MSB to dispute FDA finding in Type A meeting, page-320

@Bigdaddio

Yes that's right and the FDA in their briefing notes did express these exact concerns (see below). It seems their view hasn't wavered and they either 1) do not consider our trial to be an "adequate and well-controlled study" or 2) they need an additional "adequate and well-controlled study". It's difficult to tell, but at least Mesoblast will be able to go into the Type A meeting to argue why either the FDA was wrong to issue a CRL or to waive the criteria of requiring an “adequate and well-controlled study” to obtain approval.

https://www.fda.gov/media/140986/download

Since 2009, FDA provided the Applicant with advice on the clinical development program for treatment of aGVHD in six meetings. Key points emphasized by FDA included:
- A single-arm trial that is designed to provide a quantitative evaluation of outcomes in the face of heterogeneity in the patient population may fulfill the regulatory requirements as noted in 21 CFR 314.126. Case-control studies or modeling from historical controls are two potential methods to achieve this when the eligible population is exceedingly small. Such a study would need to be designed and reviewed prior to its conduct.
- Protocol 275 is not an adequate and well-controlled trial and does not provide confirmatory evidence of efficacy to support a license application.
- Protocol 280 is a negative trial, so subgroup analyses would not be sufficient to support a marketing application.
- The results of Protocol 275 and 280 may inform a hypothesis for design of a prospective trial. The sponsor should consider conducting a randomized clinical trial to provide confirmatory evidence of the efficacy of the study agent in the treatment of GVHD.
- FDA recommended a new randomized trial of remestemcel-L versus standard of care for treatment of steroid-refractory acute GvHD, indicating that such a study would likely be feasible in the adult population. A randomized, controlled study in the adult population could potentially also confirm clinical benefit in the pediatric population, depending on the results.
- MSB-GVHD001, a single-arm trial in pediatric patients permits use of other agents, such as those used in prophylaxis, that may affect efficacy outcomes. This confounds the interpretation of the treatment effect of remestemcel-L. In the absence of an appropriate concurrent or historical control, the treatment effect of remestemcel-L will be difficult to discern.
- The null hypothesis for MSB-GVHD001 is not based on data from a historical control population. In the absence of data from appropriate historical controls, FDA is unable to agree that the proposed null hypothesis is acceptable. - Given the absence of appropriate concurrent or historical controls, MSB-GVHD001 does not appear to be an adequate and well-controlled study. Thus, the trial as designed may not be sufficient to provide primary evidence of effectiveness to support a marketing application.
- Any claim of efficacy based on MSB-GVHD001 needs to take into account all studies of remestemcel-L for treatment of aGVHD, including the failed trials.