Naproxcinod review sparks debate over role of off-label promotion in FDA approval decisions
17 May 2010
Sue Sutter
The recent US FDA advisory panel review of NicOx's anti-inflammatory agent naproxcinod sparked a debate between the agency and its outside experts over whether the potential effects of off-label promotion and literature on unapproved uses should be considered in drug approval decisions.
The FDA's view that the panellists and the agency should take into account the potential for "subtle" off-label promotion of naproxcinod's potential blood pressure-moderating effects was repulsed by some committee members, who believed it inappropriate to speculate on whether the company would engage in illegal marketing.
Concerns about the potential for questionable promotional practices are often discussed at advisory committee meetings, particularly those involving opioid formulations purported to be abuse-resistant. However, the discourse between FDA staff and members of the agency's arthritis and drug safety/risk management advisory committees was striking given the forcefulness of FDA staff views and the resistance by some panellists to impute the past conduct of some pharmaceutical firms to a company that has never before marketed a product.
Naproxcinod is a first-in-class cyclooxygenase-inhibiting nitric oxide donator (CINOD). After oral ingestion, it is hydrolysed to naproxen and nitric oxide. Naproxcinod was developed with the intent of reducing the toxicities associated with nonsteroidal anti-inflammatory drugs (NSAIDS), specifically blood pressure elevation and gastropathy. The nitric oxide component is thought to stimulate GI protective factors that are negatively affected by NSAIDS and to counteract the rise in blood pressure seen with the older drugs.
The advisory panel overwhelmingly recommended against approval of naproxcinod for osteoarthritis ( scripnews.com, 13 May 2010). Panellists were not convinced that naproxcinod was non-inferior to naproxen, and they said longer-term safety data were needed, particularly since other NSAIDS used in the treatment of arthritis, such as the COX-2 inhibitors, were shown to have adverse CV outcomes only after long-term studies. Most of the safety data in the NicOx NDA was limited to a duration of 52 weeks or less.
In addition to a CV outcomes study, committee members called for more research on the drug's effects in the elderly and interactions with other medicines that could lead to hypotension, such as PDE-5 inhibitors, nitrates, anti-platelet therapies and antihypertensives. Some panellists also recommended longer-term study of naproxcinod's GI effects to assure that the drug's nitric oxide component does not cause bleeding.
While NicOx seeks an indication only for treatment of the signs and symptoms of osteoarthritis, it is requesting that data on naproxcinod's purported blood pressure-moderating effects be included in other sections of the product label. Inclusion of this data is critical for NicOx, as it would allow the company to use this information in its advertising and promotional materials. Without the ability to market naproxcinod's BP-moderating effects, NicOx or any future commercial partner would have difficulty creating a niche market for a drug that is purported to be comparable in efficacy to naproxen, which is available as a cheaper generic.
If the data were excluded from the label, company sales reps would still be able to supply physicians with reprints of published studies about the drug's BP effects, although these would not reflect the FDA's or panels' evaluation of the data.
How physicians would likely use this information factors into the agency's ultimate decision on the drug's approvability, FDA officials said. "We can't ignore what's been proposed as benefit," Dr Sharon Hertz, deputy director of the FDA's division of anaesthesia and analgesia products, said of the purported safety advantages of naproxcinod compared with naproxen. "We have to look at the whole picture and look at what all of that does in terms of the overall risk/benefit to the public and how it's going to influence the clinicians."
Panellist Dr Sidney Wolfe, director of Public Citizen's Health Research Group and an ardent critic of the pharmaceutical industry's promotional practices, said that even if NicOx labelling excluded any mention about harm reduction or BP moderation, there is nothing stopping NicOx from engaging in the type of "subtle off-label promotion" practised by other companies.
"They will not be able to take an ad out because it's not in the labelling, but clearly in every way they will do whatever they can because otherwise there's nothing unique about this drug," Dr Wolfe said. "Why would someone pay four or five or 10 times more for [naproxcinod] unless it had an advantage?"
Panellist Dr Christy Sandborg, a paediatric rheumatologist from Stanford University in Palo Alto, California, said most clinicians are unlikely to read the evidence base behind a drug. Approving naproxcinod without including the BP data in the label "could actually even be worse" because any subtle communication by sales reps about the drug's BP effects would lack fair balance on the risks and safety concerns, she said.
physician incompetence
"I'm not convinced that there's a demonstration of safety but I do have some concern about some of the direction of this discussion," said panellist Dr Michael Domanski, chief of the atherothrombosis and coronary artery disease branch of the National Heart, Lung and Blood Institute. "I don't think it's fair in a regulatory proceeding like this to project that there are going to be some nefarious or inappropriate activities ... by the sponsor.
"I don't think that's a hill they should have to climb. We've been presented with no data to suggest that's the case. I really think that extrapolates things far beyond what's appropriate. They either demonstrate safety and efficacy or they don't.... There's no way you can ask the sponsor to account for physician incompetence. It's not their job."
"We see this type of under-the-table information going out to practitioners all the time," countered Dr Bob Rappaport, FDA division director for anaesthesia and analgesia products. "The fact is this information's already out there. It was all over the press this week. The company's stocks were discussed in every newspaper. ... The word gets around, and you need to take into consideration the impact that's going to have on use by people who don't read the evidence base."
"We're not saying the sponsor is doing anything inappropriate or illegal," Dr Rappaport added, to which Dr. Domanski countered, "I don't think the fact that other people do should be a factor in their regulatory submission."
"Fortunately, we have a public health mandate and Congress is very interested in assuring that the public is protected," Dr Rappaport said.
Panellist Dr William Greene, chief pharmaceutical officer for St Jude Children's Research Hospital in Memphis, Tennessee, agreed that data on the BP effects would be in the public domain and may or may not be correctly interpreted by practitioners. "Historically, the FDA simply decided ... is it safe and is it effective compared to the placebo, and then they allowed the marketplace, medical practitioners, to determine whether the drug should be used or not. It seems to me we're maybe ratcheting things up a little higher towards the consciousness of public safety and comparative effectiveness. And I'm fine doing that, I want to be sure that's our charge before I do that."
Not surprisingly, the panel's industry representative took a dim view of the FDA's stance that the potential effects of promotion should be factored into an approvability decision. "In a regulatory context the FDA is supposed to be making its decisions in the framework of the Food, Drug and Cosmetic Act, which provides specific requirements for what it takes to get a drug approved and specific requirements for what it takes for the FDA to deny it," said Dr Bruce Burlington, said industry consultant. "Speculation about what might happen when doctors read publications in the literature are not one of those reasons for the FDA to deny approval."
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