1. Preclinical Submissions to the FDA From Reviewer’s Perspective Harry M. Geyer, PhD Manager, Regulatory Affairs Teva USA harry.geyer @tevausa.com (305) 575-6083

2. 2 Background Basics

3. 3 Do NOT Underestimate the Reviewer (1) Reviewers have seen more INDs in their first two years than most industry personnel have seen in an entire career. There is an “Institutional Memory.” They have seen it - so do not try to “pull the wool over their eyes.” –“once burned, twice cautious”

4. 4 Do NOT Underestimate the Reviewer (2)  Reviewers appreciate it if the sponsor sends information/literature relating to a new, cutting-edge field or when there are issues in a submission or in development.  The reviewers do want to assist your development – not hinder it  If the reviewer needs more information on a subject they can go to in-house experts and/or academic experts – and they do.

5. 5 Do NOT Underestimate the Reviewer (3)  All submission reviews are reviewed a second time by the team-leader and for NDAs a tertiary review is also conducted.  The original data is usually re-reviewed only if there is conflict between the evaluations of the sponsor and the primary reviewer.

6. 6 Do NOT Overestimate the Reviewer The reviewer may need a study for a specific toxicity. Often suggestions are supplied with the request. Reviewers do not have the time to design your study for you, but should be consulted on the adequacy of the final design prior to study initiation.

7. 7 Reviewers are people too, actually they are there to help you Aggression is not useful. You may think you can bully the reviewer, but you are only a small part of their job but they are very large part of your job. Reviewers are supported by team leaders and Division Directors and, if you try to jump levels for support of your position, it will most likely delay the review. However, with conflicts, there are official methods of addressing them and this is a separate subject.

8. 8 Nonclinical Study Reports The following proposals are based on regulation (federal law), guidances or common courtesy. All are to facilitate the efficiency of reviews and eventual approval of your therapeutic products.

9. 9 General Considerations - 1 Use the same format to create reports which the reviewer uses to evaluate it, (CTD). The Review Template follows. Keep the units the same! Between animals and man and between and within studies. Compare to human data, blood levels, pharmacokinetics, metabolites, toxicities. This is the purpose of these studies.

10. 10 General Considerations - 2 The Reviewers do not have the time to search volume by volume. Therefore, make it as easy to navigate as possible - Use tabs or separators in every desk copy and paper submission and use continuous pagination. [F113, B87 are not acceptable – too difficult to find]

11. 11 General Considerations - 3 If the study is not a standard design, state rationale for the study. Help the reviewer evaluate. A study may be inadequate for certain regulatory criteria but adequate for your internal questions, or it may be inherited from a prior owner. Explain so that the reviewer does not need to ask.

12. 12 General Considerations - 4 Tell the reviewer your development scheme. They would like to assist, but it is sometimes difficult to evaluate a study without this context. Gantt charts or tables of studies completed/in progress and planned are helpful to many reviewers

13. 13 General Considerations - 5 When a finalized version of a submitted study draft is completed, notify the reviewer ASAP that the data and conclusions do not differ from the draft version or if they do differ tell the reviewer and send in the changes. Send the final report.

14. 14 Table of Contents - 1 The reviewers must be able to find all information quickly, including tables, figures, graphs, sections and appendices (with pages numbered consecutively). The study TOC should be detailed and accurate and should accompany any study submission of length.

15. 15 Table of Contents (2) Include appendices, tables and graphs in the TOC of each Study Report. In CTD format for paper, there is a place for appendices in Module TOC, but not eCTD. Important that the appendices are in each Study TOC, with page numbers. Use the study name in the TOC, and the number.

16. 16 Study Summary (1) Summary should read as a stand-alone document. The more “upfront” in the Summary the better. Do not make the reviewer wait until the Discussion to present significant results and your explanation of why some results are or are not significant.

17. 17 Study Summary - 2 The Reviewers are juggling many projects at once and their review is seldom without interruptions When cross-referencing studies, name the study in addition to the study number. Stating “results in A402c” may not be significant to the reviewer. However, “results in 28-day rat study (A402c)” may make it easier to resume review.

18. 18 Mortality When an animal is in the narrative description of mortality, follow with all results of the measured parameters for that animal in order to adequately assess the potential cause of death. Make your evaluation. Repeat your evaluations of mortality in the Summary.

19. 19 Pharmacokinetics Keep the units the same! For example, Do Not use ng.hr/mL for animals and µg.hr/mL for humans unless you provide a comparison table using the same units. Do Not use mol or mmol units without accompanying mg, µg unit conversions for comparison.

20. 20 Data Presentation Pathology tables should include Site- (total N), pathology (N), then progressive rows of grades of severity and the number of subjects per grade. (See Table 10) Quantitative group mean data tables, i.e. Clinical Chemistry, include means and SD, range, percent change from control, and statistical significance, if present. (See Table 11)

21. 21 Table 10 (preferred) HISTOPATHOLOGY Group1234 Dose (mg/kg)Control 01.02.520 SexMFMFMFMF Injection site 1 (N)10 9 hemorrhage33434568 Grade 132312323 Grade 2.1122133 Grade 3.....112 necrosis02124576 Grade 1.2112323 Grade 2...12253 Injection site 2 (N)10 9 hemorrhages43453456 Grade 142332110

22. 22 Table 11 (preferred) Serum Clinical Chemistry Day 13 Male, 0 mg/kg (control) Prot g/L Alb g/L Glob g/L A/G ratio Mean7943361.2 SD4340.2 N9999 Range72-8239-4634-381.0-1.8 Male, 5 mg/kg Mean8245371.2 SD3340.2 N7777 Range80-8439-4834-381.1-1.7 % change from control + 3.8*+ 4.7+ 2.8± 0

23. 23 Statistics When the group size is <5, do not just say “no statistically significant differences” in the narrative. The small N has very little statistical power and is often inadequate for the description of differences between or within groups.

24. 24 Show You Know Your Data (1) When test results for a subject are outside the group/normal range, statistically significant or not, follow the subject through related evaluations and evaluate the composite. This is especially important with small group size.

25. 25 Show You Know Your Data (2) eg. #23M has ALT value outside range of remainder of the treatment group and beyond the ULN. What are the other values related to the liver? Other liver enzyme levels? Absolute and relative liver weight? Liver histopathology? Show you know your data and explain why this is or is not toxicologically significant.

26. 26 Show You Know Your Data (3) If the reviewer alone finds 1 of 4 male dogs has liver enzymes > ULN, elevated liver weight and significant histopathology, either you are trying to hide something or you do not know your data. This can cause extra effort for both the reviewer and the sponsor. Time lost

27. 27 Providing the Reviewer with Needed Information Look at the following (un)official Review Template Provide all the information requested How long did it take you to do? The reviewer must do this without previously seeing the document. Help make reviewing more efficient!

28. 28 Review Template 2.6.6.3Repeat-dose toxicity Study title: Key study findings: Study no.: Conducting laboratory and location: Date of study initiation: GLP compliance: QA report: yes ( ) no ( ) Drug, lot #, and % purity: Methods Doses: Species/strain: Number/sex/group or time point (main study): Route, formulation, volume, and infusion rate: Satellite groups used for toxicokinetics or recovery: Age: Weight: Sampling times: Unique study design or methodology (if any): Histopathology: specify groups examined, special stains, etc Adequate Battery: yes ( ), no ( )—explain Peer review: yes ( ), no ( ) Results: Mortality:

29. Nonclinical Study Reports IND and NDA Submissions From the Reviewer’s Perspective

30. 30 Table of Contents The reviewers must be able to quickly find all information, including tables, figures, graphs and sections. Difficult searches can lead to a RTF or the visit of an "emergency team" to correct the submission within a few days to prevent a RTF.

31. 31 Genotoxicity (1) (CTD Format of 2.6.6.4 and any format used) (Reports are in Module 4) Study report should include a cross- reference when Genotoxicity studies have been done on impurities and or degradants (2.6.6.8). If these studies have been done they also must appear in the TOC. Genotoxicity issues may be reviewed by internal experts and there should be links to all genotoxicity testing in the submission.

32. 32 Genotoxicity (2) All genotoxicity testing should also be included in the Summary (2.6.7.8 and 2.6.7.9). When metabolites, degradants or impurities are tested, percents in the lots used for animal and human studies should be included when possible (specifying in vitro and in vivo data) and reference to the section on metabolism for details (2.6.5.x.).

33. 33 Metabolites, Degradants and Impurities When these are tested, provide the estimated level in humans at therapeutic doses and, if available, provide or reference the pharmacokinetic properties. Provide a discussion of degradants and impurities which exceed the ICH threshold values.

34. 34 First-in-Man Submissions Provide appropriate toxicity studies with submission!! The MTD or maximum feasible dose are required. This is to know which toxicity is most likely in man and human toxicity has been observed at doses 1000-fold the NOAEL. A NOAEL of 125X the starting dose, with no toxicity observed, is an inadequate study to justify first-in-man. The dosing will probably not stop there.

35. 35 Critical Points in Development (End-of-Phase II, NDA) Provide a table: 1) drug lot numbers with 2) level of each impurity 3) preclinical studies and clinical trials in which each lot was used. This can greatly facilitate the reviews and reduce the calls for this information.

36. 36 Providing the Reviewer with Needed Information Look at the following (un)official Review Template Provide all the information requested How long did it take you to do? The reviewer must do this without previously seeing the document. Help make reviewing more efficient!

37. 37 2.6 PHARMACOLOGY/TOXICOLOGY REVIEW 2.6.1INTRODUCTION AND DRUG HISTORY IND (NDA) number: Sponsor and/or agent: Manufacturer for drug substance: Drug: Trade name: Generic name: Code name: Chemical name: CAS registry number: Molecular formula/molecular weight: Structure: Relevant INDs/NDAs/DMFs: Drug class: Intended clinical population: Clinical formulation: Route of administration: Proposed clinical protocol: IND only [start dose, dose escalation increments, maximum dose ] Previous clinical experience: