Ann: Change in substantial holding, page-92

Hi @Bazsa, @reginaldp,

personally, I'm almost expecting adult use to be right up there printed in large letters on the label from the date of RYONCIL's initial marketing approval. No reason IMO to now think that FDA will limit the approved indication population to pediatric populations, apart from perhaps considering the dosage and treatement prep/ administration differences with adults. We haven't heard anything AFAIK that indicates e.g. that FDA sees any adverse reactions that are novel or unique in paediatric patients or that occur at a different frequency or severity (greater or lesser) than in adults.

I appreciate & agree that you both have been talking about the primary evidence for standard approval i.e. the paediatric trial GVHD-001, which expressly targeted a paediatric population, & the supporting evidence from the earlier Protocols (incl. for 280 and EAP 275). However, I think MSB has been submitting material supporting the more general indication i.e. for both adults and paediatric patients since before the 2nd CRL.

Adult usage can & I think will be attended to now, IMO, simply as part of the labelling process discussions with CBER under the heading 'INDICATIONS & USAGE' - I don't think there's any real need for it to be approached analogously to a label expansion if GVHD-001 is now considered by the FDA to be adequate.

So, I consider it likely that the final settled indication statement will read something like:

" RYONCIL^® is indicated for the treatment of steroid-refractory acute graft-versus-host disease (GVHD) in
adult and pediatric patients.”

However, it's possible that CBER would want RYONCIL's pediatric indication marked only for use in the specific pediatric age group which was supported by eligibility for GVHD-001, in which case the indication statement would likely specify the minimum age of the indicated pediatric age group e.g. something like:

“RYONCIL^® is indicated for the treatment of steroid-refractory acute graft-versus-host disease (GVHD) in
adults and pediatric patients aged 2 years and older.”"

If it's reviewing adult usage in the indication, I don't think the FDA would go so far as to limit the maximum age of the indicated pediatric population e.g. by saying:

" ...in adults and pediatric patients aged between 2 years and 17 years."

Principally I say this because I'd see the distinction between a designated upper limit of the pediatric population as introducing possible confusion on the overlapping bounds of the adult and paediatric populations i.e. it would be an artificial distinction, without utility.

But, of course there'd still need to be a Pediatric Use statement in the relevant label section as well.

Again, I expect it will follow the guidelines for the required regulatory statement (i.e. a specific paediatric use statement) or a reasonable alternative statement if RYONCIL is approved in paediatric patients (either all paediatric patients or in a specific paediatric age group(s)) for the same indication as is intended to be approved at that time for adults. This is the most likely scenario, IMO, as spelled out in the US Federal Regs at 21 CFR 201.57(c)(9)(iv)(C) and (D). Link here.

So, given that the paediatric use indication is not derived from well-conducted adult trials (as is often the case), but rather from a dedicated paediatric trial, the necessary statement - in the first line of the Pediatric Use statement in the labelling - might simply read something like:

“The safety and effectiveness of RYONCIL (for the treatment of steroid-refractory acute graft-versus-host disease (GVHD)) have been established in pediatric patients aged 2 years and older.”

Of course, all this is speculation on my part. However, for those interested in the background, I recommend reading the FDA's Guidelines, including the March 2019 guidance i.e. Pediatric Information Incorporated Into Human Prescription Drug and Biological Product Labeling Guidance for Industry.

Link here.




Cheers all &
GLTALTH