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Vital Directions from the National Academy of Medicine
September 26, 2016

Innovation in Medicine and Device Development, Regulatory Review, and Use of Clinical Advances

Author Affiliations
  • 1Flagship Ventures, Cambridge, Massachusetts
  • 2Merck and Co Inc, Kenilworth, New Jersey
  • 3National Health Council, Washington, DC
  • 4Schaeffer Center for Health Policy and Economics, University of Southern California, Los Angeles
  • 5Anthem Inc, Indianapolis, Indiana

Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.

JAMA. Published online September 26, 2016. doi:10.1001/jama.2016.12486

Breakthrough advances in the understanding of fundamental biology and the dawn of an era of precision medicine coupled with access to “big data” and research conducted in clinical care settings herald a new age of innovation for drug discovery and devices with the promise of improved health. However, these clinical advances need to be both affordable and accessible. There are competing national priorities for investment, including education and other social determinants of health. To realize the health benefits deriving from new scientific insights, increased discovery and translation of innovation through more efficient clinical trials and rapid deployment of effective advances to appropriate patient populations will be essential.

Medical Product Development

Given the technical dimensions and safety implications of medical products, the development and testing process is complex and costly. Although estimates vary and are often debated, some suggest that the cost of bringing a new drug from early-stage drug discovery through regulatory approval may have increased by 70% in the past decade to a level as high as $2.6 billion.1 Furthermore, about 85% of therapies fail through early clinical development, and only half of those surviving to phase 3 will be approved.2 These challenges are forcing all sectors to evaluate opportunities to replace traditional drug development with newer and more efficient models. Favorable trends in new-product approvals and breakthrough therapies (such as those to treat hepatitis C) indicate that efforts to adapt to the new landscape of increasing innovation are starting to lead to drugs that cure or transform disease.

However, much current effort in drug discovery and development is in the most challenging therapeutic areas, such as neurodegenerative, autoimmune, and inflammatory diseases. Given the gaps in knowledge of the pathogenesis of such illnesses, it is essential that industry, government, and academia work together. Breakthroughs will depend on more precompetitive collaborations. Government, academia, and industry could do more to overcome barriers to collaboration by reaffirming their common goals and encouraging scientists to work at the interfaces of these sectors.

More than two-thirds of the total cost, in both dollars and time, of the discovery and development of new drugs is embedded in the clinical testing phase. Hence, it is important that advances in such arenas as biomarkers, patient-reported outcomes, innovative clinical trial designs, use of evidence from clinical practice, and precision medicine be deployed as effectively as possible to optimize the time line for clinical results and allow assessment in settings that reflect use of these drugs. New technologies—such as the use of biosensors, electronic sourcing, risk-based monitoring, electronic medical record–linked recruitment tools, and web-enabled trials—are being piloted, positioning the discipline of clinical research for substantial change.

Quickening the Pace

The US Food and Drug Administration (FDA) is responding to the challenge of increasing numbers of new drug candidates by establishing breakthrough therapy and other fast-track mechanisms to facilitate rapid and responsible movement of important advances to patients, but moving such advances to patients rapidly is challenging. Novel designs for clinical trials may reduce development time and expense. Such designs are especially effective in demonstrating proof of concept and efficacy. These study designs can facilitate arriving at “no-go” decisions, saving time and resources.

However, there is no shortcut for assessing safety in humans. Confidence in a given level of safety for a drug, vaccine, or device is established by the number of people exposed, the duration of exposure, and the magnitude of exposure. Shorter trials with fewer participants have lower levels of confidence. The potential compromises arising from speedier drug development and earlier regulatory approval place inventors of drugs and possibly patients at greater vulnerability, especially when society and the media assume that FDA approval means a new drug is absolutely safe and effective for everyone. The legal and educational issues in this arena would benefit from strategic government intervention that allows earlier dialogue among pharmaceutical companies, physicians and other health care professionals, health insurers, and patients to determine label indications and populations that may best benefit from emerging therapies. The FDA’s Sentinel Initiative based in health care delivery systems is transforming the ability to assess the safety of drugs and vaccines after they reach the market and serves as a model for advancing clinical science using diverse groups of data partners.

Stronger Patient Engagement and Precision Medicine

Historically, patient engagement in medical product development has been confined to participation in clinical trials. However, patient input from early-stage research and development through postapproval, including insurance coverage decisions, is increasingly recognized as valuable.3 Many stakeholders, including the FDA, are starting to engage patients. Many challenges must be overcome to achieve a patient-centered process for progress in therapeutic innovation, including how best to incorporate patient input, the need to build patient skills so that they are better prepared to engage and report the outcomes they experience, and guidance from the FDA regarding industry interactions with patients because of concerns that such communication might be considered promotional. There is a compelling need for practical approaches to provide established and emerging clinical knowledge and the evidence basis of care to clinicians and their patients. Both primary care physicians and specialists are inundated by information. Health information systems do not provide sufficient clinical support and advanced analytics to guide care or innovative care models. The health care system exists in an age of big data but is not optimizing its use.

Improvements, even transformation, in this respect are even more compelling if the promise of precision medicine is to be realized. Of course, improving the flow and use of data and information for better targeted patient care is but one dimension of the challenge. As advances in genotyping and proteomics identify more subpopulations in a given disease category, the business model for biopharmaceuticals is challenged. For example, although the cost of developing a precise therapy for a 10% subpopulation with a disease is likely to be less than that of developing an agent via conventional methods, the accompanying decrease in cost is unlikely to be a proportionate 90% less. Although the intrinsic value of such precision products is greater (with regard to efficacy and safety), the market will be much smaller than the market for products prescribed without “precision” to the general population for a given disease. New approaches to determining value will be essential to provide incentives for drug invention without placing an onerous financial burden on individuals and society.

International Considerations

Because biology relevant to medical product development likely varies at least as much within countries as between countries, harmonization or convergence of regulation among countries and regions is a pressing need with respect to new medications, vaccines, and devices. Convergence will reduce development costs and may speed worthy innovations to those in need globally. The global stakes go beyond the need for more efficiency and effectiveness in making medical products available.

Antibiotic resistance and bioterrorism are other domains in which the business model is challenging, but the needs are great. World health impels physicians to be good stewards of antibiotics to slow the emergence of antibiotic resistance. However, creating antibiotics with the hope that they will rarely if ever be used conflicts with the conventional business model. The same conundrum arises in the invention of vaccines and anti-infective agents to counter bioterrorism. Without government programs to address the need for innovative anti-infective agents and vaccines, there is little incentive to invest, especially when other therapeutic areas do not face this challenge. Given the threat of virulent epidemics and bioterrorism, it might be possible to address needs through multinational programs; for example, the United States and other countries could divide up research efforts and financial costs of programs directed at global solutions.

Summary Recommendations for Vital Directions

In the midst of great promise for human health inherent in the number and nature of emerging medical products, significant progress is needed to ensure their appropriate availability and access.

  • Accelerate progress toward real-time evidence generation. As clinical data move toward universal storage on digital platforms, the possibility exists to reduce the time and expense involved in the development of evidence on the effectiveness, safety, and applicability of medical interventions. Priorities include initiatives to develop data and interoperability standards to improve data quality and accessibility; capacity to facilitate protected data sharing; and regulatory policies that allow phased introduction with evidence generation.

  • Invest in and apply the promise of cognitive computing. With rapidly expanding computing capability to integrate, process, and assess very large databases, opportunities develop for accelerated learning, understanding individual variation, and developing predictive modeling. Priorities include public-private initiatives targeting the science of large data set computing, integrating individually generated data, and communicating results.

  • Position and equip patients and families as partner stakeholders. To capture the advantages of patient-generated data for clinical management, priorities include initiatives to enable and facilitate the roles of patients and families in all clinical decision making and to enlist their guidance and involvement in the capture, design, and use of clinical data for new knowledge.

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Article Information

Corresponding Author: Michael Rosenblatt, MD, Flagship Ventures, One Memorial Drive, Cambridge, MA 02142 (

Published Online: September 26, 2016. doi:10.1001/jama.2016.12486

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rosenblatt reported being an employee of Flagship Ventures and a shareholder of Radius Pharmaceuticals and Merck and Co Inc. Dr Nussbaum reported being a shareholder of Anthem Inc; receiving support to HealthCore (a wholly owned Anthem subsidiary) from the US Food and Drug Administration for the Sentinel Initiative and from the Patient-Centered Outcomes Research Institute; and serving as a strategic consultant to Epstein Becker Green advisers and life science clients. No other disclosures were reported.

Funding/Support: The National Academy of Medicine’s Vital Directions initiative is sponsored by the California Health Care Foundation, The John A. Hartford Foundation, the Robert Wood Johnson Foundation, and the National Academy of Medicine’s Harvey V. Fineberg Impact Fund.

Disclaimer: This Viewpoint on innovation in development, regulatory review, and use of clinical advances provides a summary of a discussion paper developed as part of the National Academy of Medicine’s initiative on Vital Directions for Health & Health Care ( Discussion papers presented in this initiative reflect the views of leading authorities on the important issues engaged, and do not represent formal consensus positions of the National Academy of Medicine or the organizations of the participating authors.

Additional Contributions: Coauthors of the National Academy of Medicine discussion paper included Christopher P. Austin, MD (National Center for Advancing Translational Sciences, National Institutes of Health), William W. Chin, MD (Pharmaceutical Research and Manufacturers of America), Stephen K. Galson, MD (Amgen Inc), Sachin H. Jain, MD (CareMore Health Group), Michelle McMurry-Heath, MD, PhD (Johnson & Johnson), John Orloff, MD (R&D Biopharmaceutical Executive), Steven E. Weinberger, MD (American College of Physicians), and Janet Woodcock, MD (Center for Drug Evaluation and Research, US Food and Drug Administration). Assistance was provided by Christopher Lines, PhD (Merck and Co Inc). Elizabeth Finkelman, MPP (National Academy of Medicine) served as the initiative director.

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