domingo, 1 de septiembre de 2013

Patenting the PKU Test — Federally Funded Research and Intellectual Property — NEJM

Patenting the PKU Test — Federally Funded Research and Intellectual Property — NEJM

History of Medicine

Patenting the PKU Test — Federally Funded Research and Intellectual Property

Diane B. Paul, Ph.D., and Rachel A. Ankeny, Ph.D.
N Engl J Med 2013; 369:792-794August 29, 2013DOI: 10.1056/NEJMp1306755
In 1960, microbiologist Robert Guthrie and technician Ada Susi invented a bacterial inhibition assay that reliably detected phenylketonuria (PKU) in newborns. The damage caused by PKU, including often profound cognitive impairment, results from an inability to metabolize phenylalanine, an amino acid necessary for protein synthesis and normal growth and development. To be effective, treatment with a low-phenylalanine diet must begin in early infancy, before the onset of irreversible neurologic impairment. Although a ferric chloride urine test for PKU existed in the 1950s, it was unreliable until the infant was 6 to 8 weeks old. The new assay was also more sensitive than the urine test and much easier to administer. Invention of the “Guthrie test” coincided with both marketing approval of Lofenalac, the first commercially available low-phenylalanine infant formula, and a new national focus on mental retardation. John F. Kennedy, who had a cognitively impaired sister, was determined to make prevention of mental retardation a federal priority, and parents of affected children had begun organizing to promote research on causes and cures. The Guthrie test inspired hope that mental retardation could be successfully treated.1 Uptake of the test was rapid. In 1963, Massachusetts mandated screening of all infants for PKU, and other states quickly followed. But efforts to patent and license the Guthrie test generated controversy, a little-known historical episode that presaged current debates over commercialization in biomedicine. In 1961, the U.S. Children's Bureau (USCB) embarked on a field trial of the test, requiring rapid production of kits to screen more than 400,000 babies. Guthrie, who had a cognitively impaired son and a niece with PKU, was involved in a parents' group, the National Association for Retarded Children (NARC). In consultation with the NARC, he decided that commercial production of test kits would be most efficient. Dr. Robert Guthrie Overseeing a Nurse Administering the PKU Test. Guthrie favored the Ames Company, a division of Indiana-based Miles Laboratories, which marketed the earlier PKU tests. Although Guthrie assumed that the government would enter a contract with Ames, the company said it would manufacture the kits only if a patent were issued. In 1962, Guthrie filed a patent application in his own name and signed an exclusive licensing agreement with Miles, under which he would receive no royalties but 5% of net proceeds would be divided among the NARC Research Fund, the Association for Aid of Crippled Children, and the University of Buffalo Foundation (affiliated with the Buffalo Children's Hospital, Guthrie's employer). There was no pricing provision, an omission that Guthrie later deeply regretted.2 Miles, however, couldn't quickly produce test kits in the required quantity. So with financial support from the USCB, Guthrie rented a house in which to produce and assemble kits containing the materials necessary to perform and interpret 500 tests, at a cost of about $6 each. But when Guthrie visited the Ames Company in June 1963, he discovered that it planned to charge $262 for what were essentially the same kits. He was appalled, and when appeals to the company proved futile, he alerted USCB officials. They recommended that Miles not be granted exclusive commercial rights, in light of the large public expenditure on the test, the potential effect on states that planned to manufacture their own materials, and the steep price Miles planned to charge. Although the test had been developed with support from various organizations, the majority of the funds had come from the Public Health Service (PHS), which provided $251,700, and the USCB, which contributed $492,000 plus $250,000 through the states, chiefly for the trial. Given this federal funding, the surgeon general of the PHS determined that the invention belonged to the United States and abrogated the exclusive licensing agreement. This dispute came to the attention of Senator Russell B. Long (D-LA), chair of the Monopoly Subcommittee of the Select Committee on Small Business. In a May 1965 hearing of that subcommittee, Long denounced the award of private patent rights on federally funded research, charging that the “granting of private patent monopolies to the results of research paid for by the public is concentrating economic and political power in the hands of a few, is retarding our economic growth, and is stifling our capacity to protect ourselves.” He was particularly outraged by such patents in the domain of medical research, declaring, “when the desire to make monopoly profits at the public's expense can adversely affect the health of our children, it is time to call a halt to this immoral and evil practice.” Long also noted that under the conditions of his funding, Guthrie had been required to report any invention to the surgeon general for determination of patent-related issues. Yet he had filed his report nearly a year late, well after submission of his patent application. Guthrie insisted that the delay resulted from bureaucratic mishaps, but to Long, it appeared that the report had been “held up for almost a whole year so that a patent could be filed.”3 The episode was painful for Guthrie, who realized he'd seriously erred in signing the licensing agreement. With politics well to the left on the American political spectrum, Guthrie shared Long's view that government should play a larger role in promoting public health; his belief in government's power to do good was integral to his commitment to universal screening. Distrustful of commercial interests in screening, he never intended to earn anything from the test for himself. In May 1965, Geoffrey Edsall of the National Institutes of Health (NIH) testified in the Senate hearings that the “granting of such exclusive rights for a device developed with the support of an NIH research grant would be contrary to the spirit — if not the letter — of the unwritten rules that govern the use of such public money.” He assumed that this view would be “shared by the majority of scientists, health workers, and educators” and “that most lay persons would take the same position as regards public policy and the public interest.”4 In reality, there was no consensus in the 1960s on the ethics of privately profiting from research conducted with public funds, and throughout the 20th century, patenting was not uncommon in industry–university collaborations, especially for pharmaceuticals and chemical compounds. Nevertheless, norms governing what should count as a freely available public good have fundamentally changed since 1965.5 The shift began in the 1970s, when an “economic competitiveness agenda,” prompted by the oil crisis and concern about Japanese competition, began displacing narratives of science's role in fighting communism and defeating disease. During the monopoly subcommittee hearings, the Ames Company's position was vigorously defended by Senator Birch Bayh (D-IN). Although Bayh lost that battle, he eventually won the war: in 1980, he and Senator Robert Dole (R-KS) introduced legislation permitting universities and small businesses to retain title to inventions resulting from federally funded research without obtaining special approval (see Perspective article by Markel, pages 794–796). The Bayh–Dole Act was followed by other bills promoting the commercialization of publicly funded research, a phenomenon soon exported worldwide. Aggressive commercialization of university research has since become the norm, with universities embracing patenting as an efficient way to transform knowledge into products, generate new income sources, recoup product-development costs, and motivate scientists. This shift in attitudes toward commercialization in biomedicine would probably have been as distasteful to Guthrie as to Long. The story of the Guthrie test reminds us that many clinicians and researchers still find that this “new normal” conflicts with their responsibilities to patients and society, particularly in relation to publicly funded research. The story also underscores how industrial partnerships can go wrong, given the often diverse and conflicting goals of participants. The key principles debated in the Guthrie case underlie the conflicts that remain to this day between political and economic imperatives to commercialize research and the social and moral imperatives to promote public health.
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Source Information

From the University of Massachusetts Boston, Boston (D.B.P.); the Museum of Comparative Zoology, Harvard University, Cambridge, MA (D.B.P.); and the School of History and Politics, University of Adelaide, Adelaide, SA, Australia (R.A.A.).

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