Sdrawkcabeman: the pediatric waiver is a concrete marker of progress towards EU market authorization

[Fishermangents]

By Sdrawkcabeman, YMB, 28 August 2016

Some further deliberation on Anne’s post about the waiver, http://www.ema.europa.eu/docs/en_GB/doc ... 212174.pdf

Firstly, the decision refers to:
“Having regard to Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No. 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004"

That refers to this document: http://ec.europa.eu/health/files/eudral ... 901_en.pdf

which basically outlines a framework for making a concerted effort for pediatric drug discovery by stitching together different directives to facilitate the process. What should interest us is the section “Marketing Authorization Requirements,” Article 7, Part B, where it lists a set of conditions of which one must be met before submitting an application for marketing authorization, in our case that’s “(b) a decision of the Agency granting a product-specific waiver.” Now that section additionally makes another reference to Article 6 and Article 8.3 in this document:

http://www.ema.europa.eu/docs/en_GB/doc ... 004481.pdf

And this reference, under “Placing On The Market” Article 6, again regards further conditions for market authorization. And Article 8.3 lists many requirements (labeled “a” through “n”) for authorization application, which are either already fulfilled for Imet, or are simple, quotidian things to fulfill, like packaging, etc; as far as I can see, the results of the clinical trials are the only substantial requirement yet to be fulfilled for a marketing authorization application.

The waiver decision also notes Regulation (EC) No 726/2004 as regards the authorization and supervision of medicinal products for human and veterinary use. I jumped the gun earlier in calling this a move for compassionate use; it could be, but the regulation is far broader, it’s the mandate for the approval process of the EMA. The waiver decision is specifically referring to TITLE II, AUTHORISATION AND SUPERVISION OF MEDICINAL PRODUCTS FOR HUMAN USE, and the articles under this section regard applications for marketing authorization. Here’s a link to that document:

http://eur-lex.europa.eu/legal-content/ ... 32004R0726

The waiver decision’s reference to Article 13 of Regulation (EC) No 1901/2006 regards the schedule of the pediatric committee’s response to a waiver application; and once an opinion is adopted, Article 25 procedures are to be enacted. Note the seventh point of Article 25:

“7. Decisions of the Agency shall be made public after deletion of any information of a commercially confidential nature.”

The sum of all this is unequivocally pointing to Janssen’s preparation for a marketing authorization application. I think it was Anne who suggested a marketing authorization application was made in concert with the orphan application late last year, now we know that wasn’t possible b/c a waiver for the pediatric pop wasn’t granted. But now it is granted. And as far as I can see, the only remaining requirement to fulfill for a marketing authorization application under Article 8.3 is the clinical trial results. But considering the unique circumstance of Imet achieving unprecedented CR/PR in MF in contrast to the unmet need, will Janssen and EMA require meeting the primary completion, or will they submit an expedited application based on early-but-mature data? I think either is plausible. But as regards Anne’s find, this is nice and concrete proof that they are moving towards applying.

Let me put a finer point on this in case it wasn't clear to some. Any company seeking a marketing authorization from EMA must include in their application their plans for pediatric use; in the case that regulations allow for a waiver in that condition, then that waiver nullifies the requirement for pediatric investigation. In other words, the waiver in Imet's case isn't to pursue pediatric investigation; the waiver is a box to check off in regards to pediatric use, CATEGORICALLY, which is required for ANY application for market authorization. This is clear if you read the documents I linked in the original post. That's why I'm saying Janssen is preparing the application for marketing authorization. In the list of requirements under Article 8.3, the only significant milestones remaining for a complete application were the pediatric use and clinical results; and now the pediatric use has been resolved, leaving only the clinical results to be determined. So again, Janssen had to receive some sort of decision in pediatric use in order to file a marketing authorization application for use in adult MF. They ARE preparing to file, and the waiver is a concrete marker of progress towards that application; there is no other reason for the waiver.

Furthermore, the "product-specific waiver" means Janssen doesn't have to keep applying for a waiver for MDS, and whatever other indication they pursue. So all future marketing authorization applications for Imet will not have to address the pediatric use again. And lastly, the waiver doesn't preclude future investigations in pediatric use, as was disclosed in the previous PDCO minutes. Janssen may still pursue pediatric investigation in the future should they choose to, the committee even suggested various other potential indications for pediatric use; but the point is, Janssen doesn’t have to have any pediatric investigation for application for marketing authorization in any of Imet's trials.

[cheng_ho]

We went over this two months ago when it came out. All this did was say that Jannsen doesn't have to test in kids for a geriatric medicine. It's good as far as it goes, but it has nothing to do with approval.... and it's from June.

[Fishermangents]

At least I give credits for Sdrawkcabeman for having put this waiver into the perspective of the complex EMA approval process. I agree with him that it is ticking a box on the way to market authorization, although it is just a formality.

[biopearl]

I am with Cheng on this one. This all ages and all indications sounds pretty encompassing but it appears to refer only to all pediatric ages where the drug clearly as yet has virtually no niche. Annie has been tracking this for a while. There is little doubt that Janssen has done and been doing all the paperwork required to pounce on a filing once the data is available. Right now it is a question of what the EMEA will require as a minimum of proof. Why is Dr. Tefferi's initial pilot study inadequate? The findings are unique. Truly unique. Re the ongoing Janssen study it is notable that there is no control group. Why? Because again this is a unique patient population that is essence are their own control since they have failed everything so there is nothing to compare them to except no treatment. Therefore how to do a statistical analysis in this group? Any improvement means something. This means that the usual larger groups required for statistical significance lose their relevance with a study of this type. I submit that the current enrollment of (at least) 40 patients, 20 in each arm, should do it. Despite Scarlett's protestations I suspect it will be hard for Dr. T to accept his award at ASH without providing an update on the pilot study. Regards, bp

[cheng_ho]

Maybe JNJ will just send one of those iPad remotes to ASH with Tefferi's face on it... he has to be bursting to say something by now, good or bad.