There is a long history of discussions about what is a minimal clinically important difference (MCID) and how this term applies to clinical research. This paper deals with a practical framework for MCID and its applicability to clinical trials. A literature review on the topic confirmed the fundamental role of MCID for the clinical research, although no guide on how to best use the MCID in clinical trials was identified. We propose a framework that takes into account (1) the definition of MCID as a term when random variable is discussed, (2) a 4-level approach for classifying the MCID evidence to be considered in a clinical development program, and (3) a method of MCID evaluation, defined in a scientifically sound protocol. The proposed framework can prompt and steer stakeholders to improve the methodological sense of clinical trials based on the definition of MCID at the level of efficacy or safety, increase the quality of data derived from clinical trials and reporting of results, and allow effective planning of drug development programs.
International Conference on Harmonisation. E9: Statistical Principles for Clinical Trials. 1998. http://www.ich.org.
2.
KayR. Statistical Thinking for Non-Statisticians in Drug Regulation. New York, NY: John Wiley; 2009.
3.
MoherDHopewellSSchulzKF. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomized trials. BMJ. 2010;340:c869.
4.
JaeschkeRSingerJGuyattG. Measurement of health status: ascertaining the minimal clinically important difference. Control Clin Trials. 1989;10:407–415.
5.
GatchelRJMayerTGChouR. What does/should the minimum clinically important difference measure? A reconsideration of its clinical value in evaluating efficacy of lumbar fusion surgery. Clin J Pain. 2012;28:387–397.
6.
Man-Son-HingMLaupacisARourkeO’. Determination of the clinical importance of study results. J Gen Intern Med. 2002;17:469–476.
7.
BarrettBBrownDMundtMBrownR. Sufficiently important difference: expanding the framework of clinical significance. Med Decis Making. 2005;25:250–261.
8.
GuyattGOsobaDWuAW. Methods to explain the clinical significance of health status measures. Mayo Clin Proc. 2002;77:371–383.
9.
RingashJO’SullivanBBezjakARedelmeierD. Interpreting clinically significant changes in patient-reported outcomes. 2007. www.interscience.wiley.com. Accessed January 21, 2011.
10.
SprattKF. Patient-level minimal clinically important difference based on clinical judgment and minimally detectable measurement difference: a rationale for the SF-36 physical function scale in the SPORT intervertebral disc herniation cohort. Spine. 2009;34:1722–1731.
11.
GatchelRJLurieJDMayerTG. Minimal clinically important difference. Spine. 2010;35:1739–1743.
12.
JacobsonNSTruaxP. Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. J Consult Clin Psychol. 1991;59:12–19.
13.
JacobsonNSRobertsLJBernsSBMcGlincheyJB. Methods for defining and determining the clinical significance of treatment effects: description, application, and alternatives. J Consult Clin Psychol. 1999;67:300–307.
14.
KendallPCMarrs-GarciaANathSRSheldrickRC. Normative comparisons for the evaluation of clinical significance. J Consult Clin Psychol. 1999;67:285–299.
15.
CellaDBullingerMScottCBarofskyI;Clinical Significance Consensus Meeting Group. Groups vs individual approaches to understanding the clinical significance of differences or changes in quality of life. Mayo Clin Proc. 2002;77:384–392.
16.
van der HeijdeDLassereMEdmondsJKirwanJStrandVBoersM, for the OMERACT Imaging Task Force. Minimal clinically important difference in plain films in RA: group discussions, conclusions, and recommendations. OMERACT Imaging Task Force. J Rheumatol. 2001;28:914–917.
17.
WellsGLiTMaxwellLMacLeanRTugwellP. Determining the minimal clinically important difference in activity, fatigue, and sleep quality in patients with rheumatoid arthritis. J Rheumatol. 2007;34:280–289.
18.
BeatonDEBoersMWellsG. Many faces of the minimal clinically important difference (MCID): a literature review and directions for future research. Curr Opin Rheumatol. 2002;14:109–114.
19.
CopayAGSubachBRGlassmanSDPollyDWJrSchulerTC. Understanding the minimum clinically important difference: a review of concepts and methods. Spine J. 2007;7:541–546.
20.
StratfordPWBinkleyJMRiddleDLGuyattGH. Sensitivity to change of the Roland-Moriss Back Pain Questionnaire: part 1. Phys Ther. 1998;78:1186–1196.
21.
TubachFRavaudPBaronG. Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement. Ann Rheum Dis. 2005;64:29–33.
22.
StratfordPWBinkleyJSolomanPFinchEGillCMorelandJ. Defining the minimum level of detectable change for the Roland-Morris questionnaire. Phys Ther. 1996;76:359–368.
23.
EtonDTCellaDYostKJ. A combination of distribution- and anchor-based approaches determined minimally important differences (MIDs) for four endpoints in a breast cancer scale. J Clin Epidemiol. 2004;57:898–910.
24.
Food and Drug Administration. Guidance for industry. Patient-reported outcome measures: use in medical product development to support labeling claims: draft guidance. Health Qual Life Outcomes. 2006;4:79.
25.
HébertRSpiegelhalterDJBrayneC. Setting the minimal metrically detectable change on disability rating scales. Arch Phys Med Rehabil. 1997;78:1305–1308.
26.
EhrichEWDaviesGMWatsonDJBologneseJASeidenbergBCBellamyN. Minimal perceptible clinical improvement with the Western Ontario and McMaster Universities osteoarthritis index questionnaire and global assessments in patients with osteoarthritis. J Rheumatol. 2000;27:2635–2641.
27.
BarberBLSantanelloNCEpsteinRS. Impact of the global on patient perceivable change in an asthma specific QOL questionnaire. Qual Life Res. 1996;5:117–122.
28.
AngstFAeschlimannAStuckiG. Smallest detectable and minimal clinically important differences of rehabilitation intervention with their implications for required sample sizes using WOMAC and SF-36 quality of life measurement instruments in patients with osteoarthritis of the lower extremities. Arthritis Care Res. 2001;45:384–391.
29.
LassereMNvan der HeijdeDJohnsonKR. Foundations of the minimal clinically important difference for imaging. J Rheumatol. 2001;28:890–891.
30.
BruynesteynKvan der HeijdeDBoersM. Determination of the minimal clinically important difference in rheumatoid arthritis joint damage of the Sharp/van der Heijde and Larsen/Scott scoring methods by clinical experts and comparison with the smallest detectable difference. Arthritis Rheum. 2002;46:913–920.
31.
GuyattGMontoriVDevereauxPJSchünemannHBhandariM. Patients at the center: in our practice, and in our use of language. ACP J Club. 2004;140:A11–A12.
32.
Food and Drug Administration (FDA). Guidance for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Silver Spring, MD: FDA; December 2009.
33.
van TulderMMalmivaaraAHaydenJKoesB. Statistical significance versus clinical importance: trials on exercise therapy for chronic low back pain. Spine. 2007;32(16):1785–1790.
34.
MolnarFJMan-Son-HingMFergussonD. Systematic review of measures of clinical significance employed in randomized controlled trials of drugs for dementia. J Am Geriatr Soc. 2009;57(3):536–546.
BurnardBKernantWNFeinsteinAR. Indexes and boundaries for “quantitative significance” in statistical decisions. J Clin Epidemiol. 1990;43:1273–1284.
37.
RedelmeierDGuyattGGoldsteinR. On the debate over methods for estimating the clinically important difference. J Clin Epidemiol. 1996;49:1223–1224.
38.
WellsGATugwellPKraagGRBakerPRGrohJRedelmeierDA. Minimum important difference between patients with rheumatoid arthritis: the patient’s perspective. J Rheumatol. 1993;20:557–560.
39.
BellamyNCarrADougadosMSheaBWellsG. Towards a definition of “difference” in osteoarthritis. J Rheumatol. 2001;28:427–430.
40.
CrosbyRDKolotkinRLWilliamsGR. Defining clinically meaningful change in health-related quality of life. J Clin Epidemiol. 2003;56:395–407.
41.
RedelmeierDAGuyattGHGoldsteinRS. Assessing the minimal important difference in symptoms: a comparison of two techniques. J Clin Epidemiol. 1996;49:1215–1219.
42.
de VetHCTerweeCBOsteloRWBeckermanHKnolDLBouterLM. Minimal changes in health status questionnaires: distinction between minimally detectable change and minimally important change. Health Qual Life Outcomes. 2006;4:54.
43.
SloanJA. Assessing the minimally clinically significant difference: scientific considerations, challenges, and solutions. COPD. 2005;2:57–62.
44.
Project Management Institute. A Guide to the Project Management Body of Knowledge. 4th ed. http://www.pmi.org. Accessed December 2, 2010.
45.
European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on risk management systems for medicinal products for human use. 2005 updated in Volume 9a. http://www.ema.europa.eu. Accessed January 5, 2011.
46.
TimmermansSMauckA. The promises and pitfalls of evidence-based medicine. Health Aff. 2005;24:18–28.
47.
ElsteinAS. On the origins and development of evidence-based medicine and medical decision making. Inflamm Res. 2004;53:184–189.
