Assessment of added activity of an antitumor agent.

An unprecedented number of novel oncology drugs are under preclinical and clinical development, and nearly all are developed in combinations. With an over-reliance on biological hypotheses, there is less effort to establish single agent activity before initiating late clinical development. This may be contributing to a decreased success rate going from phase 1 to approval in the immunotherapy era. Growing evidence in clinical trial data shows that the treatment benefit from most approved combination therapies can be explained by the independent drug action model. Using this working model, we develop a simple index to measure the added antitumor activity of a new drug based on mean response duration, an endpoint that naturally combines both response status and duration information for all patients, which is shown to be highly predictive of clinical benefit of FDA-approved anti-PD-(L)1 immunotherapies. This index sheds light on challenges and opportunities in contemporary oncology drug development and provides a practical tool to assist with decision-making in early clinical trials.

Evaluation of early efficacy endpoints for proof-of-concept trials.

A Phase II proof-of-concept (POC) trial usually uses an early efficacy endpoint other than a clinical endpoint as the primary endpoint. Because of the advancement in bioscience and technology, which has yielded a number of new surrogate biomarkers, drug developers often have more candidate endpoints to choose from than they can handle. As a result, selection of endpoint and its effect size as well as choice of type I/II error rates are often at the center of heated debates in design of POC trials. While optimization of the trade-off between benefit and cost is the implicit objective in such a decision-making process, it is seldom explicitly accounted for in practice. In this research note, motivated by real examples from the oncology field, we provide practical measures for evaluation of early efficacy endpoints (E4) for POC trials. We further provide optimal design strategies for POC trials that include optimal Go-No Go decision criteria for initiation of Phase III and optimal resource allocation strategies for conducting multiple POC trials in a portfolio under fixed resources. Although oncology is used for illustration purpose, the same idea developed in this research note also applies to similar situations in other therapeutic areas or in early-stage drug development in that a Go-No Go decision has to rely on limited data from an early efficacy endpoint and cost-effectiveness is the main concern.

The cost effectiveness and budget impact of natalizumab for formulary inclusion.

BACKGROUND: Crohn's disease (CD) and multiple sclerosis (MS) are debilitating autoimmune diseases, which represent a substantial cost burden in the context of managed care. As a corollary, there is an unmet pharmacotherapeutic need in patient populations with relapsing forms of MS, in addition to populations with moderately to severely active CD with evidence of inflammation who have experienced an inadequate response to other mainstream therapies. The purpose of this study was to analyze the clinical and economic data associated with natalizumab (Tysabri) and to determine the potential impact of its formulary inclusion in a hypothetical health plan. FINDINGS: Regarding MS, the implemented cost-effectiveness and budget-impact models demonstrated an anticipated reduction in relapse rate of 67% over 2 years, and a total therapy cost of $72,120 over 2 years, equating to a cost per relapse avoided of $56,594. With respect to the model assumptions, the market share of natalizumab would experience an increase to 8.5%, resulting in a total per-member, per-month healthcare cost increase of $0.003 ($0.002 for pharmacy costs and $0.001 for medical costs). Regarding CD, over a 2-year period outlined by the model, natalizumab produced the highest average time in remission, steroid-free remission, and remission or response in comparison to the other agents. The mean total costs associated with the initiation of natalizumab, infliximab, and adalimumab were $68,372, $62,090, and $61,796, respectively. Although natalizumab's costs were higher, the mean time spent in remission while on this medication was 4.5 months, as opposed to 2.4 months for infliximab and 2.9 months with adalimumab. This shift in market share was used to estimate the change in total costs (medical + pharmacy), and the per-member per-month change for the model's base case was calculated to be $0.035. LIMITATIONS: The aforementioned cost-effectiveness results for natalizumab in the treatment for CD and MS were limited by the model's predetermined assumptions. These assumptions include anticipated reduction in relapse rate after 2 years of therapy and acquisition costs in the MS model, as well as assuming a certain percentage of patients were primary and secondary failures of TNFalpha inhibitor therapy in the CD model. CONCLUSION: The evidence presented here demonstrates that natalizumab provides clinical practitioners with another tool in their fight against both MS and CD, albeit by way of a different mechanism of action. After a thorough review of the evidence, the authors find that natalizumab has been shown to be relatively cost effective in the treatment of both conditions from a payer perspective; the therapy adds a new option for those patients for whom conventional treatment was unsuccessful.