# Presentation: 783932

## 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

- Hep Tx Steering Committee

- 5 February 2004

## 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”

- Hep Tx Steering Committee

- 5 February 2004

## 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%

- Hep Tx Steering Committee

- 5 February 2004

## 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)

**Hepatotoxic**

**Non-hepatotoxic**

- Hep Tx Steering Committee

- 5 February 2004

## 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

- Hep Tx Steering Committee

- 5 February 2004

## 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

- Hep Tx Steering Committee

- 5 February 2004

## 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

- Hep Tx Steering Committee

- 5 February 2004

## Hepatotoxic: Where Were Data ?

| Drug | AST | ALT | Hy’s Law |
| --- | --- | --- | --- |
| ticrynafen |  --- | --- | --- |
| bromfenac | --- | MOR | --- |
| tolcapone | MOR/ISS | MOR/ISS | --- |
| felbamate | ISS | ISS | ---** |
| dilevalol | MOR | MOR | --- |
| labetolol | --- | --- | --- |
| trovafloxacin | MOR/ISS | MOR/ISS | MOR |
| zileuton | MOR/ISS | MOR/ISS | --- |
| isoniazide |  --- | --- | --- |
| valproic acid | MOR/ISS | --- | --- |
| perhexilene | MOR | MOR | --- |
| tacrine | MOR/ISS | MOR/ISS | MOR |

- ** Found in PM reports only

- Hep Tx Steering Committee

- 5 February 2004

## Non-Hepatotoxic: Where Were Data?

| Drug | AST | ALT | Hy’s Law |
| --- | --- | --- | --- |
| metformin | MOR/ISS | MOR/ISS | MOR/ISS |
| rosiglitazone | MOR/ISS | MOR/ISS | MOR/ISS |
| entacapone | MOR | MOR | --- |
| moxifloxacin | ISS | ISS | ISS |
| rofecoxib | MOR/ISS | MOR/ISS | --- |
| celecoxib | MOR/ISS | MOR/ISS | MOR/ISS |
| irbersartan | ISS | ISS | --- |
| zolipidem | MOR/ISS | MOR/ISS | --- |
| oxcarbazepine | MOR | --- | --- |
| topiramate | MOR/ISS | MOR/ISS | MOR/ISS |
| ziprasadone | MOR/ISS | MOR/ISS | --- |
| pantoprazole | MOR | MOR | --- |

- Hep Tx Steering Committee

- 5 February 2004

## Existence of Documented Data

|  | Hepatotoxic
 Drug |  |  | Non-hepatotoxic Drug |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Hepatotoxic Variable | Yes | No | Unclear | Yes  | No | Unclear |
| AST ≥ 3x ULN | 6 | 3 | 3 | 9** | 0 | 3 |
| ALT ≥ 3x ULN
 | 5 | 5 | 2 | 8 | 1 | 3 |
| Hy’s Law | 1 | 10 | 1 | 2 | 7 | 3 |
| Increased Rate of Transaminase (≥ 3 %) | 2 | 0 | 0 | 2 | 0 | 0 |

- ** *two applications had no patients meeting criteria**	** *

- Hep Tx Steering Committee

- 5 February 2004

**Notes:**
When I say documented data, I mean that at least it was mentioned, regardless of whether no patients met the criteria

## 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”

- Hep Tx Steering Committee

- 5 February 2004

## 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

- Hep Tx Steering Committee

- 5 February 2004

## HepatotoxicALT ≥ 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)”

- Hep Tx Steering Committee

- 5 February 2004

## Non-Hepatotoxic ALT ≥ 3x ULN

- metformin
- rosiglitazone
- identified various TA elevations (3 x, 5- >8x)
- entacapone
- moxifloxacin
- irbesartan
- zolpidem
- topiramate
- ziprasadone

- Hep Tx Steering Committee

- 5 February 2004

## 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

- Hep Tx Steering Committee

- 5 February 2004

## 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”

- Hep Tx Steering Committee

- 5 February 2004

## 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**

- Hep Tx Steering Committee

- 5 February 2004

## 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. . .”

- Hep Tx Steering Committee

- 5 February 2004

## 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)

- Hep Tx Steering Committee

- 5 February 2004