Negative phase 3 randomized controlled trials: Why cancer drugs fail the last barrier?

Cancer drugs have a very poor probability of successfully transitioning from a Phase 1 study to FDA approval. One study estimated that only 5.1% drugs make this successful journey with the transitions from Phase 2 to Phase 3 being the most challenging to success.1 Failure of a new drug at Phase 3 stage of development is often disappointing to patients and investigators, and absorbs scarce resources, since phase 3 trials are also traditionally quite expensive. Hence, it's important to understand why cancer drugs fail in Phase 3 trials. We searched all the negative Phase 3 randomized controlled trials (RCTs) published between January 1, 2016 and December 31, 2016 in the New England Journal of Medicine (NEJM), Lancet, Lancet Oncology and Journal of Clinical Oncology (JCO)—the top journals that publish cancer drug trials based on impact factor. A trial was considered negative if the primary endpoint was not met. For this analysis, we included only the RCTs testing a new drug that had not yet been approved by the FDA for the specific indication being studied. We then searched the literature, without any restrictions and including relevant conference abstracts, for any preceding Phase 2 trials supporting the conduct of these negative Phase 3 RCTs. The outcomes of this search were categorized as “Yes, positive” if a previous positive Phase 2 was available, “Yes, negative” if this Phase 3 RCT was conducted despite a previous negative Phase 2, “Not done” if no previous Phase 2 trials were found, “yes, inconclusive” if the previous Phase 2 couldn't be objectively discerned as positive or negative and “Earlier trial” if this was a trial in early lines of therapy or an adjuvant trial of a drug already approved for later lines the same disease. A phase 2 trial was considered positive, negative or inconclusive based on whether the primary endpoint was met, unmet or not stated. In 2016, NEJM and Lancet published no negative cancer drug RCTs. Of the 24 and 25 Phase 3 RCTs published by Lancet Oncology and JCO respectively in 2016, 9 and 17 were negative Phase 3 RCTs of which 16 (7 + 9) trials involving 20,775 patients were those of new cancer drugs (Table 1). Of these 16 RCTs, 4 (25%) were “earlier trials,” i.e. they tested a drug approved for metastatic setting in adjuvant setting or an already approved drug for early lines of therapy in the same disease. One RCT (6.3%) was conducted without any previous Phase 2. For 5 RCTs (31.3%), there were only inconclusive previous Phase 2 studies because the criteria for considering them as positive were not prospectively defined. Three RCTs (18.8%) were conducted despite negative previous Phase 2 trials. Only 3 RCTs (18.8%) were conducted on the basis of previous positive Phase 2 trials (Fig. 1). Fifteen RCTs reported OS data of which 5 (33.3%) had a hazard ratio of >1 for overall survival—one of them was statistically significant implying harm. Negative phase 3 RCTs and their corresponding phase 2 trials. [Color figure can be viewed at wileyonlinelibrary.com] Although negative trials are important to advance our knowledge, a trial of a new cancer drug at Phase 3 stage of development represents use of substantial human, financial and logistic resources. These failed Phase 3 RCTs also contribute to the high Research & Development costs.2 Therefore, it is important to consider whether it is ethical to conduct large phase 3 RCTs of new cancer drugs despite evidence of lack of efficacy in phase 2. Although some previous studies have shown that negative Phase 3 trials are being conducted without Phase 2,3, 4 we found that Phase 3 RCTs were also conducted despite a preceding negative Phase 2. Previous studies have also shown that the response rates of drugs fall in Phase 3 versus Phase 2 trials, hence the chances for success of a drug that has already failed a Phase 2 is low.5 Because every cancer drug approval represents a potentially multibillion dollar market, current market provides incentives to undertake overpowered Phase 3 RCTs designed to detect marginal significances.6, 7 The Institutional Review Boards and approval authorities should take proactive steps to discourage Phase 3 RCTs that don't have positive data from previous Phase 2, especially those Phase 3 that are being planned despite negative Phase 2. Another important step would be to define when a Phase 2 would be considered positive a priori, because a significant proportion of Phase 2 trials in our study were inconclusive. The limitations of our study are that the selected studies may not be representative of all negative Phase 3 RCTs of cancer drugs because many such studies are never published. Because our sample included negative Phase 3 RCTs published in top cancer journals, we believe our estimates are conservative and that the actual percentage of negative Phase 3 RCTs that are conducted without a prior positive Phase 2 is higher. In conclusion, we found that among recent negative Phase 3 RCTs of cancer drugs, some were conducted despite a negative Phase 2, many trials were based on inconclusive data and only a few were conducted based on previous positive Phase 2 trials supporting the Phase 3.