Nice to finally get some news – and what’s more, it’s positive!...

Nice to finally get some news – and what’s more, it’s positive!

There were a few points to note in yesterday’s announcement of the outcome of POH’s pre-IND meeting with the FDA regarding the TPM oxymorphone patch:

It appears that the FDA’s decision to withdraw Endo's abuse-deterrent formulation of oxymorphone ER from the market in June 2017 had cast a shadow over whether the planned 505(b)(2) drug approval pathway could be used. This abbreviated approval pathway can be a much faster and cheaper route to market because the sponsor may rely on the FDA’s finding of safety and/or effectiveness for the listed drug which the proposed drug references. However, the FDA’s definition of a “listed drug” excludes any drug which has been “withdrawn from sale for what FDA has determined are reasons of safety or effectiveness.” The complication here, in my opinion, was not only that Endo’s abuse-deterrent oxymorphone product had been withdrawn from the market for safety reasons but that Endo had also originally requested that the FDA rule that its previous, non-abuse-deterrent formulation of oxymorphone was also withdrawn from the market for safety reasons (clearly, a tactic to fend off generics). The FDA determined that it wasn’t. Still, I would suggest that there would have been sufficient uncertainty around the status of Endo's Opana as a listed drug to deter prospective partners unless favourable FDA guidance was received. The good news is that the FDA has agreed that the 505(b)(2) pathway remains a feasible path for approval of the patch



The FDA agreed at the meeting that “a broad chronic indication/label similar to that granted to Opana ER is potentially achievable.” Opana ER was approved for “the relief of moderate to severe pain in patients requiring continuous, around-the-clock opioid treatment for an extended period of time”. Normally, one would assume that POH's proposed drug would be allowed the same indication but the current “war on drugs’ in the US probably cast doubt on this assumption. Obviously, a broader indication implies a larger and more valuable market, so this agreement by the FDA is good news for POH.



The FDA expressed hesitation over use of the patch in opioid naïve patients, despite Opana ER having been labelled as suitable for opioid-naïve patients. The FDA noted “growing concern around the use of chronic opioids in opioid-naïve patients” but didn’t shut the door completely, suggesting that “access to the opioid-naive population may require further specific justification.” I see possible use in opioid-naïve patients as highly valuable both in a monetary sense and patient care sense. I think it would be well worthwhile to pursue the required "specific justification".


A further point of note was that any NDA would require a minimum safety database of at least 750 patients. By way of comparison, the clinical trial program for oxymorphone ER  included more than 2,000 opioid-naive and opioid-experienced patients with chronic cancer pain and non-cancer pain.


The announcement said that it was of particular note that the Agency suggested some additional studies (not required for product approval) for Phosphagenics to consider that could potentially enable abuse deterrent label claims. In my view, there is probably no real choice about completing the suggested studies for any new opioid product. Certainly, the guidance doesn’t require that abuse-deterrence be demonstrated as a condition of marketing approval. However, as payers have made it clear that they won’t add abuse-deterrent opioids to their formularies or preferred drug lists until a product is granted this labelling claim, it would be extremely foolhardy, in my opinion, for any opioid drug sponsor not to complete such “suggested” studies.


In my view, it’s unlikely that the two “external experts” who attended the meeting with Ross Murdoch and Paul Gavin were prospective partners. It is a requirement of the FDA that a list of planned attendees be supplied in advance of the meeting. It is stated that  

The list should…include the names, titles, and affiliations of consultants and interpreters, if applicable.

Also, the FDA advises that, because such meetings are multi-disciplinary, appropriate technical experts to cover all those disciplines, representing both the sponsor and the FDA, should be present.

Usually the format of meetings prior to and during the IND stage is multidisciplinary, involving Agency personnel in clinical, pharmacology, pharmacokinetics, chemistry, microbiology, statistics, and other disciplines. Sufficient time should be allotted during multidisciplinary meetings to discuss CMC issues. Of particular importance are CMC-related issues that affect other disciplines. The sponsor can provide a brief introductory presentation of CMC information; however, the majority of the meeting time allotted to CMC should be used to discuss specific CMC issues. Appropriate technical experts (e.g., chemists, microbiologists, biologists) representing the sponsor and the Agency should be present during all discussions of CMC-related issues.

It was stated in the announcement that the FDA fielded a 15 member panel from the FDA Division of Anesthesia, Analgesia, and Addiction Products for the meeting. Well-qualified as Dr Murdoch and Dr Gavin may be in their particular disciplines, I think that there would surely be areas where the assistance of external experts would be required.


The key significance of the outcome of this meeting with the FDA, in my opinion, is that it will likely unblock previous hurdles to partnering the TPM oxymorphone patch. Pharma decisions about whether to take on an asset for development and how much to pay for it are informed by lengthy calculations that include forecasting development costs and sales revenues and then discounting for time and risk. The FDA guidance provided on the TPM oxymorphone patch should assist any prospective partner in making such calculations.


It’s been a tortuous and torturous path to date for the TPM oxymorphone patch. It’s now over 5 years since POH  announced successful delivery results for a TPM oxymorphone patch containing only roughly 25% of the amount of the drug normally used in high dosage strengths of Opana ER over the same 3-day dosage period (24/10/13). Three years later (12/12/16) it was announced that a tesa-reformulated patch had increased transdermal flux in-vitro compared to the previous clinical patch, as well as enhanced physical and chemical stability across a range of standard stress tests. Last year (20/03/18), after considerable work and investment put towards a I day patch for the Japanese market for Terumo, it was stated that a number of technical improvements had been enabled which should result in the 3-day patch being much better suited to address the requirements of the global pain market. As POH has now perfected its patch and clarified the regulatory pathway ahead, it’s time to partner. It will be interesting to see the response of Strides, which, to my knowledge, has no presence in either the opioid or transdermal patch space.