the study and if any sponsor obligations will be transferred to the CRO. If sponsor responsibilities will be transferred, a list of the obligations transferred and the name and address of the CRO must be attached to the 1571 form.

34. Institutional Review Board (IRB) A board or committee formally designated by an institution to review and approve the initiation of biomedical research involving human subjects. The primary purpose of the IRB is to protect the rights and welfare of human subjects.

37. The Content and Format of an IND Application These are significant commitments and the sponsor should be aware that Signing the 1571 is more than a formality Making a willfully false statement on the 1571 is a criminal offense.

39. The TOC should include all required

40. Sections,

41. Appendices,

42. Attachments,

43. Reports, and

45. Table of Contents —13.23(a)(2) Many sponsors begin planning the IND submission by laying out the table of contents first. This allows the team to clearly see what information is required for the submission and how the document will be structured and It allows the TOC to be updated as the application is being built.

46. Introductory Statement and General Investigational Plan — 312.23(a)(3) This section should provide a brief, three- to four-page and provides Overview of the investigational drug and The sponsor’s investigational plan. The goal of this section is simply To provide a brief description of the drug Lay out the development plan for the drug.

47. Introductory Statement and General Investigational Plan — 312.23(a)(3) The introductory statement should begin with a description of the drug and the indication(s) to be studied and include the Pharmacologic class of the compound, The name of the drug and All active ingredients, The structural formula of the drug and The dosage form and Route of administration.

49. The introductory statement should include a brief summary of human clinical experience to date, focusing mainly on safety of the drug in previous studies

50. If the drug was withdrawn from investigation or marketing in any country for safety reasons,

51. The name of the country and

53. The IB presents, in summary form,

54. The key nonclinical,

55. Clinical and

56. CMC data that support the proposed clinical trial.

57. The IB provides the clinical investigators with the information necessary to understand

58. The rationale for the proposed trial and

60. Investigator’s Brochure — 312.23(a)(5) A summary of all relevant nonclinical Pharmacology, Toxicology, Pharmacokinetic, Drug metabolism information generated to support human clinical studies. It should include a tabular summary of Each nonclinical study conducted, Outlining the methodology used and The results of each study.

61. Investigator’s Brochure — 312.23(a)(5) If human clinical studies have been conducted with the drug, a summary of information relating to safety and effectiveness should be presented, It should also include information from studies on the metabolism, Pharmacokinetics, Pharmacodynamics, Dose response, other Pharmacological activities.

62. Investigator’s Brochure — 312.23(a)(5) A summary of data and guidance for the investigator in the management of subjects participating in the trial. An overall discussion of the nonclinical and clinical data presented. Discussion of the Possible risks and adverse reactions associated with the investigational drug product, and The specific tests, observations, and precautions that may be needed for the clinical trial.

63. Investigator’s Brochure — 312.23(a)(5) It is important to remember that the IB is a living document Must be updated by the sponsor as new information becomes available from ongoing clinical and nonclinical studies.

65. It describes

66. The objectives of the study,

67. The trial design,

68. How subjects are selected and

69. How the trial is to be carried out.

70. The initial IND is required to have a clinical protocol for each planned study.

72. A statement of the objectives and the purpose of the study

73. Name, address, and qualifications(curriculum vitae) of each investigator and each sub investigator participating in the study;

75. Study subject inclusion and exclusion criteria

77. The planned maximum dose, the duration of patient exposure to the drug, and the methods used to determine the doses to be administered.

78. A description of the measurements and observations to be made to achieve the study objectives.

81. Chemistry Manufacturing and Controls Information —312.23(a)(7) Key section of an IND describes Composition, Manufacturing process, and Control of the drug substance and drug product. The CMC section must provide sufficient detail and information to demonstrate the Identity, Quality, Purity, and Potency of the drug product.

83. Product made with unknown or impure components.

84. Product has a chemical structure(s) of known or highly likely toxic.

86. Chemistry Manufacturing and Controls Information —312.23(a)(7) The FDA requires that any drug product intended for administration to humans be manufactured in conformance with cGMP. Adherence to GMP provides a minimum level of control over the manufacturing process and final drug product and helps to ensure the Identity, Quality, Purity, and Potency of the clinical trial material.

88. CMC Introduction

89. Information on the drug substance in the form of a summary report

92. These data must provide a good level of confidence that the new drug product is reasonably safe for administration to human subjects at the planned dosage levels.

95. Safety pharmacology studies (often conducted as part of the toxicity studies).

97. Reproduction toxicity studies (nonclinical animal studies conducted to reveal any effects the investigational drug may have on mammalian reproduction).

99. Additional Information —312.23(a)(10) This section is used to present information on special topics. Drug dependence and abuse potential. Radioactive drugs. Pediatric studies. Any plans the sponsor has for assessing the safety and effectiveness of the drug in the pediatric population. Other information. Any other relevant information that might aid in the evaluation of the proposed clinical investigations.

100. Relevant Information —312.23(a)(11) Any information specifically requested by the FDA that is needed to review the IND application.

104. The FDA can request that a sponsor submit additional copies of a particular submission at any time.

106. The FDA Review of the IND All these areas review the data submitted with the primary purpose to ensure appropriate safety of the individuals who will be enrolled in the study Once an IND is submitted, the study cannot be initiated until a period of 30 days has passed If there are any major issues relating to the safety of the volunteers or patients in the proposed study, the FDA can institute a “clinical hold.”

107. The FDA Review of the IND A clinical hold may be either a “complete clinical hold” — a delay or suspension of all clinical work requested under an IND, or a “partial clinical hold” — a delay or suspension of only part of the clinical work (e.g., a specific protocol or part of a protocol)

109. The annual report must contain the following information:

110. Individual study information

111. Summary Information

112. The general investigational plan for the coming year.

114. Classification of INDs INDs can be classified on four dimensions: Commercial / Noncommercial, Standard / Emergency, Paper / Electronic, Original / 505(b)(2).

115. Commercial and Non commercial INDs Commercial INDs (those intended to lead to eventual production and marketing of a drug) are subject to greater scrutiny and review than INDs submitted by universities, research laboratories, and other not - for - profit organizations. For the noncommercial organizations, IND review tends to focus on the study design and the role of the Institutional Review Board (IRB).

116. Emergency INDs Emergency INDs (often supplements to or amendments of standard INDs) receive priority review and accelerated consideration. As supplements, emergency INDs are generally abbreviated formats referencing the original IND (with a newly filed 1571 form). Most often, they represent corrections or modifications in the experimental design, chemistry, and/or control of the new drug.

118. Purely electronic submissions are still rare, in large part because of a lack of standardization and electronic sophistication on the part of the FDA.

119. There is currently a Clinical Data Interchange Standards Consortium (CDISC) test underway.

123. sponsor wants to initiate a new clinical study that is not described in the existing IND or

124. When the sponsor makes changes to an existing protocol including adding a new investigator to a trial.

125. New protocols are submitted

126. When clinical development of the drug advances to the next phase, e.g., from Phase I to Phase II, or

130. An increase in drug dosage or duration of exposure of the subjects to the drug beyond that listed in the current protocol

131. A significant increase in the number of subjects participating in the trial

132. A change in the design of the protocol, such as adding or dropping a control group

133. Adding a new test procedure to monitor for, or reduce the risk of, an adverse event.

136. An information amendment may include

137. New toxicology or pharmacology information,

138. Final study reports for completed nonclinical or other technical studies,

139. New CMC information,

140. Notice of discontinuation of a clinical study, or