March Breakfast

1. March Breakfast Pre-IND and IND Development: Lessons LearnedBIOCOM’s CRO Workshop28 July 2010Sybille Sauter, Ph.D., RACCato Researchssauter@cato.com www.biocom.org

2. March Breakfast Workshop Schedule www.biocom.org

3. March Breakfast Agenda • Pre-IND meetings • Investigational New Drug (IND) applications • Looking at Europe (CTA, scientific advice, protocol assistance) • Panel Discussion, Q&A www.biocom.org

4. March Breakfast Drug Development Process NDA/BLA IND Pre-IND Phase Marketing Application Phase Post Marketing Phase IND Review Phase Development Preclinical IND Review CLINICAL TRIALS Ph I Ph II Ph III ND/BLA Review Post Marketing Pre IND Meeting Pre IND Meeting End of Ph 2 Meeting Pre-NDA/BLA Meeting Safety Meetings End of Ph 3 Meeting Post NDA/BLA Meeting IND review - 30 Days www.biocom.org

5. March Breakfast Pre-IND Meetings www.biocom.org

6. March Breakfast Pre-IND Meeting Facts • Not required but highly recommended • FDA grants 1 pre-IND meeting per application • Usually held 6-12 months before IND submission • FDA provides clear guidance for pre-IND meeting process and associated documents • Guidance for Industry: “Formal Meetings Between the FDA and Sponsors or Applicants”, 2009 • SOPP 8101.1: Scheduling and Conduct of Regulatory Review Meetings with Sponsors and Applicants (CBER) • Guidance for Industry: “IND Meetings for Human Drugs and Biologics, CMC Information”, 2001 • Trend: FDA grants less pre-IND meetings! www.biocom.org

7. March Breakfast FDA: PDUFA Meeting Workload www.biocom.org

8. Cons • Requires time and resources March Breakfast Why Have a pre-IND Meeting? Pros • Introduces your product/company to FDA • Minimizes risk for clinical hold • Solidifies regulatory and development path for CMC, nonclinical and clinical aspects before finalizing the IND www.biocom.org

9. March Breakfast Meetings Are Not Appropriate when… • Timing is off (premature, too late for full benefit) • Key people are not available to meet • Important information is missing www.biocom.org

10. March Breakfast Pre-IND Meetings May Not be Necessary if… • Not a first-in-class product, accepted clinical trial designs and well established endpoints • High level of familiarity with FDA Division, repeated IND filings for similar indications for several years www.biocom.org

11. March Breakfast Pre-IND Meetings Are Recommended if…. • Questions are not answered by regulations and guidances • Novel indication • Sponsor new to drug development • Pharmacologic or toxicologic signals of concerns • New molecular entity • Unique molecular entity or studies • Sponsor wishes to discuss methods to enhance development (i.e., orphan or fast track designation, accelerated approval) • Drug intended to treat a serious and life-threatening illness www.biocom.org

12. Clinical Dev Time NDA Review Time IND: Clinical Hold Rate (Vaccines) 100 100 50 80 80 40 60 60 30 Months Months Percentage 40 40 20 20 20 10 No mtg Mtg 0 0 0 March Breakfast Do pre-IND Meetings Really Make a Difference? Source: DL Miller, JJ Ross. Vaccine INDs: review of clinical holds. Vaccine, 23(9), pp1099–1101, 2005. DiMasi and Manocchia, DIA Journal 1997 www.biocom.org

13. March Breakfast Maximize the Benefit of your Pre-IND Meeting • Establish a good relationship with your FDA project manager • Do not have a meeting until you are ready • Spend most of your time discussing your questions (avoid background presentation) • Receive feedback for all aspects of your IND • CMC, nonclinical, clinical, regulatory www.biocom.org

14. March Breakfast Pre-IND Meeting: Type B Meeting Source: Guidance for Industry: “Formal Meetings Between the FDA and Sponsors or Applicants”, May 2009 www.biocom.org

15. March Breakfast Pre-IND Meeting: Overall Timeframe • Assumptions • All information for pre-IND package available • FDA grants pre-IND mtg request • Pre-IND mtg scheduled within 60 days following request Step 2 Step 4 Step 1 Step 5 Hold Pre-IND mtg Submit pre-IND package Submit mtg minutes Request pre-IND mtg Step 3 Draft questions Meeting preparation FDA review response Mtg minutes Generate pre-IND package Months 1 2 3 4 5 www.biocom.org

16. March Breakfast If Your Don’t Hear from FDA by Day 21 after Sending the Request… CENTER FOR DRUG EVALUATION AND RESEARCH PRE-IND Consultation Contacts Source:http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/Overview/UCM166356.pdf www.biocom.org

17. March Breakfast Pre-IND Questions: Remember… • Sponsor is expected to have the drug development thought through with data/science supporting the rationales for proposal • Do not ask FDA what to do next! • instead, make a proposal and ask whether FDA concurs • Make sure that answers to your questions are not already available in the guidances • Only ask questions that FDA can answer, be specific, avoid open-ended questions • Number of questions: varies (~ 4-8) www.biocom.org

18. March Breakfast Not so Helpful Questions • Will a designated FDA preclinical reviewer work with the sponsor to provide feedback on the optimal design of the proposed preclinical study? • How appropriate is study design A and is there a preference regarding specific endpoints? • In regards to shipping and handling, what are the minimum and maximum periods of cold storage stability that FDA would find acceptable for the assembled biologic/device? • Is <infectious agent> testing of the source animals required, and if yes, what actions should be taken in the event of a positive finding? • What limits must be established for decrease in platelets and hematocrit during the treatment procedure? www.biocom.org

19. March Breakfast Helpful Questions: Examples • Does the Division agree with the proposed starting dose and dose escalation scheme for the Phase 1/2 study in <study population>? • Does the Division agree that the current nonclinical safety studies conducted with <drug> in rats and dogs are sufficient to support the proposed Phase 1 study in <study population>? • Does the Division agree with <Sponsor’s> assessment of the NOAEL (no observable adverse effect level) and derivation of the initial safe starting dose? • Does the Division agree that the analytical test procedures used to manufacture and characterize the master cell bank are adequate to support manufacture of the active ingredient ? • Does the Division agree that the proposed release specifications, analytical tests, and acceptance criteria for drug substance and initial clinical drug product are sufficient to begin Phase 1 studies? www.biocom.org

20. March Breakfast Common Shortcomings Identified by FDA • Inadequate CMC information • Insufficient pre-clinical support • Unacceptable clinical trial design • Lack of information on selection of dosage www.biocom.org

21. Pre-IND Phase IND Review Phase Marketing Application Phase Post Marketing Phase Pre Pre IND Meeting (Informal) March Breakfast Pre-pre-IND Meetings Development Preclinical IND Review CLINICAL TRIALS Ph I Ph II Ph III BLA Review Post Marketing Pre IND Meeting End of Ph 2 Meeting Pre-BLA Meeting Safety Meetings End of Ph 3 Meeting Post BLA Meeting IND review - 30 Days Source: Celia Witten, Ph.D., M.D.,Office Director, Office of Cellular, Tissue, and Gene Therapies (OCTGT), CBER/FDA, ISSCR/CIRM/ISCT Workshop, June 15, 2010 www.biocom.org

22. March Breakfast Pre-pre-IND Meetings • Limited to products reviewed by CBER’s Office of Cellular, Tissue, and Gene Therapies (OCTGT) • Sponsor can get informal general advice from CBER pharmacology/toxicology reviewers • Intended to be a focused, scientific dialogue based on preliminary work • Pre-pre IND package: max 25 pages • Description of intended product • Outline of proposed clinical trial • Summary of preclinical data • Specific questions concerning the pharmacology/toxicology aspect • Additional information • http://www.gtrp.org/Home/Documents/Information/VectorDev.doc www.biocom.org

23. March Breakfast Recombinant Advisory Committee (RAC) Meetings • Conduct public review and discussion of science, safety and ethics for products containing recombinant DNA (gene transfer protocols) • May request in-depth review and public discussion (20-30%) • Protocols discussed at quarterly meetings • RAC recommendation provided to the PI, Institutional Review Board, Institutional Biosafety Committee, FDA • RAC minutes posted on Office of Biotechnology Activities website www.biocom.org

24. March Breakfast Pre-IND Meetings: Case Study 1 • Background • Pre-pre-IND meeting to discuss complex gene therapy product with two types of nucleotides plus liposome • Target population: end-stage cancer patients • Had a pre-IND meeting and asked whether initial trial in target population could be a repeated dose study • Pre-IND Meeting outcome • FDA said YES! • Consequence • Fast-forwarded drug development plan • Sponsor needed more product, funds, and time for multiple dose GLP toxicology and clinical studies www.biocom.org

25. March Breakfast Lessons Learned: Pre-IND Meeting • Determine whether you need a pre-IND meeting • Request meeting only when you are ready • Submit a high-quality pre-IND briefing package • Ask specific and clear questions that can be answered • Take great care in evaluating FDA’s preliminary responses • Be well prepared for the pre-IND meeting, anticipate questions, identify back-up positions • State your case confidently • Know your regulations and guidances www.biocom.org

26. March Breakfast IND Submissions www.biocom.org

27. March Breakfast The IND – It’s a Process • Project management • Internally: scientists, senior management • Externally: vendors, consultants, inventors • Agree on milestones, objectives, timelines, resource allocation, responsibilities • Medical writing (style guide, document templates) • CMC, nonclinical, clinical experts • Regulatory experts (strategy, operations/submissions) www.biocom.org

28. March Breakfast www.biocom.org

29. March Breakfast Effective Management Tools Time Kickoff Meetings Table of contents Communication plan Target product profile Global program timeline Rolling submission management Cost Quality www.biocom.org

30. March Breakfast Integrated Table of Contents www.biocom.org

31. March Breakfast Key IND Requirements • First-in-human (FIH) study protocol • Rationale for intended use (in vitro and in vivo pharmacology) • Toxicology data supporting the starting dose and duration of the FIH study • Assurance of quality of drug substance/product used in toxicology studies and in the FIH study www.biocom.org

32. March Breakfast Inexperienced Sponsors Tend to… • Have difficulty finding the right balance for the most efficient drug development route • Do more than is necessary • Don’t perform all the studies necessary • Conduct activities in series rather than in parallel • Solicit advice from multiple parties • Contradicting advice can be confusing www.biocom.org

33. March Breakfast IND Submissions – Facts to Consider • Resources to understand FDA’s thinking • FDA approval packages of similar drugs/indications • Advisory Committee Meetings • Recent changes at FDA • 38% of FDA’s drug review staff have < 2 years experience • Emphasis on safety impacts decision making (appears more conservative) • Electronic submissions in the common technical document format (eCTD) are encouraged by FDA www.biocom.org

34. March Breakfast eCTD Submissions – Background • eCTD implemented in 2005 by FDA • Applies to INDs, NDAs, ANDAs, BLAs, DMFs and associated submissions • United States • 01 Jan ‘08: electronic submissions must be in eCTD format (not mandatory but industry standard) • Europe • 01 Jan ‘10: electronic submissions must be in eCTD format (centralized procedure, EMA) www.biocom.org

35. Submission Media of Original INDs 3,500 3,000 2,500 2,000 Number of Submissions 1,500 1,000 500 0 2005 2006 2007 2008 2009 Paper or mixed Gateway or electronic March Breakfast Electronic Submissions – an FDA Perspective • 12.5% of original INDs in electronic format • 56.2% of original NDAs in electronic format Source: DIA EDM Meeting, 2010, Theresa Mullin www.biocom.org

36. March Breakfast Recommended: CTD Format and Electronic Not partof the CTD Regionaladministrative information Module 1 Non-clinical overview Module 2 Clinical overview The CTD Quality overallsummary Non-clinical summary Clinical study Non-clinical study reports Module 4 Clinical study reports Module 5 Quality Module 3 CTD: common technical document www.biocom.org

37. Module 1 (Regional Information) Module 2 (Summaries) Module 3 (Quality) Module 4 (Nonclinical Reports/Safety) Module 5 (Clinical Reports/Efficacy) March Breakfast Traditional IND (US) Format CTD Format 1. Form FDA 1571 2. Table of Contents* 3. Introductory Statement 4. General Investigational Plan 5. Investigator’s Brochure 6. Clinical Study Protocol 7. Chemistry, Manufacturing, and Controls Data 8. Pharmacology/Toxicology Data 9. Previous Human Experience 10.Additional Information a. pre-IND correspondence b. Literature References c. Investigational Drug Labeling www.biocom.org

38. March Breakfast Two Most Common Questions for Creation of IND in eCTD Format • Timelines? - yes, an eCTD application can be faster than a paper submission 2. Authoring best practices? www.biocom.org

39. March Breakfast IND Submission – Overall Timeframe • Assumptions • Nonclinical studies with audited final reports ~ 3-4 months, all other information available • FDA clears IND after 1st round of review FDA Decision Site initiation visit/CTM Identify/evaluate clinical site and PI Protocol to IRB Submit IND pre-IND mtg FDA review Generate and compile IND Nonclin toxicology final report 1 2 3 4 5 6 7 months www.biocom.org

40. March Breakfast Best eCTD Authoring Practices – Your Main Goal is … • Effective communication! www.biocom.org

41. March Breakfast Best Authoring Practices • Adhere to CTD hierarchy • Use appropriate level of granularity • Generate comprehensive study tagging files • Make clear references to study reports • Use smart hyperlinking practices • Use meaningful file names www.biocom.org

42. March Breakfast Advice from FDA: 5 Most Common Technical Errors with eCTD Submissions • Always send Module 1 with any eCTD submission • Check your numbers • Don’t submit “extra” files • Don’t use “bad” characters in file or folder names (space, / \ : ? “< > |) • Learn to use the Electronic Submissions Gateway www.biocom.org

43. March Breakfast Advice from FDA: 5 Ways to Make Your eCTD Submission Reviewer-friendly • Use the fillable PDF version of all forms • Avoid the use of scanned documents • Make your documents easy to navigate • Don’t go crazy with granularity • Ask “If I were a reviewer..” www.biocom.org

44. March Breakfast IND Submission: Case Study 1 • Inhaled drug for pulmonary disease • Toxicology studies: 2 animals had died at a dose 1000-fold higher than biologically active dose, iv • IND put on hold due to toxicology findings (spleen abnormalities?) • Resolution • Spleen from all animals in toxicology studies examined by independent pathologist (compared with historical controls) • IND cleared following submission of pathology report • No additional toxicology study necessary www.biocom.org

45. March Breakfast IND Submission: Case Study 2 • Topical combination product for wound healing • On Day 29 after IND submission, FDA announced in a t-con that the IND will be put on hold due to concerns with the clinical protocol (safety assessments) • Resolution • FDA accepted a letter of commitment letter from the sponsor to make all suggested protocol changes • IND was not put on hold • Protocol changes filed as amendment later www.biocom.org

46. March Breakfast Lessons Learned: IND Submission • Take pre-IND input from FDA seriously • IND should be driven by science and data • Avoid incomplete data • Determine NOEL/NOAEL in toxicology studies • Ensure that impurity profile of the drug substance is the same in the material for toxicology studies and the first clinical study • Develop a clear positive benefit/risk argument • High quality submission • Understand regulatory guidances and requirements www.biocom.org

47. March Breakfast Looking at Europe… www.biocom.org

48. March Breakfast Scientific Advice and Protocol Assistance - Differences Scientific Advice (SA) • SA given on all medicinal products for human use on questions concerning quality (CMC), non-clinical, clinical and risk management aspects, irrespective of whether or not the product is a centralized procedure candidate • Subject to a fee Protocol Assistance (PA) • PA given for orphan products on the same above questions; orphan products reviewed via the centralized procedure • Eligible for fee reductions for all fees payable www.biocom.org

49. March Breakfast Scientific Advice and Protocol Assistance – Common Features • SA/PA with individual agencies in Europe or with the European Medicines Agency (EMA) • SA/PA can be requested several times during initial product development but also during the post authorization phase • Procedure typically 3 months: • Request SA/PA via letter of intent • Send briefing package with questions and company’s position at least 5 days prior to the internal EMA meeting • Written report provided on Day 40 (without) or 70 (with discussion meeting) after review start www.biocom.org

50. March Breakfast Scientific Advice and Protocol Assistance – Common Features (cont’d) • Advice/Assistance is non-binding • PA and SA are not made public Source: EMEA-H-4260-01-Rev. 6 http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004089.pdf www.biocom.org