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Industry Priorities

The Medicine Cabinet: What’s In It, Why, And Can We Change The Contents?

Abstract

 
The failure of the pharmaceutical industry to produce drugs for common chronic diseases, emerging diseases, and the potential threats of bioterrorism or the spread of tropical diseases contrasts sharply with the industry’s output of lifestyle and "me-too" drugs. In this paper we review the decision-making process that resulted in our current portfolio of medicines and offer several alternatives to better align business incentives with medical need.

You who are skilled in Alchemy...promise yourselves great riches or chiefly desire to make gold and silver, which Alchemy in different ways promises.

Paracelsus, Coelum Philosophorum

Current controversy regarding the pharmaceutical industry focuses primarily on prices, yet there is another fundamental question that warrants attention: Is our current portfolio of medicines the one that best meets society’s most pressing medical needs? If it is not, as we argue is the case, then developing new policies to change the pharmaceutical industry’s decisions about what drugs it produces requires an in-depth understanding of the way the industry makes such decisions. In this paper we review the current U.S. portfolio of drugs and a decision model that is common throughout the U.S.-based industry, and we discuss several policy options that could alter the contents of tomorrow’s medicine cabinet.

The Current Portfolio Of Medicines

Top Editor's Notes The Current Portfolio Of... Pharmaceutical Investment... Influencing Pharmaceutical... Notes

 
Based on the long-standing belief that markets offer the best mechanism to provide a continuous flow of innovative drugs, the U.S. pharmaceutical industry is structured as investor-owned, profit-seeking firms.¹ With regard to decisions to produce new drugs, the breakdown of this essential market structure can occur in two distinct ways. The first concerns the absence of drugs needed to prevent or treat common diseases. The second involves production of drugs when there is little need.

Defining the need for specific new drugs is in itself complex but also central to any discussion about the benefits of our current portfolio of drugs relative to alternatives. Burden-of-disease data and traditional epidemiological measures such as mortality contrast with assessments of quality of life. Perceptions of need among consumers largely drive demand, but that demand is highly sensitive to marketing. Despite these complexities and the lack of consensus about which drugs we need, there are unambiguous examples of both too many drugs for some conditions and too few or none at all for others.

Infectious diseases represent the clearest examples of failure to develop drugs when there is need. More than 1,500 people worldwide die each hour from infectious diseases, with most the result of just six conditions: HIV/AIDS, malaria, measles, pneumonia, tuberculosis, and various forms of dysentery.² The potential threat from infectious diseases within the United States is also growing. More than 170,000 Americans now die annually from infectious agents, twice the number in 1980. At least thirty new infectious diseases appeared in the United States in the second half of the twentieth century, and new introductions continue, such as severe acute respiratory syndrome (SARS) and monkeypox.³ There is also renewed interest in known diseases such as smallpox because of the threat of bioterrorism and in drugs for reproductive health, such as microbicides that could prevent the spread of HIV/AIDS.

The threat of multiple drug resistance is a growing problem within the United States. Many common infections are now associated with high levels of resistance, such as tuberculosis, gonorrhea, Streptococcus pneumoniae (itself the cause of 100,000 hospitalizations for pneumonia, 3,300 cases of meningitis, and six million cases of ear infections in children in any year), and even head lice.⁴ Each year more than 100,000 cases of life-threatening bloodstream infections and pneumonia among hospitalized patients and nursing home residents are caused by forms of Staphylococcus aureus that are resistant to methicillin and related antibiotics, yet only two new drugs are in development for infections caused by these bacteria.⁵

There are also many common chronic diseases for which there are few or no drug treatments, and some of these have been neglected in pharmaceutical research. Degenerative arthritis affects more than a quarter of Americans over age fifty, yet there are few drugs in development for this condition.⁶ The newest treatments are the COX-2 inhibitors, which relieve the pain but do nothing for the underlying condition. Congestive heart failure, the end result of many cardiovascular conditions, is less common but has a greater functional impact than arthritis. It, too, is largely ignored by the drug industry. At their end stages, both disorders are treated with expensive organ replacement, which should make new drug treatments that would replace surgery a priority.

The shortage of drugs in development for chronic and emerging diseases contrasts with what appears to be excessive investment in new drugs in other areas, even when a disease represents a substantial social burden. For example, there are more than two dozen new drugs in human testing for depression.⁷ Because fewer than half of those with depressive disorders now receive treatment, and most cases of treated depression do not completely resolve with current drug treatments, pharmaceutical companies view the antidepressant market as large and likely to grow in the foreseeable future.⁸

From a societal perspective, however, the case for new antidepressants is less compelling. At least nine antidepressants have been approved for use in the United States in the past fifteen years, but their impact on the overall burden of depression is not yet clear. Many drugs in development appear to be similar to existing products, such as production of pure isomer forms of citalopram and fluoxetine, and the combination of fluoxetine with the antipsychotic olanzapine. Furthermore, because only a third of antidepressant users receive a course of treatment consistent with professional guidelines, the answer to current levels of nonresponse could well be to improve the system of care rather than to invest in developing "me-too" antidepressants.⁹

The absence of investment in drugs for chronic diseases contrasts with the development and marketing of "lifestyle" drugs for such ailments as infected toenails (ketoconazole), baldness (finasteride), and wrinkles (Botox). While these products would not be successful if they were not desired or needed in the pharmaceutical marketplace, the question arises as to whether society values these drugs more than it does new treatments for potentially life-threatening diseases. In effect, we need to ask whether we should simply accept the pharmaceutical industry’s output without question.

Exhibit 1 compares disease-specific, disability-adjusted life years (DALYs), obtained from the World Health Organization’s (WHO’s) Global Burden of Disease Study, with the number of drugs in development, obtained from Pharmaceutical Research and Manufacturers of America (PhRMA) data.¹⁰ While the latter are merely a proxy for investment and do not include all drugs in development in other countries, the exhibit provides a snapshot of the discrepancy between one measure of medical need—in this case, the burden of disease—and the industry’s response.

If a different portfolio of drugs, one perhaps more heavily weighted toward diseases with significant burden, would serve us better, the question then is why haven’t we gotten it. Industry managers, like those throughout the economy, undoubtedly respond in rational ways to the incentives before them, so the answer is likely to be found in the decisions they make. In the next section we describe the current decision model used in different ways throughout the industry, with particular attention to the weaknesses of the process and to the external incentives that drive decisions about new drugs.

Pharmaceutical Investment Decisions

Top Editor's Notes The Current Portfolio Of... Pharmaceutical Investment... Influencing Pharmaceutical... Notes

 
The early history of pharmaceutical innovation is littered with anecdotes of serendipity. Streptozon, for instance, the first of the sulfonamide antibiotics, was synthesized in 1931 as a red dye, and its antibiotic properties were discovered during laboratory testing in mice.¹¹ Luck does not sustain modern business, however, and the risk of drug development is well documented. During the 1980s and early 1990s, scientific management of large pharmaceutical companies began to develop more formal and explicit mechanisms to manage this risk and maximize profits.¹² These mechanisms, in the context of a regulated market environment, have resulted in today’s portfolio of available drugs.

Decisions about new drugs are made in the context of four primary domains: scientific opportunity, market assessment, resources required for development, and medical need. Each of these factors is integrated into sophisticated and highly developed risk and portfolio management processes that span the discovery, preclinical, and clinical phases of development.¹³ However, the complex mathematical foundations and appearance of precise outputs from these models obscure an often messy and inefficient decision-making process in which the quality of the output is determined largely by the variable quality of inputs. Cleaning up the process could be an important step in rationalizing our drug portfolio.

Scientific opportunity. Scientific opportunity could be the single most important factor that explains much of today’s portfolio of drugs. We know a great deal about the neurobiology of depression, providing many potential molecular targets for exploration and new drug candidates. At the other extreme, we lack fundamental understanding of the basic mechanisms associated with tobacco addiction, microbial resistance, degenerative arthritis, and heart failure. Moreover, many of today’s most successful lifestyle drugs have been recycled from prior drug development programs or represent new uses for existing drugs that are then aggressively marketed in ways that might artificially create demand. For example, sildenafil (Viagra), for erectile dysfunction, was initially created as a treatment for hypertension. Finasteride, an effective treatment for benign prostatic hypertrophy, showed an effect on hair growth as a side effect during clinical trials. Similarly, ketoconazole, a broad-spectrum antifungal agent, has an important use in the treatment of yeast infections related to chemotherapy for cancer.

From a policy perspective, public funding of basic research, especially through the National Institutes of Health (NIH), in areas of high medical need has created most of the new opportunities for biotechnology and pharmaceutical companies, and it will undoubtedly continue to do so.¹⁴ However, the principal good from public funding of basic research comes from investment in areas where there are few current opportunities for direct application. The NIH’s priority-setting process includes scientific opportunity as one dimension, but the real need is in areas where little opportunity for immediate drug development exists.¹⁵ By reducing the importance of scientific opportunity in its planning process, the NIH would help to create new opportunities for the industry to pursue and, in the process, reduce the reliance on existing molecules to fill otherwise empty pipelines.

Market assessment. The conventional wisdom about the importance of market assessment as a simple estimation of potential revenues and profits does not adequately reflect the extensive process that goes beyond the calculation of net present value. At early stages, the focus of market assessment is on determining the size of the market and the likelihood of being the first or second product of a particular class to be approved. In the absence of expected significant clinical advantage over existing treatment, it is rare for pharmaceutical companies to select likely "me-too" drugs early in the development process.¹⁶ However, concurrent development of similar drug candidates with potentially large markets has still given us too many drugs in some therapeutic areas.

As more is known about the characteristics of a specific drug candidate, pharmaceutical companies develop expected product profiles—essentially a list of "hoped-for" clinical characteristics. These profiles are tested with physicians (but rarely patients) to assess those characteristics that are most valued and to develop price estimates based on willingness-to-pay methodology. The goal of market research at this phase is to find the minimum product profile that physicians will prescribe at levels sufficient to justify further development, a feature that could result in incremental as opposed to "breakthrough" innovation.

From a policy perspective, these market research activities might be expected to approximate, if imperfectly, the need for a new drug, at least in insurance-based markets that can afford the price. However, imprecise methods of determining market size, focus on minimally acceptable product profiles, and uniformly positive net present values once phase 3 clinical development has occurred combine to give market assessment a poor track record. Historically, only two out of every ten marketed drugs recoup their development costs, leaving much room for improvement.¹⁷

The growing trend toward use of economic evaluation of drugs, the so-called fourth hurdle, to determine their inclusion in pharmacy benefit plans represents a potential strategy to influence perceptions of market opportunity. The Australian Pharmaceutical Benefits Scheme has recently rejected reimbursement of Viagra, Herceptin, and Zyban.¹⁸ Although such rejection in Australia, a country of only fifteen million people, is unlikely to make a major difference in industry investment decisions, widespread application of similar processes in larger markets, such as the evaluations from the United Kingdom’s National Institute for Clinical Excellence (NICE), could have a major impact.

Resources. The third dimension in pharmaceutical investment decisions is the resources that will be needed for development. New drug development is both time-consuming and costly, taking an average of more than fourteen years and financial outlays excluding time costs of about $403 million per approved new chemical entity, according to one recent estimate.¹⁹

A number of factors influence the development process for new drug candidates. Discovery research is the hardest to predict, largely because the outcome of the basic research effort required to find a molecular target, develop appropriate model systems, and find specific chemical inhibitors is uncertain. Industry reports suggest that this phase usually lasts from two to ten years and consumes more than a third of total development expenditures, but the length and expense of this phase are dependent on many factors.²⁰

The steady flow of new drugs for HIV/AIDS demonstrates the accelerating effect of high levels of public funding for basic research on drug development. As reviewed elsewhere in this volume, biotechnology also assumes a special role at this stage of the development process. The payoff for biotechnology investors is a drug that is successful enough in preclinical testing to attract investment and partnership with large pharmaceutical firms for expensive human testing.²¹ Both public and private funding of discovery research allows pharmaceutical firms to limit the risk of costly early-phase failures while concentrating on scaling up the development process in specific therapeutic areas.

Compared with discovery research, the resources and time needed for preclinical testing are much more predictable, and the industry appears to increasingly rely on this phase of testing in its decision process.²² Scientists become experienced and knowledgeable about model systems, so that chemicals can be rapidly screened in "assembly-line" fashion. This, of course, also means that companies tend to focus on areas in which their existing scientists have become specialists rather than venturing into less familiar but more urgent areas.

The expense of the clinical development process has received a great deal of attention. On average, it appears to consume more time and resources than it did in the past, but pharmaceutical companies are able to manage this phase with a great deal of precision.²³ Only the Food and Drug Administration (FDA) review process remains outside the control of the industry, although recent reforms, such as user fees and accelerated reviews for "breakthrough" drugs, have shortened review times overall. Continued development of priority setting for review times represents further opportunity to influence industry incentives.

Medical need. Medical need is an explicit criterion in decisions throughout the development cycle, from the selection of therapeutic areas to the evaluation of specific new drug candidates, but it is the least well developed from a technical standpoint. Historically, decisions about medical need were based largely on the personal assumptions of a trusted scientist or company leader. For example, the Lilly Laboratory for Clinical Research was established in the 1920s to study treatment for pernicious anemia, a disease from which Mrs. J.K. Lilly, wife of the company president, suffered.²⁴ Committees rather than individuals now make research and development (R&D) decisions, yet the methods continue to be awkward and inward looking.

The scientists and physicians working in a particular disease or therapeutic area are asked to determine the need for new drugs in that area, a task that requires interpretation of complex epidemiological and economic data in a situation where there are no accepted definitions of need. While the practice of relying on their scientific staff might bring comfort to senior executives and moral persuasion to the decision process, the rigors of doctoral programs in molecular biology, chemistry, and medicine do not provide the tools to evaluate complex, population-based data. The task of comparing the need for new treatments for rare diseases with high levels of mortality to preventive or palliative drugs for more common diseases that cause major disability is daunting for even the best-trained economists. That such assessments are left in the hands of untrained company scientists and physicians is only slightly less arbitrary than using Mr. Lilly’s family health history for priority setting.

Take, for example, the case of antibiotic resistance. The scientific leadership of most pharmaceutical companies began their careers at a time when much of the medical establishment believed that infectious diseases had been conquered, and this perspective has perpetuated itself within the industry.²⁵ Today there are few champions for the study of infectious disease mechanisms, and few within the industry are able to interpret the epidemiological data in a way that translates into business decisions. Compare this with the number of internal champions that might exist in a company with a history of successful development of antidepressants. There is a strong natural bias based on comfort and familiarity among company staff that could unduly influence the decision process. Providing incentives within the industry to promote more rigorous population-based methods to assess health needs could have the useful side effect of improving the assessment of both medical need and market opportunity.

Influencing Pharmaceutical Decisions

Top Editor's Notes The Current Portfolio Of... Pharmaceutical Investment... Influencing Pharmaceutical... Notes

 
The basic market structure of the pharmaceutical industry is influenced by a variety of environmental factors that have evolved since the 1906 Food, Drug, and Cosmetic Act established the FDA. On the supply side, the industry relies on patents and trade restrictions that protect its high-fixed-cost structure and confer temporary monopolistic power. On the demand side, most people in the developed world have some form of third-party insurance coverage, either provided by their employer or sponsored by their government. Through their approval processes, the FDA and its international equivalents provide the structure and rules in which the drug development process and subsequent marketing take place.

The entry point for efforts to restructure pharmaceutical industry incentives is medical need, and the prerequisites for such an effort are consensus on the definition of medical need and a priority-setting process. As pointed out in the Institute of Medicine’s (IOM’s) report on research priority setting, determining need is not an easy or straightforward task, as various measures produce vastly different priorities.²⁶ The IOM, however, is in an excellent position to extend its work to develop a process for determining national health priorities and achieving stakeholder consensus. The experience of Healthy People 2010 represents one possible model to use in obtaining the necessary public input.

Align research with national priorities. Once a mechanism for determining national priorities is in place, existing market, regulatory, and review processes that influence pharmaceutical investment decisions should be aligned with these priorities. The NIH, including its intramural, extramural, and training programs, should align its research with the priorities established for medical need. NIH disease-specific funding is now loosely associated with the burden of illness, at least by some measures, but NIH investment that merely reflects relative disease burden might not be adequate in high-priority areas when little is known about the basic pathological mechanisms.²⁷ However, explicitly increasing NIH funding with the goal of providing the pharmaceutical industry with new scientific opportunities could be difficult politically.²⁸ Furthermore, the NIH already has multiple constituencies. Simply adding one more could add much complexity to an already intricate system, which could mitigate any benefit on pharmaceutical incentives.

Modify rules for FDA reviews. The order in which the FDA reviews new drugs could also be based on the priorities. Such a change would be a minor modification of current rules that allow for accelerated review of potential "breakthrough" drugs but could be a powerful incentive for the industry. Faster reviews by even one day can mean sizable revenues, greatly affecting market assessment.²⁹ We suggest further study to determine the possible impact of changes in drug review priorities.

Tie patent regulation to medical need. Other supply-side incentives could also provide strong inducement for the industry to develop drugs for diseases with high global burden. Trade restrictions and patent protection have an impact on the decision process primarily by affecting the assessment of market opportunity through their effect on prices, discussed elsewhere in this volume. These mechanisms could be extended to high-priority areas in a manner similar to the current orphan drug model. One recent proposal, public purchase of drug patents following successful development, would require governments to determine the value of that patent by assessing the need for that drug, thus explicitly tying payment to medical need.³⁰

Improve cost-effectiveness review processes. On the demand side, continuing development of public and private mechanisms to review the effectiveness, cost-effectiveness, and value of new drugs with respect to reimbursement decisions offers a further opportunity to influence perceptions of market opportunity. Review processes in Australia, Canada, and much of Western Europe have attracted much attention from the industry. Recent developments in the United States, such as the process used by California’s Medicaid program (Medi-Cal) and that recommended by the Academy of Managed Care Pharmacy, include explicit discussion of the need for a new drug, providing a structure that links medical need with market opportunity.³¹ Although they occur following the successful development of new drugs, there is now limited evidence that these mechanisms can affect the development decisions of the U.S.-based pharmaceutical industry.³² Further research in this area will be critical in developing policies regarding these mechanisms in the United States. For example, in the large U.S. market, having one review body or process could put excessive decision authority in one place, thus limiting diversity of opinion in an area of research that is not fully established.

Encourage insurers to assess the cost burden. Private insurers can also play an important role in affecting demand and industry market assessment. Through their claims data, insurers have the opportunity to assess one important component of burden: cost. Papers in the medical literature from insurance industry–based sources that clearly articulate their key priorities for new drugs over the next ten years could have a strong influence on pharmaceutical industry priorities.³³

We have raised the question about the adequacy of our current portfolio of new drugs. At first glance, it appears to us that it is insufficient to meet our current or future needs, but this fundamental question merits more attention from researchers and policymakers. If a different portfolio of drugs is indeed needed, our review of the way in which industry decisions about new medicines are made offers both a framework for aligning business objectives with medical need within a market structure and some potential ways to do so.

Although the industry has resisted change, it has historically adjusted its investment decisions to the evolution of its environment. The causal relationship between these environmental shifts and drug mix is not readily apparent because of the long drug development process, but there is little doubt that the industry can and will adapt. In the meantime, failure to produce drugs for tropical diseases should be framed not as an isolated market flaw, but rather as one that forms part of a larger systemic weakness that demands our attention.

Editor's Notes

Top Editor's Notes The Current Portfolio Of... Pharmaceutical Investment... Influencing Pharmaceutical... Notes

 
Tom Croghan is a senior natural scientist at RAND in Arlington, Virginia. Polly Pittman is director for international projects at AcademyHealth in Washington, D.C.

The authors thank Dick Rettig for his insightful comments on an earlier version of this manuscript.

Notes

Top Editor's Notes The Current Portfolio Of... Pharmaceutical Investment... Influencing Pharmaceutical... Notes

 

1. U.E. Reinhardt, "Perspectives on the Pharmaceutical Industry," Health Affairs (Sep/Oct 2001): 136–149.
2. World Health Organization, World Health Organization Report on Infectious Diseases: Removing Obstacles to Healthy Development, 1999, www.who.int/infectious-disease-report/pages/textonly.html (20 August 2003).
3. J. Brower and P. Chalk, The Global Threat of New and Emerging Infectious Diseases: Reconciling U.S. National Security and Public Health Policy (Santa Monica, Calif.: RAND, 2003).
4. U.S. Centers for Disease Control and Prevention, "Technical Fact Sheets," www.cdc.gov/drugresistance/factsheets/index.htm (2 June 2003); and WHO, "World Health Organization Report on Infectious Diseases 2000: Overcoming Antimicrobial Resistance," www.who.int/infectious-disease-report/2000/index.html (2 June 2003).
5. Pharmaceutical Research and Manufacturers of America, "New Medicines in Development," 2002–2003, www.phrma.org/newmedicines/newmedsdb/drugs.cfm (2 June 2003).
6. Ibid.; and E. Yelin et al., "A National Study of Medical Care Expenditures for Musculoskeletal Conditions: The Impact of Health Insurance and Managed Care," Arthritis and Rheumatism 44, no. 5 (2001): 1160–1169.[CrossRef][ISI][Medline]
7. PhRMA, "New Medicines in Development: Depression," www.phrma.org/newmedicines/newmedsdb/drugs.cfm?indicationcode=Depression|86 (2 June 2003).
8. M. Fava and K.G. Davidson, "Definition and Epidemiology of Treatment-Resistant Depression," Psychiatric Clinics of North America 19, no. 2 (1996): 179–200.[CrossRef][ISI][Medline]
9. A.S. Young et al., "The Quality of Care for Depressive and Anxiety Disorders in the United States," Archives of General Psychiatry 58, no. 1 (2001): 55–61.[Abstract/Free Full Text]
10. C.J.L. Murray and A.D. Lopez, The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020 (Cambridge, Mass.: Harvard University Press, 1996); and PhRMA, "New Medicines in Development."
11. D. Healy, The Antidepressant Era (Cambridge, Mass.: Harvard University Press, 1997), 20–21.
12. N. Nichols, "Scientific Management at Merck: An Interview with CFO Judy Lewent," Harvard Business Review (Jan/Feb 1994): 88–99; and T.W. Croghan, "The Economics of Antibiotics: An Exploratory Study," in Measuring the Prices of Medical Treatments, ed. J.E. Triplett (Washington: Brookings Institution Press, 1999), 144–146.
13. See, for example, G. Blau et al., "Risk Management in the Development of New Products in Highly Regulated Industries," Computers and Chemical Engineering 24, nos. 2–7 (2000): 659–664[CrossRef]; and S.B. Graves, J.L. Ringuest, and R.H. Case, "Formulating Optimal R&D Strategies," Research-Technology Management 43, no. 3 (2000): 47–51.
14. Joint Economic Committee, United States Senate, "The Benefits of Medical Research and the Role of the NIH" (Washington: U.S. Congress, May 2000); and I. Cockburn and R. Henderson, "Public-Private Interaction and the Productivity of Pharmaceutical Research," NBER Working Paper no. 6018 (Cambridge, Mass.: National Bureau of Economic Research, April 1997).
15. Institute of Medicine, Scientific Opportunities and Public Needs: Improving Priority Setting and Public Input at the National Institutes of Health (Washington: National Academies Press, 1998).
16. A recent exception to this general rule has coincided with the discovery and feasibility of separating drug isomers. Thus, L-citalopram and R-fluoxetine have appeared as new antidepressant candidates. These products tend to appear as the older version’s patent expires.
17. H.G. Grabowski and J.M. Vernon, "Returns to R&D on New Drug Introductions in the 1980s," Journal of Health Economics 13, no. 4 (1994): 383–406[CrossRef][ISI][Medline]; and H.G. Grabowski, J. Vernon, and J.A. DiMasi, "Returns on Research and Development for 1990s New Drug Introductions," Pharmacoeconomics 20, supp. 3 (2002): 11–29.
18. J. Hall and R. Viney, "Controlling Pharmaceutical Costs: The Australian Experience" (Paper presented at the AcademyHealth Annual Meeting, Nashville, Tennessee, 29 June 2003).
19. J.A. DiMasi, R.W. Hansen, and H.G. Grabowski, "The Price of Innovation: New Estimates of Drug Development Costs," Journal of Health Economics 22, no. 2 (2003): 151–185.[CrossRef][ISI][Medline]
20. PhRMA, Pharmaceutical Industry Profile 2001 (Washington: PhRMA, 2001).
21. Merck’s 1997 agreement with Biogen, in which Merck initially paid Biogen $15 million with milestone payments of up to $130 million to develop VLA-4 inhibitors, represents a typical example.
22. J.A. DiMasi, "New Drug Development in the United States from 1963 to 1999," Clinical Pharmacology and Therapeutics 69, no. 5 (2001): 286–296.[CrossRef][ISI][Medline]
23. DiMasi et al., "The Price of Innovation."
24. Lilly Laboratory for Clinical Research, "About the Clinic," www.lillyclinic.com/about/history.htm (25 March 2003).
25. For example, in 1978 United Nations member states signed the Health for All 2000 agreement, which predicted a fundamental health transition in developing countries based on the ability to respond to infectious diseases.
26. IOM, Scientific Opportunities and Public Needs; M.J. Field and G.M. Gold, eds., Summarizing Population Health: Directions for the Development and Application of Population Metrics (Washington: National Academies Press, 1996); and C.P. Gross, G.F. Anderson, and N.R. Powe, "The Relation between Funding by the National Institutes of Health and the Burden of Disease," New England Journal of Medicine 340, no. 24 (1999): 1881–1887.[Abstract/Free Full Text]
27. Gross et al., "The Relation between Funding."
28. Public Citizen, Rx R&D Myths: The Case against the Drug Industry’s R&D Scare Card, July 2001, www.citizen.org/documents/rdmyths.pdf (9 October 2003).
29. Sales of today’s top-selling drug, Lipitor, amount to more than $21 million per day. Pfizer Inc., Annual Report 2002, www.pfizer.com/are/investors_reports/annual_2002/index.html (10 November 2002).
30. B. Weisbrod, "Solving the Drug Dilemma," Washington Post, 22 August 2003.
31. T.W. Croghan et al., "Information Needs for Medication Coverage Decisions of a State Medicaid Program," Medical Care 37, no. 4 (1999): AS24–AS31[CrossRef][ISI][Medline]; and P.C. Langley, "Formulary Submission Guidelines for Blue Cross and Blue Shield of Colorado and Nevada: Structure, Application, and Manufacturer Responsibilities," Pharmacoeconomics 16, no. 3 (1999): 211–224.[CrossRef][ISI][Medline]
32. Anne-Toni Rodgers, corporate affairs director, National Institute for Clinical Excellence, personal communication, 10 June 2003.
33. R.A. Rettig, Health Care in Transition: Technology Assessment in the Private Sector (Santa Monica, Calif.: RAND, 1997); and R.A. Rettig, "Publication of a Research Priorities Proposal," in The Role of Purchasers and Payers in the Clinical Research Enterprise (Washington: National Academies Press, 2002), 25.

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