Osteoarthritis and Cartilage 23 (2015) 671e673
Editorial
Osteoarthritis Research Society International Initiative on Recommendations for Conducting Clinical Trials in Osteoarthritis: Overview
Background and remit In 1995, the Osteoarthritis Research Society (later renamed the Osteoarthritis (OA) Research Society International [OARSI]) conducted a workshop on issues related to the design of clinical trials in knee and hip OA. Individuals from academia, industry, and government regulatory agencies participated in the workshop. A manuscript describing the process and results was published in Osteoarthritis and Cartilage in 19961. Subsequently, Maheu and colleagues published a similar set of recommendations for conducting clinical trials in hand OA2. In 2012, the Board of Directors of the OARSI initiated a process to update the recommendations for conducting clinical trials in knee, hip, and hand OA. Much had happened since the initial recommendations, including advances in magnetic resonance and other imaging techniques, development and testing of local and systemic biomarkers of joint metabolism, and evolution of scientific rigor to address methodologic issues involved in the conduct of surgical trials, non-pharmacologic trials, implementation trials, and primary prevention trials. The goal of the OARSI Initiative on Recommendations for Conducting Clinical Trials in Osteoarthritis was (1) to gain consensus regarding clinical trials methodology in OA using currently accepted processes, (2) to develop recommendations with associated rationale for various approaches to key issues, and (3) to propose strategies for an ongoing research agenda. Administrative structure and procedures The administrative structure consisted of a Chair and co-Chair, a Steering Committee, and a series of Working Groups, each composed of a Chair, co-Chair and Members. Joanne M Jordan, MD MPH of the University of North Carolina at Chapel Hill in the United States was appointed Chair of the Initiative, and Yves Henrotin, PhD of University of Liege, Belgium was appointed co-Chair. The Steering Committee consisted of the Chair and co-Chair and four additional individuals with experience in clinical trial design and regulatory issues. These included Marc C Hochberg, MD MPH of the University of Maryland School of Medicine in Baltimore, Maryland; Timothy McAlindon, MD MPH of Tufts University School of Medicine in Boston, Massachusetts; Lee Simon, MD, former Director of the Division of Analgesic, Anti-inflammatory and Ophthalmologic Drug Products within the Center for Drug Evaluation and
Research of the Food and Drug Administration; and Kim Bennell, PhD of the University of Melbourne, Australia. Working groups were formed to deal with different aspects of the task at hand, and chairs and co-chairs invited and appointed (Table I). Broad international representation from academia, industry, and government was sought to constitute the members of the Working Groups. In all, approximately 100 individuals with expertise in different aspects of OA participated in the Initiative. All individuals completed a conflict of interest statement per OARSI policy for such initiatives (see below). The Steering Committee devised an overall procedure for the respective Working Groups to follow, with consensus procedures varying somewhat among the Working Groups, depending upon the breadth of the topic and the presence and extent of controversy in the scientific literature. All groups thoroughly reviewed the literature, some performing systematic reviews where indicated. Where appropriate, voting by the members of a Working Group on specific recommendations occurred; in accordance with procedures from the Ethics Committee of the OARSI, those individuals with a significant conflict of interest or owning companies with a stake in the outcome of a specific recommendation, were not permitted to vote. Strong recommendations regarding use or non-use of a specific procedure or technique were made in the face of overwhelming evidence. More common, however, dogmatic
Table I Working Groups for Osteoarthritis Research Society International Initiative on Recommendations for Conducting Clinical Trials in Osteoarthritis Working Group
Chair/co-Chair
Statistical and design issues Biomarkers Imaging: Knee, hip, hand KNEE OA: structure and symptoms
Elena Losina/Jonas Ranstam Virginia Byers Kraus David Hunter/Garry Gold Timothy McAlindon/Thomas Schnitzer Nancy Lane/Marc Hochberg Margreet Kloppenburg/Emmanuel Maheu Stephen Messier
HIP OA: structure and symptoms HAND OA: structure and symptoms Non-pharmacologic trials: diet and exercise Surgical Trials Rehabilitation Trials Joint injury prevention Implementation Trials
http://dx.doi.org/10.1016/j.joca.2015.03.016 1063-4584/© 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Jeffrey Katz G Kelley Fitzgerald Carolyn Emery Kelli Allen
672
Editorial / Osteoarthritis and Cartilage 23 (2015) 671e673
recommendations were deliberately avoided, in acknowledgment of the rapidity with which scientific and technical advances occur. The Steering Committee and chairs/co-chairs of each Working Group met in-person at the 2013 and 2014 OARSI World Congresses to review procedures and progress. Additionally, working groups communicated in-person, by telephone, and by email. Each Working Group submitted a detailed work plan to the Steering Committee for approval, including plans for literature review, consensus procedures, and a research agenda. The working chairs had the opportunity to consult the Steering Committee if any major disagreement occurred in their working groups. The Working Group on Statistical and Design Issues and the Imaging Working Group served as sources of reference for the other groups. Posting of critical appraisal manuscripts to a secure file-sharing website allowed direct input by Working Group Committee members and the Steering Committee. All manuscripts underwent review by the Steering Committee before submission to the journal, after which they underwent further peer review per the journal's usual procedure.
Knee, hip and hand structure- and symptom-modification trials The next three articles are devoted to symptom- and structuremodification trial issues in the knee, hip, and hand, respectively. McAlindon and colleagues propose 25 consensus-driven recommendations regarding randomization, blocking and stratification, blinding, enhancing accuracy of patient-reported outcomes, describing patient-reported and physical performance measures, structural outcomes measures, biochemical biomarkers, and reporting recommendations. Lane and Hochberg and the Working Group on hip OA describe advances in radiographic and MRI assessment of hip OA for structure-modification trials, as well as issues for symptom-modification trials; their paper also reviews recent results on local and systemic biomarkers of joint metabolism in hip OA. Kloppenburg and Maheu and colleagues provide a detailed and updated review of recent developments in the assessment and evaluation of hand OA. These inform the description of core outcome measurement sets for trials in hand OA, methods and instruments to be used to assess symptoms and structure, and a robust research agenda to move the field forward.
Organization of this issue Non-pharmacologic trials This issue is divided into two parts. The first part, composed of six articles, deals with topics applicable to multiple types of OA clinical trials: statistical design and reporting issues; regulatory procedures; biomarker qualification procedures; and musculoskeletal imaging relevant to OA of the knee, hip, and hand. The second part deals with specific types of OA trials, including separate papers on OA of the knee, hip, and hand; non-pharmacologic trials, specifically, diet and exercise trials, rehabilitation trials, and injury prevention trials; surgical trials; and implementation trials. Analytic, reporting, and regulatory issues This special issue opens with an overview by Losina and colleagues of key analytic, design, and reporting issues involved in the conduct of pharmacologic and non-pharmacologic OA trials. Special attention is given to approaches to missing data, economic analyses, and requirements for reporting. An abbreviated look at regulatory requirements and procedures for product approval of pharmaceuticals and devices follows. Advances in understanding of the pathologic processes involved in OA initiation and progression have allowed soluble biomarker development to be considered as potential critical components of an OA clinical trial. Kraus and colleagues describe technical requirements for soluble biomarker qualification and validation. Importantly, this article does not recommend specific biomarkers to be used in clinical trials, but sets the stage for future results from the OA Biomarkers Initiative and others that 1 day may allow early identification of OA risk, selection of participants into trials, and monitoring of drug response and safety with soluble biomarkers. Imaging Three papers on imaging for OA of the knee, hip, and hand summarize radiographic, magnetic resonance imaging, and ultrasound techniques and requirements for use in structure-modification trials. These papers address issues such as detailed acquisition methods and techniques; commonly encountered difficulties and solutions; quality assurance and control procedures; measurement methods and performance; recommendations for trials; and research recommendations. Recognition of the rapid pace of technological innovation is crucial in these recommendations and is reflected in the consensus voting on critical issues.
Messier and the Working Group on Diet and Exercise interventions provide a primer for design of non-pharmacologic trials and specific design issues unique to these types of trials, with examples from the published literature. Surgical trials have several unique challenges that are expertly reviewed by Katz and members of the Surgical Trials Working Group. Rehabilitation trials also have specific challenges to scientific integrity inherent in their design; these are outlined by Fitzgerald and colleagues. Finally, an example of primary prevention of OA is presented by Emery and colleagues in their overview of joint injury prevention trials, and Allen and colleagues describe challenges associated with implementation trials. Summary This special issue of Osteoarthritis and Cartilage represents the combined expertise and work of many individual experts from academia, industry, and regulatory agencies to inform the research community about advances in clinical trial design and execution and support key recommendations for structure- and symptom-modification trials in OA. It also outlines a research agenda to inform future trial development. It is hoped that this will provide a crucial resource for those interested in designing and executing clinical trials of multiple different interventions for OA, regulatory agencies, and those interested in moving the research agenda forward for the betterment of people with OA worldwide. Author contributions Dr Jordan drafted the Overview article and Dr Henrotin made critical edits. Both authors take responsibility for the integrity of the article. Conflict of interest Dr Jordan has consulted for Samumed and PolyActiva and is Deputy Editor for Clinical Science for Osteoarthritis and Cartilage; a member of the Board of Directors of the American College of Rheumatology; and chair of the US Bone and Joint Initiative's Chronic Osteoarthritis Management Initiative. Dr Henrotin has received honoraria from Artialis, Bioiberica, Danone, Expanscience, Ibsa, Merck, Pierre Fabre, Synolyne Pharma, and Tilman.
Editorial / Osteoarthritis and Cartilage 23 (2015) 671e673
with osteoarthritis of the hand: recommendations from a task force of the Osteoarthritis Research Society International. Osteoarthritis Cartilage 2006 Apr;14(4):303e22.
He is the founder and owner of Artialis SA a biomarker manufacturer and Synolyne Pharma, two spin-off companies of the Unige. He has also received unrestricted educational versity of Lie grants from Bioiberica, Expanscience, Royal Canin, Artialis, and Nestle.
J.M. Jordan* Department of Medicine, Thurston Arthritis Research Center, University of North Carolina, 3300 Doc J. Thurston, Jr. Bldg., CB# 7280, Chapel Hill, NC, 27599-7280, USA
Acknowledgments The authors wish to acknowledge Antoine Baldassari, Carol C Patterson and Vanessa Wise of the Thurston Arthritis Research Center at the University of North Carolina and Diann Stern, Executive Director of the OARSI, for their administrative assistance. OARSI gratefully acknowledges support to defer in part the cost of printing of the Clinical Trial Recommendations from Abbvie, BioClinica, Boston Imaging Core Lab, and Flexion. The funding sources for printing had no role in the outcome of this manuscript. References 1. Altman R, Brandt K, Hochberg M, Moskowitz R, Bellamy N, Bloch DA, et al. Design and conduct of clinical trials in patients with osteoarthritis: recommendations from a task force of the Osteoarthritis Research Society. Results from a workshop. Osteoarthritis Cartilage 1996 Dec;4(4):217e43. 2. Maheu E, Altman RD, Bloch DA, Doherty M, Hochberg M, Mannoni A, et al. Design and conduct of clinical trials in patients
673
Department of Orthopaedics, Thurston Arthritis Research Center, University of North Carolina, 3300 Doc J. Thurston, Jr. Bldg., CB# 7280, Chapel Hill, NC, 27599-7280, USA Y. Henrotina Institute of Pathology, University of Liege, (B23) þ5, CHU Sart-Tilman, 4000 Li ege, Belgium E-mail address: [email protected]. *
Address correspondence and reprint requests to: J.M. Jordan, Department of Medicine, Thurston Arthritis Research Center, University of North Carolina, 3300 Doc J. Thurston, Jr. Bldg., CB# 7280, Chapel Hill, NC, 27599-7280, USA. Tel: 1-919-966-0559; Fax: 1-919-966-1739. E-mail address: [email protected] (J.M. Jordan).
a
Tel: 32-4-242-77-97.
Editorial
Osteoarthritis Research Society International Initiative on Recommendations for Conducting Clinical Trials in Osteoarthritis: Overview
Background and remit In 1995, the Osteoarthritis Research Society (later renamed the Osteoarthritis (OA) Research Society International [OARSI]) conducted a workshop on issues related to the design of clinical trials in knee and hip OA. Individuals from academia, industry, and government regulatory agencies participated in the workshop. A manuscript describing the process and results was published in Osteoarthritis and Cartilage in 19961. Subsequently, Maheu and colleagues published a similar set of recommendations for conducting clinical trials in hand OA2. In 2012, the Board of Directors of the OARSI initiated a process to update the recommendations for conducting clinical trials in knee, hip, and hand OA. Much had happened since the initial recommendations, including advances in magnetic resonance and other imaging techniques, development and testing of local and systemic biomarkers of joint metabolism, and evolution of scientific rigor to address methodologic issues involved in the conduct of surgical trials, non-pharmacologic trials, implementation trials, and primary prevention trials. The goal of the OARSI Initiative on Recommendations for Conducting Clinical Trials in Osteoarthritis was (1) to gain consensus regarding clinical trials methodology in OA using currently accepted processes, (2) to develop recommendations with associated rationale for various approaches to key issues, and (3) to propose strategies for an ongoing research agenda. Administrative structure and procedures The administrative structure consisted of a Chair and co-Chair, a Steering Committee, and a series of Working Groups, each composed of a Chair, co-Chair and Members. Joanne M Jordan, MD MPH of the University of North Carolina at Chapel Hill in the United States was appointed Chair of the Initiative, and Yves Henrotin, PhD of University of Liege, Belgium was appointed co-Chair. The Steering Committee consisted of the Chair and co-Chair and four additional individuals with experience in clinical trial design and regulatory issues. These included Marc C Hochberg, MD MPH of the University of Maryland School of Medicine in Baltimore, Maryland; Timothy McAlindon, MD MPH of Tufts University School of Medicine in Boston, Massachusetts; Lee Simon, MD, former Director of the Division of Analgesic, Anti-inflammatory and Ophthalmologic Drug Products within the Center for Drug Evaluation and
Research of the Food and Drug Administration; and Kim Bennell, PhD of the University of Melbourne, Australia. Working groups were formed to deal with different aspects of the task at hand, and chairs and co-chairs invited and appointed (Table I). Broad international representation from academia, industry, and government was sought to constitute the members of the Working Groups. In all, approximately 100 individuals with expertise in different aspects of OA participated in the Initiative. All individuals completed a conflict of interest statement per OARSI policy for such initiatives (see below). The Steering Committee devised an overall procedure for the respective Working Groups to follow, with consensus procedures varying somewhat among the Working Groups, depending upon the breadth of the topic and the presence and extent of controversy in the scientific literature. All groups thoroughly reviewed the literature, some performing systematic reviews where indicated. Where appropriate, voting by the members of a Working Group on specific recommendations occurred; in accordance with procedures from the Ethics Committee of the OARSI, those individuals with a significant conflict of interest or owning companies with a stake in the outcome of a specific recommendation, were not permitted to vote. Strong recommendations regarding use or non-use of a specific procedure or technique were made in the face of overwhelming evidence. More common, however, dogmatic
Table I Working Groups for Osteoarthritis Research Society International Initiative on Recommendations for Conducting Clinical Trials in Osteoarthritis Working Group
Chair/co-Chair
Statistical and design issues Biomarkers Imaging: Knee, hip, hand KNEE OA: structure and symptoms
Elena Losina/Jonas Ranstam Virginia Byers Kraus David Hunter/Garry Gold Timothy McAlindon/Thomas Schnitzer Nancy Lane/Marc Hochberg Margreet Kloppenburg/Emmanuel Maheu Stephen Messier
HIP OA: structure and symptoms HAND OA: structure and symptoms Non-pharmacologic trials: diet and exercise Surgical Trials Rehabilitation Trials Joint injury prevention Implementation Trials
http://dx.doi.org/10.1016/j.joca.2015.03.016 1063-4584/© 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Jeffrey Katz G Kelley Fitzgerald Carolyn Emery Kelli Allen
672
Editorial / Osteoarthritis and Cartilage 23 (2015) 671e673
recommendations were deliberately avoided, in acknowledgment of the rapidity with which scientific and technical advances occur. The Steering Committee and chairs/co-chairs of each Working Group met in-person at the 2013 and 2014 OARSI World Congresses to review procedures and progress. Additionally, working groups communicated in-person, by telephone, and by email. Each Working Group submitted a detailed work plan to the Steering Committee for approval, including plans for literature review, consensus procedures, and a research agenda. The working chairs had the opportunity to consult the Steering Committee if any major disagreement occurred in their working groups. The Working Group on Statistical and Design Issues and the Imaging Working Group served as sources of reference for the other groups. Posting of critical appraisal manuscripts to a secure file-sharing website allowed direct input by Working Group Committee members and the Steering Committee. All manuscripts underwent review by the Steering Committee before submission to the journal, after which they underwent further peer review per the journal's usual procedure.
Knee, hip and hand structure- and symptom-modification trials The next three articles are devoted to symptom- and structuremodification trial issues in the knee, hip, and hand, respectively. McAlindon and colleagues propose 25 consensus-driven recommendations regarding randomization, blocking and stratification, blinding, enhancing accuracy of patient-reported outcomes, describing patient-reported and physical performance measures, structural outcomes measures, biochemical biomarkers, and reporting recommendations. Lane and Hochberg and the Working Group on hip OA describe advances in radiographic and MRI assessment of hip OA for structure-modification trials, as well as issues for symptom-modification trials; their paper also reviews recent results on local and systemic biomarkers of joint metabolism in hip OA. Kloppenburg and Maheu and colleagues provide a detailed and updated review of recent developments in the assessment and evaluation of hand OA. These inform the description of core outcome measurement sets for trials in hand OA, methods and instruments to be used to assess symptoms and structure, and a robust research agenda to move the field forward.
Organization of this issue Non-pharmacologic trials This issue is divided into two parts. The first part, composed of six articles, deals with topics applicable to multiple types of OA clinical trials: statistical design and reporting issues; regulatory procedures; biomarker qualification procedures; and musculoskeletal imaging relevant to OA of the knee, hip, and hand. The second part deals with specific types of OA trials, including separate papers on OA of the knee, hip, and hand; non-pharmacologic trials, specifically, diet and exercise trials, rehabilitation trials, and injury prevention trials; surgical trials; and implementation trials. Analytic, reporting, and regulatory issues This special issue opens with an overview by Losina and colleagues of key analytic, design, and reporting issues involved in the conduct of pharmacologic and non-pharmacologic OA trials. Special attention is given to approaches to missing data, economic analyses, and requirements for reporting. An abbreviated look at regulatory requirements and procedures for product approval of pharmaceuticals and devices follows. Advances in understanding of the pathologic processes involved in OA initiation and progression have allowed soluble biomarker development to be considered as potential critical components of an OA clinical trial. Kraus and colleagues describe technical requirements for soluble biomarker qualification and validation. Importantly, this article does not recommend specific biomarkers to be used in clinical trials, but sets the stage for future results from the OA Biomarkers Initiative and others that 1 day may allow early identification of OA risk, selection of participants into trials, and monitoring of drug response and safety with soluble biomarkers. Imaging Three papers on imaging for OA of the knee, hip, and hand summarize radiographic, magnetic resonance imaging, and ultrasound techniques and requirements for use in structure-modification trials. These papers address issues such as detailed acquisition methods and techniques; commonly encountered difficulties and solutions; quality assurance and control procedures; measurement methods and performance; recommendations for trials; and research recommendations. Recognition of the rapid pace of technological innovation is crucial in these recommendations and is reflected in the consensus voting on critical issues.
Messier and the Working Group on Diet and Exercise interventions provide a primer for design of non-pharmacologic trials and specific design issues unique to these types of trials, with examples from the published literature. Surgical trials have several unique challenges that are expertly reviewed by Katz and members of the Surgical Trials Working Group. Rehabilitation trials also have specific challenges to scientific integrity inherent in their design; these are outlined by Fitzgerald and colleagues. Finally, an example of primary prevention of OA is presented by Emery and colleagues in their overview of joint injury prevention trials, and Allen and colleagues describe challenges associated with implementation trials. Summary This special issue of Osteoarthritis and Cartilage represents the combined expertise and work of many individual experts from academia, industry, and regulatory agencies to inform the research community about advances in clinical trial design and execution and support key recommendations for structure- and symptom-modification trials in OA. It also outlines a research agenda to inform future trial development. It is hoped that this will provide a crucial resource for those interested in designing and executing clinical trials of multiple different interventions for OA, regulatory agencies, and those interested in moving the research agenda forward for the betterment of people with OA worldwide. Author contributions Dr Jordan drafted the Overview article and Dr Henrotin made critical edits. Both authors take responsibility for the integrity of the article. Conflict of interest Dr Jordan has consulted for Samumed and PolyActiva and is Deputy Editor for Clinical Science for Osteoarthritis and Cartilage; a member of the Board of Directors of the American College of Rheumatology; and chair of the US Bone and Joint Initiative's Chronic Osteoarthritis Management Initiative. Dr Henrotin has received honoraria from Artialis, Bioiberica, Danone, Expanscience, Ibsa, Merck, Pierre Fabre, Synolyne Pharma, and Tilman.
Editorial / Osteoarthritis and Cartilage 23 (2015) 671e673
with osteoarthritis of the hand: recommendations from a task force of the Osteoarthritis Research Society International. Osteoarthritis Cartilage 2006 Apr;14(4):303e22.
He is the founder and owner of Artialis SA a biomarker manufacturer and Synolyne Pharma, two spin-off companies of the Unige. He has also received unrestricted educational versity of Lie grants from Bioiberica, Expanscience, Royal Canin, Artialis, and Nestle.
J.M. Jordan* Department of Medicine, Thurston Arthritis Research Center, University of North Carolina, 3300 Doc J. Thurston, Jr. Bldg., CB# 7280, Chapel Hill, NC, 27599-7280, USA
Acknowledgments The authors wish to acknowledge Antoine Baldassari, Carol C Patterson and Vanessa Wise of the Thurston Arthritis Research Center at the University of North Carolina and Diann Stern, Executive Director of the OARSI, for their administrative assistance. OARSI gratefully acknowledges support to defer in part the cost of printing of the Clinical Trial Recommendations from Abbvie, BioClinica, Boston Imaging Core Lab, and Flexion. The funding sources for printing had no role in the outcome of this manuscript. References 1. Altman R, Brandt K, Hochberg M, Moskowitz R, Bellamy N, Bloch DA, et al. Design and conduct of clinical trials in patients with osteoarthritis: recommendations from a task force of the Osteoarthritis Research Society. Results from a workshop. Osteoarthritis Cartilage 1996 Dec;4(4):217e43. 2. Maheu E, Altman RD, Bloch DA, Doherty M, Hochberg M, Mannoni A, et al. Design and conduct of clinical trials in patients
673
Department of Orthopaedics, Thurston Arthritis Research Center, University of North Carolina, 3300 Doc J. Thurston, Jr. Bldg., CB# 7280, Chapel Hill, NC, 27599-7280, USA Y. Henrotina Institute of Pathology, University of Liege, (B23) þ5, CHU Sart-Tilman, 4000 Li ege, Belgium E-mail address: [email protected]. *
Address correspondence and reprint requests to: J.M. Jordan, Department of Medicine, Thurston Arthritis Research Center, University of North Carolina, 3300 Doc J. Thurston, Jr. Bldg., CB# 7280, Chapel Hill, NC, 27599-7280, USA. Tel: 1-919-966-0559; Fax: 1-919-966-1739. E-mail address: [email protected] (J.M. Jordan).
a
Tel: 32-4-242-77-97.
