Announcing a Drug Approval with a Twist
United Therapeutics just got US Food and Drug Administration (FDA) approval for their new oral prostacyclin agent for the treatment of pulmonary arterial hypertension. The basics, per Bloomberg, were:
United Therapeutics Corp. (UTHR)’s gained U.S. marketing approval for the oral version of its treatment for high blood pressure in the arteries that supply the lungs.
The Food and Drug Administration cleared orenitram, an extended-release tablet, for the treatment of pulmonary arterial hypertension to improve exercise capacity in some types of patients, the Silver Spring, Maryland-based company said today in a statement.
The pill’s active ingredient, treprostinil, is the same as in the company’s approved injection and inhalation solution for PAH, a life-threatening disorder, United Therapeutics said. The FDA had rejected the oral version of the therapy in March and in October>
'This approval marks the first time that the FDA has approved an orally administered prostacyclin analogue for any disease -– and our fifth approval from the FDA for treatment of PAH -- supporting our mission of providing a wider choice of PAH therapies for physicians and patients,' Roger Jeffs, the company’s president and chief operating officer, said in the statement. 'We are grateful for the FDA’s thorough review and will continue to build clinical support for the use of Orenitram.'
But the triumphant announcement by the company CEO had some unusual twists. As reported on National Public Radio's (NPRs) Shots blog,
'When I started the company 17 years ago, the only option for treating pulmonary hypertension was intravenous ,' Martine Rothblatt, CEO of United Therapeutics told investors in a celebratory conference call Monday. 'My young daughter looked at me and said, 'Can't there be a pill?''
Now there is
'What it has resulted in is something that as the parent of a lovely young lady with pulmonary hypertension, I cannot even put into words, the emotional meaning that it has to have a pill form of prostacyclin,' Rothblatt said.
It appears to be such a warm and happy story. A mother is so concerned about her daughter's serious illness that she founds a company to develop treatments for it. Now many years later they have come up with something groundbreaking.
How could anyone not shed a tear? How could anyone not be happy about this triumph of commercial drug development.
However, while it may seem snarky to point this out, drug development is usually about issues other than "emotional meaning," and this discussion of emotional meaning took place during the public relations/ marketing blitz put on after the approval of the marketing of a new drug, so maybe closer examination, and some skepticism are warranted.
How Well Does Orenitram Work?
The quote above from the CEO was about "emotional meaning," not efficacy or effectiveness. In fact, the blog post by Mr Hensley hinted at and a review of the one relevant published article strongly suggested that the drug really had minimal efficacy, and possibly benefits that failed to outweigh its harms.
Mr Hensley wrote,
The FDA approved Orenitram on the basis of a study that gauged its safety and effectiveness as a standalone treatment. The drug helped people walk a little farther in a timed walking test. The most common side effects seen in the study were headache, nausea and diarrhea.
On my review of the evidence....
A single randomized controlled trial(1) showed that patients given treprostinil could walk on average 26 meters (less than 100 feet) more in 6 minutes after 12 weeks of treatment than they could at the beginning of the treatment, while those given placebo were only able to walk about as far as they did before. The treated patients also had some improvement in their shortness of breath. On the other hand, they were substantially more likely to experience adverse effects, particularly nausea, vomiting, diarrhea, flushing, jaw pain, or pain in the extremities.
Furthermore, the study lasted only 12 weeks, and provided no information about outcomes after that. Treated patients were not spared overall worsening of their clinical situation compared to untreated patients. Treated patients were no less likely to be hospitalized or to die.
Various aspects of its design may increase doubts about its validity, including emphasis on a "modified intention-to-treat population" which was not clearly defined, a relatively high rate of premature study drug discontinuation, and a complex statistical analysis scheme which seemed unnecessary to assess the main results of a randomized controlled trial.
Finally, the generalizability of the study was limited to patients already optimally treated with conventional therapy, and perhaps by ist predominantly Asian female population.
So the only apparently positive trial of trepronsinil did not provide good evidence that its benefits outweighed its harms. At best, some patients might find that the modest increases in exercise capacity and decreases in dyspnea it may produce may be worth nausea, vomiting, diarrhea, flushing, or jaw or extremity pain.
Note that treprostinil is an oral version of a type of compound called a prostacyclin. As noted above, United Therapeutics markets other forms of prostacyclin. However, the latest (2005) Cochrane Collaboration systematic review of this class of drugs for pulmonary arterial hypertension only found evidence that the drugs helped when added to first-line drugs to improve symptoms for the short-term, no more than 12 weeks. It found no evidence that prostacyclin prolongs survival, or lessens complications of the illness(2)
So having an oral prostacyclin treatment for PAH may have emotional meaning, but the pill, while likely more convenient than an injectable prostacyclin, does not seem to have sufficient efficacy to outweigh its harms for many patients.
What Does Orenitram Cost, and Why?
But United Therapeutics may have been able to make one aspect of this drug superlative, - its price. Per Scott Hensley in the Shots blog,
Orenitram won't be available for sale for about six months, the company said, and its exact price hasn't been determined either. But it will be very expensive, about $150,000 a year, according to an estimate by Dr. Mark Schoenebaum, an industry analyst with ISI.
That would be about three times the median US family income. But the CEO shrugged concerns about the price off,
Rothblatt acknowledged that the cost of the drugs is high but manageable, because pulmonary hypertension remains pretty rare, though the exact prevalence is hard to pin down.
One explanation for that amazingly high price comes from a post on Forbes by Matthew Herper,
She commercialized [prostacyclin] ..., and was able to get investors interested because she realized there was no maximum price insurers would pay for an effective drug. United Therapeutics became one of biotech’s great success stories.
A lack of an upper limit on pricing has other effects of course. According to Morningstar, the company's sky high pricing enabled a net profit margin over 33% in 2012-13. According to the United Therapeutics 2013 proxy statement, CEO Martine Rothblatt's total compensation is $7,958,328. Three other executives got more than $4.5 million.
So I imagine that marketing a drug that may produce so much revenue may have emotional meaning for company executives. On the other hand, in this era of high insurance deductibles and co-payments it may have considerable negative emotional meaning for patients.
Some Off-Key Notes
The recent publicity about the new oral prostacyclin did not dwell on an issue that appeared earlier in a December, 2013, press release from United Therapeutics about its other prostacyclin products,
United Therapeutics Corporation (NASDAQ: UTHR) announced today that it has received a subpoena from the Office of the Inspector General of the Department of Health and Human Services reflecting an investigation by the United States Department of Justice, principally represented by the United States Attorney's Office in Baltimore. The subpoena requests documents regarding Remodulin® (treprostinil) Injection, Tyvaso® (treprostinil) Inhalation Solution and Adcirca® (tadalafil) Tablets, including the company's marketing practices relating to these products.Instead, as we discussed above, the CEO of the company that will market this very expensive but not very efficacious drug went out of her way to bring up emotional issues about her own daughter's illness. Certainly, anyone can believe the CEO was motivated to develop prostacyclins for PAH by concerns about her daughter's own illness. However, focusing on such emotional issues may also distract from concerns about other aspects of the company's marketing.
So maybe it is not a surprise that she decided to name the new drug in a personal way,... But she did not name it for her daughter. Again per Scott Hensley,
Now there is: Orenitram. The name comes from 'Martine Ro,' as in Martine Rothblatt, backward.
Instead, Martine Rothblatt names her company's new drug for.... herself.
So what is this very emotional and personal drug marketing/ public relations campaign really about?
On Smarm in Health Care
So it appears that United Therapeutics and its CEO used what may now be called smarm to promote their vested interests and divert attention from uncomfortable facts.
In a now widely read and commented upon article in Gawker, Tom Scocca asserted that smarm has become "an omnipresent, unnamed cultural force." Some aspects of smarm, as discussed in the article,
Smarm is a kind of performance—an assumption of the forms of seriousness, of virtue, of constructiveness, without the substance.
it expresses one agenda, while actually pursuing a different one. It is a kind of moral and ethical misdirection. Its genuine purposes lie beneath the greased-over surface.
Smarm, whether political or literary, insists that the audience accept the priors it has been given. Debate begins where the important parts of the debate have ended.
So the smarmy element in the public relations about Orenitram was the misdirection created by invoking the CEO's daughter's illness and its emotional ramifications. By focusing on an emotional issue which apparently only the callous could dismiss, the issues of the drug's minimal efficacy, frequent side effects and very high price were eclipsed. Yet they, not the emotional connection between a particular parent and chile should be salient to patients, doctors, regulators, and the general public.
(The issues of the investigation of the company's marketing of other prostacyclin products, and the egotism implied by the drug's name were certainly eclipsed as well.)
Presumably by raising these truths which might be unpleasant to United Therapeutics executives, I am now guilty of "snark." As Scocca pointed out, one aspect of smarm is to exile reasonable criticism and skepticism as "snark,"
What is snark reacting to?
It is reacting to smarm.
So snarky as it may be, I believe that the major considerations for patients and physicians when considering a therapy - like Orenitram - should be the benefits versus harms of the the therapy for the individual patient, and the strength of the evidence supporting both. The more marketers, public relations functionaries, and executive try to distract from that, and the more smarm they employ to do so, the more skepticism is required.
1. Jing ZC, Parikh K, Pulido T et al.Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation 2013; 127: 624-633. Link here.
2. Paramothayan NS, Lasserson TJ, Wells A et al. Prostacyclin for pulmonary hypertension in adults. Cochrane Review 2005; Link here.