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Research Report - Final – Feb. 12, 2014

Design and Implementation of N-of-1 Trials: A User's Guide

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Table of Contents

Preface

Design and Implementation of N-of-1 Trials: A User’s Guide provides information on the design and implementation of n-of-1 trials (a.k.a. single-patient trials), a form of prospective research in which different treatments are evaluated in an individual patient over time. The apparent simplicity of this study design has caused it to be enthusiastically touted in some research fields and yet overlooked, underutilized, misunderstood, or erroneously implemented in other fields. With the advent of comparative effectiveness research and patient-centered outcomes research, there is a renewed interest in n-of-1 trials as an important research method for generating unique scientific evidence on patient health outcomes. A core aspect of this interest is that the n-of-1 approach may overcome some important limitations of other methodologies that involve larger samples of subjects. As a result, findings from n-of-1 trials may be especially useful in informing key health care decisions by patients and providers, particularly when combined with other scientific evidence. Likewise, the expansion of electronic health information technology into all areas of clinical care and the increasing recognition that new systems may also be deployed for research and quality improvement have further driven interest in conducting more n-of-1 trials as part of a learning health care system.1

AHRQ commissioned this User’s Guide as an informational resource to researchers, health care providers, patients, and other stakeholders to improve general understanding of n-of-1 trials and strengthen the quality of evidence that is generated when an n-of-1 trial is conducted. The overarching aim of this User’s Guide is to guide readers by identifying key decisions and tradeoffs in the design and implementation of n-of-1 trials, particularly when used for patient-centered outcomes research. Patient-centered outcomes research includes investigations of a wide range of research problems, particularly studying the outcomes, effectiveness, benefits, and harms of diagnostic tests, treatments, procedures, or health care services. This User’s Guide identifies key elements to consider in applying the n-of-1 trial methodology to patient-centered outcomes research, describes some of the important complexities of the method, and provides readers with checklists to summarize the main points.

The production of this document was modeled on similar AHRQ initiatives to publish methods guides on topics such as systematic reviews,2 medical tests,3 patient registries,4 and protocol development.5 For this User’s Guide, experts in the field of n-of-1 studies were identified and invited to participate in the development of the document as authors. Authors subsequently worked together to outline and write the document, which was subject to multiple internal and external independent reviews. All of the authors had the opportunity to discuss, review, and comment on the recommendations that are provided in this document, and these authors take responsibility for its scientific content.

Many individuals contributed to the production of this User’s Guide and are acknowledged for their contributions to the project. Foremost among these are the authors and editors of the Guide. Each author has substantial expertise and experience with conducting or using n-of-1 trials and worked in an extremely thoughtful, collegial, and highly efficient manner to produce the Guide as a scholarly endeavor intended to benefit others in the researcher, patient, and health care practice communities.

This User’s Guide would not have been possible without the leadership of Drs. Richard L. Kravitz and Naihua Duan, who served as editors of the Guide and authored chapters in it. Their scholarship in the field of n-of-1 trials, respected leadership, and hard work in all aspects of producing this document created an intellectually stimulating environment that inspired everyone who participated in the project. Likewise, Dr. Sebastian Schneeweiss, Dr. John D. Seeger, and Ms. Elizabeth Robinson Garry of Harvard Medical School and Brigham and Women’s Hospital and Dr. Parivash Nourjah of AHRQ provided valuable scientific insights, technical assistance, and organizational support to ensure the successful publication of this User’s Guide.

It is the hope of this entire team that researchers, clinicians, patients, and other stakeholders will find this User’s Guide to be a valuable new resource in conducting patient-centered outcomes research. In particular, it is anticipated that:

  • Investigators will find this document informative for planning and carrying out n-of-1 studies
  • Clinicians will find this document useful for identifying patients who may benefit from participation in n-of-1 studies and informing them of the pros and cons of participation
  • Patients who are active or prospective participants in n-of-1 studies will discover herein key concepts relevant to their participation and ultimate clinical decision; the document might be especially relevant to the emerging segment of patients who are interested in taking an active role in understanding their health outcomes and pathways to improvement
  • Institutional Review Board (IRB) members and grant review boards will find this document useful to inform them on the goals and methods of n-of-1 trials, particularly the ethical aspects
  • Health system administrators will find this document useful to inform them how to assess the value proposition for n-of-1 studies
  • Statisticians will find useful information on how to provide statistical support to n-of-1 programs and
  • Information technology (IT) directors and staff will find this document contains critical information on how to select hardware and software needed to support n-of-1 studies.

Undoubtedly, new approaches to n-of-1 trials will develop and the standards of practice will change or evolve over time, which will necessitate periodic updates of this User’s Guide. Nonetheless, this document brings together the current knowledge of experts to lay the groundwork for designing and implementing high-quality n-of-1 trials for patient-centered outcomes research. As with other documents by AHRQ, this User’s Guide is not intended to be prescriptive and is one of many resources that investigators and other stakeholders should consult when designing or appraising the results from an n-of-1 study. As new research methods, standards, and statistical tools develop, this User’s Guide will need to be updated periodically in order to be useful to users. As a result, comments from investigators, stakeholders, and other users are welcome so they can be considered for incorporation into future versions of this User’s Guide.


Jean Slutsky, P.A., M.S.P.H.
Director, Center for Outcomes and Evidence
Agency for Healthcare Research and Quality

Scott R. Smith, Ph.D.
Center for Outcomes and Evidence
Agency for Healthcare Research and Quality

Chapters in the User's Guide

Acknowledgments

The editors and the DEcIDE Methods Center N-of-1 Guidance Panel would like to acknowledge Sebastian Schneeweiss, John D. Seeger, and Elizabeth Robinson Garry of the Brigham and Women's Hospital DEcIDE Methods Center, and Parivash Nourjah and Scott R. Smith of AHRQ for their guidance and assistance throughout this project. We consider ourselves fortunate to have worked with such smart, energetic, and committed colleagues.

Special thanks are due to Jiang Li (Chapter 1), Salima Punja (Chapter 2), and Elizabeth Staton (Chapter 3) for their contributions to the respective chapters, providing invaluable support to the Panel.

We also would like to thank Kristen Greenlee (UC Davis) for invaluable administrative support and the staff of AHRQ's Office of Communications and Knowledge Transfer (OCKT) for assistance with the editorial process. Their work occurred quietly in the background but was essential to the success of this project.

Disclosures

This report was produced under contract to AHRQ by the Brigham and Women's Hospital DEcIDE (Developing Evidence to Inform Decisions about Effectiveness) Methods Center under Contract No. 290-2005-0016-I. The AHRQ Task Order Officer for this project was Parivash Nourjah, Ph.D. The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ or the U.S. Department of Health and Human Services. Therefore, no statement in this report should be construed as an official position of AHRQ or the U.S. Department of Health and Human Services.

The following investigators acknowledge financial support:

Dr. Naihua Duan was supported in part by NIH grants 1 R01 NR013938 and 7 P30 MH090322, Dr. Heather Kaplan is part of the investigator team that designed and developed the MyIBD platform, and this work was supported in part by Cincinnati Children's Hospital Medical Center. Dr. Richard Kravitz was supported in part by National Institute of Nursing Research Grant R01 NR01393801. Dr. Ida Sim is a co-investigator on an NINR R01 with Dr. Richard Kravitz (R01-NR13938) titled N-of-1 Trials Using mHealth in Chronic Pain. Dr. Sunita Vohra receives salary support as the recipient of an Alberta Innovates-Health Solutions Health Scholar Award.

Dr. Ian Eslick reports personal fees from Cincinnati Children's Hospital and Medical Center in support of the MyIBD system development. He owns an interest in the MyIBD technology through his company Vital Reactor LLC, which has plans to develop commercial offerings based on MyIBD. None of the other investigators have any affiliations or financial involvement that conflicts with the material presented in this report.

Copyright

Design and Implementation of N-of-1 Trials: A User’s Guide is copyrighted by the Agency for Healthcare Research and Quality (AHRQ). The product and its contents may be used and incorporated into other materials on the following three conditions: (1) the contents are not changed in any way (including covers and front matter), (2) no fee is charged by the reproducer of the product or its contents for its use, and (3) the user obtains permission from the copyright holders identified therein for materials noted as copyrighted by others.

The product may not be sold for profit or incorporated into any profit-making venture without the expressed written permission of AHRQ. Specifically:

  1. When the document is reprinted, it must be reprinted in its entirety without any changes.
  2. When parts of the document are used or quoted, the following citation should be used.

Citation

Kravitz RL, Duan N, eds, and the DEcIDE Methods Center N-of-1 Guidance Panel (Duan N, Eslick I, Gabler NB, Kaplan HC, Kravitz RL, Larson EB, Pace WD, Schmid CH, Sim I, Vohra S). Design and Implementation of N-of-1 Trials: A User’s Guide. AHRQ Publication No. 13(14)-EHC122-EF. Rockville, MD: Agency for Healthcare Research and Quality; January 2014. http://www.effectivehealthcare.ahrq.gov/N-1-Trials.cfm.

Suggested citations for the individual chapters can be found on their individual Web pages.

The DEcIDE Methods Center N-of-1 Guidance Panel

Naihua Duan
Division of Biostatistics
Department of Psychiatry
Columbia University

Ian Eslick
MIT Media Laboratory

Nicole B. Gabler
Center for Clinical Epidemiology and Biostatistics
Perelman School of Medicine
University of Pennsylvania

Heather C. Kaplan
Perinatal Institute and James M. Anderson Center for Health Systems Excellence,
Cincinnati Children’s Hospital Medical Center
Department of Pediatrics, University of Cincinnati College of Medicine

Richard L. Kravitz
Department of Internal Medicine
University of California, Davis

Eric B. Larson
Group Health Research Institute

Wilson D. Pace
Department of Family Medicine
University of Colorado Denver

Christopher H. Schmid
Center for Evidence-Based Medicine and
Department of Biostatistics
Brown University

Ida Sim
Division of General Medicine
University of California San Francisco

Sunita Vohra
Department of Pediatrics
University of Alberta

References

  1. Institute of Medicine. Best Care at Lower Cost: The Path to Continuously Learning Healthcare in America. Washington, DC: National Academy Press; 2012
  2. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(12)-EHC063-EF. Rockville, MD: Agency for Healthcare Research and Quality. April 2012. Chapters are available at http://www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displayproduct&mp=1&productID=318.
  3. Chang SM, Matchar DB, Smetana GW, et al., editors. Methods Guide for Medical Test Reviews. AHRQ Publication No. 12-EC017. Rockville, MD: Agency for Healthcare Research and Quality; June 2012.
  4. Gliklich RE, Dreyer NA, eds. Registries for Evaluating Patient Outcomes: A User’s Guide. 2nd ed. (Prepared by Outcome DEcIDE Center [Outcome Sciences, Inc. d/b/a Outcome] under Contract No. HHSA29020050035I TO3.) AHRQ Publication No.10-EHC049. Rockville, MD: Agency for Healthcare Research and Quality. September 2010.
  5. Velentgas P, Dreyer NA, Nourjah P, Smith SR, Torchia MM, eds. Developing a Protocol for Observational Comparative Effectiveness Research: A User’s Guide. AHRQ Publication No. 12(13)-EHC099. Rockville, MD: Agency for Healthcare Research and Quality; January 2013. www.effectivehealthcare.ahrq.gov/Methods-OCER.cfm.
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