ReportsRegulatory Science

Impact of guidance documents on translational large animal studies of cartilage repair

Science Translational Medicine  21 Oct 2015:
Vol. 7, Issue 310, pp. 310re9
DOI: 10.1126/scitranslmed.aac7019

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Advise and consent

Cicero1 was wrong: Sometimes someone CAN give you wiser advice than yourself. In the case of preclinical study design, sound advice can come from those who regulate the next steps in translation. For example, new therapy development for cartilage repair relies on costly preclinical studies in large animal models—horses, pigs, sheep, and others—for translation to human clinical trials. To ensure the efficacy and safety of these therapies before testing in human subjects, regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency have published guidance documents that outline best practices for study design and execution as well as appropriate metrics for data analysis. These documents were expected to influence the design and execution of large animal studies. Here, Pfeifer et al. put that hypothesis to the test with a systematic review of more than 100 publications stretching back two decades.

Surprisingly, and somewhat disappointingly, the availability of the documents appears to have little effect on adherence by researchers to the recommendations therein. Although overall adherence has been slowly increasing over time, the authors observed no correlation with the publication of guidance documents. In fact, the authors subjected one of their recent studies to the same analysis and found that it fared no better than average for the industry when it came to adherence to the regulatory guidance documents. Possible explanations for poor compliance include access to necessary infrastructure and expertise, differing intents for the data, and expense. The authors call for an increased effort by the field to conform to the guidance documents and for regulatory agencies to provide additional resources to facilitate the transition.

1Cicero (106 BC–43 BC) was a Roman philosopher credited for counseling that “Nobody can give you wiser advice than yourself.”

Abstract

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, R2 = 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.

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