1. Briefing Documents

2. Presentation Overview What is a BD BD preparation process Tips 2

3. What Is a Briefing Document (BD)? Definition:Dossier of information sent to a regulatory agency to enable it to provide desired scientific or regulatory guidance May also be called: briefing package, briefing packet, briefing materials, information package, information packet, etc. 3

4. Situations Involving Briefing Documents FDA: BDs are associated with a scheduled meeting. BDs are sent 2 to 4 weeks before the meeting to familiarize agency participants with the issues to be discussed. Type A meeting: To discuss an urgent issue that is delaying development Type B meeting: To discuss a particular stage of drug development: pre-IND, end of Phase 2 (or end of Phase 1), pre- NDA (most common type) Type C meeting: Any that does not fit into prior 2 categories Advisory Committee briefing document: To provide information to an FDA Advisory Committee in preparation for Ad Comm meeting. 4

5. Situations Involving Briefing Documents CHMP (EU Regulatory Agency): Meetings encouraged, but process is different: Submit info, then CHMP either invites for a meeting or responds in writing. You may also request presubmission meetings. CHMP does not use terminology “briefing document,” but document requirements are very similar. Fees: CHMP has fees associated with providing scientific advice. FDA does not impose fees for the meetings; instead fees are associated with the larger IND/NDA submissions themselves. 5

6. Content of Briefing Documents List of questions/issues to be discussed, with sponsor position on each question or issue and appropriate rationale. Questions are grouped by discipline. Background information needed for the agency to develop responses to the questions. Content of package should support intended objectives of meeting— no more, no less. Rest of slides focus on Type B FDA briefing documents, but most concepts can be applied to other types of briefing documents (exception is Advisory Committee BDs). 6

7. Briefing Document Development Process ACT Submit CHECK Review, approvals, editing & QC DO Draft the BD PLAN Assemble team and prepare 7

8. Planning Determine whether a meeting is needed (consult regulatory guidances) Assemble team –Usually led by regulatory personnel and writer –Other participants: CMC, toxicology, ADME, PK, clinical pharmacology, physicians, statisticians, study managers, project managers, etc. as needed. Arrange kick-off meeting 8

9. Planning: Kick-off Meeting Identify key issues/questions (brainstorm) Pre-IND meeting: Seek approval of proposed Phase 1/2 clinical plan including first protocol, anticipated exposure in humans, safety plan given what is known in animals, etc. End of Phase 2 meeting: Seek approval of proposed Phase 3 clinical plan including adequacy of protocol, endpoints, statistical plans, etc. Pre-NDA meeting: Seek approval of NDA format and content. Typically this meeting is more regulatory in nature than scientific with very little discussion of actual data. Organize and prioritize issues/questions; assign responsibilities Establish tentative timeline for process (coordinate with meeting request) If a team already has regular issues meetings, the kick-off may be done virtually 9

10. Planning: Pre/Post Kick-off 1.Position/Proposal State Position/Proposal Rationale to support Position/Proposal List of data supporting Rationale 2.Question X (appropriately worded) Gather information to address the issues. This can be done at various times for various issues: Ahead of kick-off, done by regulatory representative or by the writer At kick-off, done by team After the kick-off, by designated individuals 10

11. Doing Use the information gathered in each box to draft the briefing document. Methods vary: –Writer can pull everything together once team members provide appropriate information –Team members can provide drafted text; writer has more of a coordinating/editing role Upshot, though, for each issue: –Clear, powerful position statement for each issue/question –Brief scientific rationale for each position, and if needed, a more detailed background section 11

12. Doing: Writing Briefing Document Questions Each question should have a unique number. Each question should be specific enough to stand on its own, though it may refer to other sections for complete information. Ex. “Does FDA agree with our proposal to do XYZ, as described in Section X?” (not just “Does FDA agree with our proposal?”) Provide brief rationale, and reference to more detailed information. Avoid open-ended questions in favor of yes/no questions. 12

13. Doing: Writing Briefing Document Questions An example: Question 2: Dosing The proposed dose range of 2 mg/day, a potentially ineffective dose, to 32 mg/ day, likely a maximal dose, is expected to adequately inform the dose-response relationship. Does the Division agree? Rationale: As described in Section 4.3, an efficacious dose of fixidol for the treatment of Disease X is considered to be 16 mg/day, based on efficacy and safety information from proof-of-concept Study A. Safety and efficacy of doses higher and lower than 16 mg/day were evaluated in Study B, a 4-week, dose-ranging study that evaluated fixed doses of fixidol including 2, 8, 16, and 32 mg/day. The primary analyses from Study B failed to demonstrate that any of the 4 fixidol doses or the active control drugapil was more efficacious than placebo, perhaps due to a higher than anticipated observed effect in the placebo group. However, overall tolerability of fixidol at all 4 doses was consistent with results from Study A. Safety and efficacy of fixidol doses higher and lower than 16 mg/day thus continue to require further exploration. The proposed clinical studies will further explore the dose-response following administration of 2, 8, 16, and 32 mg/day. The sponsor believes the dose range should be adequate to define a minimally efficacious dose and an optimally efficacious dose of fixidol for the treatment of Disease X. 13

14. Doing: Writing Briefing Document Questions An example: Question 2: Dosing The proposed dose range of 2 mg/day, a potentially ineffective dose, to 32 mg/ day, likely a maximal dose, is expected to adequately inform the dose-response relationship. Does the Division agree? Rationale: As described in Section 4.3, an efficacious dose of fixidol for the treatment of Disease X is considered to be 16 mg/day, based on efficacy and safety information from proof-of-concept Study A. Safety and efficacy of doses higher and lower than 16 mg/day were evaluated in Study B, a 4- week, dose-ranging study that evaluated fixed doses of fixidol including 2, 8, 16, and 32 mg/day. The primary analyses from Study B failed to demonstrate that any of the 4 fixidol doses or the active control drugapil was more efficacious than placebo, perhaps due to a higher than anticipated observed effect in the placebo group. However, overall tolerability of fixidol at all 4 doses was consistent with results from Study A. Safety and efficacy of fixidol doses higher and lower than 16 mg/day thus continue to require further exploration. The proposed clinical studies will further explore the dose-response following administration of 2, 8, 16, and 32 mg/day. The sponsor believes the dose range should be adequate to define a minimally efficacious dose and an optimally efficacious dose of fixidol for the treatment of Disease X. Question can stand alone. 14

15. Doing: Writing Briefing Document Questions An example: Question 2: Dosing The proposed dose range of 2 mg/day, a potentially ineffective dose, to 32 mg/ day, likely a maximal dose, is expected to adequately inform the dose-response relationship. Does the Division agree? Rationale: As described in Section 4.3, an efficacious dose of fixidol for the treatment of Disease X is considered to be 16 mg/day, based on efficacy and safety information from proof-of-concept Study A. Safety and efficacy of doses higher and lower than 16 mg/day were evaluated in Study B, a 4- week, dose-ranging study that evaluated fixed doses of fixidol including 2, 8, 16, and 32 mg/day. The primary analyses from Study B failed to demonstrate that any of the 4 fixidol doses or the active control drugapil was more efficacious than placebo, perhaps due to a higher than anticipated observed effect in the placebo group. However, overall tolerability of fixidol at all 4 doses was consistent with results from Study A. Safety and efficacy of fixidol doses higher and lower than 16 mg/day thus continue to require further exploration. The proposed clinical studies will further explore the dose-response following administration of 2, 8, 16, and 32 mg/day. The sponsor believes the dose range should be adequate to define a minimally efficacious dose and an optimally efficacious dose of fixidol for the treatment of Disease X. Brief rationale provided. 15

16. Doing: Writing Briefing Document Questions An example: Question 2: Dosing The proposed dose range of 2 mg/day, a potentially ineffective dose, to 32 mg/ day, likely a maximal dose, is expected to adequately inform the dose-response relationship. Does the Division agree? Rationale: As described in Section 4.3, an efficacious dose of fixidol for the treatment of Disease X is considered to be 16 mg/day, based on efficacy and safety information from proof-of-concept Study A. Safety and efficacy of doses higher and lower than 16 mg/day were evaluated in Study B, a 4- week, dose-ranging study that evaluated fixed doses of fixidol including 2, 8, 16, and 32 mg/day. The primary analyses from Study B failed to demonstrate that any of the 4 fixidol doses or the active control drugapil was more efficacious than placebo, perhaps due to a higher than anticipated observed effect in the placebo group. However, overall tolerability of fixidol at all 4 doses was consistent with results from Study A. Safety and efficacy of fixidol doses higher and lower than 16 mg/day thus continue to require further exploration. The proposed clinical studies will further explore the dose-response following administration of 2, 8, 16, and 32 mg/day. The sponsor believes the dose range should be adequate to define a minimally efficacious dose and an optimally efficacious dose of fixidol for the treatment of Disease X. Reference to details given. 16

17. 1.Background/Introduction Description of compound (chemical structure, relevant information about drug class, rationale for development in proposed indication) Regulatory history (IND #, status of previous commitments, actions by other regulatory authorities if applicable) High-level objectives for meeting 2.Questions for Discussion 3.Chemistry, Manufacturing, and Control 4.Preclinical Development 5.Clinical Pharmacology 6.Clinical Development 7.Regulatory/Administrative Example Table of Contents 17

18. Checking: Refining the BD Reviews Team members, management, editor Strategy review, if required by company Revise content accordingly Things to consider Ensure consistency for all portions of the BD For joint preclinical/clinical + CMC briefing documents: –Ensure communication between personnel from all areas –Determine “FDA Time” needed to address issues; ensure that meeting time will be sufficient to address everything. 18

19. Checking/Submitting Check Final editorial and quality reviews Assemble briefing document package, including any forms Submit to FDA (electronic gateway) Team follow-up tasks –Prepare for meeting –Meeting –Post-meeting debrief, sponsor meeting minutes, FDA meeting minutes 19

20. Potential Pain Points Participants fail to “do homework” (come up with issues, write questions, rationales, etc). To head off: –Brainstorm ideas for BD before kick-off –Provide participants with draft questions/text to react to…more productive than starting from scratch Team has difficulty deciding/articulating company position on an issue. To head off: –With regulatory, ensure that team strategy is well- thought-out before beginning process. –Convene regular meetings for team; ensure that “the deciders” are all there, together. 20

21. Useful Links Code of Federal Regulations 312.47 (Laws relating to FDA meetings for INDs and NDAs) http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.47 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=312.47 Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants, adopted May 2009 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM153222.pdf http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM153222.pdf European Medicines Agency (EMEA)/Committee for Medicinal Products for Human Use (CHMP) Links to guidances on seeking scientific advice and protocol assistance: http://www.ema.europa.eu/htms/human/raguidelines/sa_pa.htm http://www.ema.europa.eu/htms/human/raguidelines/sa_pa.htm 21