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Blimey, ERP actually fessing up to the supply issue..is this their entry for the HKEX 2022 Omnishambles award? Still, nice to have something provide a belly laugh in these dark times.

Eight years on and still no viable manufacturing process, but one can't entirely blame the Oompa-Loompas for this. PGAK-1 (probably named for a spike on a HPLC trace) is obviously not a new beastie, and the 0.5% limit (ICH threshold for a specified impurity) was set in the original submission (referencing Catalent manufactured material). Possibly a hydrolysis product, with increase related to moisture ingress, hence the proposed valve change. Upping the threshold to 1% may require lack of harmful potential to be formally established (genotox, perhaps other tests) depending on the nature of the impurity. FDA is more picky with respect to thresholds and potential harm assessment than the EMA, and will add further complication when it comes to the combination rule.

Clearly not without significant implications. Grant of variation by no means a slam dunk, and in view of past stability nightmares and need for real time data, could be looking at mid to late 2023 for next batch release, (squeaky bum time until 24 month real time data is available). But it's not as though Recordati (or OPE) will lose sleep over lost sales. And anyone reviewing the CMC dossier in the context of diligence better have a tremendous sense of humour.

Despite ERP's claim that the China study has "commenced", no such study registered in the Chinese clinical trials registry (updated on an almost daily basis). Anyone got a ChiCTR number? Perhaps Wangbang has the sense not to commence a study with a dodgy formulation and/or is understandably nervous about future product availability.

2021 consolidated financials released this morning. Fortacin sales stated as €1m (down 17.3%).

Can't be faffed checking, but didn't ERP state royalties as being something like $54,000? Should be closer to $150,000 at a 15% royalty rate.

https://www.recordati.com/resources/Pubblicazione/___f52c6713d93641e2bc6566b1e741a304_/consolidated-financial-statements-2021.pdf

Nah, you're right...

Can't tell whether JG is trying to be humorous or is inappropriately sharing his wet dream fantasy. Perhaps both. As always, only the going concern issue should be believed.

Or even the licensees...perhaps rarity will make old tins of Fortacin a collector's item, offering some compensation for absence of sales?

"Maybe not" is the safe bet, since no credible explanation of the stability/impurity problem has been volunteered in seven years.

The mediocrity of talent at the PSNW Chocolate Factory is not the issue, nor is capacity. True, as relative small-fry, API or excipient shortages might have hit them harder, but that does not explain extended periods of no supply. Having talked with those who know their stuff, the manufacturing process itself is very simple indeed.

Going back to the six dose debacle, early time point stability problems, subsequent tweaks to enclosures and valves (presumably to address headspace and/or leakage issues) and the number of pre-expiry withdrawals, short shelf life and post-actuation expiry, and the physical chemistry of the formulation, this all points towards low aqueous volume and high gaseous volume being the real and continuing cause of headache.

If so, this can't be resolved by tweaking, but will require reformulation (addition of another solvent, for example), and subsequent back to basics bridging studies. The 7.5ml (20 dose) presentation may not be so fragile, and nothing to stop this being used in clinical study, although obviously not viable as a commercial presentation, well other than a cheap n' cheerful knob spray. All this and the HFA134a phase out on the horizon...

Wonder what the licensors are thinking right now?

That's an interesting interpretation of "control" Bothwell.

The same rascally PSNW Oompa-Loompas are responsible for China clinical trial supply (and, if ever launched, commercial supply). And, as of this morning 14th March, no study has been registered in China in the 13 months since CTA acceptance.

Recent circular from the Italian Medicines Agency indicates that Fortacin supply problems are set to continue. First flagged last November following the national withdrawal by Recordati of close-to-expiry product, shortage was set to continue until March 2022. Supply is now not expected before February 2023.

Difficult to assess the situation in countries where Fortacin is OTC (which now includes Spain), since supply not monitored by national agencies. Looks to be very sparse wholesaler uptake in Germany and no availability in France.

API shortage does not explain an almost 15 month expected absence from the market. Together with the history of pre-expiry batch withdrawals (February 2021, Italy and Germany, derailing the pilot OTC rollout), pre-launch stability issues and short shelf life, it looks increasingly likely that small volume presentation is inherently unworkable.

Perhaps not overly surprising in a formulation reliant on physical chemistry and with very little scope for tweaking by the PSNW Oompa-Loompas.

So, medication not really helping, then?

"USA approval and success"...bless...

There's been sporadic availability in Germany via online pharmacies since the Feb 2021 recall, although at 25-30% discount to the launch price, makes me wonder whether it's close to expiry stock. On the other hand, may just reflect the intense pricing competition between German online pharmacies. Recently available in Portugal (for pharmacy collection).

OTC in France but no supply. Still Rx in Italy and Spain, supply issues flagged by national formularies since December.

There is a continuing problem with lidocaine availability, but the fact that Recordati have left manufacture with a minnow such as PSNW (which has no clout when it comes to API purchase) and the complete absence of promotion (not that it would do much good for a product with zero pre-switch traction), gives you a sense of Fortacin's importance in the scheme of things.

OTC sales (the bulk being cough & cold remedies) took a knock during the pandemic, and assuming that Recordati retains an OTC component (by no means certain, given the shift in the Rx product mix towards high margin offerings), I'd predict any OTC marketing spend to be directed towards the recovery of their pre-pandemic top sellers, not some unknown knob spray offering miniscule return.

I can appreciate the confusion, but it's not that complicated.

The 505(b)(2) route is the only way in which ERP can satisfy the fixed-dose combination rule (in essence, that each active is essential for efficacy without compromising safety- the nature of the product means that this cannot be determined separately for lidocaine and prilocaine). The big hope is that the FDA will accept safety through reference to data accumulated for comparable products, actual product safety to be confirmed by a bridging study with a selected reference product.

Clinical data still needs to be generated through one or more pivotal studies, the complication being that the PEBEQ endpoint only goes out to 1 month, whereas the optimal Tx endpoint is 3 months, hence the shift to an "adaptive design". Very intrigued to see what this will look like and how it impacts on label claims.

Cutting through whimsy, there's no cunning plan involving OTC- combination of actives rules out monograph submission. There's no "vast database" of safety or efficacy data (have a read of the full CHMP switch document), only the EudraVigilance adverse event capture. Fortacin was never reimbursed so no filled script tracking, actual usage is unknown. Since the manufacturing process for the 20 dose can has never changed, safety data gathered over a decade ago (and for the more recent Ph II- total of under 300 subjects?) could be included in a US submission.

I wouldn't fret Bothwell. This has the whiff of vapourware around it. And, with no evidence to the contrary, Fortacin is probably at least as good as the hundreds of delay sprays and wipes which have been marketed for years.

No, you are right- approval will require efficacy data, since no predicate device. Approval, as with other novel neurostimulatory devices, will be by the de novo path. What "efficacy" means will depend on the label claim- objective change in IELT from baseline compared with sham device (or active comparator?) might not be enough.

Concept itself not novel, recollect being approached by an Israeli VC a couple of years back which had backed a company (something like "Virility Health" or "Virility Medical") which had generated clinical data using an off-the-shelf TENS machine, and was looking to develop and test a patch-based electrode set-up. We politely passed on this "opportunity".

@dougie- short answer "no". FDA process now comes with added faff. FDA have already seen ex-US clinical trial data back at the Sciele-requested pre-NDA meeting (2010?), history confirms their indifference.

As to post-marketing data, not only not relevant but nothing captured beyond the EUDAMED adverse events submissions. Being a non-reimbursed product, Recordati (as admitted to the CHMP) could only tell what had been shipped to wholesalers, and did not have a clue about actual prescribing rates.

@Heimdal, this is not about "speeding things up", but the necessity of resolving a core issue, namely satisfying the fixed-dose combination rule.

Now looks that approval will be via the 505(b)(2) route, a hybrid of product-specific clinical and efficacy data which will reference approved product data (the "RLD") and that a bridging study will be required ("the RLD protocol"). Obvious complication here is the RLD, EMLA being the only approved lidocaine-prilocaine combination product (and with no history of chronic use), although individual lidocaine or prilocaine data might also be referenced. This makes for a very challenging bioequivalence study.

As to "adaptive design", I suspect that this is to reduce the risk inherent in taking a barely validated co-primary endpoint into a pivotal study. This might entail a two-parter, first part aimed at confirming "bother" as an endpoint with interim analysis and target enrolment adjustment as necessary. Enrolment will still need to be large enough to hit the stats, but does give more wiggle room over fixed design.

Difficult to tell what this might add to what ERP laughingly refer to as "timelines", clearly more regulatory to-ing and fro-ing involved, plus an additional clinical study, may not become clear before mid-2022.

My bad- should read "registered listed drug"- RLD. And, should it ever comes up in a pub quiz "

"The RLD “is the listed drug identified by FDA as the drug product upon which an applicant relies in seeking
approval of its ANDA.” 21 CFR 314.3(b). Because an ANDA applicant is relying upon FDA’s finding that the
RLD is safe and effective, FDA’s practice is to designate as RLDs drug products that have been approved for safety
and effectiveness.

Ironic that ERP are adding to the embarrassment around PE with deal terms such as these- and you thought the Orient deal was bad... Panto season, but SKP not willing to stretch to even five magic beans.

Now, always dangerous interpreting anything that JG attempts to quote verbatim, but there does appear to be a shift in regulatory strategy. Type C meetings are generally requested to discuss novel endpoints or outcomes offered as a primary basis for approval, but the release states "RLD"- registered, licenced product, that is the reference product for ANDA submissions, and references a "RLD protocol". But no existent RLD for PE...

Meeting the fixed-dose combination rule has always been the very big gorilla hiding in the shadows, and I can only suppose that ERP are hoping to slide with reference to EMLA safety data and a supportive equivalence study. Good luck with that...

And, if confidence high in the PEBEQ data and strategy, why not go straight for an EOP2 meeting?

As to "adaptive design", first thought is that if the PEBEQ data is weak (just remember how small the Ph II numbers were), safety shot would be to go for something where you can compensate for being underpowered after commencement. Not entirely in my wheelhouse, but I know enough that playing with design (and possibly an extra study arm) is clearly not going to reduce numbers from a plain vanilla 2:1 randomised study, or otherwise "streamline" the process. Might look different after explanation by a grown-up, but this is looking very slippery for a new indication approval.

Bothwell, as always, more than welcome.

I'm saddened that you feel so negative about your investment. You need to focus on the boundary-pushing "GuessMyAge" app and online CME which will no doubt assist healthcare professionals tell genuine old people from those only pretending to be old- aetate miraculorum!

And spare a thought for the seven, perhaps even as many as eight, chaps throughout Europe who were hoping that Santa might slip a can of Fortacin into their stocking, only to be disappointed by the complete absence of supply. Can't entirely blame the Runcorn oompa loompas, as the continuing lidocaine shortage means that earliest delivery will be courtesy of the Easter Bunny.

But, the short shelf life of Fortacin can't be helping, and of course there's the looming HFA 134a phase out and replacement which will make for a world of manufacturing grief.

It's a continuing source of puzzlement (and amusement), that expectation still exists regarding the quantum and probability of a US licensing deal.

Back in ancient times (2007), PLE concluded an exclusive US licence with Sciele on what might charitably be described as generous terms: no upfront (but $7m equity purchase, around 5.6% of the company); no development costs; a $7m approval milestone, 10% royalty and $23m in commercial milestones (with ludicrously high annual sales triggers). Anyone seeing the basis for terms being multi-billion annual sales here? And this at a time where there was still some life in the patents and a fighting chance of PTE.

So, what's changed since the Sciele days? Still no FDA approved PE product, despite the technically low barrier to entry, which gives you a clue as what industry thinks the market is worth. Plus, the mass abandonment of urology/men's health by both big and small pharma. Space is now occupied by online marketers offering monograph and off-label treatments, $3 a dose including medical consultation. The continuing European sales (and manufacturing) debacle is hardly a turn-on.

No commercial protection worth a flying one, Kimble v Marvel and the three-year FDA mandated exclusivity period kick the prospect of a royalty-bearing licence into touch. Alternatives such as outright purchase of the IND would be priced to reflect the risk of regulatory rejection and cost/risk of de novo market development, so no or only token initial payment, with perhaps 50% on approval, the remainder subject to sales.

Very few PE deals to benchmark against, but in the unlikely event that Sensted is ever approved, you might look to the December 2020 Preboost acquisition: $20 million total, with $15m on the nail, $2.5m million after 12 months and $2.5m after 18 months. Bear in mind this was for a product with c. $3m annual sales and on which Roman were paying a royalty.

Wild thought here, Bothwell, but root cause might be in believing that an overpriced run-of-the mill knob spray with manufacturing issues, and of only peripheral interest to minor industry players (along with with a joke of a value proposition ) might actually sell?

Well, that plus putting faith in a bunch of chuckleheads with no operational or deal-making experience.

Cheer up, just think of the megabucks to come from DLI's Guess My Age(TM) app.