It is time to revamp the design of clinical trials, according to the American Society of Clinical Oncology (ASCO). The organization is calling on the scientific community to strive for more clinically meaningful results.
Clinical investigators, patient advocates, trial sponsors, and the community of patients must "collectively raise the bar in our expectations of the benefits of new therapies," write Lee M. Ellis, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, and his colleagues in an ASCO report published online March 17 in the Journal of Clinical Oncology.
They challenge the current trend of seeking limited improvements, and would like to see investigators strive for larger incremental gains than have been achieved in the past.
As molecularly targeted drugs become more common, larger gains will be seen, but they will be in select and carefully identified patient groups. This will result in "smaller and smarter clinical trials" being conducted much faster than trials that aim for smaller benefits in larger patient populations, Dr. Ellis and colleagues note.
They outline the recommendations of the ASCO Cancer Research Committee, which put together working groups to consider the design of future clinical trials and to better define clinically meaningful outcomes in advanced pancreatic, lung, breast, and colon cancers. Dr. Ellis is immediate past chair of that committee.
The recommendations of the working groups are not intended to set standards for regulatory approval or insurance coverage; instead, they are intended to encourage patients and investigators to demand more from these studies, such as significantly improved survival or quality of life, or both, Dr. Ellis and colleagues explain.
The draft recommendations were released last year and discussed at the 2013 ASCO annual meeting, as reported at that time by Medscape Medical News.
Hitting the Target
"We're urging our colleagues to implement clinical trials that, if successful, would provide a significant and clinically meaningful improvement in survival," said Dr. Ellis.
"People with cancer are living longer due to new therapies that target specific molecular drivers of cancer," he said in a statement. "As our understanding of the molecular drivers of cancer expands, we should be able to design clinical trials that achieve better results."
In many cases, however, targeted agents are being developed without a complete understanding of the drug's target and without a companion diagnostic tool to help in the selection of appropriate patients, he and his colleagues point out.
To address that issue, the working groups recommend that trial sponsors establish comprehensive biospecimen banks, with informed consent from patients, so that investigators can "ask scientific questions before and after trials are completed" that will facilitate the discovery and validation of biomarkers.
Recommended Targets
The working groups decided on overall survival as the primary measure of clinically meaningful outcomes, although Dr. Ellis and colleagues emphasize that this does not diminish the value of progression-free survival or other surrogate end points that might be valid in certain clinical situations.
The groups established 0.8 as the hazard ratio threshold to indicate improvement in median overall survival. They established a range of 2.5 to 6.0 months, depending on the clinical context, as the minimum incremental improvement in survival over standard therapy.
In addition, the working groups decided that incremental gains in survival should be accompanied by little or no increase in toxicity, compared with current regimens. If new therapies are substantially more toxic, then they need to show large increments in overall survival.
Table. Recommendations for Median Overall Survival Goals
| Patient Population | Current Baseline (Months) | Meaningful Improvement (Months) | Target Hazard Ratios |
| Pancreatic cancer | |||
| Eligible for FOLFIRINOX | 10–11 | 4–5 | 0.67–0.69 |
| Eligible for gemcitabine or gemcitabine/nab-paclitaxel | 8–9 | 3–4 | 0.60–0.75 |
| Lung cancer | |||
| Nonsquamous cell carcinoma | 13 | 3.25–4 | 0.76–0.80 |
| Squamous cell carcinoma | 10 | 2.5–3 | 0.77–0.80 |
| Breast cancer | |||
| Metastatic triple-negative (previously untreated for metastatic disease) | 18 | 4.5–6 | 0.75–0.80 |
| Colon cancer | |||
| Disease progression with all previous therapies (or not a candidate for standard second- or third-line options) | 4–6 | 3–5 | 0.67–0.67 |
Challenges to Goals?
It might be difficult to reach the goals recommended by the working groups, writes David M. Dilts, PhD, from the Knight Cancer Institute at the Oregon Health and Science University in Portland, in an accompanying editorial.
He notes that advocates for trial investigators, patients, regulators, and funding agencies are needed.
"For trialists in industry, it is an opportunity to set the future direction of the entire industry, something that will allow for better, more meaningful treatments" to be delivered to patients sooner, he writes.
Dr. Dilts adds that "funding agencies must balance their research portfolios among maintenance, incremental, and radical trials. It has been well documented that the existing government funding system can discourage support for radical innovation."
But not everyone agrees that there will be major challenges to implementing the recommendations made by the working groups.
This process, in fact, has already begun, said Robert Dreicer, MD, chair of the Department of Solid Tumor Oncology at the Cleveland Clinic.
"There has been a call for better trials, and trial designs are changing," he told Medscape Medical News. In fact, "the move for more relevant end points has been underway for some time."
Pharmaceutical manufacturers have been looking for ways to answer questions more efficiently, Dr. Dreicer noted. "This will allow us to get to the end points with fewer patients."
Public funding is also more limited. "We are going to have to be more thoughtful about the patients included and the types of trials," he said. "We want to run trials that have an impact, instead of conducting large trials that cost millions of dollars and find an improvement in progression-free survival of 5 weeks, for example."
As a community, "we need to address questions in a more robust way, to look at correlates in a more robust way, and to use the tissue and biomarkers," Dr. Dreicer continued. "We need to find the patients who will derive the most benefit."
"This is not just a call to arms," he said. "We have to understand that the environment has changed, and we have to use the situation to our best advantage."
Several of the report authors have disclosed financial relationships, as detailed in the paper.
J Clin Oncol. Published online March 17, 2014. Abstract, Editorial
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Cite this: Time for 'Smaller and Smarter' Clinical Trials, Says ASCO - Medscape - Mar 18, 2014.
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