The recent approval by the FDA of the first non-hormonal product for the treatment of menopausal hot flashes (vasomotor symptoms) in women is interesting for at least two reasons associated with its drug-repurposed basis, one to do with regulation and the other to do with litigation.
The product, Brisdelle, contains the well-known anti-depressant paroxetine, a selective serotonin reuptake inhibitor (SSRI), and which as a class have been claimed for many years to have effects in this area. Another SSRIs also showing clinical efficacy is escitalopram; in 2011, a randomized, placebo controlled Phase II clinical trial of 205 menopausal women also reported a significantly reduced number of hot flashes treated with escitalopram over an 8-week period.
Though uncomfortable, hot flashes are not life-threatening, and the risk-benefit for any new drug product for this condition is subject to a pretty stringent safety review. In the case of Brisdelle, the FDA’s Reproductive Health Drugs Advisory Committee concluded that the overall benefit/risk profile did not support approval by a 10-4 margin; nevertheless, the eventual FDA decision came down the other way. One of the main areas of concern for the new product was suicidality.
The excess risk of suicide associated with SSRI use, particularly with paroxetine, derived from studies in depressed children and adolescents conducted by Glaxo in the period leading up to 2003. On the contrary, to my knowledge, studies with adults do not show increased risk of suicidal thoughts or behaviour. Depression is of course a risk factor generally for suicidal thoughts and behaviour, and as I have pointed out before, that risk is greater in certain groups of patients than others. One can assume that the risk is very significantly lower in the patients with hot flashes, namely middle aged women, many of whom will be mothers and most of whom will not be depressed, than in depressed teenage boys. Moreover, the dose of paroxetine in Brisdelle is lower, at 7.5mg, compared to 20mg in the lowest treated group in any of the Glaxo trials. Nevertheless, to cover all the bases as it were, the FDA decided to include a black box warning on the Brisdelle product.
Although it has not yet appeared on the FDA Orange Book website, I would expect Brisdelle to command a 3-year period of data exclusivity around the regulatory submission package protecting the marketing company, Noven Pharmaceuticals Inc., a subsidiary of Hisamitsu Pharmaceutical Co. Inc.. A brief search of the patent databases could identify no separate use patent claiming the use of paroxetine for the treatment of hot flashes.
So that’s the regulatory picture: the first non-hormonal product in this class, getting FDA approval (just) but with some caveats.On the litigative side, these caveats may actually be of some help to Noven. Their main concern, I would think, would be competition from the large number of generic companies that market paroxetine, and could benefit from the clinical studies showing its benefit in hot flashes without having invested in regulatory standard studies supporting this new indication. The generic products are not labelled for treatment of menopausal hot flashes. However, the medical profession can prescribe them perfectly legally, (even within the 3-year FDA regulatory stay), and this greatly limits the commercial opportunity for Noven’s product. The slightly lower dose of paroxetine (7.5mg) employed in Brisdelle compared to the generic formulations for depression (10mg and up) serves to a certain extent to differentiate the two classes of product, but to my mind, the greater protection comes from the way insurance companies view reimbursement and evolving framework for legal liability surrounding off-label use in the USA.
Firstly, from the viewpoint of the patient, there is no assurance that insurance companies will reimburse patients for off-label prescription costs. But a far greater area for concern surrounds the physician’s own liability in case of a side effect or adverse event. In the case of Brisdelle, the black box warning about suicidality, however small the risk, is something to consider very carefully indeed.
Consider the medical liability in a hypothetical case involving a menopausal mother of 4 who is prescribed a course of generic 10mg paroxetine rather than the branded 7.5mg alternative, and subsequently commits suicide. I do not intend to argue the legal merits here and now, but the essential difference in dose of paroxetine used in the treatment of menopausal hot flashes relative to that used in depression would seem to me to be a bear trap for the physician, making it difficult to argue patient benefit in a decision to substitute an off-label generic product for a branded on-label alternative. On the issue of whether the drug is causal of the outcome, the low intrinsic rate of suicidal thoughts and behaviour in patients with hot flashes, offers the litigant the opportunity to argue more strongly that a suicidal event resulting from a prescription is indeed drug-associated rather than caused by another factor.
Support for this position comes from a case against a pediatric nurse practitioner who prescribed fluoxetine off-label to an adolescent girl, for whom anti-depressants were not (according to the judgment) ‘indicated or appropriate’. In that case, the patient attempted suicide 3 weeks after she had begun antidepressant treatment and, from the brain damage she suffered as a result, died some 3 years later. The fact that the risk of suicidal behaviour had been highlighted by the FDA was a factor in the size of the award, of $3,459,892.
In my view, litigative liability, more than regulatory data protection, is more likely to protect Noven’s US franchise from generic substitution in the near term; but this factor is enhanced in its power by the finely balanced risk/benefit regulatory decision taken by the FDA, such that Brisdelle was approved against the advice of the Advisory Committee.