Phase-0/Microdosing: Wong Estimation of Clinical Trial Success Rates 2019 and the importance of early first-in-patient studies

Wong, C. H., Siah, K. W. & Lo, A. W. Estimation of clinical trial success rates and related parameters. Biostatistics (Oxford, England) 20, 273-286, (2019)

Wong et al. from MIT used the largest database to date, 185,994 unique trials and 21,143 compounds, developed between 2000 and 2016 to estimate the productivity of clinical development and found the probability of technical success (pTS), i.e., of bringing a drug that enters human testing to the market, to range between 5.2% and 13.8% per year. Consistent with FDA new drug approval data, this analysis finds some improvement in recent years, but otherwise confirms earlier reports of very low success rates in clinical development overall, in the face of rising costs.

First-in-patient-studies, analysis findings, and relevance to Phase-0 studies:

As demonstrated by Network member DiMasi et al. (2010) and Pammolli et al (2011) the Wong et al data also confirm that the highest attrition in clinical development is in the first-in-patient stage, typically, Phase 1b, or 2a, up to twice as high as in Phase-1 and Phase-3 (typically, Phase-1 ~30%, Phase 2 ~60 %, Phase-3 ~ 25% attrition rates). This is perhaps no surprise as it is in such trials that the real test of translation is undertaken: whether the drug arrives at its intended tissue/organ, establishes adequate dynamic concentrations there, binds to its intended molecular target, and initiates specific pharmacological modulations consistent with the intended therapeutic effects. In many cases, these can only be meaningfully studied in the target patients, rather than the healthy volunteers of Phase-1.

It is obviously of considerable value to be able to obtain such data about drug effects in patients as early as possible. You want to prioritize identifying the most likely reason for your failure as soon as possible so you can terminate the expensive investment.

First-in-patient trials can be done with Phase-0 approaches as the first-in-human study. This is encouraged by the ICH M3 guidelines (Section 7, p. 8, attached). Patients are usually excluded from first-in-human studies in part because they are a vulnerable population, for safety reasons, and in part because of concerns about confounding effects of concomitant medications, e.g., drug-drug interactions (DDIs), both concerns alleviated considerably with Phase-0 approaches, especially microdosing. Phase-0 allows collection of PD, biomarker, and MOA data in the molecular, tissue, and population targets, and if they lead to termination of nonviable candidates, will do so up to 2.5 years prior to traditional approaches. The emphasis on the importance of de-risking candidates early in the increasingly expensive clinical development process has been made recently (Morgan et al. 2018).


  1. Pammolli, F., Magazzini, L. & Riccaboni, M. The productivity crisis in pharmaceutical R&D. Nat Rev Drug Discov 10, 428-438, (2011).
  2. DiMasi, J. A., Feldman, L., Seckler, A. & Wilson, A. Trends in risks associated with new drug development: success rates for investigational drugs. Clin Pharmacol Ther 87, 272-277, (2010).
  3. Morgan, P. et al. Impact of a five-dimensional framework on R&D productivity at AstraZeneca. Nat Rev Drug Discov 17, 167-181, (2018)

Posted in