The patient population problem
Drug discovery is already a tough endeavour: fewer than 10% of drug candidates entering clinical trials ever reach approval¹. Much of the conversation around why drugs fail centers on toxicity or lack of efficacy. However, an often overlooked issue is that drugs are sometimes studied in the wrong patient groups. Even when a molecule shows promise, regulators will ask not only “does it work?” but “for whom does it work?” Without a clear, well-defined answer, the odds of success collapse.
Learning from Blenrep’s failure
The story of GSK’s Blenrep is a cautionary example. Despite encouraging signs of efficacy in multiple myeloma, its confirmatory studies fell short of showing sufficient benefit in the proposed patient groups. The FDA rejected Blenrep for this indication, citing concerns about safety, tolerability, and whether the population enrolled truly reflected those most likely to benefit². Here, the drug itself was not dismissed as biologically irrelevant; it was the risk–benefit balance in the chosen patients that proved fatal to the program.
What we learnt from 24,000 trials
This is not an isolated case. Analyses of thousands of clinical trials underscore the scale of the issue. A 2023 review of over 24,000 studies found overall success rates of just 7.9%, and identified trial quality, including how well the patient population is defined or matched, as a statistically significant predictor of outcome³. Phase II trials are not always reliable indicators, and occasionally drugs move into Phase III only to show reduced efficacy in wider or inadequately stratified populations⁴. In other words, defining the wrong population is enough to doom an otherwise promising drug.
Safety in context
The stakes are even higher when dealing with drugs that carry safety risks. A toxicity signal may be intolerable in a broad population, yet acceptable and even life-saving in a smaller, clearly identified subgroup. Regulators are attuned to this distinction where real-world evidence, biomarkers and stratified trial designs are becoming increasingly important to close this gap and demonstrate that risks can be justified for the right patients.
Regulatory shift: from failure to successThis shift is reshaping the way we think about failed drugs. Instead of writing them off entirely, the question becomes whether we can show, with supporting evidence, that a specific group of patients could truly benefit from this treatment. The importance of demonstrating a clear and relevant population cannot be overstated. Without it, strong biology and novel mechanisms will continue to be lost in translation. With it, however, we stand a far greater chance of turning past failures into future therapies.
Author: Omar Alkhatib
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