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Consumer activism, genetic information, andsocial networking technologies are creating Repurposing with a Difference
many opportunities for drug repurposing.
Mark S. Boguski,1* Kenneth D. Mandl,2 Vikas P. Sukhatme3
There is widespread belief that current number ofremarkable examples of repur- gerous side effects became tragically evident in the late 1950s and early 1960s only after were discovered serendipitously (8). For an epidemic of severe birth defects occurred instance, buproprion (Wellbutrin) was origi- in children exposed to the drug in utero (9).
research and development (R&D) more pre- dictable, reliable, and less costly. We suggest ket but, several years later, was accidentally a novel approach to this challenge that in- (marketed as Zyban for this indication).
discovered to be uniquely effective in treat- ing severe complications of leprosy. It is now to treat depression, but was hypothesized— marketed for this use under the trade name based on mechanism of action, not serendip- Thalomid. Twenty years later, Thalomid’s use ity—as a treatment for stress urinary incon- tinence. It was successfully developed and patent (see below) as a treatment for a type of ogy, as well as an increasingly sophisticated public eager for solutions to their unmet rescue of an abandoned drug) is thalidomide.
treat a condition other than that for which will be critical to fulfill this promise and to morning sickness during pregnancy, its dan- the drug was approved by the FDA (10).
science, technology development, and exper- not how medicine is practiced; physicians are free to prescribe approved drugs for any product development still requires at least 10 exhausted “standard-of-care” approaches to 15 years and costs between $500 million and have reason to believe that the off-label and $2 billion (1, 2). Furthermore, there is a use will be of clinical benefit. Because of our increasingly sophisticated understand- development spending continues to increase, yet the number of new therapeutic chemical pathways of disease, one would expect there and biological entities approved by the U.S.
to be increasing opportunities for expand- ing off-label use based on fully elucidated been declining since the late 1990s (3). Over- pathways and mechanisms of action, a situ- ation that has been called a “new grammar increased productivity may require an over- of drug discovery” (11). A classic example haul of the R&D paradigm (4); some have called for a “disruptive” transformation of and Glivec), a drug originally developed to indications were expanded to other cancers drug “repurposing” (6, 7) or “repositioning” on the basis of common underlying molecu- (8)—terms that refer to the identification lar pathways (11, 12).
potential of existing drugs for repurposing covery and development (8). There are a safety monitoring (13) is regulated by theFDA in the United States and the European 1Department of Pathology, Beth Israel Deaconess Medical Medicines Agency in Europe (14, 15). The Center and Center for Biomedical Informatics, Harvard detection of potential adverse drug reactions Medical School, 10 Shattuck Street, Boston, MA 02115,USA. 2Children’s Hospital Informatics Program at has traditionally depended on voluntary and Harvard-MIT, Division of Health Sciences and Technology spontaneous reporting by individual patients and Center for Biomedical Informatics, Harvard Medical and physicians, using the FDA’s Adverse School, Boston, MA 02115, USA. 3Beth Israel Deaconess Medical Center and Department of Medicine, Harvard More than one use. Prior examples of repurposed Medical School, Boston, MA 02115, USA.
pharmaceutical companies monitor the liter- drugs include bupoprion and thalidomide (8). A moresystematic approach involving postclinical-trial patient ature for case reports that may indicate a *To whom correspondence should be addressed. data could yield many more repurposed drugs.
safety problem with their medicines. In addi- tion, more proactive approaches, such as sta- apparent during their development or use.
tistical data-mining of hospital records, are This “type 2” pharmacovigilance could be overcoming the inadequate incentives of cur- beginning to emerge (1619).
carried out, for example, by professionals rent business models and regulatory regimes An increasingly important and influential that contribute to the productivity gap in resource is groups of patients who can access potential beneficial events in electronic pharmaceutical R&D. This approach lever- medical information on the Internet and see health records (16). However, we also antici- ages the talents, motivations, and resources themselves as equal partners with—if not the pate another approach, in which potential of individuals and groups whose unmet med- primary drivers of—the medical profession in beneficial side effects of existing drugs are managing their health (20). Special online resources, such as Resounding Health, have recently been developed to serve this popula- nologies in a process that has been called tion. In a growing number of cases, patients or “crowdsourcing” (24, 25). Potential benefi- 1. C. P. Adams, V. V. Brantner, Health Aff. (Millwood) 25, their relatives not only initiate, but also design cial side effects (or new indications) for 2. J. A. DiMasi, R. W. Hansen, H. G. Grabowski, J. Health and carry out, research programs that have, for existing drugs identified in this way could be example, advanced understanding and treat- assessed in a manner conceptually similar to 3. H. Grabowski, Pharmacoeconomics 22, 15 (2004).
ment of gastrointestinal stromal tumor, gas- the formal methods by which causality crite- 4. K. I. Kaitin, Clin. Pharmacol. Ther. 83, 210 (2008).
5. C. M. Christensen, J. H. Grossman, J. Hwang, The troesophageal reflux disease, autism, and the ria are applied to adverse events (15).
Innovator’s Prescription: A Disruptive Solution for Health genetic disorder pseudoxanthoma elasticum Care (McGraw-Hill, New York, 2009).
(20). Most such efforts to date have been car- would be prioritized for further investiga- 6. D. W. Carley, IDrugs 8, 306 (2005).
7. D. W. Carley, IDrugs 8, 310 (2005).
ried out as part of a “gift economy,” in which tion, including some form of clinical trials.
8. T. T. Ashburn, K. B. Thor, Nat. Rev. Drug Discov. 3, 673 patients and their families volunteer time and Validation would be most straightforward for effort to bypass what they consider the “lethal those phenomena that could be rationalized 9. W. G. McBride, Lancet 278, 1358 (1961).
lag time” of professional research processes on the basis of known disease pathways or 10. K. R. Loughlin, J. A. Generali, The Guide to Off-Label Prescription Drugs: New Uses for FDA-Approved Prescription Drugs (Simon & Schuster, New York, 2006).
Such efforts are aided by the fact that con- that are not consistent with known disease 11. M. C. Fishman, J. A. Porter, Nature 437, 491 (2005).
mechanisms might generate hypotheses that 12. D. Vasella, R. Slater, Magic Cancer Bullet: How a Tiny for disease associations for as little as $399 could lead to the discovery of new biological Orange Pill May Rewrite Medical History (HarperCollins,New York, 2003).
and can share these data electronically with 13. World Health Organization (WHO), The Importance of their families, friends, or self-defined net- Definitive clinical trials for novel uses of Pharmacovigilance: Safety Monitoring of Medicinal works of individuals (21). A notable recent existing drugs will remain costly, and phar- Products (WHO, Geneva, 2002); case is that of Google cofounder Sergey Brin, maceutical companies are reluctant to invest 14. E. G. Brown, L. Wood, S. Wood, Drug Saf. 20, 109 in such efforts without patent protection.
high risk of developing Parkinson’s disease.
New information about the uses of existing 15. H. S. Rehan, D. Chopra, A. K. Kakkar, Eur. J. Intern. Med. Brin is personally funding a study of 10,000 drugs may create intellectual property in the patients through two nonprofit companies, 16. J. S. Brownstein et al., PLoS One 2, e840 (2007).
17. L. Harmark, A. C. van Grootheest, Eur. J. Clin. Pharmacol.
including the Michael J. Fox Foundation for patents are generally considered to be more 18. M. Hauben, A. Bate, Drug Discov. Today 14, 343 valuable than MOU patents, but this differ- 19. J. Weaver, M. Willy, M. Avigan, AAPS J. 10, 35 (2008).
ential valuation may be changing because, as 20. T. Ferguson, e-Patients: How They Can Help Us Heal Eisenberg points out, “Drugs are informa- Healthcare (2007); communities to advance the translation of tion-rich chemicals that in many respects are research into new treatments. Google Health, 21. M. S. Boguski, in Genomic and Personalized Medicine, H.
F. Willard, G. S. Ginsberg, Eds. (Elsevier, San Diego, CA Microsoft HealthVault, and Indivo (deployed (such as databases) than they are to other by the Dossia consortium of employers) have 22. A. Pollack, New York Times, 12 March 2009; www.nytimes.
created personally controlled, electronic com/2009/03/12/business/12gene.html?emc=eta1.
health records for individuals or groups to exclusively focused on safety issues, can 23. K. D. Mandl, I. S. Kohane, N. Engl. J. Med. 358, 1732 share their medical conditions with health produce information that is of considerable 24. J. Howe, Crowdsourcing: Why the Power of the Crowd Is care providers, researchers, and others (23).
social value for patients, physicians, and Driving the Future of Business (Crown Business, New insurers at the expense of economic value to activism, along with access to genetic infor- pharmaceutical companies (26). Thus, repur- 25. C. Li, J. Bernoff, Groundswell: Winning in a World Transformed by Social Technologies (Harvard Business, mation services and sophisticated, advanced, posed pharmacovigilance that is focused on and accessible information technologies, has beneficial new uses will need to be based on 26. R. S. Eisenberg, Yale J. Health Policy Law Ethics 5(2), created unprecedented opportunities to bring new business models [such as open-sourcing worldwide human resources and data to bear (27)] apart from the traditional, vertically 27. B. Munos, Nature Rev. Drug Discov. 5, 723 (2006).
28. B. N. Roin, Texas Law Rev. 87, 503 (2009).
integrated R&D enterprise (5). It would also 29. M.S.B. is a former vice president of the Novartis Institutes for Biomedical Research and the founder of Resounding covigilance is to identify adverse side effects Congress or new doctrinal interpretations of Health Inc. K.D.M. is a principal developer of Indivo, anopen-source, personally controlled health record that has of drugs (13), the new kind of pharmacovig- current law by the FDA and the courts, as has been deployed through Dossia, Inc. V.P.S. is a cofounder ilance we envision aims to detect, assess, and understand beneficial drug side effects (or expanded drug indications) that may become ilance, outlines a new approach to drug and



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