10转化医学研究的意义和重要性

COMMENTARY The Meaning of Translational Research and Why It Matters Steven H. Woolf, MD, MPH TRANSLATIONAL RESEARCH MEANS DIFFERENT THINGSto different people, but it seems important to al-most everyone. The National Institutes of Health(NIH) has made translational research a priority, forming centers of translational research at its institutes and launching the Clinical and Translational Science Award (CTSA) program in 2006.With 24 CTSA-funded academic centers already established, other universities are trans- forming themselves to compete for upcoming CTSA grants. By 2012, the NIH expects to fund 60 such centers with a budget of $500 million per year.1 Besides academic cen- ters, foundations, industry, disease-related organizations, and individual hospitals and health systems have also estab- lished translational research programs and at least 2 jour- nals (Translational Medicine and the Journal of Transla- tional Medicine) are devoted to the topic. By some accounts, translational research has become a centerpiece of the European Commission’s €6 billion budget for health- related research, and the United Kingdomhas invested £450 million over 5 years to establish translational research centers.2 What exactly is translational research? Formany, the term refers to the “bench-to-bedside” enterprise of harnessing knowledge from basic sciences to produce new drugs, de- vices, and treatment options for patients. For this area of research—the interface between basic science and clinical medicine—the end point is the production of a promising new treatment that can be used clinically or commercial- ized (“brought to market”). This enterprise is vital, and has been characterized as follows: “effective translation of the new knowledge, mechanisms, and techniques generated by advances in basic science research into new approaches for prevention, diagnosis, and treatment of disease is essential for improving health.”3 For others—especially health services researchers andpub- lic health investigators whose studies focus on health care and health as the primary outcome—translational research refers to translating research into practice; ie, ensuring that new treatments and research knowledge actually reach the patients or populations for whom they are intended and are implemented correctly. The production of a new drug, an end point for “bench-to-bedside” translational research, is only the starting point for this second area of research. Ac- cording to McGlynn et al,4 US patients receive only half of recommended services. The second area of translational re- search seeks to close that gap and improve quality by im- proving access, reorganizing and coordinating systems of care, helping clinicians and patients to change behaviors and makemore informed choices, providing reminders andpoint- of-care decision support tools, and strengthening the patient- clinician relationship. The distinction between these 2 definitions of transla- tional research was articulated by the Institute of Medi- cine’s Clinical Research Roundtable,5 which described 2 “translational blocks” in the clinical research enterprise and which some now label as T1 and T2. The first roadblock (T1)was described by the roundtable as “the transfer of new understandings of disease mechanisms gained in the labo- ratory into the development of new methods for diagnosis, therapy, and prevention and their first testing in humans.” The roundtable described the second roadblock (T2) as “the translation of results from clinical studies into everyday clini- cal practice and health decision making.” Referring to T1 and T2 by the same name—translational research—has become a source of some confusion.6 The 2 spheres are alike in name only. Their goals, settings, study designs, and investigators differ. T1 research requires mas- tery of molecular biology, genetics, and other basic sci- ences; appropriately trained clinical scientists working in strong laboratories and with cutting-edge technology; and a supportive infrastructure within the institution—all ele- ments the CTSA seeks to nurture. In contrast, the “laboratory” for T2 research is the com- munity and ambulatory care settings, where population- based interventions and practice-based research networks7 bring the results of T1 research to the public. T2 requires different research skills: mastery of the “implementation sci- ence”8 of fielding and evaluating interventions in real- world settings and of the disciplines that inform the design of those interventions, such as clinical epidemiology and evi- dence synthesis, communication theory, behavioral sci- ence, public policy, financing, organizational theory, sys- Author Affiliation: Departments of Family Medicine and Epidemiology and Com- munity Health, Virginia Commonwealth University, Richmond. Corresponding Author: Steven H.Woolf, MD,MPH, Departments of FamilyMedi- cine, Epidemiology, and Community Health, Virginia Commonwealth University, WestHospital, 1200 E Broad St, POBox 980251, Richmond, VA23298-0251 (swoolf @vcu.edu). ©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, January 9/16, 2008—Vol 299, No. 2 211 at Emory University, on April 9, 2008 www.jama.comDownloaded from Administrator 高亮 Administrator 高亮 Administrator 高亮 Administrator 高亮 Administrator 高亮 tem redesign, informatics, and mixed methods/qualitative research. T1 and T2 face different challenges. T1 struggles more with biological and technological mysteries, trial re- cruitment, and regulatory concerns. T2 struggles more with human behavior and organizational inertia, infrastructure and resource constraints, and the messiness of proving the effectiveness of “moving targets” under conditions that in- vestigators cannot fully control.9,10 Both T1 and T2 research are vital, but T1 seems to over- shadow T2 in the United States.6 Most individuals have T1 in mind when they use the term translational research and T1 attracts more funding. According to Moses et al,11 the $22.1 billion NIH budget for 2002 included $9.1 billion for “applied and development research” ($13.0 billion for basic research) but only $787 million for health services re- search. The NIH maintains an active program in “dissemi- nation” research,12 but across all funding sources in 2002— federal and foundations—spending on health services research represented only 1.5% of biomedical research fund- ing.11 National Institutes ofHealth leaders and theCTSApro- gram advocate both T1 and T2, but the focus is on T1. The CTSA program does encourage “community engagement,” but whether this entails T2 is often unclear. Rather than pro- moting the efferent process of exporting research findings to the community and facilitating their implementation in practice, CTSA often portrays community engagement as an afferent process for researchers; ie, a way to “foster col- laborative research partnerships and enhance public trust in clinical and translational research, facilitating the recruit- ment of research participants from the community.”13 Arguably, the federal responsibility for T2 research lies not with the NIH but with the Agency for Healthcare Research and Quality (AHRQ). According to its recent report to Congress, “the ultimate goal [of AHRQ] is research translation—that is, making sure that findings from AHRQ research are widely disseminated and ready to be used in everyday health care decisionmaking.”14 But Congress allocates AHRQ only approximately $300 mil- lion per year for this work: just over 1% of the NIH bud- get. AHRQ does what it can—in 1999 and 2000 it issued 27 Translating Research into Practice (TRIP) grants,15 and it has also sponsored TRIP conferences—but funding for TRIP later declined as congressional earmarks began carv- ing out much of AHRQ’s budget for specific topics (eg, patient safety, information technology). In 2000, AHRQ spent $7 million (3% of its budget) on TRIP studies,16 but by 2004 it spent only $2 million (1%).17 The T2 research community is still defining itself, both in name and in scope. Being named TRIP, T2, or even trans- lational research is unsatisfactory to many in the disci- pline, but no consensus has coalesced around alternative terms (eg, dissemination, health services, knowledge trans- lation/transfer, implementation, or quality improvement re- search). The scope of T2 research is also unclear. The round- tablemodel5 portrays T2 as one step—the translation of new knowledge into clinical practice—but the process is rarely that simple.8,18 Westfall et al19 redrew the model to include a third step (T3), practice-based research,7 which is often necessary before distilled knowledge (eg, systematic re- views, guidelines) can be implemented in practice. Even this expanded model is incomplete because it sees knowledge implementation only through the eyes of phy- sicians, but practitioners other than health care profession- als also translate research into practice. Science informs choices about health habits (eg, diet, smoking), environ- mental policy, injury prevention, parenting, healthy work- places and schools, population health campaigns, and other interventions outside the clinic. The “practitioners” who ap- ply evidence in these settings include patients, public health administrators, employers, school officials, regulators, prod- uct designers, the food industry, and other consumers of evidence. Trials that test the implementation of evidence in these settings can be just as vital as similar T2 work in clini- cal settings.20 How attention and resources are apportioned to T1 and T2 matters because, for many diseases, T2 could save more lives than T1. The “bench-to-bedside” T1 enterprise occa- sionally yields breakthroughs that markedly improve the prognosis for a disease,21,22 but most new drugs and inter- ventions produced by T1 only marginally improve effi- cacy. These incremental advances are certainlywelcome, but patientsmight benefit evenmore—andmore patientsmight benefit—if the health care system performed better in de- livering existing treatments than in producing new ones. For example, greater fidelity in administering aspirin to eli- gible patients might prevent more strokes than developing more potent antiplatelet agents.23 At a time when experts warn of the fragmented health care system and of a widen- ing “chasm”24 in access, quality, and disparities, interven- tions to close these gaps—the work of T2—may do more to decreasemorbidity andmortality than a new imaging de- vice or class of drugs. Public interest therefore requires T2 to come out from under the shadow of T1. It needs a new name; translational research is now too vague a term for T2 (or T1) and not using the same label for both endeavors would help to reduce con- fusion. More than a new name, however, T2 needs new rec- ognition and emphasis. Policy makers and the academic re- search community must come to a clearer understanding of the distinction between inventing treatments and get- ting them used in practice. Those who fund research must weigh carefully the relative capacity of each research sphere to improve health and economic outcomes and should fund each endeavor accordingly. Disproportion has conse- quences,25 and the current policy of spending 1.5% of re- search dollars on health services research11 is probably cost- ing lives. Moreover, adequate investment in T2 research is vital to fully salvage investments in T1 research. Bringing a drug to market without knowing how to bring it to patients un- COMMENTARIES 212 JAMA, January 9/16, 2008—Vol 299, No. 2 (Reprinted) ©2008 American Medical Association. All rights reserved. at Emory University, on April 9, 2008 www.jama.comDownloaded from Administrator 高亮 dermines its larger purpose and can only diminish its prof- itability for investors. A consequence of a stronger commitment to T2, espe- cially outside clinical settings, is to expand the boundaries of basic science beyond the bench research that T1 typi- cally showcases. Successful health interventions in hospi- tals, homes, and statehouses require the translation of other “basic sciences”—such as epidemiology, behavioral sci- ence, psychology, communication, cognition, social mar- keting, economics, political science—not only the transla- tion of biotechnological insights and novel therapies. These disciplines deserve their place not only in definitions of ba- sic science but also in funding priorities. Poverty matters as much as proteomics in understanding disease. Discovering better ways to ensure that patients receive the care they need—safely, compassionately, andwhen they need it—is not easy and poses formidablemethodologic chal- lenges. Scientific discoveries and spectacular new devices are more fascinating to the public and more lucrative for industry. The betterment of health, however, should dic- tate priorities in health research. Funders should strike a balance between areas of research—T1 vs T2, clinical vs population-based research—and emphasize each en- deavor in proportion to its ability to improve health. Financial Disclosures: None reported. REFERENCES 1. National Institutes of Health. Re-engineering the clinical research enterprise: translat ional research. http://nihroadmap.nih.gov/cl inicalresearch /overview-translational.asp. Accessed November 17, 2007. 2. Travis K. Translational research careers. Science. August 17, 2007. http: //sciencecareers.sciencemag.org/career_development/previous_issues/articles /2007_08_17/caredit_a0700116/(parent)/68. Accessed November 17, 2007. 3. Fontanarosa PB, DeAngelis CD. Basic science and translational research in JAMA. JAMA. 2002;287(13):1728. 4. McGlynn EA, Asch SM, Adams J, et al. The quality of health care delivered to adults in the United States. N Engl J Med. 2003;348(26):2635-2645. 5. Sung NS, Crowley WF Jr, Genel M, et al. 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Cochrane Effective Practice andOrganisation of Care Group. http://www.epoc.cochrane.org/en/index.html. Accessed November 17, 2007. 11. Moses H III, Dorsey ER, Matheson DH, Thier SO. Financial anatomy of bio- medical research. JAMA. 2005;294(11):1333-1342. 12. National Cancer Institute. Research dissemination and diffusion. http: //cancercontrol.cancer.gov/d4d. Accessed November 17, 2007. 13. National Institutes of Health. Institutional Clinical and Translational Science Award (U54). http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-07-007 .html. Accessed November 17, 2007. 14. Agency for Healthcare Research and Quality. Budget estimates for appro- priations committees, fiscal year (FY) 2008: performance budget submission for congressional justification. Performance budget overview 2008. http://www.ahrq .gov/about/cj2008/cjweb08a.htm#Statement. Accessed November 17, 2007. 15. Agency for Healthcare Research and Quality. Translating Research Into Prac- tice (TRIP)-II: fact sheet. 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Washington, DC: National Academy Press; 2001. 25. Woolf SH. Potential health and economic consequences of misplaced priorities. JAMA. 2007;297(5):523-526. COMMENTARIES ©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, January 9/16, 2008—Vol 299, No. 2 213 at Emory University, on April 9, 2008 www.jama.comDownloaded from