Combination Products: Is A Different Regulatory Approach Needed? 
Posted by Carlos on Sep 15, 2014

 

This morning, California-based Avanir Pharmaceuticals announced that their combination of dextromethorphan HBr and quinidine sulfate (AVP-923) hit their Phase II endpoints in Alzheimer’s Disease:

Treatment with AVP-923 was associated with significantly reduced agitation as measured by the primary endpoint, the agitation/aggression domain score of the neuropsychiatric inventory (NPI) compared to placebo (p=0.00008).  The reduction in agitation was observed in both stage 1 (p=0.0002) and stage 2 (p=0.021) of the Sequential Parallel Comparison study design.

In addition, improvements were also seen in a majority of the secondary endpoints including the NPI total score (p=0.014), clinical global impression of change-agitation (p=0.0003), patient global impression of change (p=0.001) and measures of caregiver burden (p≤0.05).

This comes 9 months after this same drug combination failed to hit Phase II endpoints in a study of central neuropathic pain secondary to multiple sclerosis.

The Phase II success comes on the heels of a recent meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee in which a combination of nevibolol and valsartan (Actavis) was not recommended for approval.

In that meeting, detractors against the combination voted against a recommendation for approval for several reasons:

Lack of Clinical Benefit – Some committee members concluded that the combination did not deliver a meaningful clinical benefit over the individual drugs.

Perceived Efficacy Benefit –  Some committee members eschewed the combination by arguing that prescribers might view the combination as “better” than single drug alternatives.

Both reasons were countered by other committee members who concluded that the combination “makes sense.” Further, some argue that the combination could improve compliance, thereby resulting in an improved clinical benefit.

This notion spilled over into the next day’s meeting, during which a theoretical discussion of another logical combination of an anti-hypertensive, aspirin, and a statin was discussed.

A rather puzzling argument against combinations was presented by a physician who argued that combinations can cause confusion.

Patients, for example, may not realize what drugs they are taking with the polypill and, as a result, physicians may end up prescribing one of the medications in the polypill, giving patients a double dose of the same medication. 

These events, and other recent combination product regulatory rulings, led to an internal discussion on the merits of applying the same rules to combination products versus stand-alone products.

In our non-scientific, distinguished panel-less debate, two categories of combination products were identified:

Straight Clinical Benefit – These are combinations which demonstrate a superior clinical benefit to either the individual components (alone or in combination) or existing standard of care. This is where novel combinations result in unexpected clinical outcomes, such as the combination of naltrexone and bupropion in Contrave.

Compliance Benefit – No direct clinical benefit in a short-term clinical trial, but the mere act of improving compliance results in a clinical benefit. This is similar to the made by oral controlled release drug delivery companies who develop QD formulations of drugs normally taken TID or even BID.

Now the insurers will argue, perhaps rightly, that compliance is not demonstrable in a clinical trial, and therefore no clinical benefit can be demonstrated.

But herein lies the problem. Any compliance benefit may be immeasurable within the relatively short-term confines of a clinical trial, especially cardiovascular clinical trials.

To put it another way, can you detect a favorable clinical outcome in a 52-week clinical trial?

Perhaps. Perhaps not.

One way to address the issue is to have an approval based on non-inferiority, with an obligation to follow patients over a longer period of time. This will allow researchers to detect benefits from compliance that the combination is purported to provide.

In our view, we think we need a bit more flexibility from the FDA with respect to the approvals of combination products. Even if they are combinations of existing drugs without incremental efficacy or safety claims, there may be patients who, in the eyes of the physician, will benefit from this combination.

Pharmacists can play a key role in ensuring that patients are not prescribed or taking two doses of a single drug.

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