Clinical investigators perform a critical role in the process of drug development that is often overlooked by industry.
References
Lis, Y. & Walker, S.R. Novel medicines marketed in the UK (1960–87). Br. J. Clin. Pharmacol. 28, 33–343 (1989).
DiMasi, J.A., Seibring, M.A. & Lasagna, L. New drug development in the United States from 1963 to 1992. Clin. Pharmacol. Ther. 55, 609–22 (1994).
DiMasi, J.A., Hansen, R.W., Grabowski, H.G. & Lasagna, L. Cost innovation in the pharmaceutical industry [see comments]. J. Health Econ. 10, 107–42 (1991).
DiMasi, J.A., A.Risks, regulation, and rewards in new drug development in the United States. Regul. Toxicol. Pharmacol. 19, 228–35 (1994).
DiMasi, J.A., Bryant, N.R. & Lasagna, L. New drug development in the United States from 1963 to 1990. Clin. Pharmacol. Ther. 50, 471–86 (1991).
Prentis, R.A., Lis, Y. & Walker, S.R. Pharmaceutical innovation by the seven UK-owned pharmaceutical companies (1964-1985). Br. J. Clin. Pharmacol. 25, 387–396 (1988).
Fischer, W.A. & Rosen, B. The search for the latent information star. R & D Manage. 12, 61–66 (1982).
Armstrong, J.M. & Hicks, P.E. An industrial approach to drug discovery: A pharmacologist's eye view. Clin. Exp. Pharmacol. Physiol. 19, 51–56 (1992).
Lee, S. & Treacy, M.E. Information technology impacts on innovation. R&D Manage. 18, 257–271 (1988).
Globe, S., Levy, G.W. & Schwartz, C.M. Key factors and events in the innovation process. Res. Manage. (Jul.), 8–15 (1973).
Hitchings, G.H., Elion, G.B., Falco, E.A., Russell, P.B. & VanderWerff, H. Studies on analogs of purines and pyrimidines. Ann. N. Y. Acad. Sci. 52, 1318–1335 (1950).
Hitchings, G., Jr. Nobel lecture in physiology or medicine — 1988. Selective inhibitors of dihydrofolate reductase. In Vitro Cell Dev. Biol. 25, 303–10 (1989).
Elion, G.B., Callahan, S.W., Hitchings, G.H., Rundles, R.W. & Lazlo, J., Experimental, clinical, and metabolic studies of thiopurines. Cancer Chemother. Rep. 16, 197–202 (1962).
Elion, G.B., Callahan, S., Nathan, H., Bieber, S., Rundles, R.W. & Hitchings, G.H. Potentiation by inhibition of drug degradation: 6-Substituted purines and xanthine oxidase. Biochem. Pharmacol. 12, 85–93 (1963).
Rosenberg, N. Critical issues in science policy research. Sci. Pub. Policy 18, 335–346 (1991).
Rose, N.R., Barron, A.L., Crane, L.R. & Menna, J.H. Microbiology: Basic Principles and Clinical Applications. 1–647 (Macmillan, New York, 1983).
Bynum, W.F. & Porter, R. Companion Encyclopedia of the History of Medicine. (Routledge, New York, 1993).
Myrvik, Q.N. & Weiser, R.S. Fundamentals of Immunology. 1–510 (Lea & Febiger, Philadelphia, 1984).
Burchenal, J.H. et al. Preliminary studies on the effect of 2,6-diaminopurine on transplanted mouse leukemia. Cancer 2, 119–120 (1949).
Burchenal, J.H. et al. The effects of folic acid antagonists and 2,6-diaminopurine on neoplastic disease: With special reference to acute leukemia. Cancer (Philadelphia) 4, 519–569 (1951).
Burchenal, J.H., Burchenal, J.R., Kushida, M.N., Johnston, S.F. & Williams, B.S. Studies on the chemotherapy of leukemia. Cancer (Philadelphia) 2, 113–118 (1949).
Nathan, H.C., Bieber, S., Elion, G.B. & Hitchings, G.H. Detection of agents which interfere with the immune response. Proc. Soc. Exp. Biol. Med. 107, 796–799 (1961).
Calne, R.Y., Alexandre, G.P.J. & Murray, J.E. A study of the effects of drugs in prolonging survival of homologous renal transplants in dogs. Ann. N. Y. Acad. Sci. 99, 743–761 (1962).
Schwartz, R., Stack, J. & Dameshek, W. Effect of 6-mercaptopurine on antibody production. Proc. Soc. Exp. Biol. Med. 99, 164–167 (1958).
Schwartz, R. & Dameshek, W. Drug-induced immunological tolerance. Nature 183, 1682–1683 (1959).
Calne, R.Y. The rejection of renal homografts: Inhibition in dogs by 6-mercaptopurine. Lancet i, 417–418 (1960).
Elion, G.B., Mueller, S. & Hitchings, G.H. Studies on condensed pyrimidine systems. XXI. The isolation of synthesis of 6-mercapto-2,8-purinediol (6-thiouric acid). J. Am. Chem. Soc. 81, 3042–3045 (1959).
Hitchings, G.H. & Elion, G.B. Layer on layer: the Bruce F. Cain Memorial Award Lecture. Cancer Res. 45, 2415–2420 (1985).
Elion, G.B. Nobel lecture in physiology or medicine — 1988. The purine path to chemotherapy. In Vitro Cell Dev. Biol. 25, 321–30 (1989).
Rundles, R.W., Metz, E.N. & Silberman, H.R. Allopurinol in the treatment of gout. Ann. Intern. Med. 64, 229–257 (1966).
Rundles, R.W., Wyngaarden, J.B., Hitchings, G.H., Elion, G.B. & Silberman, H.R. Effects of a xanthine oxidase inhibitor on thiopurine metabolism, hyperuricemia, and gout. Trans. Assoc. Am. Physicians 76, 126 (1963).
Hamilton, L. & Elion, G.B. The fate of 6-mercaptopurine in man. Ann. N.Y. Acad. Sci. 60, 304–314 (1954).
Elion, G.B., Rideout, J.L., deMiranda, P., Collins, P., & Bauer, D.J., Biological activities of some purine arabinosides. Biological activities of some purine arabinosides. Ann. N.Y. Acad. Sci. 255, 468–480 (1975).
Kaufman, H.E., Nesburn, A.B. & Maloney, E.D., lUdR therapy for herpes simplex. Arch. Ophthalmol. 67, 583 (1962).
Kaufman, H.E. & Heidelberger, C. Therapeutic antiviral action of 5-trifluoromethyl-2′-deoxyuridine in herpes simplex keratitis. Science 145, 585 (1964).
Heidelberg, C. et al. Fluorinated pyrimidines, a new class of tumor-inhibitory compounds. Nature 179, 663–666 (1957).
Ellison, R.R. et al. Arabinosytcytosine: A useful agent in the treatment of acute leukemia in adults. Blood 32, 507–523 (1968).
Talley, R. & Vaitkevicius, V.K. Megaloblastosis produced by cytosine antagonist, 1 —D-arabinofuranocylcytosine. Blood 21, 352–362 (1963).
Elion, G.B., scovery, mechanism of action, and selectivity. J. Med. virol. 1, 2–6 (1993).
Thompson, R.L. et al. The effects of antagonists on the multiplication of vaccinia virus in vitro. Science 110, 454 (1949).
Thompson, R.L., Price, M.L., Menton, S.A., Elion, G.B. & Hitchings, G.H. Effects of purine derivatives an analogs on multiplication of the vaccinia virus. J. Immunol. 65, 529–534 (1950).
Schabel, F.M.J. The antiviral activity of 9-beta-D-arabinofuranosyladenine (ARA-A). Chemotherapy 13, 321–338 (1968).
Schaeffer, H.J. et al. 9-(2-Hydroxyethoxymethyl) guanine activity against viruses of the herpes group. Nature 272, 583–5 (1978).
Elion, G.B. The purine path to chemotherapy. Science 244, 41–7 (1989).
Verheyden, J.P.H., Ganciclovir. in Chronicles of Drug Discovery (ed. Lednicer, D.) 299–326 (Wiley, New York, 1993).
Crumpacker, C., Marlowe, S., Zhang, J.L., Abrams, S. & Watkins, P. Treatment of cytomegalovirus pneumonia. Rev. Infect. Dis. 10, S53846 (1988).
Crumpacker, C.S. Treatment of opportunistic viral infections. AIDS 2, S191–S193 (1988).
Crumpacker, C. Molecular targets of antiviral therapy. N. Engl. J. Med. 321, 163–72 (1989).
Calne, R.Y. et al. Cyclosporin A in clinical kidney grafting from cadaver donors. Proc. Eur. Dial. Transplant. Assoc. 16, 305–9 (1979).
Calne, R.Y., Cyclosporin. Nephron 26, 57–63 (1980).
Kostakis, A.J., White, D.J. & Calne, R.Y. Prolongation of rat heart allograft survival by Cyclosporin A. IRCS (Int. Res. Common. Syst.) J. Med. Sci. 5, 280 (1977).
Kostakis, A.J., White, D.J. & Calne, R.Y. Toxic effects in the use of Cyclosporin A in alcoholic solution as an immunosuppressant of rat heart allografts. IRCS (Int. Res. Commun. Syst.) J. Med. Sci. 5, 243 (1977).
Allen, T.J. Managing the Flow of Scientific and Technological Information (MIT Press, Cambridge, MA, 1966).
Allen, T.J. Managing the Flow of Technology (MIT Press, Cambridge, MA, 1984).
Mohr, L.B. Determinants of innovation in organization. Am. Polit. Sci. Rev. 63, 111–126 (1969).
Pierce, J.L. & Delbeq, A.L. Organization structure, individual attitudes, and innovation. Acad. Manage. Rev. 2, 27–37 (1977).
Gerwin, D. Control and evaluation in the innovation process: The case of flexible manufacturing systems. IEEE (Inst. Electr. Electron. Eng.) Trans. Eng. Manage. EM–28, 62–70 (1981).
Galbraith, J.R. Designing the innovating organization. Organ. Dyn. (Winter), 5–25 (1982).
Damanpour, F. & Evan, W.M. Organizational innovation and preference: The problem of organizational lag. Administr. Sci. Q. 29, 392–409 (1984).
Chakrabati, A.K. The role of champion in product innovation. Calif. Manage. Rev. 17, 58–62 (1974).
Chakrabati, A.K. & Hauschildt, J. The division of labour in innovation management. R&D Manage. 19, 161–171 (1989).
Pearson, R.A. Innovation strategy. Technovation 10, 185–192 (1990).
Thier, S.O. The social and scientific value of biomedical research. J. R. Coll. Physicians Land. 28, 541–543 (1994).
Kelley, W.N. & Randolph, M.A. (eds.) in Careers in Clinical Research: Obstacles and Opportunities. 1–21 (National Academy Press, Washington, DC, 1994).
Henderson, R. Managing innovation in the information age. Harvard Bus. Rev. 72, 100–105 (1994).
Henderson, R.M. & Clark, K.B. Architectural innovation: The reconfiguring of existing product technologies and the failure of established firms. Administr. Sci. Q. 35, 9–30 (1990).
Elion, G.B., Hitchings, G.H. & VanderWerff, H. Antagonists of nucleic acid derivatives. VI. Purines. J. Biol. Chem. 192, 505–518 (1951).
Clarke, D.A. et al. 6-mercaptopurine: Effects in mouse sarcoma 180 and in normal animals. Cancer Res. 13, 593–604 (1953).
Burchenal, J.H. et al. Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leukemia and allied diseases. Blood: J. Hematol. 8, 965–999 (1953).
Murray, J.E., Merrill, J.P., Harrison, J.H., Wilson, R.E. & Dammin, G.J. Prolonged survival of human-kidney homografts by immunosuppressive drug therapy. N. Engl. J. Med. 268, 1315–1323 (1963).
Hitchings, G.H., Elion, G.B., VanderWerff, H. & Falco, E.A. Pyrimidine derivatives as antagonists of pteroylglutamic acid. J. Biol. Chem. 174, 765–766 (1948).
Elion, G.B. & Hitchings, G.H. Antagonists of nucleic acid derivative. IV. Reversal studies with 2-aminopurine and 2,6-diaminopurine. J. Biol. Chem. 187, 511–521 (1950).
Hitchings, G.H., Elion, G.B., Falco, E.A., Sherwood, M.B. & VanderWerff, H. Antagonists of nucleic acid derivatives. I. The Lactobacillus easei model. J. Biol. Chem. 183, 1–8 (1950).
Elion, G.B., Callahan, S.W., Rundles, R.W. & Hitchings, G.H. Relationship between metabolic fates and antitumor activities of thiopurines. Cancer Res. 23, 1207–1217 (1963).
Yü, T.F., & Gutman, A.B., Effect of allopurinol (4-hydroxypyrazolo-(3,4-d)pyrimidine) on serum and urinary uric acid in primary and secondary gout. Am. J. Med. 37, 885–898 (1964).
Elion, G.B. et al. Selectivity of action of an antiherpetic agent, 9-(2-hydroxy-ethoxymethyl)-guanine. Proc. Notl. Acad. Sci. USA 74, 5716–5720 (1977).
Verheyden, J.P. et al. Synthesis of certain 4′-substituted nucleosides. Ann. N. Y. Acad. Sci. 255, 151–65 (1975).
Verheyden, J. & Moffatt, J.G. 4'-Substituted nucleosides. I. Synthesis of 4′-methoxyuridine and related compounds. J. Am. Chem. Soc. 97, 4386–95 (1975).
Selby, P.J. et al. Parenteral acyclovir therapy for herpesvirus infections in man. Lancet 2, 1267–1270 (1979).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Flowers, C., Melmon, K. Clinical investigators as critical determinants in pharmaceutical innovation. Nat Med 3, 136–143 (1997). https://doi.org/10.1038/nm0297-136
Issue Date:
DOI: https://doi.org/10.1038/nm0297-136
This article is cited by
-
Exploring network dynamics in science: the formation of ties to knowledge translators in clinical research
Journal of Evolutionary Economics (2021)
-
Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer
Nature Reviews Cancer (2008)
-
Research Funding: Clinical investigators: The driving force behind drug discovery
Nature Biotechnology (1997)
-
Cyclosporin and the clinical investigator
Nature Medicine (1997)
-
Cyclosporin and the clinical investigator
Nature Medicine (1997)
