02816nas a2200337   4500000000100000008004100001260001500042653001900057653002100076653002700097653002900124653001700153100002100170700002500191700001400216700001800230700002000248700002000268700001700288700002000305700002100325700001600346700002200362700002700384700001800411245010900429856007200538300001100610520184300621022001402464       2026                            d  c2026-07-2110adrug attrition10aDrug development10alikelihood of approval10areasons for drug failure10asuccess rate1 aDilyana Filipova1 aWolfgang Boomgaarden1 aLeyla Fox1 aAndrew Knight1 aBettina Lickiss1 aChristian Maass1 aGaby Neumann1 aJustine Watkins1 aKathrin Herrmann1 aLorna Ewart1 aMatthias Gossmann1 aMerel Ritskes-Hoitinga1 aTamara Zietek00aNeed for NAMs: A systematic evidence synthesis revealing over half a century of drug development failure  uhttps://www.sciencedirect.com/science/article/pii/S3050620426000448  a1001193 aBackground
Preclinical assessment of drug safety, efficacy and pharmacokinetics still relies largely on animal‑derived data, despite their limited ability to predict human outcomes. New Approach Methodologies (NAMs) are emerging as more human‑relevant preclinical tools. This systematic evidence synthesis examines (1) current levels and temporal trends in clinical drug attrition and (2) the proportion of failures attributed to biological factors such as safety, efficacy and pharmacokinetics that are routinely evaluated during preclinical testing, to identify priority areas for NAM implementation.
Methods and Findings
We systematically searched PubMed on March 5, 2024, for peer-reviewed, English-language studies since 1963 reporting numerical primary data on clinical drug attrition rates and/or reasons for failure. The protocol was prospectively registered (osf.io/46mw5). We excluded non-original research and studies on specific cases, diseases, or single drug classes. Thirty-two publications met the criteria, yielding 60 attrition and 36 failure-reason datasets (1963–2017). Across six decades, mean clinical attrition ranged from ∼80 to ∼91 % with the highest rates within the past two decades. Overall, biological factors (safety, efficacy, pharmacokinetics) accounted for ∼77% of reported causes. Limitations include heterogeneous reporting, restriction to English, and exclusion of grey literature.
Conclusions
Clinical drug attrition has not improved in the last six decades, peaking at ∼91% in the 2000s–2010s, with most failures linked to biological factors. These findings suggest that prevailing preclinical approaches – many of which heavily rely on animal models – often have limited ability to predict clinical outcomes and highlight the urgent need for more predictive, human-relevant NAMs.  a3050-6204