FDA Should Create Separate Division To Review Drug-Induced Liver Toxicity – Consultant

The new division would allow for standardized evaluation of drugs with evidence of hepatoxicity, consultant Thomas Garvey says. He also recommends strengthening post-marketing reporting requirements.

FDA should create a review division to examine possible drug-induced hepatotoxicity in product submissions, Garvey Associates President Thomas Garvey, MD, suggested.

"I propose that the agency create a new division at CDER responsible for centralized, systematic assessment of evidence of potential liver injury for a drug in development," the former FDA Supervisory Medical Officer-Cardio/Renal Drug Products said at a drug-induced hepatotoxicity conference in Philadelphia Sept. 21.

This new division would recommend action based on evidence of potential liver injury for a new drug, Garvey said. The division should also "seek consultative advice from a standing committee of hepatologists," he said.

Reviewers in the new division, Garvey said, should use "uniform analyses" of data for drugs with evidence of liver toxicity by paying attention to "deaths, drop-out studies, treatment-emergent abnormalities [and] patients who are subject to concomitant abnormalities in liver tests."

The former FDAer also supports standardized hepatotoxicity language in labeling.

"I write labels all the time, and I have difficulty finding the information that I need to have in the label….When you look at the labeling for liver toxic drugs across divisions it's all over the line. I think it should be systematized."

In the label "there should be prominent display of data related to potential for liver injury," Garvey suggested. "Quantitative information should be presented in a consistent label location, because when you look now it's all over the place."

Garvey cited the labeling for Johnson & Johnson's Tylenol (acetaminophen) as an example. "It doesn't even say liver information. It says alcohol information….You can call it liver information and make it red."

The consultant also addressed the issue of monitoring. "I think probably any drug known to have a potential for liver injury when it is first approved needs monitoring….I'm not sure we need a Clozaril situation."

Patients on Novartis' antipsychotic Clozaril or generic clozapine are required to have weekly white blood cell count testing during the first six months of treatment.

"We need to improve the attributes of the post-marketing reporting and Phase IV study tools" in order to increase adherence to the monitoring recommendations.

"I think there should be more systematic scrutiny and far more regular attention to these potentially very important data" from post-marketing monitoring, Garvey said.

FDA has already begun to focus on liver toxicity issues.

The agency "is paying a lot of attention to hepatotoxicity," Garvey said, as part of the "Critical Path" research initiative. "It's dealt with in a risk management action plan concept referred to as RISKMAP."

A May 4 FDA draft guidance establishes three categories of risk minimization tools: targeted education and outreach, reminder systems and performance-linked access systems (¹ (Also see "FDA Risk Management Plan Proposes Three Categories of Tools" - Pink Sheet, 4 May, 2004.)).

- Andrew Shelton