Drug warning update: withdrawn drugs and drugs that carry a black box warning

The drug warning information in ChEMBL has been updated for version 32. In particular, the withdrawn drug data has been fully reviewed and, to assist the manual curation process, our rules have been updated, clarified and formally written. 

In ChEMBL, a withdrawn drug is an approved drug (ie Phase 4) that has subsequently been withdrawn for toxicity reasons. For example, a drug is assigned as 'withdrawn' if:

• All doses are withdrawn (and not just the highest dose).
• The drug is withdrawn for all populations (and not just infants).
• The drugs is withdrawn for all indications. 
• Any drug withdrawn for a lack of evidence of efficacy is not included. 
• Any drug withdrawn for drug-drug interactions is included if it is a safety-related withdrawal.

A regulatory body (e.g. EMA, FDA) is the preferred source of information for the withdrawn status. The withdrawn status is mapped to an individual drug form (e.g. a parent (salt-stripped) or salt drug form within a family of compound structures). Terminology such as ‘banned', ‘prohibited’ or ‘revoked’ is considered to be equivalent to withdrawn status, however, the mention of ‘suspended’ requires additional source references or checks to confirm that the drug was not re-introduced. The earliest year of withdrawal is assigned as the warning year. The region of the world that the withdrawn status applies to is recorded as the warning country.

Each drug flagged as withdrawn includes a citation to regulatory document or similar (with url). In addition, the specific (granular) withdrawn reason has been manually mapped to the Experimental Factor Ontology (EFO) e.g. the phrase 'cardiac arrthymia' would be mapped to EFO ontology. Further, a high level toxicity class has been assigned as the warning class, and mapped to EFO (e.g. cardiotoxicity).

In summary there are 203 parent drugs flagged as withdrawn for ChEMBL version 32 (cf previously 177). This includes 38 drugs newly annotated as withdrawn (e.g. ALMITRINE, BENZBROMARONE, BIOALLETHRIN, etc), while 12 drugs that were previously flagged as withdrawn do not meet the updated selection criteria and therefore are no longer considered withdrawn (e.g. CELECOXIB which has not been withdrawn for all indications, DIETHYLSTILBESTROL which is still used to treat prostate cancer, etc).

For example, NEFAZODONE HYDROCHLORIDE was withdrawn in 2003 from Canada for causing adverse hepatic events. However, it remains available in the United States but carries a black box warning for hepatoxicity and psychiatric toxicity. 

In addition to the withdrawal status of drugs, ChEMBL also curates black box warning data. FDA drugs carry a black box warning if they have severe or life-threatening side effect(s). These warnings are captured using the 'black box warning' flag and an associated high level toxicity class is assigned as the warning class using natural language processing models (Hunter et al. 2021). For ChEMBL version 32, the high level warning class for each black box warning has been mapped to EFO, and there have been some minor changes of warning class names as a result of expert toxicological review (gastrotoxicity is now called gastrointestinal toxicity, metabolism toxicity is now called metabolic toxicity, and misuse is now called drug misuse).

The drug warning information can be accessed via the drug warning browser or via individual compound report cards (e.g. for ROSIGLITAZONE MALEATE).