Affairs of the Heart: Innovation in Cardiovascular Research and Development.

Cardiovascular disease represents the single largest contributor to morbidity and mortality, yet the flow of therapeutic innovation is lagging. Globally, academia, industry, and regulatory agencies must work together to address this gap, and ensure new disruptive therapeutic modalities to address growing needs of patients and society.

Adaptive Biomedical Innovation.

Adaptive Biomedical Innovation (ABI) is a multistakeholder approach to product and process innovation aimed at accelerating the delivery of clinical value to patients and society. ABI offers the opportunity to transcend the fragmentation and linearity of decision-making in our current model and create a common collaborative framework that optimizes the benefit and access of new medicines for patients as well as creating a more sustainable innovation ecosystem.

"Threshold-crossing": A Useful Way to Establish the Counterfactual in Clinical Trials?

A central question in the assessment of benefit/harm of new treatments is: how does the average outcome on the new treatment (the factual) compare to the average outcome had patients received no treatment or a different treatment known to be effective (the counterfactual)? Randomized controlled trials (RCTs) are the standard for comparing the factual with the counterfactual. Recent developments necessitate and enable a new way of determining the counterfactual for some new medicines. For select situations, we propose a new framework for evidence generation, which we call "threshold-crossing." This framework leverages the wealth of information that is becoming available from completed RCTs and from real world data sources. Relying on formalized procedures, information gleaned from these data is used to estimate the counterfactual, enabling efficacy assessment of new drugs. We propose future (research) activities to enable "threshold-crossing" for carefully selected products and indications in which RCTs are not feasible.

Pharmacotherapy for Neurodegenerative Diseases: Are We Approaching the Tipping Point?

Neurodegenerative diseases continue to represent major unmet medical and public health needs and will increasingly strain the healthcare system as people live longer due to medical advances in other diseases. Hopefully the emergence of increased understanding of the biology of these conditions coupled with novel clinical pharmacology tools, clinical trial designs, and regulatory innovation will allow the emergence of highly effective symptomatic and disease modifying pharmacotherapies.

From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients.

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life-span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade-off, help de-risk drug development, and lead to better outcomes for patients.

Intelligent pharmaceuticals: beyond the tipping point.

Confluences of key factors can transform apparently isolated or random events into trends. The ongoing and growing pressures facing the pharmaceutical industry have "tipped" the industry toward a new direction in the choice of which new medicines to develop and how to develop them. We examine the factors that are at the tipping point.

Recent trends and success factors in reducing the lag time to approval of new drugs in Japan.

For many years, approvals of new drugs in Japan have lagged behind those in the United States and Europe. As a result of simultaneous global development strategies, more widespread inclusion of Japan in multiregional clinical trials, and significant reforms and investment in Japan's Pharmaceuticals and Medical Devices Agency reviewer capacity and capability, the drug lag appears to be diminishing. This is allowing new medicines to be approved sooner in Japan, improving the efficiency of drug development and benefiting patients.

A proposal for integrated efficacy-to-effectiveness (E2E) clinical trials.

We propose an "efficacy-to-effectiveness" (E2E) clinical trial design, in which an effectiveness trial would commence seamlessly upon completion of the efficacy trial. Efficacy trials use inclusion/exclusion criteria to produce relatively homogeneous samples of participants with the target condition, conducted in settings that foster adherence to rigorous clinical protocols. Effectiveness trials use inclusion/exclusion criteria that generate heterogeneous samples that are more similar to the general patient spectrum, conducted in more varied settings, with protocols that approximate typical clinical care. In E2E trials, results from the efficacy trial component would be used to design the effectiveness trial component, to confirm and/or discern associations between clinical characteristics and treatment effects in typical care, and potentially to test new hypotheses. An E2E approach may improve the evidentiary basis for selecting treatments, expand understanding of the effectiveness of treatments in subgroups with particular clinical features, and foster incorporation of effectiveness information into regulatory processes.

Reinventing bioinnovation.

The landscape for bioinnovation is undergoing a seismic shift as drug developers, regulators, academic institutions, and government research organizations adapt to the formidable challenge of bringing new medicines to market. The inability to translate current advances in the scientific understanding of disease into new therapeutics is forcing all sectors to replace traditional drug development paradigms with newer and more efficient models. This issue of Clinical Pharmacology & Therapeutics explores these changes to the bioinnovation ecosystem.

Advancing the science of pharmacovigilance.

The importance of detecting postmarketing safety signals earlier and with a high degree of fidelity is increasingly important and of great interest to industry, regulators, and the public. This issue of Clinical Pharmacology & Therapeutics contains two companion articles that represent exciting new advances in the field of pharmacovigilance and postmarketing safety signal detection. Given that drug safety evaluation and pharmacovigilance science are core competencies in the discipline of clinical pharmacology, these articles should be of interest to clinical pharmacologists as well as drug safety professionals.

Adaptive licensing: taking the next step in the evolution of drug approval.

Traditional drug licensing approaches are based on binary decisions. At the moment of licensing, an experimental therapy is presumptively transformed into a fully vetted, safe, efficacious therapy. By contrast, adaptive licensing (AL) approaches are based on stepwise learning under conditions of acknowledged uncertainty, with iterative phases of data gathering and regulatory evaluation. This approach allows approval to align more closely with patient needs for timely access to new technologies and for data to inform medical decisions. The concept of AL embraces a range of perspectives. Some see AL as an evolutionary step, extending elements that are now in place. Others envision a transformative framework that may require legislative action before implementation. This article summarizes recent AL proposals; discusses how proposals might be translated into practice, with illustrations in different therapeutic areas; and identifies unresolved issues to inform decisions on the design and implementation of AL.

Systematic reviews and meta-analyses in the new age of transparency.

Systematic reviews and meta-analyses are useful in integrating large amounts of data to inform medical practice, and it is likely that the already large number of published meta-analyses will increase further as the provisions in the Food and Drug Administration Amendments Act and other forces result in dramatically increased transparency about the design and results of clinical trials. It is critical for readers of these analyses to be capable of assessing the quality of this research.