What were the FDA’s concerns in Mesoblast’s prior complete response letters and how were they addressed for pediatric aGVHD approval?
Executive summary
The FDA’s earlier complete response letters (CRLs) for Mesoblast’s remestemcel‑L (Ryoncil) centered on two buckets of concern: the adequacy of clinical evidence—specifically a preference for randomized, controlled data to confirm efficacy despite advisory‑committee support—and manufacturing, potency and chemistry, manufacturing and control (CMC) issues tying the commercial product to the clinical material; Mesoblast addressed these by providing additional Phase 3 data, refining potency assays and submitting expanded CMC documentation while engaging the agency in formal meetings to define an acceptable regulatory path [1] [2] [3] [4].
1. The FDA wanted randomized evidence, even after an ODAC vote
Although the FDA’s Oncologic Drugs Advisory Committee voted strongly in favor of remestemcel‑L’s efficacy for pediatric steroid‑refractory aGVHD, the agency nonetheless issued a CRL in October 2020 requesting at least one additional randomized, controlled trial in adults and/or children to provide confirmatory evidence — a classic example of FDA caution when single‑arm or pooled datasets carry uncertainty about generalizability and effect size [1] [2] [5].
2. Potency assay and CMC linkage became a decisive technical hurdle
In later interactions culminating in an August 2023 CRL, FDA reviewers highlighted that the potency assay used in the pivotal pediatric Phase 3 (MSB‑GVHD001) was not considered suitable to demonstrate that the commercial product would perform the same way as the clinical material, prompting requests for additional potency data and standardized CMC documentation to link the trial product to commercial manufacturing [3] [6] [4].
3. Mesoblast’s regulatory choreography: meetings, trials and new data
Mesoblast responded with a sequence of regulatory maneuvers — Type A meetings to agree a path forward, plans for additional targeted clinical studies (including a proposed adult high‑risk SR‑aGVHD trial and single‑arm designs with external controls), and collection of data from the MSB‑GVHD001 trial that the company and FDA later agreed could support resubmission once CMC and potency gaps were filled [3] [7] [8].
4. What Mesoblast actually resubmitted to calm FDA’s technical worries
Resubmissions in 2023–2024 emphasized three concrete fixes: presentation of the Phase 3 MSB‑GVHD001 dataset that FDA later judged sufficient to support the pediatric filing, new or improved potency assay data intended to demonstrate equivalence between the clinical and commercial product, and expanded CMC documentation addressing manufacturing controls — changes the company says were developed after direct FDA feedback [8] [4] [3].
5. Outcomes, remaining caveats and competing perspectives
By mid‑2024 the FDA accepted Mesoblast’s resubmitted BLA as a complete response and set a PDUFA target date, signaling that the technical dossiers on clinical efficacy, potency assays and CMC had at least reached a docketed review state; however, public accounts show the agency previously continued to press for additional adult or randomized data and for robust post‑approval commitments, reflecting the tension between urgent pediatric need and regulator insistence on rigorous evidence [4] [6] [2]. Mesoblast framed its actions as meeting an unmet medical need and praised productive FDA meetings, which also serves the company’s commercial and investor interests in advancing a first‑in‑class pediatric cellular therapy [9] [8].