Description
This guidance is intended to assist the pharmaceutical industry and other investigators who are conducting new drug development in assessing the potential for a drug2 to cause severe liver injury (i.e., irreversible liver failure that is fatal or requires liver transplantation). In particular, the guidance addresses how laboratory measurements that signal the potential for such druginduced liver injury (DILI) can be obtained and evaluated during drug development. This evaluation is important because most drugs that cause severe DILI do so infrequently; typical drug development databases with up to a few thousand subjects exposed to a new drug will not show any cases. Databases may, however, show evidence or signals of a drug’s potential for severe DILI if the clinical and laboratory data are properly evaluated for evidence of lesser injury that may not be severe, but may predict the ability to cause more severe injuries. This guidance describes an approach that can be used to distinguish signals of DILI that identify drugs likely to cause severe liver injury from signals that do not suggest such a potential. This guidance does not address issues of preclinical evaluation for signals of DILI, nor the detection and assessment of DILI after drug approval and marketing.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
4Excluded from the scope of this guidance
ximelagatran is an oral anticoagulant
bromfenac was a nonsteroidal anti-inflammatory drug (NSAID)
Products for which batch/lot information is particularly important
Stakeholders
6The intended audience for the guidance.
discussed potential liver toxicity of ximelagatran in September 2004
FDA advisory body reviewing Exanta
Entity submitting development data and knowledge; Entity performing the work process for change
Entities submitting supplements to BLAs
Personnel who must receive local retesting results immediately
Regulatory Context
Regulatory Activities
5New Drug Application
New Drug Application for Troglitazone
Trials conducted to support approval of drugs
Investigational New Drug submissions
Biologics License Application
Document Types
5Used to delineate dose and timing of administration
issued to warn about severe hepatotoxicity
User Safety Warnings section of the package insert
Must conform to requirements of 21 CFR 107.10-107.30.
Required for each Hy's Law case and for subjects who died of hepatic illness.
Attributes
6A characteristic of predictable toxicity often discovered in preclinical testing.
seen in 2.8 percent of patients on bromfenac
marked elevations of aminotransferases as a signal of injury
Statistical calculation used to estimate the upper limit of the rate for severe DILI.
Term for reactions dependent upon an individual person's constitution.
Upper limit of normal used as a reference for laboratory abnormalities
Technical Details
Substances
10A drug withdrawn from the market due to hepatotoxicity.; drug associated with severe clinical and histologic hepatotoxicity; approved by the FDA in January 1997 for Type 2 diabetes mellitus
Example drug with multiple serious drug interactions.
associated with mitochondrial and cellular toxicity
drug associated with acute liver failure and liver transplantation; nonsteroidal anti-inflammatory drug (NSAID) studied for analgesia and arthritis
System responsible for oxidative metabolism of most hepatotoxic drugs.
Measured as AT, AST, or ALT to detect hepatocellular injury.
A novel anticoagulant tested against warfarin in the SPORTIF V study.; Compared with warfarin for prevention of thromboembolism.
Mild elevations are often seen during drug development.
ALT values used to identify potential DILI candidates
Reflected as AST; used to indicate hepatocellular injury.
Testing Methods
10Enzymes measured to detect leakage from injured liver cells.
monitoring method for evidence of liver injury
used to account for differences in trial duration
Combined elevations with aminotransferases are analyzed for DILI signals.
A diagnostic procedure mentioned as having no pathognomonic findings for DILI.; Special study used to evaluate the nature of liver injury.
A measure of liver function suggesting potential for severe injury.
Alanine aminotransferase monitored for liver injury.
Aspartate aminotransferase monitored for liver injury.
Alkaline phosphatase test used to detect liver injury
Total bilirubin test used to detect liver injury
Processes
2General Drug Development Considerations
Assessment of how a drug is metabolized to hepatotoxic metabolites.
Clinical Concepts
10Potential safety concern (DILI) in subjects with underlying liver disease.; Event requiring adjudication recorded in ZA domain; assessing potential DILI likelihood; To aid evaluation of potential DILI; potential DILI injury workup flags; Analysis of DILI injury and washout parameters
prevention after joint replacement surgical procedures
time from jaundice to hepatic encephalopathy was rapid
Insulin products intended for the treatment of patients with Type 2 diabetes
severe hepatic failure cases requiring liver transplant
Events requiring prompt reporting to FDA.
A signal used to identify drugs likely to cause severe liver injury.; A combination of AT and bilirubin elevations indicating potential for severe DILI.; used to predict the rate of severe drug-induced liver injury
Irreversible liver failure that is fatal or requires liver transplantation.; severe outcome of drug-induced liver injury; rates for bromfenac were estimated to be in the range of 1/10,000
Risk increased by concomitant use of hepatotoxic drugs with DRUG-X.
A pattern of liver injury that is generally reversible.; Must be ruled out (indicated by elevated ALP) to identify Hy's Law cases.
Identified Hazards
Hazards
1Potential harm from overdose due to dosing schedule deviation
Standards & References
Specifications
2Used as a baseline (ULN) for measuring enzyme elevations.
Threshold for aminotransferase abnormalities signaling potential DILI.; threshold for ALT elevations in clinical trials
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- E11A Pediatric Extrapolation
- M15 General Principles for Model-Informed Drug Development
- Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
- Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
- Rare Diseases: Considerations for the Development of Drugs and Biological Products
- Q3C Impurities: Residual Solvents_2011
- Providing Regulatory Submissions in Electronic Format --Content of the Risk Evaluation and Mitigation Strategies Document Using Structured Product Labeling: Guidance for Industry
- Q4B Annex 5: Disintegration Test General Chapter