Sounding Board

Biomedical Research and Health Advances

Hamilton Moses, III, M.D., and Joseph B. Martin, M.D., Ph.D.

N Engl J Med 2011; 364:567-571February 10, 2011DOI: 10.1056/NEJMsb1007634

Article

In 1945, the President's science advisor, Vannevar Bush, wrote in Science, the Endless Frontier 1 that basic scientific research was “the pacemaker of technological progress” and that “new products and new processes do not appear full-grown. They are founded on new principles and new conceptions, which in turn are painstakingly developed by research in the purest realms of science.” He recommended the creation of what would become the National Institutes of Health (NIH), which was created in 1948, and the National Science Foundation, created in 1950.

The biomedical-research enterprise in the United States soon became the envy of other nations, as well as the primary source of the world's new drugs and medical devices. Since 1945, biomedical research has been viewed as the essential contributor to improving the health of individuals and populations, in both the developed and developing world.

Financing of research was ensured by the successes in the early 1950s of polio vaccination, antibiotics, and antipsychotic agents. Equally dramatic advances in surgery and medical devices, such as cardiopulmonary bypass, dialysis, and organ transplantation, followed in the 1960s. In the 1990s, the conversion of the acquired immunodeficiency syndrome and some cancers from uniformly fatal diseases to chronic conditions created an expectation that similar advances would occur for other devastating diseases.

These accomplishments led to mutual trust among supporters in Congress, disease advocacy groups, universities, and companies. The clinical advances would not have come about without such trust. Moreover, progress was based on an underlying faith that new technology was valuable and that it would produce effective preventive measures and treatments as long as the translation of basic science to clinical application was sustained.

Today, the primacy of biomedical research and technology development is being challenged. Patients, physicians, insurers, and policymakers are all questioning the slow pace of advance, escalating cost, dubious clinical value, inappropriate commercial exploitation, and lure of false hope for patients with serious diseases.2 The backdrop is growing skepticism of the value of science itself as a solution to global problems.3

Moreover, the mutual trust among patients, clinicians, and researchers, which was so apparent after the 1950s, is in danger of forfeiture.4 This is due to suspicion that economic self-interest is disrupting medicine's compact with patients, as exemplified by a number of high-profile ethical lapses in the protection of human research subjects and the involvement of physicians in the marketing activities of companies.

Illustrative is recent commentary in both the general5 and scientific6 press about slow progress in the decade after elucidation of the first human genome sequences. Despite the justified scientific excitement about using knowledge of the genome as a fundamental exploratory tool, unrealistic expectations for a quick route to clinical application have produced disappointment, especially among disease advocacy groups and companies. It is a reminder that with few exceptions, new scientific discoveries require 15 to 25 years for their application. This interval has not shortened in more than a century.7

Given that different perceptions and priorities color the debate over the value and role of biomedical research, we believe that the biomedical community must take stock and recommit its efforts to diseases that have a major effect on the population. This requires a reexamination of funding priorities, open interactions among researchers, and more effective relations among companies, government, foundations, and universities. Old assumptions and old models must be replaced.

Biomedical Research in 2011

Biomedical research in the United States is a $100 billion enterprise, with approximately 65% supported by industry, 30% by government (predominately the NIH), and 5% by charities, foundations, or individual donors. Although total sponsorship tripled between the mid-1990s and mid-2000s,8 the rate of increase has fallen since 2003 and declined in real (inflation-adjusted) terms since 2007.9 The number of new drugs entering human trials has also fallen during the past two decades, especially for new molecular entities and entirely new classes of drugs. In contrast, the number of approvals of medical devices by the Food and Drug Administration (FDA) has increased steadily each year.10 Driven by demand, total medical spending on devices has increased at a rate that is several times that for health services and twice that for drugs.11

Since the mid-1990s, the United States has invested approximately 4.5% of its total health expenditures on biomedical research. In contrast, only 0.1% supports research in health services, comparative effectiveness, new care models, best practices, and quality, outcome, or service innovations.9 This funding will increase to approximately 0.3% from appropriations in 2010 health legislation.

Misconceptions regarding the scientific process are common. Research is costly, capital-intensive, and collaborative. Researchers in both academic and industrial settings require access to much the same information, samples and tissue, instrumentation, and specialized technical skills. They also depend on one another as a source of new ideas. It is a paradox, during this decade of growing scrutiny of ties between academic institutions and companies, that academic investigators value their nonfinancial company ties (with access to technology or research materials) more than personal compensation or support of their laboratory.12 Moreover, the notion that “pure” (basic) and “applied” (clinical) research exist as distinct activities is belied by their source of sponsorship and the self-reports of how researchers actually spend their time.12 Such multimode researchers are more productive, as judged by the number of publications, impact factor, success at winning peer-reviewed NIH funding, and number of patents. This reality was cited by a recent U.S. Federal Court opinion overturning the patentability of several genes that predispose women to breast cancer. The court called for patenting practices that favor openness whenever basic discovery is inhibited.13

Sponsors have sought to improve their research productivity through the NIH Roadmap initiative (especially Clinical and Translational Science Awards) by encouraging alliances between companies and universities, alternative organizational models, and joint investment in costly facilities, such as imaging or gene sequencing.14,15 We reviewed the lessons from 70 such alliances from the mid-1960s through 2000.16 Although it is too soon to judge the success of the most recent models, in the main, earlier ones have not accelerated the pace of either discovery or clinical application. The sources of difficulty are idiosyncratic, but recurrent problems are a failure at inception to agree on intellectual-property provisions, excessive secrecy, and disagreements over research aims. In our view, the most salient reason for failure is the centralization of authority within large, inherently cautious bureaucracies in government, universities, foundations, and companies. Collectively, such factors inhibit scientists' creativity by disregarding the pluralism of ideas and the diversity of approaches that are necessary for innovation. Conversely, the most successful collaborations have found a balance between external direction and scientists' curiosity. Many of the most experienced observers from government, industry, and academia concur with this viewpoint.17-19

Economic forces are also relevant. In the United States, the gain in life expectancy between 1970 and 1990 added $2.4 trillion per year to the gross domestic product by 2000.20 Moreover, biomedical research bolsters employment, economic development, balance of trade, and exports. Studies from many countries show that investment in new technology of all types is the primary source of economic growth, especially when such investment is made by the private sector.21 In contrast, in areas in which public spending on technology is dominant, the rates of productivity and growth are lower. The differences are most marked in medical research.22

Despite these observations, some federal policymakers express doubt that scientific advance is a prerequisite for improved health. They favor predictable, low-cost public health measures and expanded access to basic care during the current decade of austerity.23 Other policymakers question whether spending on new devices and high-cost bioengineered drugs produces commensurate clinical value.24 Such criticism is driven by estimates that new technology of marginal benefit (as measured by reduced disease burden or improved longevity) accounts for one half to two thirds of health care inflation in Western countries.25 Even the commercial value of biomedical research is questioned by some companies, as is reflected by their reduced rates of research and development because of unfavorable returns as compared with marketing26 or mergers and acquisitions.27

Other observers assert that social, educational, and macroeconomic factors are more important than medicine or public health practice in promoting a population's health.28 They see technology as a distraction from enlightened social, tax, and regulatory policies. Debate over the goals has already begun.29,30

As a consequence, we believe that steps must be taken to reestablish public confidence in researchers and clinicians, along with their institutions. Measures are needed that go beyond those recommended by the Institute of Medicine,31 the Council of Medical Specialty Societies,32 and the NIH.33 These reports emphasize remedies that focus primarily on competing interests without dealing with the opportunities. We are concerned that the recommendations overlook the potential for new models to foster productivity.

Seven Remedies for Consideration

The discontent arising from the current circumstances demands the consideration of sweeping changes in the way we conduct biomedical research. We believe that seven measures should be considered to reconcile competing goals. They require recognition of the multilayered sources of conflict, especially those based on different scientific aims and social values.34

Improve Data on Clinical Value

We must develop and apply better objective information about clinical value. This goal implies a higher standard for adopting new devices (including clinical trials similar to those for drugs) and better information on the effectiveness of existing drugs and devices, especially data that are available only from proprietary insurance databases. It is unlikely that provisions for comparative-effectiveness research in the 2010 health care legislation or the changes proposed by the FDA for device approval will be sufficient. New incentives are needed for private and government insurers to disclose clinical data to researchers, along with expanded access to device registries, easier access to data from Medicare and Medicaid, and development of more robust analytical techniques for ascertaining clinical value. Moreover, physicians and surgeons must commit to a new level of objectivity in judging clinical value, while resisting the influence of commercial potential or personal financial interests.35

Change the Role of Teaching Hospitals

The roles of academic health centers and teaching hospitals must be modified to improve their ability to conduct early-stage (proof-of-concept) clinical trials. Here, entirely new models for interaction are required, probably involving freestanding independent institutes or autonomous units within academic centers, where patients come specifically for access to such early-stage studies and where the mutual expectations for investigators, companies, and patients are clear and unambiguous. This change will hasten the divergence between institutions that offer routine care (and that are managed to provide low-cost, reproducible high quality) and those with capability for scientific innovation (where early-stage investigations occur). Making these interactions effective and avoiding the shortcomings of past attempts will require new models of intellectual property, patents, and licensing by moving these aspects farther down the chain of discovery.36 Two very different approaches should be tried: creating patent pools involving multiple companies and universities37 and a renunciation of patenting in return for more latitude to conduct high-risk laboratory experimentation and initial clinical trials.38 It is likely that only some of the 130 academic health centers will choose to undertake such changes.

Develop New Models for Collaboration and Financing

In asserting the need for an increase of total spending on biomedical research and the need to foster the diversity of scientific approaches, consideration should be given to new models of collaboration and cooperation. Such measures would allow the NIH to concentrate on basic biomedical science and large, multi-institutional projects, where its scale can be most valuable, while providing offset to industry's declining investment in research. These models might include the following:

Establish Biomedical Innovation Trusts

The formation of new nonprofit, public–private partnerships — biomedical innovation trusts — could enable individuals and corporations to receive immediate federal tax credits (not deductions) for contributions to support research in high-priority diseases. Such trusts might be administered by decentralized new foundations or new regional public entities and be directed at particular diseases, universities, freestanding laboratories, or small companies. Similar tax incentives have been used historically to preserve land, create parks, and build factories.

Create a New Class of Bonds

States and the federal government might issue bonds to support innovation in biomedical science and health services, with preference given to high-risk research and diseases important to public health. Such bonds have long been used to support athletic facilities, airports, and roads. They provide a mechanism for private investment to meet public needs.

Use Incentives to Promote Pluralism

To enhance the diversity of scientific approaches and innovation in its application, preference in funding might be given to new research institutes or entities, rather than existing universities or companies.

Defer Patents to Later in the Discovery Chain

In return for new sources of funding and greater latitude to conduct high-risk research, the new entities would forgo claims to patents or other intellectual property and place positive and negative findings immediately in the public domain.

Emphasizing new incentives, creating new entities, and mobilizing additional funding sources avoid the risk of disrupting productive research relationships currently found in universities, established research institutes, and the NIH. The measures also allow new laboratories to attract the best talent, while providing a route to enhance the productivity of research and its early clinical application.

Renew Professional Commitments

All physicians must renew their commitment to professionalism and their duty to their patients. This will not be easy in an age when commercial values are paramount and the competition of the marketplace drives personal and institutional financial decisions. Yet, without such a recommitment, no safeguards will prevent an inexorable loss of trust in our institutions and us. Professionalism, as interpreted today, means not a return to paternalism, but objectivity in judgment on behalf of the patient, with open communication and an absence of bias.39 It must be translated into action by a blanket proscription of product promotion in any guise.

Focus on Cost-Effective Targets

We must recognize that new technology creates value to the general economy and has many clinical benefits but that it also usually spurs new clinical costs. Observers who are the most critical of medicine believe we have failed to recognize that historical compromise. In an era in which many favor public-policy goals to ensure a basic level of care for all citizens and a reduction in the rate of increase of aggregate health care spending, the technological imperative will surely be challenged with greater stridency. This requires incentives for researchers to focus on diseases that are common, cannot currently be prevented or effectively treated, are expensive, and have a major effect on the patients' health.40,41 Such choices among diseases are onerous but inescapable.

Adopt Realistic Research Goals

We must embrace a new realism about the difficulty of the scientific process and what can (and cannot) be expected from it. We must not overpromise. Such realism will not be popular with patient advocacy groups, the press, politicians, benefactors, or company investors. Each of these groups has a vested interest in overstating their case. Yet to do otherwise runs the risk of eroding the trust on which so much depends. Paradoxically, a commitment to realism may itself have a positive effect on the scientific process by reducing the pressure to promote findings prematurely and by fostering openness.

Redefine the Terms of Conflict

Finally, we in medicine must recognize that those who have a public health perspective or who see social and economic factors as paramount will not be sympathetic to increasing the technology-driven momentum of the past 60 years. Inevitably, we face growing conflict over individual choice, access to the latest drug or device, the true cost of technology over a lifetime, perceptions of value, and preferences for competition versus regulation. Such tensions have long been implicit. They are now explicit. Not everyone believes biomedical research is essential.

Conclusions

These considerations will require decades of reorientation of our biomedical research efforts, not unlike those that led Vannevar Bush to propose new structures and entities in 1945. Failure to resolve conflicts, be they political, policy-related, or personal, with a deaf ear to the claims of legitimately competing priorities will limit progress and encourage new regulatory constraints. Our institutions must be willing to recognize and confront these legitimate conflicts, not look to others to do it for them. The choice is stark, but the stakes are high.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Source Information

From the Alerion Institute, North Garden, VA (H.M.); Johns Hopkins School of Medicine, Baltimore, MD (H.M.); and Harvard Medical School, Boston (J.B.M.).

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