Kaitin, Kenneth I. PhD
Over the past decade, translational research has become a significant topic of discussion and a driver of change within academic institutions, government research centers, and the biomedical products industry. Many organizations now have dedicated departments to support and promote the objectives of translation research. Despite the near ubiquitous use of the term, however, translational research is often ill-defined or misunderstood.
Translational research is typically described as a process for facilitating the movement of new medical therapies from “bench to bedside.” “Bench,” or basic research, often occurs at academic or government research centers. “Bedside,” or use of new therapies to affect disease processes and patient care, is a clinical practice issue. But what happens in the middle stage, between bench and bedside? In this article, derived from a presentation given at the American Federation for Medical Research translational research workshop, I will focus on the stages of development that represent how more than 95% of approved prescription drugs reach the pharmacy shelf. In other words, I will present bench to bedside, with a stopover in industry, for a look at how commercialization of those products occurs.
To highlight the challenges of bringing a new pharmaceutical product to market, I will present data collected and analyzed by the Tufts Center for the Study of Drug Development (CSDD). Tufts CSDD, which I direct, is an academic multidisciplinary research group based at the Tufts University School of Medicine. Founded in 1976, Tufts CSDD is committed to providing strategic information to help drug developers, regulators, and policy makers improve the efficiency of pharmaceutical innovation. The research faculty of Tufts CSDD focuses on the economic, legal, political, and regulatory issues that affect the development and regulation of pharmaceutical and biopharmaceutical products. In addition, Tufts CSDD publishes metrics on the drug development process, which I will share in this document.
In this article, I will present some of the challenges that are changing the landscape for pharmaceutical innovation, and how academic-industry partnerships represent a new and evolving model of biomedical innovation.
CHALLENGES FOR PHARMACEUTICAL DEVELOPERS
These are challenging times for the research-based drug industry. A major concern for many companies is the relatively large number of patents on many top-selling medicines that have recently expired, or will soon expire.1 Because companies typically rely on relatively few products in their marketed portfolio to generate the revenues to sustain their research and development (R&D) efforts, and because many of these products are the ones losing patent protection, companies must either substantially increase the number of new products reaching the marketplace to replace those that have gone off patent or dramatically reduce R&D expenditures. Several of the larger companies have recently announced plans to significantly cut their spending on R&D while boosting their efforts to bring more products to market.
Another challenge for the industry is that the pharmaceutical marketplace has become increasingly competitive, making it more difficult than ever to get the premium pricing and the kind of formulary coverage that most companies seek for their products.2 Companies can no longer simply develop products that are just “safe and effective”; they must develop products that are also cost-effective to compete in the market. This competitive pressure is growing, especially in the United States, as evidenced by the creation of the Patient-Centered Outcomes Research Institute and the increasing focus on comparative effectiveness research.
Other challenges for the industry include an increase in regulatory hurdles in major markets, especially in the areas of safety assessments, risk management, and postapproval research requirements. In addition, public support for the pharmaceutical industry has been, and continues to be, lacking, which has a corrosive effect on a company’s brand.
Ultimately, however, perhaps the greatest challenge facing the industry is the one issue that companies have a substantial amount of control over—the R&D process itself—that is, the time, cost, and risk of developing new products. Despite nearly 2 decades of intense effort to speed development times, decrease attrition rates, and reduce overall costs, drug developers have made very little headway in improving the drug development process.3
PHARMACEUTICAL R&D: A LONG, RISKY, AND EXPENSIVE PROCESS
The new drug development process—the process of bringing a new drug candidate through the product development process, gaining regulatory approval, and launching into the marketplace—can be viewed metaphorically as a funnel. The many candidates generated in early-stage discovery research enter the funnel at the wide end and move through a selection process, which includes identifying viable targets for development (ie, “target identification”) and selecting the optimal molecular characteristics of lead candidates for further development (ie, “lead optimization”). The overall number of candidates is quickly whittled down until a smaller number eventually reaches the preclinical, or animal testing phase, to assess safety in an animal model and learn about the pharmacokinetic properties of the candidate. For those candidates determined to be worthy of further development, an investigational new drug application is filed with the Food and Drug Administration (FDA) by the sponsor, which signals the sponsor’s intention to enter the clinical testing phase and begin studying the candidate in human subjects.
Clinical testing includes phases 1, 2, and 3, in which the safety and efficacy of the candidate is assessed. Eventually, the sponsor may submit a new drug application (NDA) or a new biologics application with the FDA. The NDA/new biologics application is reviewed to determine whether the benefits of the candidate outweigh its risks. If approval is granted, the FDA may still require phase 4 studies to assess long-term safety and effectiveness. In recent years, 80% of products that have been approved have been required by the FDA to undergo postapproval studies, postmarketing surveillance, and life-cycle management.4 Life-cycle management includes studies conducted to assess new uses for the drug. The entire product development process from synthesis to regulatory approval may take as long as 15 years.
DRUG DEVELOPMENT METRICS: TIME, RISK, AND COST
The focus of much of industry’s attention is an unwieldy drug development process, which remains stubbornly risky, time consuming, and expensive. In the United States, R&D spending on new pharmaceuticals continues to spiral upward, exceeding $65 billion in 2010. At the same time, the number of new molecular and biological entities approved by the FDA remains relatively low. The persistent low number of new molecular entities approved by the FDA, in light of the huge R&D investment by the research-based industry, is viewed by some as symptomatic of a faulty business model within the research-based sector.5
Based on recently published data by Tufts CSDD,6 the average capitalized cost to bring one new biopharmaceutical product to market, including the cost of failures, is $1.2 billion in 2005 dollars. For traditional pharmaceutical development, the cost is $1.3 billion per approved product. These costs reflect the difficulty of developing products for evermore chronic and complex indications (for example, neurologic and immunologic diseases) the rapid growth in the size of clinical studies, the difficulty recruiting and retaining subjects for these studies, and late-stage failures in the drug development process.
Current Tufts CSDD data indicate that the average time to bring a pharmaceutical product to market from synthesis to marketing approval is approximately 15 years, approximately 7 years of which is spent in the clinical testing and regulatory approval stages of development.7 Moreover, the likelihood of clinical success is a dismal 16%.8 Of course, these numbers mask considerable variability across different therapeutic areas. For example, the time from the start of clinical testing to submission of an NDA in the United States ranges from 4.6 years for acquired immunodeficiency syndrome antiviral drugs to 8.1 years for drugs to treat central nervous system diseases and disorders. Similarly, overall clinical approval success rates, that is, the likelihood that a candidate starting clinical testing will eventually be approved for marketing, ranges from 23.9% for systemic anti-infective agents to an exceedingly low 8.2% for central nervous system drugs.
REASONS FOR THE RISE IN DEVELOPMENT TIMES AND COSTS
The time, cost, and risk involved in bringing a new drug to market represent formidable obstacles for pharmaceutical developers. The reasons are varied and multifaceted. For example, the industry’s focus on more chronic and complex indications has led to profound growth in the size and complexity of clinical trials. Adding to the difficulties is the increasing challenge of recruiting and retaining study subjects; more stringent regulatory demands, especially in the area of safety; more market-oriented studies necessary to ensure payer reimbursement; and the high cost of some of the popular research and discovery tools, such as high-throughput screening, combinatorial chemistry, and pharmacogenomics, that many companies are using to increase the number of potential development candidates.
THE FUTURE OF R&D: FROM CHALLENGE TO CHANGE
To remain competitive in today’s pharmaceutical marketplace, many drug firms are focusing on operational improvements in the product development process and on the adoption of new R&D strategies to position the company for sustained growth and success. Within the area of operational improvement of the drug development process, some companies have established specific performance goals. These include increasing the number of products in the pipeline, cutting discovery and development timelines, reducing late-stage failures, containing R&D costs, increasing overall output, and focusing on breakthrough therapies. To achieve these goals, companies are working to eliminate waste and redundancy in the drug development process, establish a global development organization, create a strategic approach to in- and outsourcing, use adaptive and enhanced clinical trial designs, increase the use of new data management technologies and electronic R&D, and engage in substantive interactions with global regulatory agencies.9
For new R&D strategies, some companies have looked to mergers and acquisitions, whereas some have engaged in R&D reorganization, especially to create smaller, more autonomous research units. In addition, many companies are focusing on new forms of partnerships, in particular, with academic institutions. There are also an increasing number of risk-sharing relationships among companies, for example, between large and small firms, or through the creation of consortia. Finally, some companies are reassessing R&D strategies that focus on large-market indications and are moving toward smaller niche pharmaceutical markets, where therapeutic need is great, competition is decreased, and return on investment may be substantial.
A major shift within the commercial sector is the transformation from fully integrated pharmaceutical companies (ie, companies that can take a drug candidate from laboratory bench to market) to a network model that encompasses all the major stakeholders in drug development, including large and small pharmaceutical and biopharmaceutical firms, academic research centers (ARCs), patient groups, public-private partnerships, and contract research organizations.10 In the new model of innovation, all these stakeholders will have a place at the table and will share in the risks and the rewards of innovation.
Ultimately, new drugs and biologics may emanate from “innovation nodes”. Innovation nodes will be disease- or therapeutic area-focused, and they will allow developers to leverage the capabilities and expertise of the participating stakeholders.11
Key to this new integrated model of innovation is the relationship between pharmaceutical companies and academic institutions.12 Enabling factors include the necessity of some of the larger pharmaceutical companies to make significant cuts in R&D spending as well as the need of many ARCs to find new revenue streams in light of the paucity of available National Institutes of Health (NIH) funding. Moreover, these efforts have received the support of governments. During the past decade, the United States and the European Union (EU) have developed programs to foster translational science.13 For example, in 2001, the US NIH released its NIH roadmap,14 which was intended to invest in new pathways in drug discovery, support research teams of the future, and re-engineer the clinical research enterprise. In 2006, the Clinical and Translational Science Award program,15 which was intended to facilitate the transfer of knowledge between basic research and clinical medicine, was launched. With approximately 60 Clinical and Translational Science awards given to date, the NIH has clearly signaled its support for academic institutions as active partners in bioinnovation.
In a similar vein, in 2004, the FDA introduced the Critical Path Initiative16 to improve the translation of basic research findings into safe and effective medicines. Mirroring the goals of the EU Innovative Medicines Initiative,17 a public-private partnership formed in 2007 between the European Federation of Pharmaceutical Industries and Associations and the European Community, the Critical Path Initiative fosters precompetitive research by bringing together the respective capabilities of academia, industry, and government to identify new biomarkers and other tools to improve the selection of drug candidates and increase the likelihood of pipeline success.
Despite a shared commitment by both industry and academia and the unequivocal support of government, significant obstacles stand in the way of successful partnerships. These obstacles include language barriers (academics speak the language of science, whereas industry speaks the language of business), misaligned reward systems (academics are rewarded for research and publication through promotion and grants, whereas industry employees are rewarded for pipeline success and regulatory filings through bonuses, promotion, and meeting company goals), intellectual-property issues (academics try to retain ownership as much as possible, whereas industry requires sufficient rights to make downstream investment worthwhile), and a heightened sensitivity to conflicts of interest in academics and a reluctance to align too closely with the private sector.12
Nonetheless, there are many reasons to be encouraged about the opportunities created by academic-industry partnerships. In particular, industry gains access to cutting-edge science and new technologies, and academics gain access to drug development expertise and an increased likelihood that their research discoveries will ultimately result in new treatments and medicines.
Moreover, academic-industry partnerships represent the key to seeing the fulfillment of the ultimate objectives of translational science.
Unprecedented challenges confront pharmaceutical and biopharmaceutical companies in their quest to bring innovative new medicines to market. Rapidly growing R&D costs, increasing competitive pressures, an uncertain regulatory environment, and a highly volatile public and political climate represent significant threats to the research-based industry.
We are in a period of dynamic change in the innovation landscape. In the new environment, innovative medicines will likely result from the combined efforts of numerous stakeholders: large and small pharmaceutical and biotechnology companies, ARCs, patient groups, contract research organizations, and public-private partnerships.
The American Federation for Medical Research Symposium was supported in part by a grant from the National Center for Research Resources (R13 RR023236).
Copyright © 2012 by the American Federation for Medical Research.