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  • 7/25/2019 [Edit] Evaluacin Del Impacto de La Investigacin Biomedica

    1/3

    Cmo citar este artculo: Solans-Domnech M, Permanyer-Miralda G. Evaluacin del impacto de la investigacin biomdica: para

    quin? Med Clin (Barc). 2015. http://dx.doi.org/10.1016/j.medcli.2015.11.031

    ARTICLE IN PRESSG Model

    MEDCLI-3473; No.of Pages3

    Med Clin(Barc). 2015;xxx(xx):xxxxxx

    www.elsevier .es /medic inac l inica

    Editorial

    Evaluacin del impacto de la investigacin biomdica: para quin?

    Assessing the impact of biomedical research: For whom?

    Maite Solans-Domnecha,b, y Gaiet Permanyer-Miraldaa,c, en representacin del Grupo ISOR(Impacte Social de la Recerca)aAgncia de Qualitat i Avaluaci Sanitries de Catalunya (AQuAS), Barcelona, Espanab Centro de Investigacin Biomdica en Redde Epidemiologa y Salud Pblica (CIBERESP), Barcelona, Espanac Mdico Emrito, Unidadde Epidemiologa, Servicio de Cardiologa, Hospital Universitario Vall dHebron, Barcelona, Espana

    Laevaluacindel impactodela investigacinbiomdica, todava

    singrantradicinennuestromedio,esunaactividaden laquedebe-

    ran estar implicados no solo los gestores de la investigacin, sino

    tambin los investigadores y clnicos en cuanto corresponsables

    de ella13. Esta actividad ha adquirido una creciente importancia

    por algunas caractersticas del propio proceso de la investigacin:

    el enorme crecimiento de la produccin cientfica actual, de cali-

    dady validez variables, su nada simplepapel en la dinmica social,

    su gigantesco consumo de recursos materiales y humanos, y su

    enmaranado trayecto hasta ejercer efectos positivos y negativos

    sobre la salud y el bienestar4,5. A efectos de la presente reflexin

    se considera impacto de la investigacin cualquier efecto, cambio

    o beneficio producidos por esta sobre la economa, la sociedad,la poltica o servicios sanitarios, la salud, el medio ambiente o la

    calidad de vida6.

    La heterogeneidad de mtodos y modelos conceptuales79 es

    una caracterstica bsica de los estudios de evaluacin del impacto

    de la investigacin. Esta heterogeneidad depende de la gran varie-

    dad de tipos de impacto posibles, a veces con la consiguiente

    inconmensurabilidad; pero en buena medida, la heterogeneidad

    corresponde tambin a la gran variedadde objetivos de evaluacin

    y colectivos sociales interesados en ella (sus destinatarios, audien-

    cias diana o target audiences). No ser igual el inters que sobre la

    evaluacin del impacto tengan polticos, socilogos, economistas,

    gestores, sociedades cientficas, profesionales de la salud o ciuda-

    danos en general, y sern distintos los tipos de conocimiento que

    se busquen en ella10. Esta heterogeneidad salta a la vista con solo

    considerar las preguntas que el evaluador del impacto de la inves-

    tigacin puede querer responder. Son mltiples, y ningn estudio

    puedepretenderdarrespuestaatodas.Laspreguntasquecadaestu-

    dioplantee y el tipo de conocimientoproducido sern acordes con

    la finalidad del propio estudio y la orientacin de sus potenciales

    usuarios11, como por ejemplo: cmo deben analizarse los diver-

    sos tipos de impacto econmico y social de la investigacin?, de

    Autor para correspondencia.

    Correoelectrnico: [email protected] (M. Solans-Domnech).

    qumanera la estimacin delposible impacto de una investigacin

    puede ayudar a la promocin o priorizacin de proyectos?, cmo

    puedeusarseel conocimientode losmecanismosdegeneracin del

    impacto social de la investigacin para facilitar y estimular estos?,

    cmose transfieren los resultados de la investigacin a la prctica

    sanitaria?

    Cabe preguntarse a quin interesa la evaluacin del impacto de

    la investigacin, cules son sus audiencias diana12. En el inves-

    tigador confluyen las influencias de 2 rdenes sociales: por una

    parte, losdistintosgestores,planificadores, polticosy economistas,

    y lasgrandes industrias; son losgruposo personas situados aguas

    arriba del proceso de la investigacin. Tambin sus beneficiarios

    econmicos podran en parte situarse aqu. En 2 palabras, son per-sonas o gruposquepromueveno regulan el proceso. Aguas abajo

    estn losprofesionales sanitarios, lospacientesy losciudadanos en

    general;o sea, lamayoradelosreceptoresdelproductodela inves-

    tigacin, sus llamados usuarios finales (end users). A todos ellos

    puedeinteresarel estudio desu impacto. Elcarcterde losdistintos

    estudios realizados reflejar los intereses y objetivos de alguno de

    estos grupos, y podemos especular que ese carcter guardar rela-

    cin con las circunstancias histricas, los valores y las creencias de

    sumomentoy lugar.El tipodedestinatariode unestudio deevalua-

    cindelimpactoy elcarcterdedichoestudioestarn ntimamente

    asociados. Puede ilustrarse este punto mediante 3 estudios impor-

    tantes sobre evaluacin del impacto de la investigacin y viendo

    cmo susaudiencias diana influyen en el carcter y la metodologa

    de estos.

    El primer estudio puede interpretarse como dirigido a grandes

    inversores y consiste en una estimacin de los beneficios econmi-

    cos (o retornos) de la investigacin sobre cncer llevada a cabo en

    el Reino Unido en trminos del valor neto de los resultados clni-

    cos, realizado porRANDEurope y el Kings College de Londres13. En

    l se estim el beneficio, en trminos monetarios, que ha gene-

    rado la inversinen investigacin pblica y filantrpicaentre 1970

    y 2009. Se identific la inversin en investigacin y se calcularon

    sus beneficios monetarios netos a partir de las tasas de aplicacin

    de sus resultados, estimando luego los posibles anos de vida ajus-

    tados por calidad ganados. Se concluy que la tasa de beneficio

    http://dx.doi.org/10.1016/j.medcli.2015.11.031

    0025-7753/ 2015 Elsevier Espana, S.L.U. Todos los derechos reservados.

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  • 7/25/2019 [Edit] Evaluacin Del Impacto de La Investigacin Biomedica

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    Cmo citar este artculo: Solans-Domnech M, Permanyer-Miralda G. Evaluacin del impacto de la investigacin biomdica: para

    quin? Med Clin (Barc). 2015. http://dx.doi.org/10.1016/j.medcli.2015.11.031

    ARTICLE IN PRESSG Model

    MEDCLI-3473; No.of Pages3

    M. Solans-Domnech, G. Permanyer-Miralda / Med Clin (Barc). 2015;xxx(xx):xxxxxx 3

    Bibliografa

    1. AdamP, Permanyer-MiraldaG. Investigacin en ciencias de la salud,correspon-sabilidad e impacto social.Med Clin (Barc). 2013;141:2546.

    2. Redman S, Haynes A, Williamson A. Research impact: Neither quick nor easy.BMC Med. 2015;13:265.

    3. Newson R, King L, Rychetnik L, Bauman AE, Redman S, Milat AJ, et al. A mixedmethods study of the factors that influence whether intervention research haspolicy and practice impacts: Perceptions of Australian researchers. BMJ Open.2015;5:e008153.

    4. Gabbay J, leMayA.Evidencebased guidelinesor collectively constructed mind-

    lines? Ethnographic study of knowledge management in primary care. BMJ.2004;329:1013.

    5. Lomas J. The in-between world of knowledge brokering. BMJ. 2007;334:12931.

    6. The nature, scale and beneficiaries of research impact: An initial analysisof Research Excellence Framework (REF) 2014 impact case studies. ResearchReport 2015/01. Kings College London and Digital Science. March 2015.[Consultado 9 Nov 2015]. Disponible en: https://kclpure.kcl.ac.uk/portal/files/35271762/Analysis of REF impact.pdf.

    7. Weiss CH. The many meanings of research utilization. Public Adm Rev.1979;39:42631.

    8. Banzi R, Moja L, Pistotti V, Facchini A, Liberati A. Conceptual frameworks andempirical approachesused to assess the impactof health research:An overviewofreviews. Health Res Policy Syst. 2011;9:26.

    9. Milat AJ, Bauman AE, Redman S. A narrative review of research impact assess-ment modelsand methods. Health ResPolicy Syst. 2015;13:1824.

    10. Spaapen J, van Drooge L. Introducing productive interactions in social impactassessment. Res Eval. 2011;20:2118.

    11. Penfield T, Baker MJ, Scoble R, Wykes M.C. Assessment, evaluations, and defini-tions of research impact: A review. Res Eval. 2014;23:2132.12. Ioannidis JP. How to make more published research true. PLoS Med.

    2014;11:e1001747.

    13. Glover M, Buxton M, Guthrie S, Hanney S, Pollitt A, Grant J. Estimating thereturns to UK publicly fundedcancer-related research in terms of thenet valueofimproved health outcomes. BMC Med. 2014;12:99.

    14. Wooding S, Hanney S, Buxton M, Grant J. Payback arising from research fun-ding: Evaluation of the Arthritis Research Campaign. Rheumatology (Oxford).2005;44:114556.

    15. MilatAJ, Laws R, King L, Newson R, Rychetnik L, Rissel C, et al. Policy and prac-tice impacts of applied research: A case study analysis of theNew South WalesHealth Promotion Demonstration Research Grants Scheme 2000-2006. HealthRes Policy Syst. 2013;11:5.

    16. Ern-KjlhedeE, HanssonF. Measuringresearch performanceduringa changing

    relationship between science and society. Res Eval. 2011;20:13143.17. Solans-Domnech M, Adam P, Guillamn I, Permanyer-Miralda G, Pons JM,

    EscarrabillJ. Impact of clinical andhealth servicesresearchprojectson decision-making: A qualitative study.Health ResPolicySyst.2013;11:15.

    18. Wooding S, Hanney SR, Pollitt A, Grant J, Buxton MJ, Project RetrosightTeam. Understanding factors associated with the translation of cardiovascularresearch: A multinational case study approach. Implement Sci. 2014;9:47.

    19. Ioannidis JP. Evolution and translation of research findings: From bench towhere? PLoS Clin Trials. 2006;1:e36.

    20. Eccles MP, Mittman BS. Welcome to Implementation Science. Implement Sci.2006;1:13.

    21. Poppy G. Science must prepare forimpact. Nature. 2015;526:7.22. Greenhalgh T, Fahy N. Research impact in the community-based health scien-

    ces: An analysis of 162 case studies from the 2014 UK Research ExcellenceFramework.BMC Med. 2015;13:23241.

    23. Hanney SR, Gonzlez-Block MA, Buxton MJ, Kogan M. The utilization of healthresearch in policy-making: Concepts, examples and methods of assessment.Health Res PolicySyst.2003;1:229.

    24. Meagher L, Lyall C, Nutley S. Flows of knowledge, expertise and influence. Res

    Eval. 2008;17:16373.25. KokMO, Schuit AJ.Contribution mapping: A methodfor mapping thecontribu-

    tion of research to enhance itsimpact. Health ResPolicy Syst. 2012;10:2135.

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