ReNu’s second Phase 3 randomized trial in symptomatic knee osteoarthritis missed its primary endpoint, showing a 0.5-point advantage over saline in WOMAC pain reduction at six months (one-sided p=0.0393 vs a prespecified 0.023 threshold). The first Phase 3 trial reported a 0.7-point advantage that met the same statistical bar (p=0.0177). Functional outcomes were statistically significant in the latest study (p<0.0001), and safety remained favorable. Absolute pain reductions improved numerically in the second study versus the first (−6.9 vs −6.0 from baseline for ReNu), but the between-arm delta narrowed given a strong saline response. The company plans to seek a pre-BLA meeting with FDA to discuss a submission built on a pooled efficacy analysis across the two Phase 3 studies, supported by safety and functional data from three large RCTs totaling more than 1,300 patients. ReNu, a cryopreserved amniotic suspension allograft delivered as a single intra-articular injection, holds RMAT designation for knee OA. The second Phase 3 enrolled 594 patients with mild-to-severe disease in a double-blind, multicenter, saline-controlled design. Strategically, this is a bid to convert a mixed pivotal package into a totality-of-evidence narrative under RMAT, in a category where placebo responsiveness and procedural effects often compress effect sizes against saline. The statistical framework matters: the latest trial fell short under a one-sided alpha of 0.023, while the earlier study cleared it. A pooled analysis could recover overall significance, but the net effect size appears modest, and the FDA’s tolerance for one positive and one negative trial—particularly with subjective endpoints—has been tightening. The move also reflects a broader regulatory pivot: amniotic products have migrated from enforcement discretion to full biologics oversight, and a BLA for an orthopedic pain indication would be a meaningful precedent for the field. For sites and CROs, the readout underscores operational realities of IA injection studies: high-quality blinding, standardized injection technique, and rigorous, centralized pain assessment are essential to contain saline arm performance. If approved, site operations will need cryopreservation and cold-chain handling at scale, which could favor larger centers with established infrastructure. Sponsors across OA will note the functional signal’s strength relative to pain, suggesting future designs may benefit from hierarchies or composite endpoints that better capture functional durability. Payers will scrutinize clinical meaningfulness and durability of a small between-arm delta, heightening the importance of responder analyses, rescue use, and health-economic data. Competition, an approved BLA-regulated amniotic injection, would pressure cash-pay PRP and hyaluronic acid niches and could reframe evidentiary expectations for orthobiologics. Next, the pre-BLA dialogue will reveal whether the FDA accepts a pooled analysis plan, the handling of one-sided testing and multiplicity, and what constitutes a clinically meaningful difference in this dataset. Key watch items include durability beyond six months, consistency in severe OA subgroups, and alignment on risk–benefit when the control arm exhibits large gains. The FDA could request an additional adequate and well-controlled trial or impose postmarketing commitments around real-world effectiveness and safety. Manufacturing scalability and a reliable cold chain will be operational gatekeepers. For the broader ecosystem, expect OA programs to tighten endpoint strategies, adopt centralized outcome assessment, and consider active-comparator or enrichment designs to mitigate saline effects. The near-term signal will be whether FDA entertains a BLA on pooled data; the medium-term question is whether orthobiologics can clear a higher, more conventional bar in a symptom-driven, placebo-sensitive indication.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
