Although major pharmaceutical companies do not appear to be rejecting the proposal in FDA's draft guidance on drug-induced liver injury that trials enroll patients with preexisting liver disease, according to comments submitted on the draft, the companies would like to see more clarification on how such patients should be included.

In the draft guidance released in October 2007, FDA recommends drug developers enroll patients with preexisting liver disease in at least Phase III clinical trials, especially if the drug might eventually be used in such patients.

FDA noted that patients with abnormal liver tests at baseline or a history of liver disease are often excluded, but "there is no well-established reason to do this ... expect perhaps to avoid confusion between the previous disease and the effect of the test drug."

Pfizer is one company that agreed with the concept of including patients with preexisting liver disease, though it raised issue with the fact that "the draft guidance does not provide clear guidance on the circumstances under which this can be done safely or appropriately, nor does it provide clear guidance on how DILI might be detected in the presence of non-drug induced liver impairment."

Pfizer also pointed out that the guidance does not clarify how to assess DILI when an investigational drug is given concomitantly with other drugs "with independent and possibly synergistic potential to produce DILI."

Wyeth accepted the general idea of including patients with preexisting liver abnormalities, but suggested some limits. It asked that the guidance clarify that patients with decompensated or unstable acute or chronic liver disease be excluded unless specific treatments for those disorders are being studied.

"It would be helpful if a separate section were included for the evaluation of patients with elevated LFTs at baseline," the firm's comments state. In particular, Wyeth requested that that section "emphasize the need to differentiate the presence of direct bilirubin elevations from indirect bilirubin elevations, by obtaining both total and direct bilirubin levels."

Lilly requested that for patients with underlying liver diseases, FDA be clearer on inclusion and exclusion criteria to discuss what levels of aminotransferases and which disease states should be excluded - as well as specify what screening tests should be conducted.

Lilly also suggests the benefits of mentioning specific groups of patients who may have altered risk-benefit ratios. For example, clinical trials of anti-cancer drugs in patients with advanced malignancy, where even high levels of bilirubin would not be considered an exclusion criterion.

Lilly, Novartis, Pfizer, Sanofi-Aventis and Wyeth each commented on FDA's decision to use Hy's Law for major indicators of potential or severe DILI. Hy's Law is a set of criteria FDA uses to distinguish drugs with high and low potential for severe liver injury.

Hy's Law relies on three signals for potential liver injury in a test group as compared with controls: a sensitive, but not specific, signal, such as an excess of aminotransferase elevation to >3x upper limits of normal; a specific, but not sensitive, signal such as marked AT elevations to 5x, 10x or 20x ULN in a smaller number of subjects; and evidence of reduced overall liver function "manifested by increased serum total bilirubin, in conjunction with AT elevation, not explained by any other cause, together with an increased rate of AT elevation in the overall study population compared to control."

"It is our experience that Hy's Law may not apply directly in subjects with preexisting liver disease or those receiving concomitant therapy, due at least in part to the reliance of Hy's Law on fold increases of laboratory measures over the 'Upper Limit of Normal,'" Pfizer said in its comments. Pfizer proposed that sections describing Hy's Law and the section dealing with "Evaluating Data for Alternate Causes" contain more specific language noting this limitation.

Novartis also requested more specific information about FDA's thoughts on monitoring and assessing studies for which many patients have LFT elevations with other risk factors for liver damage, and therefore do not meet component three of Hy's Law. "In oncology studies, for example, it is common to enroll patients with advanced disease, including liver metastases, who have abnormal tests at baseline which could meet Hy's Law but for whom treatment is essential," the comments state.

Another topic that elicited comments was when to stop treatment. FDA's draft admits it is a "difficult question" and leaves it open to interpretation. Transient levels of AT are common, and patients could adapt to the drug, potentially giving false data if treatment is stopped prematurely. Yet DILI can develop very quickly, and substantial damage can occur if treatment is continued for too long.

Wyeth stressed the importance of considering the stopping of treatment, pointing out that there are instances where "application of the suggested stopping rules could result in inappropriate termination," and other times where "subjects who do not meet these criteria would still benefit from suspension of treatment."

Novartis also recommended that FDA comment on the utility of existing toxicokinetic data and in vitro liver models for predicting and assessing liver injury, and also how the models might be used as guidance in monitoring clinical trials.

Novartis further proposed that FDA consider if the guidance might be an appropriate vehicle to also describe how investigational hepatotoxicity findings could be incorporated into the draft prescribing information, as more specific label instructions on when and how to monitor liver function in the post-approval setting might be helpful for clinicians.

Looking forward, Sanofi suggested the guidance be revised again in two to three years in order to "validate the proposed recommendations for predicting drug hepatotoxicity."

- Lauren Smith (lauren.smith@elsevier.com)

Pharma Seeks More Guidance On Drug-Induced Liver Injury

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