Letters

Figure. Mean Sun Index for Infants Aged 1 to 12 Months

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Reductions in Funding for Medical Research

To the Editor It is perhaps in the nature of scientists at the National Institutes of Health (NIH) to dissect the specific causes of the reduction in national funding for the sciences, and the Viewpoint by Dr Emanuel1 elucidated several reasons. Indications are that this fiscal climate change is not an aberration but the beginning of a new cycle, and NIH-funded scientists must weigh their reactions. First, NIH scientists must thank US taxpayers for their support and funding these past 60 years because they have had their money heavily invested in science since the 1950s. The US government has chosen to reduce that investment. The NIH has taken part in the greatest period of scientific exploration in the nations history, and its scientists should thank the taxpayers for the opportunity to serve over all of these years. Second, the NIH must survive. Contraction hurts but is necessary because uninterrupted, interminable growth generates inefficiency and institutional arteriosclerosis. Now is the time to explore financial models (eg, different distributions of indirect funding) that more effectively disburse the cost burden of research among all participants. The expenses of doing the business of research should be a smaller proportion of NIH dollars than it currently is, and it is not unfair to ask universities and research institutions that have benefitted from NIH largesse in the past to sacrifice for the benefit of the science that they espouse now. In addition, the scientific community must be watchful. Funding cycles in a democracy are driven by perceived threats. The polio epidemic and the Ebola crises2 were unanticipated, and the US taxpayers poured money into the NIH and the Centers for Disease Control and Prevention to respond. The next major threat may already be on the way, and when it arrives, and the nation calls once more, the scientific community must be ready. Lem Moy, MD, PhD
Author Affiliation: University of Texas School of Public Health, Houston. Corresponding Author: Lem Moy, MD, PhD, University of Texas School of Public Health, 1200 Herman Pressler, E815, Houston, TX 77030 (lemmoye @msn.com). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving a grant and travel support from the National Heart, Lung, and Blood Institute. 1. Emanuel EJ. The future of biomedical research. JAMA. 2013;309(15):15891590. 2. Kebede S, Duales S, Yokouide A, Alemu W. Trends of major disease outbreaks in the African region, 2003-2007. East Afr J Public Health. 2010;7(1):20-29.

Sun Index, h/wk Fraction of Body Surface Area

Sun Index, h/wk % 100 of Body Surface Area

1.0 0.8 0.6 0.4 0.2 0.0 1 3 6 9 12

100 80 60 40 20 0

Age, mo

There were statistically significant (P < .05) differences in mean sun index values across time points.

presented as a whole number previously,4 the sun index values are presented in the Figure using both units to compare with Barger-Lux et al.3 The Figure shows negligible UV exposure in our infants despite values that appear inflated compared with those cited by Barger-Lux et al.3 In our study, the sun index measurement was not associated with 25-hydroxyvitamin D concentrations or any bone outcomes and thus was used only to compare whether there were any differences among treatment groups in regard to sun exposure over the course of the study. Skin color changes can be reliably estimated using quantitative measures such as reflectance spectrophotometer5; however, this technology has also not been validated in children and may be of limited use in infants in whom skin pigmentation changes during the first year.6 Sina Gallo, RD, PhD Celia Rodd, MD, MSc Hope Weiler, RD, PhD
Author Affiliations: School of Dietetics and Human Nutrition, McGill University, Montral, Qubec (Gallo, Rodd, Weiler). Corresponding Author: Hope Weiler, RD, PhD, School of Dietetics and Human Nutrition, McGill University, 21111 Lakeshore Rd, Ste-Anne-de-Bellevue, Qubec H9X 3V9, Canada (hope.weiler@mcgill.ca). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Ms Gallo reported receiving travel support from CIHR Human Development Child and Youth Health and the American Society for Bone and Mineral Research. No other disclosures were reported. 1. World Health Organization. Pocket Book of Hospital Care for Children: Guidelines for the Management of Common Illnesses With Limited Resources. Geneva, Switzerland: World Health Organization; 2005. 2. Wallace AB. The exposure treatment of burns. Lancet. 1951;1(6653):501-504. 3. Barger-Lux MJ, Heaney RP. Effects of above average summer sun exposure on serum 25-hydroxyvitamin D and calcium absorption. J Clin Endocrinol Metab. 2002;87(11):4952-4956. 4. Chan J, Jaceldo-Siegl K, Fraser GE. Serum 25-hydroxyvitamin D status of vegetarians, partial vegetarians, and nonvegetarians: the Adventist Health Study-2. Am J Clin Nutr. 2009;89(5):1686S-1692S. 5. Daniel LC, Heckman CJ, Kloss JD, Manne SL. Comparing alternative methods of measuring skin color and damage. Cancer Causes Control. 2009;20(3): 313-321. 6. Grande R, Gutierrez E, Latorre E, Arguelles F. Physiological variations in the pigmentation of newborn infants. Hum Biol. 1994;66(3):495-507. 854 JAMA August 28, 2013 Volume 310, Number 8

To the Editor Dr Emanuels recent article1 brought awareness to the decline in NIH funding. However, the conclusion that the NIH must focus research only on cost-lowering, qualityimproving interventions was based on flawed premises. This conclusion, if accepted, may obscure the true reasons for increased health care spending, higher federal deficits, and lower NIH budgets. Emanuels first premise was that the main source of advancement in biomedical technology is the NIH. Research activities at
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Letters

universities rely on NIH funding; however, this only accounts for approximately 27% of total medical research funding in the United States.2 The majority of medical research funding (approximately 61%) is from private industry.2 Fully or partially NIHsponsored clinical trials account for only 9.3% of all US-based clinical trials registered on Clinicaltrials.gov (6466 of 69 372 studies).3 Phase 3 clinical trials sponsored by the NIH accounted for only 4.9% of the US total (472 of 9630 studies), whereas only 1.8% (174 of 9630 studies) had the NIH acting as the lead sponsor.3 These data show that NIH research is actually part of a much larger picture and that its contribution to increased health care costs due to technology advancement is overstated. A second premise was that it is possible to determine an interventions cost when it is discovered in the laboratory. This is incorrect for many reasons. First, an interventions price is determined by the manufacturer, pharmacy, and hospital markups, and ultimately what the payer is willing to subsidize all of which are external to the laboratory. Second, an intervention often does not rely only on a single research achievement. For instance, alipogene tiparvovec, the gene therapy intervention approved in Europe in late 2012, relied on DNA sequencing, cloning, and viral vector modification in its development.4 These technologies are also the basis of many products in genomics, vaccine development, and others. It would be impossible to assign value to each enabling technology in an intervention and determine whether it will ultimately be cost-effective to the health care system. Third, many interventions are based on similar mechanisms and pathways. The Haemophilus influenza vaccine that Emanuel mentioned functions by activating antigen-specific cellular immunity, which is similar to the cancer vaccine sipuleucel-T (cost: $93 000/course).5 The same biomedical research enabled the development of both products. Scientific advancement in the laboratory does not increase costs. Focusing cost reduction efforts at the discovery stage of intervention development ignores more relevant causes of health care expenditure beyond the laboratory. Steven S. Ma, BS
Author Affiliation: Vaccine Research Center, National Institutes of Health, Bethesda, Maryland. Mr Ma is now an MBA student at Duke University Fuqua School of Business. Corresponding Author: Steven S. Ma, BS, Vaccine Research Center, National Institutes of Health, 40 Convent Dr, Room 3613, Bethesda, MD 20892 (steven @stevensma.com). ConflictofInterestDisclosures: TheauthorhascompletedandsubmittedtheICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Disclaimer: The views expressed in this letter are those of the author and do not necessary reflect the official position of the National Institutes of Health. 1. Emanuel EJ. The future of biomedical research. JAMA. 2013;309(15):1589-1590. 2. Dorsey ER, de Roulet J, Thompson JP, et al. Funding of US biomedical research, 2003-2008. JAMA. 2010;303(2):137-143. 3. ClinicalTrials.gov website. http://www.clinicaltrials.gov. Accessed May 11, 2013. 4. Kastelein JJ, Ross CJ, Hayden MR. From mutation identification to therapy: discovery and origins of the first approved gene therapy in the Western world. Hum Gene Ther. 2013;24(5):472-478. 5. Kantoff PW, Higano CS, Shore ND, et al; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422. jama.com

To the Editor Dr Emanuel1 ascribed much of the blame for increasing health care costs to biomedical research, and cited increasing costs as a major reason for the decrease in real dollars for NIH funding. He pointed out that the NIH must demonstrate its ability to lower costs. The true picture is far more complex. First, Emanuel used bevacizumab as an example of an expensive, noncurative drug. Other examples of noncurative drugs that have had a major effect on health are statins and antiretrovirals. These drugs do not cure coronary artery disease or human immunodeficiency virus but do prolong life. Even the example that Emanuel cited as a triumph, the Hemophilus influenzae type B vaccine, could be seen as increasing costs because individuals saved by this vaccine could eventually develop expensive diseases as the population ages. Second, a major factor in the cost of new drugs is expenditures for drug development, which need to be recouped. The average cost of drug development in the United States is in the hundreds of millions of dollars.2 Regulatory costs are the major contributor.2 In fact, the cost has become so high that advances that are made by NIH-funded research often never make it to early pharmaceutical development because even though the research shows efficacy in animal models, it is it still too risky for pharmaceutical companies to invest in the novel technology. To remove the risk of drugs in development, pharmacokinetic and toxicology studies must be performed but there are few funding mechanisms for this. Third, Emanuel discussed the politicization of science. An additional approach would be to emphasize the role of NIH research in stimulating small business development. Additional small business means increased economic growth, and economic growth is vital to addressing the budget deficits. The economic growth potential of biomedical research can be used to compete for funding with other priorities. In addition, Emanuel suggested that NIH researchers must focus on low-cost interventions. However, this could imply that if the NIH increases health care costs, eliminating the NIH would lower health care costs. In fact, this is already happening. Between historically low funding rates and the A1 system that allows only 2 opportunities to submit a research proposal, the US biomedical research system is being gutted. In contrast, China, India, South Korea, Taiwan, and Germany are increasing biomedical research efforts. In the space of a few years, the United States is becoming a consumer rather than producer of biomedical research. Jack L. Arbiser, MD, PhD

Author Affiliation: Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia. Corresponding Author: Jack L. Arbiser, MD, PhD, Emory University School of Medicine, 101 Woodruff Cir, Atlanta, GA 30322 (jarbise@emory.edu). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving grants from the National Institutes of Health and the Department of Veterans Affairs; being a cofounder of Accuitis LLC; holding stock and receiving travel expenses from Accuitis; and holding several patents on and being involved in negotiations to license compounds for anticancer efforts. JAMA August 28, 2013 Volume 310, Number 8 855

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1. Emanuel EJ. The future of biomedical research. JAMA. 2013;309(15):1589-1590. 2. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ. 2003;22(2):151-185.

medical research has been good in fueling economic growth is simply wrong. Ezekiel J. Emanuel, MD, PhD

In Reply I agree with Dr Moys point that it is important that the business of research be a smaller proportion of the NIH dollars. But it cannot simply be that research institutions absorb more costs. The NIH too must try to streamline the paperwork and bureaucracy of actually receiving a grant and complying with all of its requirements. This would be consistent with President Obamas executive order to reduce the burden of regulations.1 Mr Ma asserts NIH funding is such a small proportion of biomedical research funding that it is not responsible for much of the costly technology that drives up health care costs. If true, this claim would undermine the very argument to increase NIH funding. Assuming Mas viewpoint, opponents of NIH funding could argue that because the NIH covers such a minor part of biomedical research funding overall, cutting it will not hinder the important progress of medicine. In other words, NIH funding could be cut without worrying that new discoveries will be foregone. This seems a terrible defense of NIH funding. In addition, I did not argue that the NIH should focus only on funding research into cost-lowering advances. Instead I argued that cost-lowering advances should be part of the NIH focus in a way that it has never been. It currently plays no role in deciding what research projects to fund. My view is that it ought to be a criterion in evaluating grants for funding moving forward. Dr Arbiser seems to think that I argued against bevacizumab because it is a noncurative drug. But that is wrong. The problem with bevacizumab is that it has minimal effectiveness. It is not its noncurative properties that worry me. Imatinib does not cure chronic myeloid leukemia, but it is nevertheless a valuable addition to the anticancer armamentarium.2 If bevacizumab prolonged the life of cancer patients an average of 5 years, but cured no person of cancer, it would still be worthwhile. But unlike antiretroviral drugs for human immunodeficiency virus or imatinib, bevacizumab gives patients with metastatic colorectal cancer about an extra 4 months of life at costs of more than $100 000 per quality-adjusted life-year.3 And for other cancers (such as lung) bevacizumab adds even fewer months, and costs can exceed $500 000 per quality-adjusted life-year.4 Unlike Arbiser, I would not advocate strongly that on average NIH funding creates jobs and thriving small businesses. Doubtless there have been several successful startup biotechnology companies such as Amgen and Genentech that have generated large profits and good jobs. However, taken as a whole, the biotechnology industry is still a net financial loser.5 That is, more capital has been poured into the failing companies than the economic returns generated by the surviving successful companies. Furthermore, the current evaluations suggest that growth in health care costs have been an economic drag, not an economic boon.6 The more high technology used in medicine, such as bevacizumab, the higher health care costs, and the slower the US economy grows. The argument that bio856 JAMA August 28, 2013 Volume 310, Number 8

Author Affiliation: Department of Medical Ethics and Health Policy, University of Pennsylvania, Philadelphia. Corresponding Author: Ezekiel J. Emanuel, MD, PhD, Department of Medical Ethics and Health Policy, University of Pennsylvania, 22 College Hall, Philadelphia, PA 19104 (vp-global@upenn.edu). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Obama B. Executive Order 13563: improving regulation and regulatory review. Fed Regist. 2011;76:3821. 2. Reed SD, Anstrom KJ, Li Y, Schulman KA. Updated estimates of survival and cost effectiveness for imatinib versus interferon-alpha plus low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukaemia. Pharmacoeconomics. 2008;26(5):435-446. 3. Tappenden P, Jones R, Paisley S, Carroll C. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. Health Technol Assess. 2007;11(12):1-128; iii-iv. 4. Goulart B, Ramsey S. A trial-based assessment of the cost-utility of bevacizumab and chemotherapy versus chemotherapy alone for advanced non-small cell lung cancer. Value Health. 2011;14(6):836-845. 5. FierceBiotech.com website. Biotech industry turns a profit for the first time, but milestone overshadowed as companies struggle for survival, report finds. http://www.fiercebiotech.com/press-releases/biotech-industry-turns-profit -first-time-milestone-overshadowed-companies-struggle-su. Accessibility verified July 30, 2013. 6. Executive Office of the President, Council of Economic Advisors. The economic case for health care reform. http://www.whitehouse.gov/assets /documents/CEA_Health_Care_Report.pdf. Accessibility verified July 30, 2013.

Autism and Lyme Disease

To the Editor Ms Ajamian and colleagues1 quoted our work2,3 that found an association between autism spectrum disorder (ASD) and Lyme disease in their research letter on serological markers of Lyme disease in children with autism. Their study used the Centers for Disease Control and Prevention (CDC) testing criteria with enzyme-linked immunosorbent assays (ELISAs) followed by Western blotting. These assays, provided by Euroimmun, have only a 45% to 49% sensitivity.4 In addition, the patients were aged 2 to 18 years and developed autism as much as 18 years before the blood samples were drawn. A low sensitivity ELISA performed years later does not prove these patients were not exposed to an immune process triggered by Borrelia burgdorferi at the time the pathological process began. Only 5 of the 70 children with autism were tested with the more sensitive Western blot. In contrast, we cited studies that collectively included 130 children with ASDs and 62 controls tested by either Western blot without the full complement of specific bands or forensic polymerase chain reaction and Southern blot confirmation.3,5 Reactivity of B burgdorferispecific bands on Western blot without the full number of bands meeting the CDC surveillance criteria is a more reliable indicator of prior exposure to B burgdorferi. Robert C. Bransfield, MD Mason Kuhn, MS
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