The combination rule aye..that ‘ole chestnut. There is much...

The combination rule aye..that ‘ole chestnut. There is much discussion on this topic between analyst/analyst and analyst/management. Unfortunately we don’t have the ‘detail’ (I believe only the FDA have this), and this causes a great deal of head-scratching. My discussions have centred around; what information needs to be provided in order to get approval under the rule. In a previous post I mentioned that there was probably one stone left unturned as part of the NDA submission; and that stone is ‘abuse’. When we look at the submission under the combination rule, 2 key risks are apparent (obviously others but I view as minor):

a) Provision or lack thereof; information relating to abuse
b) Provision or lack thereof; information relating to adverse events

Point a) is anecdotal, as the NDA does not require the sponsor (QRX) to show evidence of abuse i.e the ability to chop it up and therefore get more people addicted to morphine. Point b) boarders on fact, but is actually anecdotal. Because it is more of a ‘fact’ than a) it is worth more thought. In terms of events in time, an extract would look like this:

1. May 2008 Phase III: combination rule study 008
2. June 2011 Adverse events study 022
3. August 2011 NDA filing
4. June 2012 CRL

When the CRL was received, the apparent message that the agency delivered was “more info re; safety and effectiveness of MoxDuo”. Around this time I know for certain that QRX was also reviewing the results of the 022 study, in preparation for approval (that susequently didnt happen). I believe they were doing this because they needed some clear and supportable claims relating to safety for marketing activities. This was the end-game of the study – to demonstrate safety so that they could make the marketing claims. The primary purpose was not to reference data for the NDA submission. This reconciles perfectly with the meetings post CRL, as the agency recommended refiling with more data from the 022 study to assist in the “safety and effectiveness” requirement. The fact of the matter was that 80%+ of the information and data points came from the Phase III study 008 – aptly named combination rule. Obviously the plan for the study was to use it as the basis for the submission.

One of the outcomes of the 008 study was a higher rate of adverse events within the MoxDuo group compared with the oxycodone and morphine groups. This wasn’t necessarily a bad thing, rather the outcome was the result of the IR formulation (12mg/8mg dosage) being 80-100% more potent than oxycodone and morphine as individual components. This was established in a later study (021) in ’09 – not shown in time line above. You can see why studies were conducted in the way they were..i.e slowly building a case.

In my opinion, when the FDA saw the adverse events from 008, questions started to surface, even though 021 explained why. As one of the requirements within the combination rule (for drugs) is to show superiority over the ‘components’ the FDA raised a red flag. Not an ‘X’ but a flag nonetheless. As I mentioned previously, few outcomes of the 022 study made it into the NDA submission. There is no doubt in my mind that after questioning QRX on it, the FDA recommended including data from this study to meet the requirement – again it reconciles perfectly as the FDA raised “safety…” and QRX initiated the 022 for safety purposes that were unfortunately, unrelated to filing activities. I really hope my account is clear MK.

Anyway, the resubmission has included this information. However what really pushes the belief that approval is a surety – from a company perspective – is that the 022 study went on to show that despite increases in adverse events, superiority against “safety and effectiveness..” was evidenced. This conclusion was formed from the results in 008 plus 021, plus 022:

- Increase in adverse events, limited to vomiting, dizziness, nausea and balance (normal for opioids, but explained by potency in 021).

- Decrease in severe adverse events, limited to respiratory depression.

What I am getting at is that in light of the increase in adverse events, the FDA is likely to judge the drug as superior because a simple spew (and more of them), means nothing in comparison to respiratory depression...which I have learnt kills you. As this is the most common severe adverse event when delivering an opioid, a favourable outcome is likely. BUT, as always, the devil is in the detail and by that I mean the 022 study results are ‘so, so’. Some of what is documented in there is ambiguous and this could trip them up. In saying this I have no direct experience in the medical profession, its in-direct in the form of analysis so really the job is better left to JH and the QRX team to ensure the quality is there.