The long-term progression of the fraction of Clinical compounds by phase reached in each of the PNP_Status categories (Figure ) shows near-identical time trends in all clinical phases (1-4), so Clinical compounds were combined into a single group for further analysis (Figures ). The consistent increase in PNP fraction is striking, approximately doubling every 2-3 decades, reaching 67% of all Clinical compounds in the 2010s (Figures ). Significant increases in Frag_coverage_Murcko values have occurred every second decade, with their distribution narrowing over time: after 2010 the average clinical compound has a value of 0.66, with 1 st and 3 rd quartile values of 0.50 and 0.84 respectively (Figure ). The fraction of NP compounds is falling over time (Figure ), which is consistent with the trend in NP-likeness, which falls significantly from historical levels in the 1960s-1990s, and further again from 2000 onwards (Figure ). Interestingly, NPL compounds consistently appear in all time periods at ~10-20% of the total (Figure ). NonPNPs ). By odds ratio analysis of the full dataset, a post-2008 Clinical compound is 54% more likely to be a PNP than a Reference compound (Table ). ). For this reason, the post-2008 period was selected for further analysis by target class.