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Senior Vice-President, Product Development Citeline
Current trends in oncology trial terminations as analyzed by Citeline have revealed that sponsors are learning from the past and making gains in this troubled area of drug development.
Current trends in oncology trial terminations as analyzed by Citeline have revealed that sponsors are learning from the past and making gains in this troubled area of drug development. For example, the top two reasons for terminating a trial (by absolute trial counts) were lack of efficacy and poor enrollment. On a relative basis (as percentage of total terminated trials), 27% of the trials were terminated due to missing efficacy endpoints, and 26% due to slow/inadequate enrollment. And though the third most frequently cited reason for terminating the trials was a higher than expected incidence of serious adverse events—only 10% of all trials ended for this reason.
From January 1, 2002 through December 31, 2011, Phase II, II/III, and III trial data from the first five-year period were compared to the more recent five years to reveal these trends. As such, for both Phase II and III terminated trials, an overall decrease in terminations attributed to poor/slow patient enrollment is evident for the more recent five-year time period. One reason for this trend might be attributed to sponsor's allowing enrollment periods to lengthen in order to reach a desired level of patient accrual. A decrease in attrition due to poor enrollment may also reflect improvement in site and investigator selection.
Very often a sponsor will proactively terminate a trial based on negative results obtained from full analysis of trials that read out after the start of the current trial; or due to safety issues seen in another concurrent or recently completed trial; or based on stronger efficacy signals in another patient population or disease. These decisions have little to do with an individual trial, but rather reflect company strategy to better align a drug program for success. The earlier the sponsor makes the no-go decision, the earlier unnecessary spend can be eliminated.
When all trials terminated due to a business decision (drug strategy shift, pipeline reprioritization) are combined, there is a significant positive trend to terminate for strategic reasons (Figure 1*). This is a clear signal that the industry is taking a hard look at their development programs, particularly true for the larger biopharma companies. Supporting this conclusion is the uptick in percent of terminated trials reportedly terminated due to funding issues.
However, amidst all of these reasons to celebrate is one troubling observation: a sharp decline in trials terminated due to early positive outcomes. Absolute trial counts are relatively low (23 total trials in '02 to '06 compared to 13 for the more recent period), but on a relative basis the drop from 11.1% to 6.7% of trial per phase is significant.
The companies that sponsored 10 or more terminated trials over the past decade, and the breakdown, by overall percentage of total trials for the two half-decade periods reveals a not-so surprising list of players (Figure 2*). For simplicity of comparison, the data sums trials sponsored by companies acquired by the major players during the analysis periods, and omits trials jointly sponsored by two or more companies. Among these sponsors, who shows improvement over time? Eli Lilly, Sanofi, J&J, Amgen, and Takeda all demonstrated a decrease in relative percentages of trials terminated. AstraZeneca had a smaller relative decrease overall compared to the aforementioned companies.
Early positive outcome is the best of all reasons to terminate a clinical trial, despite the overall negative trend reported across all sponsors, several of the pharma sponsors show recent positive trends. Comparing absolute trial counts, Roche, Celgene, Novartis, Sanofi, J&J, and Merck & Co all improved their termination numbers by at least one. Why the drop? Perhaps trial design complications preclude the possibility of early positive terminations? Alternatively, might the move to targeted therapies demand full trial read out?
The numbers of industry-sponsored trial terminations reported during 2007 to 2011 decreased in comparison to those reported during 2002 to 2006. In addition to this overall positive trend, it appears that company sponsors are proactively taking steps to terminate more trials, or programs in recent years.
Enrollment issues continue to plague the industry, but the five-year period comparison does reveal signs of progress. With the emergence and uptake of electronic trial management software solutions, it may be that sponsors can recognize poor performing sites or investigators sooner and replace them earlier. Alternatively, it may be that more realistic timelines for trials are on the rise.
Futility, or lack of efficacy also is a persistent issue in clinical trial performance, but a strong sign of improvement is the significant reduction in Phase III trials terminated for this reason during the second half of the analysis period. This suggests that better decisions are being made during or after Phase II completion resulting in a higher Phase III success rate.
*To view this article online, with figures, please visit: http://bit.ly/PJfsvE.
—Christine Blazynski, PhD is Senior Vice-President, Product Development at Citeline.