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Posts Tagged ‘journal national cancer institute’


 

Multiple factors related to initial trial design may predict low patient accrual for cancer clinical trials

Reporter: Stephen J. Williams, Ph.D.

A recently published paper in JCNI highlights results determining factors which may affect cancer trial patient accrual and the development of a predictive model of accrual issues based on those factors.

To hear a JCNI podcast on the paper click here

but below is a good posting from scienmag.com which describes their findings:

Factors predicting low patient accrual in cancer clinical trials

source: http://scienmag.com/factors-predicting-low-patient-accrual-in-cancer-clinical-trials/

Nearly one in four publicly sponsored cancer clinical trials fail to enroll enough participants to draw valid conclusions about treatments or techniques. Such trials represent a waste of scarce human and economic resources and contribute little to medical knowledge. Although many studies have investigated the perceived barriers to accrual from the patient or provider perspective, very few have taken a trial-level view and asked why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants. According to a study published December 29 in the JNCI: Journal of the National Cancer Institute, a number of measurable trial characteristics are predictive of low patient accrual.

Caroline S. Bennette, M.P.H., Ph.D., of the Pharmaceutical Outcomes Research and Policy Program, University of Washington, Seattle, and colleagues from the University of Washington and the Fred Hutchinson Cancer Research Center analyzed information on 787 phase II/III clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011. After excluding trials that closed because of toxicity or interim results, Bennette et al. found that 145 (18%) of NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.

The authors identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy. Bennette et al. then developed a multivariable prediction model of low accrual using 12 trial-level risk factors, which they reported had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.

The researchers conclude that “Systematically considering the overall influence of these factors could aid in the design and prioritization of future clinical trials…” and that this research provides a response to the recent directive from the Institute of Medicine to “improve selection, support, and completion of publicly funded cancer clinical trials.”

In an accompanying editorial, Derek Raghavan, M.D., Levine Cancer Institute, writes that the focus needs to be on getting more patients involved in trials, saying, “we should strive to improve trial enrollment, giving the associated potential for improved results. Whether the basis is incidental, because of case selection bias, or reflects the support available to trial patients has not been determined, but the fact remains that outcomes are better.”

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Contact info:

Article: Caroline S. Bennette, M.P.H., Ph.D., cb11@u.washington.edu

Editorial: Derek Raghavan, M.D., derek.raghavan@carolinashealthcare.org

Other investigators also feel that initial trial design is of UTMOST importance for other reasons, especially in the era of “precision” or “personalized” medicine and why the “basket trial” or one size fits all trial strategy is not always feasible.

In Why the Cancer Research Paradigm Must Transition to “N-of-1” Approach

Dr. Maurie Markman, MD gives insight into why the inital setup of a trial and the multi-center basket type of  accrual can be a problematic factor in obtaining meaningful cohorts of patients with the correct mutational spectrum.

The anticancer clinical research paradigm has rapidly evolved so that subject selection is increasingly based on the presence or absence of a particular molecular biomarker in the individual patient’s malignancy. Even where eligibility does not mandate the presence of specific biological features, tumor samples are commonly collected and an attempt is subsequently made to relate a particular outcome (eg, complete or partial objective response rate; progression-free or overall survival) to the individual cancer’s molecular characteristics.

One important result of this effort has been the recognition that there are an increasing number of patient subsets within what was previously—and incorrectly—considered a much larger homogenous patient population; for example, non–small cell lung cancer (NSCLC) versus EGFR-mutation–positive NSCLC. And, while it may still be possible to conduct phase III randomized trials involving a relatively limited percentage of patients within a large malignant entity, extensive and quite expensive effort may be required to complete this task. For example, the industry-sponsored phase III trial comparing first-line crizotinib with chemotherapy (pemetrexed plus either carboplatin or cisplatin) in ALK-rearrangement–positive NSCLC, which constitutes 3% to 5% of NSCLCs, required an international multicenter effort lasting 2.5 years to accrue the required number of research subjects.1

But what if an investigator, research team, or biotech company desired to examine the clinical utility of an antineoplastic in a patient population representing an even smaller proportion of patients with NSCLC such as in the 1% of the patient population with ROS1 abnormalities,2 or in a larger percentage of patients representing 4%-6% of patients with a less common tumor type such as ovarian cancer? How realistic is it that such a randomized trial could ever be conducted?

Further, considering the resources required to initiate and successfully conduct a multicenter international phase III registration study, it is more than likely that in the near future only the largest pharmaceutical companies will be in a position to definitively test the clinical utility of an antineoplastic in a given clinical situation.

One proposal to begin to explore the benefits of targeted antineoplastics in the setting of specific molecular abnormalities has been to develop a socalled “basket trial” where patients with different types of cancers with varying treatment histories may be permitted entry, assuming a well-defined molecular target is present within their cancer. Of interest, several pharmaceutical companies have initiated such clinical research efforts.

Yet although basket trials represent an important research advance, they may not provide the answer to the molecular complexities of cancer that many investigators believe they will. The research establishment will have to take another step toward innovation to “N-of-1” designs that truly explore the unique nature of each individual’s cancer.

Trial Illustrates Weaknesses

A recent report of the results of one multicenter basket trial focused on thoracic cancers demonstrates both the strengths but also a major fundamental weakness of the basket trial approach.3

However, the investigators were forced to conclude that despite accrual of more than 600 patients onto a study conducted at two centers over a period of approximately 2 years, “this basket trial design was not feasible for many of the arms with rare mutations.”3

They concluded that they needed a larger number of participating institutions and the ability to adapt the design for different drugs and mutations. So the question to be asked is as follows: Is the basket-type approach the only alternative to evaluate the clinical relevance of a targeted antineoplastic in the presence of a specific molecular abnormality?

Of course, the correct answer to this question is surely: No!

– See more at: http://www.onclive.com/publications/Oncology-live/2015/July-2015/Why-the-Cancer-Research-Paradigm-Must-Transition-to-N-of-1-Approach#sthash.kLGwNzi3.dpuf

The following is a video on the website ClinicalTrials.gov which is a one-stop service called EveryClinicalTrial to easily register new clinical trials and streamline the process:

Other article on this Open Access Journal on Cancer Clinical Trial Design include:

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