[Skip to Content]
[Skip to Content Landing]

Guidelines for Reporting Outcomes in Trial ProtocolsThe SPIRIT-Outcomes 2022 Extension

To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  What outcome-specific information should be included in a clinical trial protocol?

Findings  Using an evidence-based and international consensus–based approach that applied methods from the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework, 9 outcome-specific reporting items to be addressed in clinical trial protocols were identified.

Meaning  Inclusion of these items in clinical trial protocols may enhance trial utility, replicability, and transparency and may help limit selective nonreporting of trial results.


Importance  Complete information in a trial protocol regarding study outcomes is crucial for obtaining regulatory approvals, ensuring standardized trial conduct, reducing research waste, and providing transparency of methods to facilitate trial replication, critical appraisal, accurate reporting and interpretation of trial results, and knowledge synthesis. However, recommendations on what outcome-specific information should be included are diverse and inconsistent. To improve reporting practices promoting transparent and reproducible outcome selection, assessment, and analysis, a need for specific and harmonized guidance as to what outcome-specific information should be addressed in clinical trial protocols exists.

Objective  To develop harmonized, evidence- and consensus-based standards for describing outcomes in clinical trial protocols through integration with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 statement.

Evidence Review  Using the Enhancing the Quality and Transparency of Health Research (EQUATOR) methodological framework, the SPIRIT-Outcomes 2022 extension of the SPIRIT 2013 statement was developed by (1) generation and evaluation of candidate outcome reporting items via consultation with experts and a scoping review of existing guidance for reporting trial outcomes (published within the 10 years prior to March 19, 2018) identified through expert solicitation, electronic database searches of MEDLINE and the Cochrane Methodology Register, gray literature searches, and reference list searches; (2) a 3-round international Delphi voting process (November 2018-February 2019) completed by 124 panelists from 22 countries to rate and identify additional items; and (3) an in-person consensus meeting (April 9-10, 2019) attended by 25 panelists to identify essential items for outcome-specific reporting to be addressed in clinical trial protocols.

Findings  The scoping review and consultation with experts identified 108 recommendations relevant to outcome-specific reporting to be addressed in trial protocols, the majority (72%) of which were not included in the SPIRIT 2013 statement. All recommendations were consolidated into 56 items for Delphi voting; after the Delphi survey process, 19 items met criteria for further evaluation at the consensus meeting and possible inclusion in the SPIRIT-Outcomes 2022 extension. The discussions during and after the consensus meeting yielded 9 items that elaborate on the SPIRIT 2013 statement checklist items and are related to completely defining and justifying the choice of primary, secondary, and other outcomes (SPIRIT 2013 statement checklist item 12) prospectively in the trial protocol, defining and justifying the target difference between treatment groups for the primary outcome used in the sample size calculations (SPIRIT 2013 statement checklist item 14), describing the responsiveness of the study instruments used to assess the outcome and providing details on the outcome assessors (SPIRIT 2013 statement checklist item 18a), and describing any planned methods to account for multiplicity relating to the analyses or interpretation of the results (SPIRIT 2013 statement checklist item 20a).

Conclusions and Relevance  This SPIRIT-Outcomes 2022 extension of the SPIRIT 2013 statement provides 9 outcome-specific items that should be addressed in all trial protocols and may help increase trial utility, replicability, and transparency and may minimize the risk of selective nonreporting of trial results.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Nancy J. Butcher, PhD, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay St, Toronto, ON M5G 0A4, Canada (nancy.butcher@sickkids.ca).

Accepted for Publication: October 28, 2022.

Published Online: December 13, 2022. doi:10.1001/jama.2022.21243

Author Contributions: Dr Butcher had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Butcher.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Monsour.

Obtained funding: Offringa.

Administrative, technical, or material support: Monsour, Mew, Baba.

Supervision: Butcher, Offringa.

Conflict of Interest Disclosures: Dr Butcher reported receiving grant funding from CHILD-BRIGHT and the Cundill Centre for Child and Youth Depression at the Centre for Addiction and Mental Health (CAMH) and receiving personal fees from Nobias Therapeutics. Ms Mew reported receiving salary support through a Canadian Institutes of Health Research doctoral foreign study award. Dr Grimshaw reported holding a Canada research chair in health knowledge transfer and uptake and receiving funding from the Ontario Ministry of Health, the Ottawa Hospital Academic Medical Organization, the National Institute of Health Research, and the National Health and Medical Research Council. Dr Kelly reported receiving funding from the Canadian Cancer Society, Research Manitoba, the Children’s Hospital Research Institute of Manitoba, Mitacs, and the SickKids Foundation. Dr Askie reported being a co-convenor of the Cochrane Prospective Meta-Analysis Methods Group. Dr Farid-Kapadia reported currently being an employee of Hoffmann La-Roche and holding shares in the company. Dr Williamson reported chairing the COMET initiative management group. Dr Szatmari reported receiving funding from the CAMH. Dr Tugwell reported co-chairing the OMERACT executive committee; receiving personal fees from the Reformulary Group, UCB Pharma GmbH, Parexel International, PRA Health Sciences, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, Roche, Genzyme, Sanofi, Horizon Therapeutics, Merck, Novartis, Pfizer, PPD Inc, QuintilesIMS (now IQVIA), Regeneron Pharmaceuticals, Savient Pharmaceuticals, Takeda Pharmaceutical Co Ltd, Vertex Pharmaceuticals, Forest Pharmaceuticals, and Bioiberica; serving on data and safety monitoring boards for UCB Pharma GmbH, Parexel International, and PRA Health Sciences; and receiving unrestricted educational grants from the American College of Rheumatology and the European League of Rheumatology. Dr Monga reported receiving funding from the Cundill Centre for Child and Youth Depression at CAMH; receiving royalties from Springer for Assessing and Treating Anxiety Disorders in Young Children; and receiving personal fees from the TD Bank Financial Group for serving as a chair in child and adolescent psychiatry. Dr Ungar reported being supported by the Canada research chair in economic evaluation and technology assessment in child health. No other disclosures were reported.

Funding/Support: This work, project 148953, received financial support from the Canadian Institutes of Health Research.

Role of the Funder/Sponsor: The Canadian Institutes of Health Research had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimers: Dr Golub is Executive Deputy Editor of JAMA, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance. This article reflects the views of the authors, the Delphi panelists, and the consensus meeting panelists and may not represent the views of the broader stakeholder groups, the authors’ institutions, or other affiliations.

Additional Contributions: We gratefully acknowledge the additional contributions made by the project core team, the executive team, the operations team, the Delphi panelists, and the international consensus meeting panelists (eAppendix 3 in the Supplement). We thank Andrea Chiaramida, BA, for administrative project support and Lisa Stallwood, MSc, for administrative manuscript support (both with The Hospital for Sick Children). We thank Petros Pechlivanoglou, PhD, and Robin Hayeems, PhD, for piloting and providing feedback on the format of the Delphi survey (both with The Hospital for Sick Children). None of these individuals received compensation for their role in the study.

Additional Information: The project materials and data are publicly available on the Open Science Framework at https://osf.io/arwy8/.

Chan  AW , Tetzlaff  JM , Altman  DG ,  et al.  SPIRIT 2013 statement: defining standard protocol items for clinical trials.   Ann Intern Med. 2013;158(3):200-207. doi:10.7326/0003-4819-158-3-201302050-00583PubMedGoogle ScholarCrossref
Chan  AW , Tetzlaff  JM , Gøtzsche  PC ,  et al.  SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials.   BMJ. 2013;346:e7586. doi:10.1136/bmj.e7586PubMedGoogle ScholarCrossref
SPIRIT. SPIRIT statement website. Accessed April 13, 2021. https://www.spirit-statement.org/
International Conference on Harmonisation. E6: good clinical practice. Accessed November 22, 2022. https://www.ich.org/page/efficacy-guidelines
Calvert  M , Kyte  D , Mercieca-Bebber  R ,  et al; the SPIRIT-PRO Group.  Guidelines for inclusion of patient-reported outcomes in clinical trial protocols: the SPIRIT-PRO extension.   JAMA. 2018;319(5):483-494. doi:10.1001/jama.2017.21903PubMedGoogle ScholarCrossref
Butcher  NJ , Mew  EJ , Monsour  A , Chan  A-W , Moher  D , Offringa  M .  Outcome reporting recommendations for clinical trial protocols and reports: a scoping review.   Trials. 2020;21(1):620. doi:10.1186/s13063-020-04440-wGoogle ScholarCrossref
Page  MJ , McKenzie  JE , Forbes  A .  Many scenarios exist for selective inclusion and reporting of results in randomized trials and systematic reviews.   J Clin Epidemiol. 2013;66(5):524-537. doi:10.1016/j.jclinepi.2012.10.010PubMedGoogle ScholarCrossref
Yordanov  Y , Dechartres  A , Atal  I ,  et al.  Avoidable waste of research related to outcome planning and reporting in clinical trials.   BMC Med. 2018;16(1):87. doi:10.1186/s12916-018-1083-xPubMedGoogle ScholarCrossref
Chan  AW , Pello  A , Kitchen  J ,  et al.  Association of trial registration with reporting of primary outcomes in protocols and publications.   JAMA. 2017;318(17):1709-1711. doi:10.1001/jama.2017.13001PubMedGoogle ScholarCrossref
Kampman  JM , Sperna Weiland  NH , Hollmann  MW , Repping  S , Hermanides  J .  High incidence of outcome switching observed in follow-up publications of randomized controlled trials: meta-research study.   J Clin Epidemiol. 2021;137:236-240. doi:10.1016/j.jclinepi.2021.05.003PubMedGoogle ScholarCrossref
Monsour  A , Mew  EJ , Patel  S ,  et al.  Primary outcome reporting in adolescent depression clinical trials needs standardization.   BMC Med Res Methodol. 2020;20(1):129. doi:10.1186/s12874-020-01019-6PubMedGoogle ScholarCrossref
Glasziou  P , Altman  DG , Bossuyt  P ,  et al.  Reducing waste from incomplete or unusable reports of biomedical research.   Lancet. 2014;383(9913):267-276. doi:10.1016/S0140-6736(13)62228-XPubMedGoogle ScholarCrossref
Mayo-Wilson  E , Fusco  N , Li  T , Hong  H , Canner  JK , Dickersin  K ; MUDS investigators.  Multiple outcomes and analyses in clinical trials create challenges for interpretation and research synthesis.   J Clin Epidemiol. 2017;86:39-50. doi:10.1016/j.jclinepi.2017.05.007PubMedGoogle ScholarCrossref
Butcher  NJ , Monsour  A , Mew  EJ ,  et al.  Improving outcome reporting in clinical trial reports and protocols: study protocol for the Instrument for reporting Planned Endpoints in Clinical Trials (InsPECT).   Trials. 2019;20(1):161. doi:10.1186/s13063-019-3248-0PubMedGoogle ScholarCrossref
Moher  D , Schulz  KF , Simera  I , Altman  DG .  Guidance for developers of health research reporting guidelines.   PLoS Med. 2010;7(2):e1000217. doi:10.1371/journal.pmed.1000217PubMedGoogle ScholarCrossref
Gamble  C , Krishan  A , Stocken  D ,  et al.  Guidelines for the content of statistical analysis plans in clinical trials.   JAMA. 2017;318(23):2337-2343. doi:10.1001/jama.2017.18556PubMedGoogle ScholarCrossref
Butcher  NJ , Monsour  A , Mew  EJ ,  et al.  Guidelines for reporting outcomes in trial reports: the CONSORT-Outcomes 2022 extension.   JAMA. 2022;328(22):2252-2264. doi:10.1001/jama.2022.21022Google Scholar
Butcher  NJ , Mew  EJ , Saeed  L ,  et al.  Guidance for reporting outcomes in clinical trials: scoping review protocol.   BMJ Open. 2019;9(2):e023001. PubMedGoogle Scholar
Hoffmann  TC , Glasziou  PP , Boutron  I ,  et al.  Better reporting of interventions: Template for Intervention Description and Replication (TIDieR) checklist and guide.   BMJ. 2014;348:g1687. doi:10.1136/bmj.g1687PubMedGoogle ScholarCrossref
Ferreira-González  I , Permanyer-Miralda  G , Busse  JW ,  et al.  Methodologic discussions for using and interpreting composite endpoints are limited, but still identify major concerns.   J Clin Epidemiol. 2007;60(7):651-657. doi:10.1016/j.jclinepi.2006.10.020PubMedGoogle ScholarCrossref
Cordoba  G , Schwartz  L , Woloshin  S , Bae  H , Gøtzsche  PC .  Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review.   BMJ. 2010;341:c3920. doi:10.1136/bmj.c3920PubMedGoogle ScholarCrossref
Moher  D , Hopewell  S , Schulz  KF ,  et al.  CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials.   BMJ. 2010;340:c869. doi:10.1136/bmj.c869PubMedGoogle ScholarCrossref
Schulz  KF , Altman  DG , Moher  D ; CONSORT Group.  CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials.   BMC Med. 2010;8(1):18. doi:10.1186/1741-7015-8-18PubMedGoogle ScholarCrossref
Mokkink  LB , Terwee  CB , Patrick  DL ,  et al. COSMIN checklist manual. Accessed February 28, 2022. https://fac.ksu.edu.sa/sites/default/files/cosmin_checklist_manual_v9.pdf
de Vet  HCW , Terwee  CB , Mokkink  LB , Knol  DL .  Measurement in Medicine. Cambridge University Press; 2011. doi:10.1017/CBO9780511996214
Cook  JA , Hislop  J , Adewuyi  TE ,  et al.  Assessing methods to specify the target difference for a randomised controlled trial: DELTA (Difference ELicitation in TriAls) review.   Health Technol Assess. 2014;18(28). doi:10.3310/hta18280Google ScholarCrossref
Johnston  BC , Ebrahim  S , Carrasco-Labra  A ,  et al.  Minimally important difference estimates and methods: a protocol.   BMJ Open. 2015;5(10):e007953. doi:10.1136/bmjopen-2015-007953PubMedGoogle ScholarCrossref
de Vet  HC , Beckerman  H , Terwee  CB , Terluin  B , Bouter  LM .  Definition of clinical differences.   J Rheumatol. 2006;33(2):434-435.PubMedGoogle Scholar
de Vet  HC , Terwee  CB .  The minimal detectable change should not replace the minimal important difference.   J Clin Epidemiol. 2010;63(7):804-805. doi:10.1016/j.jclinepi.2009.12.015PubMedGoogle ScholarCrossref
COSMIN. Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) is an initiative of an international multidisciplinary team of researchers. Accessed April 13, 2021. https://www.cosmin.nl/
Hopewell  S , Dutton  S , Yu  LM , Chan  AW , Altman  DG .  The quality of reports of randomised trials in 2000 and 2006: comparative study of articles indexed in PubMed.   BMJ. 2010;340:c723. doi:10.1136/bmj.c723PubMedGoogle ScholarCrossref
Mokkink  L , Terwee  C , de Vet  H .  Key concepts in clinical epidemiology: responsiveness, the longitudinal aspect of validity.   J Clin Epidemiol. 2021;140:159-162. doi:10.1016/j.jclinepi.2021.06.002PubMedGoogle ScholarCrossref
Mokkink  LB , Terwee  CB , Patrick  DL ,  et al.  The COSMIN study reached international consensus on taxonomy, terminology, and definitions of measurement properties for health-related patient-reported outcomes.   J Clin Epidemiol. 2010;63(7):737-745. doi:10.1016/j.jclinepi.2010.02.006PubMedGoogle ScholarCrossref
Ferreira  ML , Herbert  RD , Ferreira  PH ,  et al.  A critical review of methods used to determine the smallest worthwhile effect of interventions for low back pain.   J Clin Epidemiol. 2012;65(3):253-261. doi:10.1016/j.jclinepi.2011.06.018PubMedGoogle ScholarCrossref
Prinsen  CAC , Mokkink  LB , Bouter  LM ,  et al.  COSMIN guideline for systematic reviews of patient-reported outcome measures.   Qual Life Res. 2018;27(5):1147-1157. doi:10.1007/s11136-018-1798-3PubMedGoogle ScholarCrossref
Cook  JA , Julious  SA , Sones  W ,  et al.  Practical help for specifying the target difference in sample size calculations for RCTs: the DELTA2 five-stage study, including a workshop.   Health Technol Assess. 2019;23(60):1-88. doi:10.3310/hta23600PubMedGoogle ScholarCrossref
Cook  JA , Julious  SA , Sones  W ,  et al.  DELTA2 guidance on choosing the target difference and undertaking and reporting the sample size calculation for a randomised controlled trial.   BMJ. 2018;363:k3750-k3750. doi:10.1136/bmj.k3750PubMedGoogle ScholarCrossref
Zarin  DA , Tse  T , Williams  RJ , Califf  RM , Ide  NC .  The ClinicalTrials.gov results database–update and key issues.   N Engl J Med. 2011;364(9):852-860. doi:10.1056/NEJMsa1012065PubMedGoogle ScholarCrossref
OMERACT. OMERACT domain resources. Accessed May 19, 2022. https://omeract.org/domain-selection/
Williamson  P , Altman  D , Blazeby  J , Clarke  M , Gargon  E .  Driving up the quality and relevance of research through the use of agreed core outcomes.   J Health Serv Res Policy. 2012;17(1):1-2. doi:10.1258/jhsrp.2011.011131PubMedGoogle ScholarCrossref
Gargon  E , Gorst  SL , Williamson  PR .  Choosing important health outcomes for comparative effectiveness research: 5th annual update to a systematic review of core outcome sets for research.   PLoS One. 2019;14(12):e0225980. doi:10.1371/journal.pone.0225980PubMedGoogle ScholarCrossref
Williamson  PR , Altman  DG , Bagley  H ,  et al.  The COMET Handbook: version 1.0.   Trials. 2017;18(suppl 3):280. doi:10.1186/s13063-017-1978-4PubMedGoogle ScholarCrossref
Kirkham  JJ , Davis  K , Altman  DG ,  et al.  Core Outcome Set-STAndards for Development: the COS-STAD recommendations.   PLoS Med. 2017;14(11):e1002447. doi:10.1371/journal.pmed.1002447PubMedGoogle ScholarCrossref
Gorst  SL , Prinsen  CAC , Salcher-Konrad  M , Matvienko-Sikar  K , Williamson  PR , Terwee  CB .  Methods used in the selection of instruments for outcomes included in core outcome sets have improved since the publication of the COSMIN/COMET guideline.   J Clin Epidemiol. 2020;125:64-75. doi:10.1016/j.jclinepi.2020.05.021PubMedGoogle ScholarCrossref
Collister  D , Bangdiwala  S , Walsh  M ,  et al.  Patient reported outcome measures in clinical trials should be initially analyzed as continuous outcomes for statistical significance and responder analyses should be reserved as secondary analyses.   J Clin Epidemiol. 2021;134:95-102. doi:10.1016/j.jclinepi.2021.01.026PubMedGoogle ScholarCrossref
Kravitz  RL , Duan  N ; DEcIDE Methods Center N-of-1 Guidance Panel, eds.  Design and Implementation of N-of-1 Trials: A User’s Guide. Agency for Healthcare Research and Quality; 2014.
Carrasco-Labra  A , Devji  T , Qasim  A ,  et al.  Minimal important difference estimates for patient-reported outcomes: a systematic survey.   J Clin Epidemiol. 2021;133:61-71. doi:10.1016/j.jclinepi.2020.11.024PubMedGoogle ScholarCrossref
Woaye-Hune  P , Hardouin  JB , Lehur  PA , Meurette  G , Vanier  A .  Practical issues encountered while determining minimal clinically important difference in patient-reported outcomes.   Health Qual Life Outcomes. 2020;18(1):156. doi:10.1186/s12955-020-01398-wPubMedGoogle ScholarCrossref
Mouelhi  Y , Jouve  E , Castelli  C , Gentile  S .  How is the minimal clinically important difference established in health-related quality of life instruments? review of anchors and methods.   Health Qual Life Outcomes. 2020;18(1):136. doi:10.1186/s12955-020-01344-wPubMedGoogle ScholarCrossref
Devji  T , Carrasco-Labra  A , Guyatt  G .  Mind the methods of determining minimal important differences: three critical issues to consider.   Evid Based Ment Health. 2021;24(2):77-81. doi:10.1136/ebmental-2020-300164PubMedGoogle ScholarCrossref
Devji  T , Carrasco-Labra  A , Qasim  A ,  et al.  Evaluating the credibility of anchor based estimates of minimal important differences for patient reported outcomes: instrument development and reliability study.   BMJ. 2020;369:m1714. doi:10.1136/bmj.m1714PubMedGoogle ScholarCrossref
Mayo-Wilson  E , Fusco  N , Li  T , Hong  H , Canner  JK , Dickersin  K ; MUDS investigators.  Harms are assessed inconsistently and reported inadequately part 1: systematic adverse events.   J Clin Epidemiol. 2019;113:20-27. doi:10.1016/j.jclinepi.2019.04.022PubMedGoogle ScholarCrossref
International Conference on Harmonisation. Harmonised Tripartite Guideline: statistical principles for clinical trials E9: current step 4 version. Accessed November 19, 2022. https://database.ich.org/sites/default/files/E9_Guideline.pdf
Mayo-Wilson  E , Li  T , Fusco  N ,  et al.  Cherry-picking by trialists and meta-analysts can drive conclusions about intervention efficacy.   J Clin Epidemiol. 2017;91:95-110. doi:10.1016/j.jclinepi.2017.07.014PubMedGoogle ScholarCrossref
Butcher  NJ , Mew  E , Monsour  A ,  et al. A scoping review of outcome-reporting recommendations for clinical trial protocols and reports. Accessed April 26, 2022. https://osf.io/6f5x7/
Freemantle  N , Calvert  M .  Weighing the pros and cons for composite outcomes in clinical trials.   J Clin Epidemiol. 2007;60(7):658-659. doi:10.1016/j.jclinepi.2006.10.024Google ScholarCrossref
Hankins  M .  How discriminating are discriminative instruments?   Health Qual Life Outcomes. 2008;6(1):36. doi:10.1186/1477-7525-6-36PubMedGoogle ScholarCrossref
Mokkink  LB , Prinsen  CAC , Patrick  DL ,  et al. COSMIN methodology for systematic reviews of Patient-Reported Outcome Measures (PROMS): user manual: version 1.0. Published 2018. Accessed November 14, 2022. https://cosmin.nl/wp-content/uploads/COSMIN-syst-review-for-PROMs-manual_version-1_feb-2018.pdf
De Los Reyes  A , Augenstein  TM , Wang  M ,  et al.  The validity of the multi-informant approach to assessing child and adolescent mental health.   Psychol Bull. 2015;141(4):858-900. doi:10.1037/a0038498PubMedGoogle ScholarCrossref
Cohen  SB , Strand  V , Aguilar  D , Ofman  JJ .  Patient- versus physician-reported outcomes in rheumatoid arthritis patients treated with recombinant interleukin-1 receptor antagonist (anakinra) therapy.   Rheumatology (Oxford). 2004;43(6):704-711. doi:10.1093/rheumatology/keh152PubMedGoogle ScholarCrossref
Basch  E , Jia  X , Heller  G ,  et al.  Adverse symptom event reporting by patients vs clinicians: relationships with clinical outcomes.   J Natl Cancer Inst. 2009;101(23):1624-1632. doi:10.1093/jnci/djp386PubMedGoogle ScholarCrossref
FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) resource. Accessed May 19, 2022. https://www.ncbi.nlm.nih.gov/books/NBK338448/
Li  G , Taljaard  M , Van den Heuvel  ER ,  et al.  An introduction to multiplicity issues in clinical trials: the what, why, when and how.   Int J Epidemiol. 2017;46(2):746-755. doi:10.1093/ije/dyw320PubMedGoogle ScholarCrossref
European Medicines Agency. Guideline on multiplicity issues in clinical trials. Accessed February 8, 2022. https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-multiplicity-issues-clinical-trials_en.pdf
REDCap Research. SPIRIT-Outcomes feedback form. Accessed February 28, 2022. https://redcapexternal.research.sickkids.ca/surveys/?s=7N847LCEJF
Qureshi  R , Mayo-Wilson  E , Li  T .  Harms in systematic reviews paper 1: an introduction to research on harms.   J Clin Epidemiol. 2022;143:186-196. doi:10.1016/j.jclinepi.2021.10.023PubMedGoogle ScholarCrossref
Howick  J , Webster  R , Knottnerus  JA , Moher  D .  Do overly complex reporting guidelines remove the focus from good clinical trials?   BMJ. 2021;374:n1793. doi:10.1136/bmj.n1793PubMedGoogle ScholarCrossref
AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity


My Saved Searches

You currently have no searches saved.


My Saved Courses

You currently have no courses saved.