Impact of guidance documents on translational large animal studies of cartilage repair.
Promising therapies for cartilage repair are translated through large animal models toward human application. To guide this work, regulatory agencies publish recommendations ("guidance documents") to direct pivotal large animal studies. These are meant to aid in study design, outline metrics for judging efficacy, and facilitate comparisons between studies. To determine the penetrance of these documents in the field, we synthesized the recommendations of the American Society for Testing and Materials, U.S. Food and Drug Administration, and European Medicines Agency into a scoring system and performed a systematic review of the past 20 years of preclinical cartilage repair studies. Our hypothesis was that the guidance documents would have a significant impact on how large animal cartilage repair studies were performed. A total of 114 publications meeting our inclusion criteria were reviewed for adherence to 24 categories extracted from the guidance documents, including 11 related to study design and description and 13 related to study outcomes. Overall, a weak positive trend was observed over time (P = 0.004, R(2) = 0.07, slope = 0.63%/year), with overall adherence (the sum of study descriptors and outcomes) ranging from 32 ± 16% to 58 ± 14% in any individual year. There was no impact of the publication of the guidance documents on adherence (P = 0.264 to 0.50). Given that improved adherence would expedite translation, we discuss the reasons for poor adherence and outline approaches to increase and promote their more widespread adoption.
McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Translational Musculoskeletal Research Center, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA 19104, USA. Department of Trauma Surgery, Regensburg University Medical Center, 93053 Regensburg, Germany.
Christian G
CG
Pfeifer
McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Translational Musculoskeletal Research Center, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA 19104, USA. Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, and North Carolina State University, Raleigh, NC 27695, USA.
Matthew B
MB
Fisher
McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Translational Musculoskeletal Research Center, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA 19104, USA.
James L
JL
Carey
McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Translational Musculoskeletal Research Center, Philadelphia Veterans Affairs Medical Center, Philadelphia, PA 19104, USA. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA. Collaborative Research Partner, Acute Cartilage Injury Program of the AO Foundation, 7270 Davos, Switzerland. lemauck@mail.med.upenn.edu.
Robert L
RL
Mauck
D000818:Animals; D002356:Cartilage / Q000503:physiopathology*; D023421:Models, Animal; D057170:Translational Research, Biomedical; D014481:United States; D014486:United States Food and Drug Administration