Opinion
VIEWPOINT
Gretchen L. Birbeck, MD Department of Neurology, University of Rochester, Rochester, New York, and Epilepsy Care Team, Chikankata Hospital, Mazabuka, Zambia. Michael G. Hanna, MD University College London Institute of Neurology, Queen Square, London, United Kingdom. Robert C. Griggs, MD Department of Neurology, University of Rochester, Rochester, New York.
Corresponding Author: Gretchen L. Birbeck, MD, Department of Neurology, University of Rochester, 265 Crittenden Blvd, Rochester, NY 14642 (gretchen_birbeck @urmc.rochester.edu). jama.com
Global Opportunities and Challenges for Clinical Neuroscience Clinical neuroscience faces 2 challenges: (1) an increasingnumberofpersonsworldwidewithneurodegenerative and neurovascular disorders and the increased expendituresnecessaryfortheircare;and(2)patientswithrareneurologic diseases who also deserve and demand attention. Demographic changes and the “epidemiologic transition” (frominfectionstochronicdiseases)haveconverged,causinganunprecedentedglobalburdenofdisablingneurologic disorders: in 2010, approximately 35 million people were living with dementia; by 2030, this population is expected to reach 70 million and by 2050 is projected to exceed 115 millionpeople,withmostlivinginlower-andmiddle-income countries.1 Stroke, the principal cause of long-term disabilityirrespectiveofage,sex,ethnicity,orcountry,causesmore deaths annually than AIDS, tuberculosis, and malaria combined; incidence of stroke is expected to increase over the next decade, primarily in regions already affected by these infectious diseases. What must be done to confront these 2 challenges? Currently available knowledge indicates that stroke can be prevented; that progress is being made in efforts to delay the onset of Alzheimer disease; and that coordinated care can help to improve the outcomes of patients with these diseases. What must be learned is (1) how to change behaviors to ensure implementation of cost-effective practices; (2) how to influence the lifestyle choices of populations; (3) how to engineer distributed systems to bring the right care to patients across the globe; and (4) how to prioritize within finite resources. Evidence-based medicine and the “implementation sciences” have evolved rapidly in settings in which financial resource limitations have dictated the health care and science agendas. In the United Kingdom and Australia, national review systems evaluate the cost-effectiveness of new drugs, diagnostics, and devices before implementation. In contrast, the United States often embraces new interventions before considering cost but is slow to adopt information technologies to improve patient care. The United Kingdom’s National Institute for Healthcare Excellence (NICE)—its successes and its failures—may offer insights to US policy makers as the Affordable Care Act is implemented. There are also lessons from resourcelimited settings. Some lower- and middle-income countries have introduced interventions aimed at achieving the millennium development goals. For instance, because of the increasing prevalence of noncommunicable disorders,Mexicoinstituteduniversalhealthcarecoveragewith alegalmandatetomodifycoveragebasedonevidenceand available resources. China’s Millennial Development Goals program has successfully targeted poverty reduction and improved health indices.2 The fact that these countries have the political will to address their unmet health care needs sets a standard that the United States and Europe
needtoemulateinaddressingthegrowingburdenofcommon and rare neurologic diseases. In recognition of the global dementia challenge, the G8 countries recently held their first disease-specific summit. These nations have committedto12majoraimsfordementiaresearchandcare that span support for discovery sciences, clinical trials, and innovation in patient care. An international envoy for dementia innovation has been appointed, and the G8 have committed to a further meeting in 2015. Clinical neuroscience must also address the challenge of rare diseases: more than 90% of neurologic diseases are rare, meaning they affect less than 0.07% of the population.3 Molecular discoveries have defined the causesofrarediseasesandidentifiednewtreatments,such as enzyme replacement therapy for diseases such as acidmaltase deficiency. The digital age has empowered patients with rare conditions and their families to join forces with neuroscientists in new ways. The collaborative consortia required to effectively study such conditions have become a reality in the United States, Italy, China, and the United Kingdom. These advances improve diagnosis, elucidate mechanisms of diseases, and raise therapeutic possibilities.3 Methods used for studying rare diseases in developed countries could be used to study neglected tropical diseases4 such as nodding syndrome. Globally, 5 of the top 15 neglected tropical diseases are primarily neurologic disorders or manifest in neurologic injury.5 Research for these diseases might yield substantial additional scientific benefits. An example is the study in the 1950s of kuru, an obscure neurologic condition unique to Papua New Guinea. Research on the contagion mechanisms and pathophysiology of kuru ultimately culminated in Nobel prize–winning work and led to studies of prion protein biology that continue to inform understanding of the protein conformational pathologies relevant to many neurodegenerative disorders today. Much of the knowledge base of clinical neuroscience has been acquired from research conducted in developed populations. Is knowledge gained from diseasespecific research conducted in developed regions applicable to other regions, particularly resource-limited settings? Several neurologic diseases common in tropical, low-income settings occur in an almost entirely “research-free” zone, despite the obvious clinical need and high likelihood of scientific discovery. Neglected tropical diseases need not be rare; for example, consider the tropical epilepsies. Epilepsy is considered by the World Bank to be among the 5 most affordable conditions to effectively treat, yet in resource-limited settings the treatment gap remains more than 80%, and research for preventive interventions is almost nonexistent. The United States could assist global efforts to improve epilepsy care and outcomes by training global researchers capable of JAMA April 23/30, 2014 Volume 311, Number 16
Copyright 2014 American Medical Association. All rights reserved.
1609
Opinion Viewpoint
developing, implementing, and evaluating interventions aimed at reducing treatment gaps, improving quality of care, and eliminating stigma. Given the lack of neurologic expertise in lower-income countries, dedicated efforts to maintain existing skilled personnel within their home countries might help to decrease losses in human resource capacity. Anticipated physician shortages in the United States could be devastating for “donor” countries if past trends in international medical graduate relocation from lower- and middle-income countries to the United States and other income-rich countries persist. Compensating low-income countries for the training costs invested in professionals who subsequently relocate to high-income countries warrants serious consideration. Barriers to successful international neuroscience research are evident.Scientificcommunitiesexistindisciplinarysilos.Publicandprivate sector funders often favor basic neuroscience and clinical trials of new agents. Translating knowledge into policy for improvements in population health (ie, T4 research) is not yet a focus of the National Institute ofNeurologicalDisordersandStroke.TheUSregulatoryburdenonclinical research is increasing at the individual (conflict of interest, training to work with human research participants, Health Insurance Portability and Accountability Act compliance), organizational (institutional reviewboards,expandedmeasuresforassuringfiscalaccountability),and national (US Food and Drug Administration) levels. These challenges, when combined with the logistical challenges of international endeavors,canfurtherdiscourageglobalcollaborations.Moreover,humanand infrastructuralresourcesforneurologiccareandresearchareleastavailable where the burden of disease is greatest. The National Institutes of Healthprovidesonly8%indirectcostsforforeignawardees.6 Moreover, globaldisparitiesindiseaseburdenandresourceallocationsarereflected within the United States’ own health-disparities dilemma. In the current economic climate, is it possible to expand the research horizon to include “T5” (global) research challenges? Although the National Institutes of Health budget for research is declining, the fact that Asian countries are rapidly expanding their research agenda and funding is encouraging. Many medical schools and neurology training programs are developing international experiences and global initiatives. Other recent initiatives may offer the framework and resources for pursuing critical lines of investigation central to clinical neurosciences globally (Box). Given the increasing cost of care in the United States for chronic, disabling neurologic disorders, US funding ARTICLE INFORMATION Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Birbeck reported receiving funds from the US National Institutes of Health and the Dana Foundation for research in sub-Saharan Africa. Dr Hanna’s research is supported by an MRC Research Centre grant 2013-2018 and by the National Institute for Health Research Biomedical Research Centre at University College London Hospitals/University College London; Dr Hanna reported serving as deputy editor of the Journal of Neurology, Neurosurgery and Neuropsychiatry. Dr Griggs reported serving as chair of the executive committee of the Muscle Study Group, which receives support from pharmaceutical companies; serving on scientific advisory boards for The National Hospital Queen Square and PTC Therapeutics; serving on the editorial boards of NeuroTherapeutics and Current Treatment Opinions in Neurology; receiving royalties from WB
1610
Box. Initiatives That May Advance Critical Global Neuroscience Endeavors National Institutes of Health Undiagnosed Disease Program http://rarediseases.info.nih.gov/ National Center for Advancing Translational Sciences http://www.ncats.nih.gov/ Patient-Centered Outcomes Research Institute http://www.pcori.org/ Rare Diseases http://www.rarediseases.org/ Fogarty International Center Brain Disorders Across the Lifespan (BRAIN) Program http://www.fic.nih.gov/programs/Pages/brain-disorders.aspx NIH Medical Education Partnership Initiative expansion into the neurosciences http://www.fic.nih.gov/programs/Pages/medical-education -africa.aspx G8 Countries Dementia summit – Global action on dementia http://dementiachallenge.dh.gov.uk/category/g8 -dementia-summit/ NeuroNext http://www.ninds.nih.gov/news_and_events/proceedings /20101217-NEXT.htm
priorities in the biomedical sciences must change. The BRIC (Brazil, India, and China) economies approach research as an engine for economic growth and intellectual innovation. Consequently, their investments(relativetogrossdomesticproduct)arehigherthanintheUnited States.7 Others have proposed that biomedical research bonds could fund research in the years ahead.8 To meet global challenges, the United States must reconsider its conceptual framework for funding and conducting research. International investments enhance capacity development for neurologic care and research in resource-limited settings. The next generation of US neurologists and neuroscientists must acquire a global perspective and the skills to lead global research endeavors. Addressing the neurologic health needs of Americans will involve overcoming barriers to the conduct of global research and prioritize training in global neurology.
Saunders; receiving research support from TaroPharma; serving on data and safety monitoring boards for PTC Pharmaceuticals, Novartis, and Viromed; serving as a consultant for Marathon Pharmaceuticals; and serving as correspondence editor for Neurology and on the editorial board of the Journal of Neuromuscular Diseases.
4. Minisman G, Bhanushali M, Conwit R, et al. Implementing clinical trials on an international platform. J Neurol Sci. 2012;313(1-2):1-6.
REFERENCES 1. Beaglehole R, Bonita R, Alleyne G, et al; Lancet NCD Action Group. UN High-Level Meeting on Non-Communicable Diseases: addressing four questions. Lancet. 2011;378(9789):449-455.
6. National Institutes of Health (NIH). NIH Grants Policy Considerations: Grants to Foreign Institutions and International Organizations. NIH website. http://grants.nih.gov/grants/policy/nihgps_2013 /nihgps_ch7.htm#preaward_preagreement_costs. 2013. Accessed February 24, 2014.
2. Birbeck GL, Wiysonge CS, Mills EJ, Frenk JJ, Zhou XN, Jha P. Global health: the importance of evidence-based medicine. BMC Med. 2013;11:223.
7. Sun GH, Steinberg JD, Jagsi R. The calculus of national medical research policy—the United States versus Asia. N Engl J Med. 2012;367(8):687-690.
3. Griggs RC, Batshaw M, Dunkle M, et al; Rare Diseases Clinical Research Network. Clinical research for rare disease. Mol Genet Metab. 2009;96(1):20-26.
8. Dorsey ER, de Roulet J, Thompson JP, et al. Funding of US biomedical research, 2003-2008. JAMA. 2010;303(2):137-143.
5. World Health Organization (WHO). The 17 Neglected Tropical Diseases. WHO website. http://www.who.int/neglected_diseases /diseases/en/. Accessed December 25, 2013.
JAMA April 23/30, 2014 Volume 311, Number 16
Copyright 2014 American Medical Association. All rights reserved.
jama.com
VIEWPOINT
Gretchen L. Birbeck, MD Department of Neurology, University of Rochester, Rochester, New York, and Epilepsy Care Team, Chikankata Hospital, Mazabuka, Zambia. Michael G. Hanna, MD University College London Institute of Neurology, Queen Square, London, United Kingdom. Robert C. Griggs, MD Department of Neurology, University of Rochester, Rochester, New York.
Corresponding Author: Gretchen L. Birbeck, MD, Department of Neurology, University of Rochester, 265 Crittenden Blvd, Rochester, NY 14642 (gretchen_birbeck @urmc.rochester.edu). jama.com
Global Opportunities and Challenges for Clinical Neuroscience Clinical neuroscience faces 2 challenges: (1) an increasingnumberofpersonsworldwidewithneurodegenerative and neurovascular disorders and the increased expendituresnecessaryfortheircare;and(2)patientswithrareneurologic diseases who also deserve and demand attention. Demographic changes and the “epidemiologic transition” (frominfectionstochronicdiseases)haveconverged,causinganunprecedentedglobalburdenofdisablingneurologic disorders: in 2010, approximately 35 million people were living with dementia; by 2030, this population is expected to reach 70 million and by 2050 is projected to exceed 115 millionpeople,withmostlivinginlower-andmiddle-income countries.1 Stroke, the principal cause of long-term disabilityirrespectiveofage,sex,ethnicity,orcountry,causesmore deaths annually than AIDS, tuberculosis, and malaria combined; incidence of stroke is expected to increase over the next decade, primarily in regions already affected by these infectious diseases. What must be done to confront these 2 challenges? Currently available knowledge indicates that stroke can be prevented; that progress is being made in efforts to delay the onset of Alzheimer disease; and that coordinated care can help to improve the outcomes of patients with these diseases. What must be learned is (1) how to change behaviors to ensure implementation of cost-effective practices; (2) how to influence the lifestyle choices of populations; (3) how to engineer distributed systems to bring the right care to patients across the globe; and (4) how to prioritize within finite resources. Evidence-based medicine and the “implementation sciences” have evolved rapidly in settings in which financial resource limitations have dictated the health care and science agendas. In the United Kingdom and Australia, national review systems evaluate the cost-effectiveness of new drugs, diagnostics, and devices before implementation. In contrast, the United States often embraces new interventions before considering cost but is slow to adopt information technologies to improve patient care. The United Kingdom’s National Institute for Healthcare Excellence (NICE)—its successes and its failures—may offer insights to US policy makers as the Affordable Care Act is implemented. There are also lessons from resourcelimited settings. Some lower- and middle-income countries have introduced interventions aimed at achieving the millennium development goals. For instance, because of the increasing prevalence of noncommunicable disorders,Mexicoinstituteduniversalhealthcarecoveragewith alegalmandatetomodifycoveragebasedonevidenceand available resources. China’s Millennial Development Goals program has successfully targeted poverty reduction and improved health indices.2 The fact that these countries have the political will to address their unmet health care needs sets a standard that the United States and Europe
needtoemulateinaddressingthegrowingburdenofcommon and rare neurologic diseases. In recognition of the global dementia challenge, the G8 countries recently held their first disease-specific summit. These nations have committedto12majoraimsfordementiaresearchandcare that span support for discovery sciences, clinical trials, and innovation in patient care. An international envoy for dementia innovation has been appointed, and the G8 have committed to a further meeting in 2015. Clinical neuroscience must also address the challenge of rare diseases: more than 90% of neurologic diseases are rare, meaning they affect less than 0.07% of the population.3 Molecular discoveries have defined the causesofrarediseasesandidentifiednewtreatments,such as enzyme replacement therapy for diseases such as acidmaltase deficiency. The digital age has empowered patients with rare conditions and their families to join forces with neuroscientists in new ways. The collaborative consortia required to effectively study such conditions have become a reality in the United States, Italy, China, and the United Kingdom. These advances improve diagnosis, elucidate mechanisms of diseases, and raise therapeutic possibilities.3 Methods used for studying rare diseases in developed countries could be used to study neglected tropical diseases4 such as nodding syndrome. Globally, 5 of the top 15 neglected tropical diseases are primarily neurologic disorders or manifest in neurologic injury.5 Research for these diseases might yield substantial additional scientific benefits. An example is the study in the 1950s of kuru, an obscure neurologic condition unique to Papua New Guinea. Research on the contagion mechanisms and pathophysiology of kuru ultimately culminated in Nobel prize–winning work and led to studies of prion protein biology that continue to inform understanding of the protein conformational pathologies relevant to many neurodegenerative disorders today. Much of the knowledge base of clinical neuroscience has been acquired from research conducted in developed populations. Is knowledge gained from diseasespecific research conducted in developed regions applicable to other regions, particularly resource-limited settings? Several neurologic diseases common in tropical, low-income settings occur in an almost entirely “research-free” zone, despite the obvious clinical need and high likelihood of scientific discovery. Neglected tropical diseases need not be rare; for example, consider the tropical epilepsies. Epilepsy is considered by the World Bank to be among the 5 most affordable conditions to effectively treat, yet in resource-limited settings the treatment gap remains more than 80%, and research for preventive interventions is almost nonexistent. The United States could assist global efforts to improve epilepsy care and outcomes by training global researchers capable of JAMA April 23/30, 2014 Volume 311, Number 16
Copyright 2014 American Medical Association. All rights reserved.
1609
Opinion Viewpoint
developing, implementing, and evaluating interventions aimed at reducing treatment gaps, improving quality of care, and eliminating stigma. Given the lack of neurologic expertise in lower-income countries, dedicated efforts to maintain existing skilled personnel within their home countries might help to decrease losses in human resource capacity. Anticipated physician shortages in the United States could be devastating for “donor” countries if past trends in international medical graduate relocation from lower- and middle-income countries to the United States and other income-rich countries persist. Compensating low-income countries for the training costs invested in professionals who subsequently relocate to high-income countries warrants serious consideration. Barriers to successful international neuroscience research are evident.Scientificcommunitiesexistindisciplinarysilos.Publicandprivate sector funders often favor basic neuroscience and clinical trials of new agents. Translating knowledge into policy for improvements in population health (ie, T4 research) is not yet a focus of the National Institute ofNeurologicalDisordersandStroke.TheUSregulatoryburdenonclinical research is increasing at the individual (conflict of interest, training to work with human research participants, Health Insurance Portability and Accountability Act compliance), organizational (institutional reviewboards,expandedmeasuresforassuringfiscalaccountability),and national (US Food and Drug Administration) levels. These challenges, when combined with the logistical challenges of international endeavors,canfurtherdiscourageglobalcollaborations.Moreover,humanand infrastructuralresourcesforneurologiccareandresearchareleastavailable where the burden of disease is greatest. The National Institutes of Healthprovidesonly8%indirectcostsforforeignawardees.6 Moreover, globaldisparitiesindiseaseburdenandresourceallocationsarereflected within the United States’ own health-disparities dilemma. In the current economic climate, is it possible to expand the research horizon to include “T5” (global) research challenges? Although the National Institutes of Health budget for research is declining, the fact that Asian countries are rapidly expanding their research agenda and funding is encouraging. Many medical schools and neurology training programs are developing international experiences and global initiatives. Other recent initiatives may offer the framework and resources for pursuing critical lines of investigation central to clinical neurosciences globally (Box). Given the increasing cost of care in the United States for chronic, disabling neurologic disorders, US funding ARTICLE INFORMATION Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Birbeck reported receiving funds from the US National Institutes of Health and the Dana Foundation for research in sub-Saharan Africa. Dr Hanna’s research is supported by an MRC Research Centre grant 2013-2018 and by the National Institute for Health Research Biomedical Research Centre at University College London Hospitals/University College London; Dr Hanna reported serving as deputy editor of the Journal of Neurology, Neurosurgery and Neuropsychiatry. Dr Griggs reported serving as chair of the executive committee of the Muscle Study Group, which receives support from pharmaceutical companies; serving on scientific advisory boards for The National Hospital Queen Square and PTC Therapeutics; serving on the editorial boards of NeuroTherapeutics and Current Treatment Opinions in Neurology; receiving royalties from WB
1610
Box. Initiatives That May Advance Critical Global Neuroscience Endeavors National Institutes of Health Undiagnosed Disease Program http://rarediseases.info.nih.gov/ National Center for Advancing Translational Sciences http://www.ncats.nih.gov/ Patient-Centered Outcomes Research Institute http://www.pcori.org/ Rare Diseases http://www.rarediseases.org/ Fogarty International Center Brain Disorders Across the Lifespan (BRAIN) Program http://www.fic.nih.gov/programs/Pages/brain-disorders.aspx NIH Medical Education Partnership Initiative expansion into the neurosciences http://www.fic.nih.gov/programs/Pages/medical-education -africa.aspx G8 Countries Dementia summit – Global action on dementia http://dementiachallenge.dh.gov.uk/category/g8 -dementia-summit/ NeuroNext http://www.ninds.nih.gov/news_and_events/proceedings /20101217-NEXT.htm
priorities in the biomedical sciences must change. The BRIC (Brazil, India, and China) economies approach research as an engine for economic growth and intellectual innovation. Consequently, their investments(relativetogrossdomesticproduct)arehigherthanintheUnited States.7 Others have proposed that biomedical research bonds could fund research in the years ahead.8 To meet global challenges, the United States must reconsider its conceptual framework for funding and conducting research. International investments enhance capacity development for neurologic care and research in resource-limited settings. The next generation of US neurologists and neuroscientists must acquire a global perspective and the skills to lead global research endeavors. Addressing the neurologic health needs of Americans will involve overcoming barriers to the conduct of global research and prioritize training in global neurology.
Saunders; receiving research support from TaroPharma; serving on data and safety monitoring boards for PTC Pharmaceuticals, Novartis, and Viromed; serving as a consultant for Marathon Pharmaceuticals; and serving as correspondence editor for Neurology and on the editorial board of the Journal of Neuromuscular Diseases.
4. Minisman G, Bhanushali M, Conwit R, et al. Implementing clinical trials on an international platform. J Neurol Sci. 2012;313(1-2):1-6.
REFERENCES 1. Beaglehole R, Bonita R, Alleyne G, et al; Lancet NCD Action Group. UN High-Level Meeting on Non-Communicable Diseases: addressing four questions. Lancet. 2011;378(9789):449-455.
6. National Institutes of Health (NIH). NIH Grants Policy Considerations: Grants to Foreign Institutions and International Organizations. NIH website. http://grants.nih.gov/grants/policy/nihgps_2013 /nihgps_ch7.htm#preaward_preagreement_costs. 2013. Accessed February 24, 2014.
2. Birbeck GL, Wiysonge CS, Mills EJ, Frenk JJ, Zhou XN, Jha P. Global health: the importance of evidence-based medicine. BMC Med. 2013;11:223.
7. Sun GH, Steinberg JD, Jagsi R. The calculus of national medical research policy—the United States versus Asia. N Engl J Med. 2012;367(8):687-690.
3. Griggs RC, Batshaw M, Dunkle M, et al; Rare Diseases Clinical Research Network. Clinical research for rare disease. Mol Genet Metab. 2009;96(1):20-26.
8. Dorsey ER, de Roulet J, Thompson JP, et al. Funding of US biomedical research, 2003-2008. JAMA. 2010;303(2):137-143.
5. World Health Organization (WHO). The 17 Neglected Tropical Diseases. WHO website. http://www.who.int/neglected_diseases /diseases/en/. Accessed December 25, 2013.
JAMA April 23/30, 2014 Volume 311, Number 16
Copyright 2014 American Medical Association. All rights reserved.
jama.com
