Rejoinder to the discussion on "LEAP: the latent exchangeability prior for borrowing information from historical data".

The discussions of our paper provide insights into the practical considerations of the latent exchangeability prior while also highlighting further extensions. In this rejoinder, we briefly summarize the discussions and provide comments.

LEAP: the latent exchangeability prior for borrowing information from historical data.

It is becoming increasingly popular to elicit informative priors on the basis of historical data. Popular existing priors, including the power prior, commensurate prior, and robust meta-analytic predictive prior, provide blanket discounting. Thus, if only a subset of participants in the historical data are exchangeable with the current data, these priors may not be appropriate. In order to combat this issue, propensity score approaches have been proposed. However, these approaches are only concerned with the covariate distribution, whereas exchangeability is typically assessed with parameters pertaining to the outcome. In this paper, we introduce the latent exchangeability prior (LEAP), where observations in the historical data are classified into exchangeable and non-exchangeable groups. The LEAP discounts the historical data by identifying the most relevant subjects from the historical data. We compare our proposed approach against alternative approaches in simulations and present a case study using our proposed prior to augment a control arm in a phase 3 clinical trial in plaque psoriasis with an unbalanced randomization scheme.

Predicting outcomes of phase III oncology trials with Bayesian mediation modeling of tumor response.

Pivotal cancer trials often fail to yield evidence in support of new therapies thought to offer promising alternatives to standards-of-care. Conducting randomized controlled trials in oncology tends to be considerably more expensive than studies of other diseases with comparable sample size. Moreover, phase III trial design often takes place with a paucity of survival data for experimental therapies. Experts have explained the failures on the basis of design flaws which produce studies with unrealistic expectations. This article presents a framework for predicting outcomes of phase III oncology trials using Bayesian mediation models. Predictions, which arise from interim analyses, derive from multivariate modeling of the relationships among treatment, tumor response, and their conjoint effects on survival. Acting as a safeguard against inaccurate pre-trial design assumptions, the methodology may better facilitate rapid closure of negative studies. Additionally the models can be used to inform re-estimations of sample size for under-powered trials that demonstrate survival benefit via tumor response mediation. The methods are applied to predict the outcomes of two colorectal cancer studies. Simulation is used to evaluate and compare models in the absence versus presence of reliable surrogate markers of survival.

Pharmacokinetic/pharmacodynamic data extrapolation models for improved pediatric efficacy and toxicity estimation, with application to secondary hyperparathyroidism.

In most drug development settings, the regulatory approval process is accompanied by extensive studies performed to understand the drug's pharmacokinetic (PK) and pharmacodynamic (PD) properties. In this article, we attempt to utilize the rich PK/PD data to inform the borrowing of information from adults during pediatric drug development. In pediatric settings, it is especially crucial that we are parsimonious with the patients recruited for experimentation. We illustrate our approaches in the context of clinical trials of cinacalcet for treating secondary hyperparathyroidism in pediatric and adult patients with chronic kidney disease, where we model both parathyroid hormone (efficacy endpoint) and corrected calcium levels (safety endpoint). We use population PK/PD modeling of the cinacalcet data to quantitatively assess the similarity between adults and children, and use this information in various hierarchical Bayesian adult borrowing rules whose statistical properties can then be evaluated. In particular, we simulate the bias and mean square error performance of our approaches in settings where borrowing is and is not warranted to inform guidelines for the future use of our methods.