Why Drugs Fail - A Study on Side Effects in New Chemical Entities

Abstract

Over 90% of the market withdrawals were caused by drug toxicity. Hepatotoxicity and cardiovascular toxicity proved to be the major causes for two out of three market withdrawals in the respective time period. In clinical phases I-III 43% of drug development project terminations were due to insufficient efficacy of the investigated compound. The second important issue, which caused one third of the projects to be closed, was toxicity. ADME parameters and economic and other reasons played a minor role. The results of our study indicate that compared with previous studies on this subject, no major improvements have been achieved in the last decade.

Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals

“…DILI is the main cause of ALF in the western world [3,44]. It is also one of the main reasons for post marketing withdrawal of drugs and discontinuation of the development of …”

“…NCE, thereby representing a substantial cost for the pharmaceutical industry [3,44]. Current human cell models are scarce or not fully adequate for toxicity screening of pharmaceuticals and other chemical compounds [16,45].…”

“…One of the major causes for the discontinuation of drug candidates is hepatic toxicity [3] and druginduced liver injury (DILI) accounts for most cases of acute liver failure (ALF) [4]. Detection of hepatotoxicity, however, often occurs only late during drug development, jeopardizing the potential marketing of these molecules [3].…”

Human Skin-Derived Stem Cells as a Novel Cell Source for In Vitro Hepatotoxicity Screening of Pharmaceuticals

“…DILI is the main cause of ALF in the western world [3,44]. It is also one of the main reasons for post marketing withdrawal of drugs and discontinuation of the development of …”

The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery

“…Lack of in vivo activity in animal models is usually attributed to suboptimal drug metabolism and pharmacokinetic (DMPK) properties (10). Furthermore, failure in the clinic has frequently been due to the same limitations (5,11).…”