Two hundred forty-nine phase 3 clinical trials from the SWOG publication portal were identified as closed and published Figure 2. Ninety-four trials One hundred thirty-one trials The most commonly investigated cancers included breast 30 [ Superiority designs accounted for trials Advanced disease trials accounted for studies Nearly all trials included systemic therapy as one of the treatments on any arm [ Median total accrual was patients per trial range, ; mean SD total accrual, patients per trial.
Overall, 82 of trials Seventy trials Rates of PI trials were also higher among intergroup trials 68 of [5. Fourteen trials were cited in NCCN guidelines but were determined not to be PI because they did not support the recommended treatment eTable 2 in the Supplement.
Among trials with positive findings, 47 of 65 Nine 4. Among trials with negative findings, 35 of Thirty-four trials Among the remaining studies with negative findings, 15 provided sufficient evidence to suggest acceptable alternatives for SOC, and 3 influenced guidelines for other reasons. Early studies may have been less likely to be identified as PI because the NCCN guidelines only became available in However, among the 42 trials published before , 16 trials were PI With these studies included as PI, the overall rate of PI trials was 87 of This study is the first, to our knowledge, to comprehensively examine the practice influence of NCTN-sponsored clinical trials for cancer using objective criteria.
Nearly half A few studies in the United Kingdom used physician surveys to show that multicenter randomized clinical trials influence clinical practice, with the effect extending beyond the participating physicians. The results in Table 1 are limited by small numbers but illuminate potentially informative associations. The high proportion of PI trials in head and neck cancers was due partly to 3 trials 26 - 28 conducted in the s showing that multimodality therapy chemotherapy and radiotherapy provided superior outcomes compared with radiotherapy alone, a strategy still commonly used today.
This multimodality approach was also successful for trials across different cancer settings, in part accounting for the higher rate of PI trials from to Trials conducted by intergroups rather than single network groups were more likely to be PI. The collaboration of multiple network groups on a trial could reflect the importance of the original research question and the increased potential for the results to guide practice.
Future research establishing a prediction model based on modifiable factors that reliably predict PI trial findings would represent a powerful use of study databases of the kind used in this analysis to influence policy. The success rate of pharmaceutical company phase 3 FDA indication studies has been examined extensively.
DiMasi and colleagues 42 used data from the largest 50 pharmaceutical companies for drug evaluations from through and found that about half of phase 3 trials were submitted for indication. Overall, 6. These rates are lower than those observed in pharmaceutical company studies.
However, the objective of NCTN trials is rarely to register a new drug indication. For pharmaceutical companies, the investment costs for each drug approval are high. This comparison is imperfect because the pharmaceutical research process supports human trials and initial drug discovery, and the regulatory oversight for early-phase trials is more costly.
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Although our estimate of costs for NCTN trials also included those supporting early-stage phases 1 and 2 trials, these trials are not often as closely tied to the eventual phase 3 trial and are not as numerous. Further, federal dollars invested in network group clinical trials frequently do not cover all of the capitation and institutional costs related to trial participation.
One striking feature of our results is the number of negative trials found to influence guideline care. This factor is important because negative trials are generally perceived as failures. However, the true underlying objective of a well-conducted trial is to reduce uncertainty about the efficacy of a new treatment rather than to achieve any particular outcome. This notion is important given the history of exciting new therapeutic approaches found to be ineffective or outright harmful when tested in comparative clinical trials.
In the s, autologous bone marrow transplants for breast cancer were thought to represent an important alternative and potentially curable avenue for women with metastatic disease, supported by the exciting results of early-stage, noncontrolled trials.
Our study was limited to the evaluation of trials directed or contributed to by a single large network group. This criterion could limit the generalizability of the overall estimate of PI trials, although importantly, other network groups led or contributed to almost 3 of every 4 trials.
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Also, our estimate may be biased high if the rate of intergroup trials was not representative because intergroup trials were more likely to influence practice. Further, although our determination of PI trials relied in part on NCCN guidelines, which are widely used by payers and health care professionals, other compendia may have generated a different set of estimates.
Moreover, the identification of a PI trial may be subject to the frequency with which NCCN guidelines are updated for selected cancers, especially more recent trials and those conducted in less common cancers. Although in some instances a SWOG PI trial was solely responsible for influencing guideline care, in others, it was only 1 of multiple studies, suggesting contributions from trials not included in our study sample.
Thus, the true value of a well-conducted, controlled randomized clinical trial for cancer treatment is in guiding the cancer clinical treatment community about the best treatment choice regardless of whether the best choice is a new, trial-proven experimental therapy or the existing SOC.
Moreover, NCTN trials also benefit research through data sharing and secondary analyses using the clinical study databases, which provide important insights into current treatments and hypotheses for future trials. Finally, the amount invested by federal funders to provide this valuable evidence was modest. The NCTN program contributes clinically meaningful, cost-efficient evidence to guide patient care. Published: September 4, Corresponding Author: Joseph M.
Author Contributions: Dr Unger had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Critical revision of the manuscript for important intellectual content: All authors. No other conflicts were reported. Home Issues Specialties For Authors. All Rights Reserved. Download PDF Comment. Figure 1. View Large Download.
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