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Phase II trials as a hurdle in drug licensing

MedUni Vienna analysis shows that efficacy is often overestimated
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(Vienna, 21 April 2020) Based on a systematic analysis of trials related to rheumatoid arthritis and psoriasis arthritis, a MedUni Vienna study group at the Division of Rheumatology at MedUni Vienna/Vienna General Hospital was able to show that many clinical phase II trials systematically overestimate the efficacy of therapeutics, so that the results of subsequent phase III trials can often be disappointing. Essentially this situation also applies in many other areas.

Phase III clinical trials are the ultimate precursors to new drugs for clinical use – in most cases, drugs that have successfully overcome this hurdle have also made it onto the market. These study programmes are on a large scale and very expensive, since they require a lot of participating volunteers, including for placebo control groups as well or possibly less effective control treatments. Usually, smaller phase II trials are conducted first of all to assess the optimum dose and the estimated efficacy of the new drug in the relevant patient group. If phase II trials are successful, they are usually followed by phase III trials.

Based on a systematic analysis of all recently published trials in the field of rheumatoid arthritis and psoriasis arthritis, the MedUni Vienna researchers led by Daniel Aletaha, found that phase II trials systematically overestimate the efficacy of therapeutics and, as a result of this, the subsequently conducted phase III trials often produce disappointing results.

This has dramatic implications for sponsors of clinical trials and also for academic groups and patients. Lead author Andreas Kerschbaumer was able to identify that the problem is primarily due to liberal inclusion criteria for phase II trials. Disappointing results can be avoided by a more careful and stringent choice of inclusion criteria and of the trial population.

Other disciplines also affected
"These results show quite clearly that the problem that has been identified does not only apply to a single disease but to others as well," explains Principal Investigator Daniel Aletaha. "Moreover, the data indicates that the problem discovered using rheumatology relates to all other disciplines."

Many existing drugs are being seen as offering hope of a successful COVID-19 treatment, but small trials conducted so far have not borne out these expectations. The researchers also draw parallels with the numerous COVID-19 trials currently underway: "Our results are particularly important in view of the many phase II trials that are to be expected for COVID drugs, because it is important to plan the phase II trials in such a way that they are actually meaningful and can then be confirmed in the costly and time-consuming phase III, rather than being refuted.

Service: Nature Medicine
"Efficacy outcomes in phase 2 and phase 3 randomized controlled trials in rheumatology"
DOI 10.1038/s41591-020-0833-4. https://www.nature.com/articles/s41591-020-0833-4