Oncology phase II proof-of-concept studies with multiple targets: Randomized controlled trial or single arm?

For oncology drug development, phase II proof-of-concept studies have played a key role in determining whether or not to advance to a confirmatory phase III trial. With the increasing number of immunotherapies, efficient design strategies are crucial in moving successful drugs quickly to market. Our research examines drug development decision making under the framework of maximizing resource investment, characterized by benefit cost ratios (BCRs). In general, benefit represents the likelihood that a drug is successful, and cost is characterized by the risk adjusted total sample size of the phases II and III studies. Phase III studies often include a futility interim analysis; this sequential component can also be incorporated into BCRs. Under this framework, multiple scenarios can be considered. For example, for a given drug and cancer indication, BCRs can yield insights into whether to use a randomized control trial or a single-arm study. Importantly, any uncertainty in historical control estimates that are used to benchmark single-arm studies can be explicitly incorporated into BCRs. More complex scenarios, such as restricted resources or multiple potential cancer indications, can also be examined. Overall, BCR analyses indicate that single-arm trials are favored for proof-of-concept trials when there is low uncertainty in historical control data and smaller phase III sample sizes. Otherwise, especially if the most likely to succeed tumor indication can be identified, randomized controlled trials may be a better option. While the findings are consistent with intuition, we provide a more objective approach.

Fracture Burden and Risk Factors in Childhood CKD: Results from the CKiD Cohort Study.

Childhood chronic kidney disease (CHD) poses multiple threats to bone accrual; however, the associated fracture risk is not well characterized. This prospective cohort study included 537 CKD in Children (CKiD) participants. Fracture histories were obtained at baseline, at years 1, 3, and 5 through November 1, 2009, and annually thereafter. We used Cox regression analysis of first incident fracture to evaluate potential correlates of fracture risk. At enrollment, median age was 11 years, and 16% of patients reported a prior fracture. Over a median of 3.9 years, 43 males and 24 females sustained incident fractures, corresponding to 395 (95% confidence interval [95% CI], 293-533) and 323 (95% CI, 216-481) fractures per 10,000 person-years, respectively. These rates were 2- to 3-fold higher than published general population rates. The only gender difference in fracture risk was a 2.6-fold higher risk in males aged ≥15 years (570/10,000 person-years, adjusted P=0.04). In multivariable analysis, advanced pubertal stage, greater height Z-score, difficulty walking, and higher average log-transformed parathyroid hormone level were independently associated with greater fracture risk (all P≤0.04). Phosphate binder treatment (predominantly calcium-based) was associated with lower fracture risk (hazard ratio, 0.37; 95% CI, 0.15-0.91; P=0.03). Participation in more than one team sport was associated with higher risk (hazard ratio, 4.87; 95% CI, 2.21-10.75; P<0.001). In conclusion, children with CKD have a high burden of fracture. Regarding modifiable factors, higher average parathyroid hormone level was associated with greater risk of fracture, whereas phosphate binder use was protective in this cohort.