Can We Predict Hepatotoxicity Based on MO Reviews of Submitted Data

1. 5 February 2004 Hep Tx Steering Committee 1 Can We Predict Hepatotoxicity Based on MO Reviews of Submitted Data? A Review of Selected NDAs Lana Pauls, MPH Director, Quality Assurance Staff Center for Drug Evaluation and Research

2. 5 February 2004 2 Hep Tx Steering Committee The DRAFT QA Analysis Retrospective analysis outlining the amount and type of hepatotoxic-predictive data available in reviews of selected NDAs 26 drugs selected Identified by Clinical Subcommittee of HepTox SC 13 �Hepatotoxic� and 13 �Non-hepatotoxic�

3. 5 February 2004 3 Hep Tx Steering Committee Variables Assessed Hy�s Law (working version): AST or ALT = 3 x ULN and bilirubin = 2x ULN Usually on a background of increased rate of high serum transaminase elevations, compared to control Other Various degrees of transaminase elevations (TA), e.g.: 3x, 5x, 8x) in drug and control groups overall increased rate of TA elevation compared to control For uncontrolled studies, a rate of = 3%

4. 5 February 2004 4 Hep Tx Steering Committee Selected drugs Selacryn (ticrynafen) Duract (bromfenac) Rezulin (bromfenac) Tasmar (tolcapone) Felbatol (felbamate) Unicard (dilevalol) Normozide (labetolol) Trovan (trovafloxacin) Zyflo Filmtab (zileuton) Isoniazid (isoniazide) Depacon (valproic acid) Pexid (perhexilene) Cognex (tacrine) Glucophage (metformin) Avandia (rosiglitizone) Comtran (entacapone) Avelox (moxifloxacin) Vioxx (rofecoxib) Celebrex (celecoxib) Avepro (irbesartan) Ambien (zolpidem) Trileptal (oxcarbazepine) Topomax (topiramate) Geodon (ziprasadone) Protonix (pantoprazole) Accolate (zafirkulast)

5. 5 February 2004 5 Hep Tx Steering Committee Data Examined Integrated Summary of Safety (ISS) provided by sponsor Not required till 1985 Medical Review (MOR) conducted by FDA for original application and any amendments PRIOR to original FDA action

6. 5 February 2004 6 Hep Tx Steering Committee Data Examined Presence/absence of the variables in question Applications/reviews were counted as containing data if the variable was examined, not necessarily if the analysis had patients/subjects meeting the criteria

7. 5 February 2004 7 Hep Tx Steering Committee Data Found or Not Found No data were available (either ISS or MOR) for two applications 4 applications were submitted before an ISS was required (data from MOR only) labetolol ticrynafen isoniazide perhexilene

8. 5 February 2004 8 Hep Tx Steering Committee Hepatotoxic: Where Were Data ?

9. 5 February 2004 9 Hep Tx Steering Committee Non-Hepatotoxic: Where Were Data?

10. 5 February 2004 10 Hep Tx Steering Committee Existence of Documented Data When I say documented data, I mean that at least it was mentioned, regardless of whether no patients met the criteriaWhen I say documented data, I mean that at least it was mentioned, regardless of whether no patients met the criteria

11. 5 February 2004 11 Hep Tx Steering Committee Hepatotoxic:AST = 3 x ULN tolcapone Only application that listed multiple transaminase elevation levels (3x, 5x, 8x) dilevalol zileuton Very little focus on AST alone; sponsor indicated AST not sufficiently specific bromfenac No data on AST only, only in combo with ALT and/or bilirubin valproic acid tacrine perhexilene 65/872 �clinically meaningful elevations in serum enzymes which assess liver function�

12. 5 February 2004 12 Hep Tx Steering Committee Non-Hepatotoxic:AST = 3 x ULN metformin rosiglitazone Listed multiple TA elevations (> 3x, 5-8x) entacapone moxifloxacin irbesartan addressed parameter; no patients zolpidem addressed parameter; no patients oxcarbazepine topiramate ziprasadone

13. 5 February 2004 13 Hep Tx Steering Committee HepatotoxicALT = 3x ULN tolcapone Listed multiple TA elevations (3x, 5x, 8x) zileuton bromfenac no info on ALT only; 4/830 had both AST and ALT = 3 tacrine dilevalol identified patients with 2x perhexilene 22/872 �clinically important drug related changes in serum enzyme values (SGOT and SGPT)�

14. 5 February 2004 14 Hep Tx Steering Committee Non-Hepatotoxic ALT = 3x ULN metformin rosiglitazone identified various TA elevations (3 x, 5- >8x) entacapone moxifloxacin irbesartan zolpidem topiramate ziprasadone

15. 5 February 2004 15 Hep Tx Steering Committee Cases Meeting Hy�s Law tacrine (hepatotoxic) 1/1061; 0/1061 placebo metformin (non) 1/357; 0/174 glyburide; 0/192 metformin + glyburide topiramate (non) criteria addressed, no patients

16. 5 February 2004 16 Hep Tx Steering Committee Unclear Documentation; Common Themes AST and/or ALT listed as �increased� � no numbers or rates provided MOR indicated numbers of patients with AST/ALT elevations, but not if same patients per MOR �no clinically meaningful changes in hematologic laboratory parameters� per MOR 75% �clinically significant labs� per MOR �14/137 liver enzyme abnormalities�

17. 5 February 2004 17 Hep Tx Steering Committee Unclear Documentation; Common Themes - 2 per MOR �clinically meaningful elevations in serum enzymes which assess liver function� Unclear what criteria were used to make these assessments, and obviously not the same for all MOs

18. 5 February 2004 18 Hep Tx Steering Committee Perhexilene:An Interesting Case no ISS (before requirement) 65/872 �clinically meaningful elevations in serum enzymes which assess liver function� 22/872 �clinically important drug-related changes in serum enzyme values (SGOT and SGPT) per MOR �In summary, perhexilene causes significant enzyme elevations (SGOT and SGPT) in approximately 9% of patients at 400 mg/day� NO documentation of Hy�s law cases original proposed labeling prior to WD before action: �perhexilene should be administered with caution to patients with a history of liver disease. . .�

19. 5 February 2004 19 Hep Tx Steering Committee Conclusions Inconsistent documentation of AST, ALT and Hy�s Law cases in both ISS and MOR More recent applications (late 90�s) have more complete documentation Measures are being taken to improve consistency of use: DRAFT safety review document includes use of these variables Revised clinical template includes use of these variables (refers to safety document)