gms | German Medical Science

Objectives: Acute cartilage injuries are known to cause pain, decrease quality of life, lead to early onset of osteoarthritis and increase health care costs. To mediate these problems, researchers are translating promising in-vitro therapies through large animal models (e.g. horse, sheep, goat, (mini-)pig, and dog) towards human application. In order to guide the field's efforts, agencies (e.g. FDA, EMA, and ASTM) have developed recommendations for pivotal large animal studies in cartilage repair. We synthesized the recommendations of these three agencies into a scoring system and performed a meta-analyis of the past 20 years of pre-clinical cartilage repair studies to test our main hypothesis that these individual guidance documents would have a significant impact on how such studies are performed.

Methods: FDA, EMA and ASTM guidance documents were analyzed and all published studies employing the five most common large animal models from 1/1994-4/2014 were searched on PubMed as well as the official journal of the ICRS 'Cartilage' on 4/18/2014 using the search term 'cartilage_ specific species name_repair'. Each publication matching the inclusion criteria was reviewed in detail for each category extracted from the agencies' recommendations, including 11 and 13 categories related to study design and outcomes, respectively. For each category, full, inconclusive, or no reporting was credited with 1, 0.5, or 0 points, respectively. Statistical analysis was carried out by computing the Pearson's correlation coefficient (CC) for study duration versus overall adherence. ANOVA with Bonferroni's post-testing was used to compare species specific statistics and ANCOVAS were performed to assess our main hypothesis.

Results and Conclusion: We identified 1187 full-length, peer-reviewed manuscripts. After applying exclusion criteria, a total of 114 studies were included, of which 20 were conducted in horses, 23 in sheep, 18 in goats, 41 in (mini-) pigs, and 12 in dogs. Adherence to the categories derived from the guidance documents showed a weak positive trend with time (p=0.004, R2=0.07, slope=0.63%/year). Overall adherence per year ranged from 32±16% to 58±14%. However, there was no tangible effect of the publication of the guidance documents on adherence levels (p=0.264-0.50 for the interaction term between time and guidance document publication). Subset analysis showed higher adherence to study descriptors/design than study outcomes. The CC relating study duration to overall adherence was 0.272 (with a p value of 0.003 ). While there certainly has been a slow increase in overall adherence to the published guidance criteria over the last two decades, these documents have not markedly impacted the field as a whole. Increasing adherence to these established criteria would accelerate progress in the field and allow greater inter-study comparisons to be made if more routinely employed.