Outlook

In 2011, AstraZeneca set out to improve its research and development (R&D) productivity by focusing decision-making using a framework with five technical determinants: the right target, right tissue, right safety, right patient and right commercial potential. Here, Pangalos and colleagues describe the progress made using this '5R framework', with metrics indicating improved success rates, and discuss where the approach has failed and the lessons learned.

Immuno-oncology has become the fastest-growing area in the pharmaceutical industry. In this Perspective, Hoos provides an overview of the history of immuno-oncology and investigates the factors that have led to its success. Moreover, he discusses the three generations of immunotherapies that have been developed since 2011 and provides an outlook to the future directions of drug discovery and development in immuno-oncology.

Chorus is a small, operationally independent organization within Eli Lilly and Company that specializes in drug development from candidate selection through to clinical proof of concept. Here, we describe its development philosophy, organizational structure, operational model and results in the decade since it was established, which indicate substantial productivity improvements in both time and cost compared to traditional drug development approaches.

Pangalos and colleagues discuss the results of a comprehensive longitudinal review of AstraZeneca's small-molecule drug projects from 2005 to 2010. They present a framework to guide research and development teams based on the five most important technical determinants of project success and pipeline quality: the right target, the right patient, the right tissue, the right safety and the right commercial potential. A sixth factor — the right culture — is also crucial in encouraging effective decision-making.

Regulation on orphan medicinal products was adopted in the European Union in 2000, with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. This article highlights the outcomes of this regulation, such as the approval of more than 60 orphan drugs, reflects on the experience gained so far and discusses key issues for the next 10 years.

Implicit in criticism of 'follow on' or 'me too' drugs is the idea that their development occurs after a first-in-class drug has made it to market and proved commercially successful. Using analysis of development and patent filing histories of entrants to new drug classes in the past five decades, this article provides new evidence that the development of multiple new drugs in a given class is better characterized as a race, rather than the imitation of successful products.

Fully human monoclonal antibodies (mAbs), which have the potential to be less immunogenic than earlier humanized and chimeric mAbs, are the most rapidly growing class of mAbs in clinical development. Here, Reichert and colleagues highlight trends in the development of human mAbs, seven of which have so far gained regulatory approval.

A lack of entrepreneurial behaviour has often been identified as a contributor to the decline in the research and development (R&D) productivity of the pharmaceutical industry. Douglas and colleagues present an assessment of entrepreneurship in the industry, based on interviews with 26 former and current leaders of R&D departments at pharmaceutical and biotechnology companies, highlighting factors that could be important in promoting entrepreneurial behaviour and revitalizing R&D productivity.

The development of drugs for rare diseases — often known as orphan drugs — is attracting increasing interest and investment, catalysed in part by incentives such as those provided by the 1983 US Orphan Drug Act. This article provides the first comprehensive analysis of 25 years of data on the designation and approval of orphan drugs by the US Food and Drug Administration, with the aim of supporting and encouraging future orphan drug development and approval.

Third-party payers typically base their reimbursement decisions for a new drug predominantly on its health benefits relative to existing treatment options — termed relative efficacy (RE). Over the past decade, the role of payers has become more prominent, and drug developers increasingly need to satisfy the sometimes divergent needs of both regulators and payers to achieve market success. This article describes the political background to the RE debate and the challenges of RE assessment, and discusses the impact of RE on drug development.

Drug repurposing, in which an established active pharmaceutical ingredient is applied in a new way — for example, in a new presentation, often combined with a new therapeutic indication — is an evolving strategy for pharmaceutical R&D. This article discusses each aspect of this strategy, highlighting commercial successes that have arisen from a focus on the presentation and therapeutic use of known active ingredients or slight variations of these compounds.

Although the potential of 'personalized medicine' to increase the quality of clinical care and decrease health-care costs has been recognized for many years, only a handful of associated diagnostic tests have made it to market so far, with mixed success. This article proposes that the major challenges to the further adoption of personalized medicine are increasingly related to economics, and discusses strategies that could help address these challenges.

The potential for cost savings from the introduction of 'follow-on' versions of protein therapeutics is a major focus of the ongoing debate around the creation of a regulatory pathway for the abbreviated approval of such products. Lanthier and colleagues explore the economic issues relevant to this debate by assessing total sales, product complexity and patent expiry for current protein products.

Specialty pharmaceuticals — drugs prescribed primarily by specialists rather than primary-care physicians — have become an increasingly important part of the global pharmaceutical landscape. Ma and colleagues analyse the key factors influencing the commercial success and failure for specialty pharmaceuticals.

The United States Congress is currently considering legislation to create a regulatory pathway for follow-on biologics. Grabowski discusses the importance of data exclusivity in allowing innovator companies to achieve a return on investment before entry of follow-on competitors, and presents an analysis that provides support for a substantial data exclusivity period.

Despite increased pharmaceutical investment, few novel molecular entities that address new pain mechanisms have entered the clinic. Dionne and colleagues discuss factors contributing to this lack of innovation and highlight strategies to translate new knowledge into more efficacious and safer treatments.

Alliances are now a key component of the research and development strategies of most major pharmaceutical companies. Jones summarizes recent trends in alliance formation and discuss approaches to minimize risk in alliances, which are growing in importance as alliance activity increases.

Monoclonal antibodies are now established as a key therapeutic modality for a range of diseases, including cancer. Reichert and Valge-Archer overview trends in the development and regulatory approval of anticancer monoclonal antibodies since 1980, with the aim of informing future research and development for this class of therapeutics.

The potential to use clinical biomarkers to better match therapies with specific patient populations — stratified medicine — is anticipated to have a major effect on both clinical practice and the development of new drugs and diagnostics. Trusheim, Berndt and Douglas discuss the implications of this approach to future product development strategies and market structures.

The open-source software movement has successfully pioneered several strategies that might also be applicable in drug discovery and development. Munos considers the challenges involved, and proposes a model to harness the potential of open-source drug R&D.