Innovation at the Intersection of Clinical Trials and Real-World Data Science to Advance Patient Care.

While efficacy and safety data collected from randomized clinical trials are the evidentiary standard for determining market authorization, this alone may no longer be sufficient to address the needs of key stakeholders (regulators, providers, and payers) and guarantee long-term success of pharmaceutical products. There is a heightened interest from stakeholders on understanding the use of real-world evidence (RWE) to substantiate benefit-risk assessment and support the value of a new drug. This review provides an overview of real-world data (RWD) and related advances in the regulatory framework, and discusses their impact on clinical research and development.

Harnessing the Potential of Emerging Digital Health and Biological Sampling Technologies for Clinical Drug Development: Promise to Reality.

Advances in emerging innovative technologies have led to optimistic outlooks on their transformative potential for healthcare and clinical trials. Given the increased attention, this white paper by the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) presents perspectives on pharmaceutical and biotechnology industry trends for innovative digital health, adherence, and outpatient sampling technologies. As stimulus for cross-company scientific dialog points to consider for adoption, implementation, and recommendations to broaden uptake are proposed.

A proposal for scientific framework enabling specific population drug dosing recommendations.

Over the last 3 decades, there has been little change in the paradigm to derive dosing recommendations for specific populations (e.g., renal failure, elderly, or obese patients) despite better understanding of clearance pathways in these groups and availability of modeling and simulation tools.

Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies.

Background & Aims: Trials of therapies for chronic hepatitis C have used detection of hepatitis C virus (HCV) at week 24 of follow-up (sustained virologic response [SVR] 24) as a primary end point. However, there is increasing evidence that most patients who have an SVR at earlier time points (such as SVR12) maintain it until week 24. Use of earlier time points for key regulatory decisions (SVR12) and dose selection (SVR4) could facilitate HCV drug development.

From in vitro EC₅₀ to in vivo dose-response for antiretrovirals using an HIV disease model. Part II: application to drug development.

The purpose of this research was to qualify a previously derived quantitative model-based framework that proposed an in vitro-in vivo linkage to predict the dose-response relationship of an antiretroviral (ARV) new molecular entity (NME) in a monotherapy trial. Human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) data from monotherapy trials in ARV naïve/experienced HIV-infected subjects for eight drugs (i.e.

From in vitro EC₅₀ to in vivo dose-response for antiretrovirals using an HIV disease model. Part I: a framework.

Plasma drug concentrations and human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) data from short-term monotherapy trials in antiretroviral (ARV) naïve/experienced HIV-infected patients for one drug (i.e., lead case, a representative drug for a given class) from four distinct classes of ARV drugs [non-nucleoside reverse transcriptase inhibitors (NNRTIs); nucleotide reverse transcriptase inhibitors (NtRTIs); co-receptor antagonists (CRAs); and integrase strand transfer inhibitors (INSTIs)] were obtained.

Response-guided telaprevir therapy in prior relapsers? The role of bridging data from treatment-naïve and experienced subjects.

The purpose of this report is to illustrate the US Food and Drug Administration's rationale for approving response-guided therapy (RGT) for telaprevir (TVR) in combination with pegylated interferon-α and ribavirin (P/R) for the treatment of adults with genotype 1 chronic hepatitis C who were prior relapsers. RGT was prospectively evaluated in two registration trials of treatment-naïve subjects. In these studies, RGT allowed subjects who achieved undetectable hepatitis C virus RNA from weeks 4 and 12, known as extended rapid virologic response (eRVR), to stop all treatments at 24 weeks.

Impact of pharmacometric analyses on new drug approval and labelling decisions: a review of 198 submissions between 2000 and 2008.

Pharmacometric analyses have become an increasingly important component of New Drug Application (NDA) and Biological License Application (BLA) submissions to the US FDA to support drug approval, labelling and trial design decisions. Pharmacometrics is defined as a science that quantifies drug, disease and trial information to aid drug development, therapeutic decisions and/or regulatory decisions. In this report, we present the results of a survey evaluating the impact of pharmacometric analyses on regulatory decisions for 198 submissions during the period from 2000 to 2008.

The need for modeling and simulation to design clinical investigations in children.

Recent legislation in the United States and Europe has resulted in an increased number of clinical trials of pharmaceutical agents in children. Creating a well-designed clinical trial that can be successfully completed is a challenging task, particularly as the study population includes younger and smaller children. Although there are some established principles for initially estimating appropriate doses of pharmaceutical agents in children based on known effective doses in adults, these rules are inadequate as the sole basis for designing a clinical trial in children.

Antiviral Information Management System (AIMS): a prototype for operational innovation in drug development.

This article presents a prototype for an operational innovation in knowledge management (KM). These operational innovations are geared toward managing knowledge efficiently and accessing all available information by embracing advances in bioinformatics and allied fields. The specific components of the proposed KM system are (1) a database to archive hepatitis C virus (HCV) treatment data in a structured format and retrieve information in a query-capable manner and (2) an automated analysis tool to inform trial design elements for HCV drug development.

Leveraging prior quantitative knowledge in guiding pediatric drug development: a case study.

The manuscript presents the FDA's focus on leveraging prior knowledge in designing informative pediatric trial through this case study. In developing written request for Drug X, an anti-hypertensive for immediate blood pressure (BP) control, the sponsor and FDA conducted clinical trial simulations (CTS) to design trial with proper sample size and support the choice of dose range. The objective was to effectively use prior knowledge from adult patients for drug X, pediatric data from Corlopam (approved for a similar indication) trial and general experience in developing anti-hypertensive agents.

Leveraging prior quantitative knowledge to guide drug development decisions and regulatory science recommendations: impact of FDA pharmacometrics during 2004-2006.

The End-of-Phase 2A meetings are proposed to identify opportunities to make innovative medical products available sooner and to increase the quality of drug applications through early meetings between sponsors and the FDA. This article summarizes the overall experience across 11 pilot End-of-Phase 2A meetings since 2004. Four case studies are presented in more detail to demonstrate the various issues and methods encountered at these meetings.

Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review.

The criterion for assessing whether a drug prolongs QT as described in the International Conference on Harmonization topic E14 guideline does not explicitly account for individual drug concentrations. The authors' experience with reviewing QT studies indicates that understanding the relationship, if any, between individual drug concentration and QT change provides important additional information to support regulatory decision making. Therefore, regulatory reviews of "thorough QT" studies routinely include a characterization of the concentration-QT relationship.

Semi-mechanistic pharmacodynamic modeling for degarelix, a novel gonadotropin releasing hormone (GnRH) blocker.

An integrated semi-mechanistic pharmacodynamic (PD) model describing the relationship between luteinizing hormone (LH) and testosterone (T) after short-term administration of degarelix was developed. Data from three clinical studies involving, intravenous (IV) and subcutaneous (SC) dosing, in healthy male subjects were available. Degarelix pharmacokinetic (PK) data from all studies were modeled simultaneously.

A new equivalence based metric for predictive check to qualify mixed-effects models.

The main objective of any modeling exercise is to provide a rationale for effective decision making during drug development. The aim of the current simulation experiment was to evaluate the properties of predictive check as a covariate model qualification technique and, more importantly, to introduce and evaluate alternative criteria to qualify models.Original concentration-time profiles (yod) were simulated using a 1-compartment model for an intravenous drug administered to 25 men and 25 women.