The newest drug for congestive heart failure, Entresto, a fixed combination of valsartan and sacubitril, has just hit the market at an elevated price. Like other drugs recently introduced as blockbusters, the high price does not seem clearly justified by clinical evidence about the drug's benefits and harms.
Questions Raised by the One Big Published Controlled Trial
Last year, we discussed the hoopla around a study of a new drug for congestive heart failure (CHF),(1) a fixed combination of valsartan and sacubitril. Also, on the now defunct CardioExchange blog, Dr Vinay Prasad discussed the same study (look here, and scroll down.) We both concluded that the (apparently multiply flawed) design of the study left important questions unanswered.
Does Sacubitril Actually Work?
The PARADIGM-HF study compared patients given valsartan plus sacubitril to patients given enalapril. Valsartan, an angiotensin receptor blocker (ARB) and enalapril, an angiotensin converting enzyme inhibitor (ACEI) have both been shown separately to improve symptoms and function, decrease morbid events, and extend life for patients with systolic CHF. However, the PARADIGM-HF study compared a high dose of valsartan, 160 mg twice a day, (plus sacubitril) to a medium dose of enalapril, 10 mg twice a day. Apparently, no trial comparing just valsartan 160 mg to enalapril 10 mg twice a day has been done. So it is quite possible that a high dose of valsartan is better than a medium dose of enalapril. Thus, PARADIGM-HF could not prove that sacubitril has any benefit independent of high dose valsartan.
What are the Adverse Effects of Sacubitril (With or Without Valsartan) Likely to be in Practice?
The PARADIGM-HF design prevented any assessment of the adverse effects of sacubitril independent of those of valsartan. Furthermore, the trial had an active run-in period which resulted in the exclusion of patients who failed to tolerate valsartan-sacubitril in a pre-trial run-in period. This effectively biased downward the prevalence of adverse effects due to the combination reported during the trial. Finally, the trial, while big, was not big enough to discover rare but severe adverse effects. Thus, one cannot easily tell how the benefits of valsartan-sacubitril compare to its harms, or how the benefits of sacubitril alone compare to its harms.
How Would Valartan-Sacubitril Work for Patients with Common Diseases in Addition to CHF?
The study excluded patients with common conditions that may afflict CHF patients, including relatively severe coronary artery disease, severe lung disease, ulcers and liver disease. CHF patients are often elderly and often have other diseases, but how the drug might work for them is unclear.
Other Doubts and Questions
In a recent Medscape post, Dr John Mandrola noted additional problems with the study that raise doubts about its validity. These included its early termination, the very large number (1000) of study sites raising doubts about quality control of implementation and data collection, and the finding, not emphasized by the authors, that valsartan-sacubril caused an apparent increase in hypotension, a significant issue for CHF patients.
As far as I can tell, there have been no other big trials of sacubitril, with or without valsartan, so there are no other source of clinical research data to address these questions. As we noted here, one of the most prominent PARADIGM-HF investigators tried to rebut Dr Prasad, but did so mainly by employing logical fallacies.
So in my humble opinion, there is only weak, ambiguous data to show valsartan-sacubitril produces benefits that outweigh its harms for congestive heart failure patients seen in usual clinical practice.
More Enthusiasm and Hype about Entresto
These questions about the one big study of valsartan-sacubitril did not deter the US Food and Drug Administration (FDA) from approving it. As soon as it was approved, the hype machine started up in a big way.
'This is one of those once-in-a-decade kind of breakthroughs, to get a drug that extends life so substantially,' David Epstein, the head of Novartis’s pharmaceutical division, said in an interview.
Clyde Yancy, chief of cardiology at Chicago’s Northwestern Memorial Hospital, said that Entresto is 'one of the few times that we have identified a medication that is better than the standard. It’s clearly superior to what we have.'
A year later, I continue to feel that this is, in fact, a reflection of a new day—for patients and for the opportunity to reenergize the community. It's also a huge endorsement for the importance of science in cardiovascular medicine.
And Dr Milton Packer (who had countered Dr Pradad's critique of PARADIGM-HF with logical fallacies, said,
I think they considered the data to be compelling and strong. And I think that when physicians look at the data, they will be convinced that this drug will become a cornerstone of treatment for heart failure.
The Medscape article did document some doubts. Dr John G Cleland of Imperial College, London, UK allowed that the active run-in group was among "issues that have yet to be settled," Dr Marriell Jessup who had written a positive editorial in the NEJM when the trial was published(2) allowed that the lack of patients with co-morbities might be a problem. Finally, Dr Yancy allowed that the early termination might be a problem. Yet each focused on a single problem with the study, and none of these physicians seemed to acknowledge the totality of the study's problem. Neither did any of them seemed to let these doubts dampen the enthusiasm, e.g., at the end of the article, quoting Dr Yancy,
Can we change the narrative? I believe it's time to take the 'failure' out of heart failure and look at what we can do to generate success.
Note that the article disclosed Dr Cleland does research funded by Novartis, maker of Entresto, and Dr Packer is a consultant to Novartis. Is is possible these commercial relationships tempered any concerns that might have had about the study design.
I realize that CHF is a miserable problem for patients, and clearly leads to severe symptoms, multiple hospitalization, and sometimes early death. So I understand why people may be enthusiastic about a new therapy for it, especially if their research or consulting is funded by the drug's manufacturer. But is it crystal clear the latest innovation is that good?
Billions of Dollars in Play
But never mind those unanswered questions and the multiple problems with the PARADIGM-HF trial, Entresto, the trade name for valsartan-sacubitril will not be cheap. Per the NY Times,
Novartis said Entresto would cost about $12.50 a day, or about $4,500 for a year....
Novartis wants to convince you that it's not really that expensive
Mr Epstein said the price was 'really quite reasonable,' given that some drugs for other diseases cost many times that amount and confer less benefit.
He is certainly right that some drugs are even more expensive. However, is argument is just an appeal to common practice. Whether the prices of other drugs are justified by strong evidence about their benefits and harms may not be clear. The benefits conferred by Entresto, and the harms it may cause as we belabored above, are really not that certain either.
In the financial news, you could almost imagine the salivation. Per the WSJ,
Wall Street predicts Entresto will be a blockbuster, with Leerink Partners estimating that annual global sales could top $6 billion by 2024.
Expectations for Entresto have been building since it won early U.S. approval and Novartis set a higher than expected price, with analysts now forecasting $4.7 billion of sales in 2020, according to Thomson Reuters Cortellis.
Chief Executive Joe Jimenez said Entresto sales would take time to ramp up but growth would accelerate in 2016. Reception to the new drug, which Novartis started shipping within 24 hours of U.S. approval this month, has been good and there was little resistance to the $12.50 daily cost.
'The average hospital stay for a heart failure patient in the United States is $11,000,' Jimenez told reporters. 'So we are not receiving pushback on the price because I think this is seen as good value.'
Compared to what? Again, it is not clear that Entresto would be better than generic enalapril dosed at 20 mg/day, which is a lot cheaper than $4,500 a year. But could it be that visions of billions of dollars have clouded some peoples' thinking, at least people paid by or owning stock in Novartis?
Summary
We have posted frequently about the blockbuster drug Sovaldi promoted as a cure for deadly hepatitis C infections. Yet while the evidence that Sovaldi and its competitors are really so good, really provide cures, and really will prevent many patients from dire consequences of hepatitis C is not so strong, the US price of these drugs is stratospheric.
Now we have Entresto, whose price is not so stratospheric, but still quite high, and whose benefits compared to its harms are not clearly supported by evidence from clinical research.
Unfortunately, Entresto (valsartan-sacubitril) is now one of a long line of new drugs that are breathlessly hyped, often by people who should know better, despite weak evidence in their favor. It is one of a long list of examples of drugs approved based on poorly designed studies whose design flaws seem likely to make their commercial sponsors' products look better. As a recent post in Health Affairs by Christopher Robertson reminds us, while many industry supporter act like allowing drug and device manufacturers to support (and usually control) most of the clinical research meant to evaluate their own products in inevitable,
When one steps back from our current practices, it should appear rather odd that we rely on companies to test the safety and efficacy of their own products. It would be as if a litigant were allowed to choose and fund its own judge, or an athlete to hire her own referee.
To convince us that we live in the best of all possible worlds, however, the media is full of proclamations that we are in a new era of marvelous medical and health care "innovations" that will bring us all untold benefits. The notion that physician-industry collaboration is necessary to continue to produce these wondrous "innovations" is a talking point used to counter those who criticize conflicts of interest affecting academic medicine (look here). Yet the evidence supporting many game-changers and blockbusters is often weak and ambiguous. This rarely seems to deter the drug, device and biotechnology industry from charging more and more for them.
The sober, evidence-based medicine approach is being lost in all the hoopla and hucksterism. We are adopting treatments of unproven value, whose benefits may be much less, and harms may be much worse than we imagine, and paying unconscionsable prices for them. The results for patients and society include our ever rising health care costs, ever challenged access, and no evidence that outcomes are better for patients.
True health care reform would encourage sober discussion of the evidence, of benefits and harms, and of fair pricing, and would challenge the hype, hucksterism, and conflicts of interest that all swirl around modern health care.
References
1. McMurray JJV, Packer M, Desai AS et al. Angiotensin - neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; DOI: 10.1056/NEJMoa1409077 Link here.
2. Jessup M. Neprilysin inhibition - a novel therapy for heart failure. N Engl J Med 2014; DOI: 10.1056/NEJMe1409898. Link here.
Former President Clinton Talkes to Pharma and Biotech Executives
In mid June, 2015, the Philadelphia Inquirer reported that former US President
Clinton was the keynote speaker at Klick Ideas Exchange, sponsored by Klick Health, a Toronto-based digital marketing agency, along with Veeva Systems and the Biotechnology Industry Organization. BIO, the Washington-based trade association, is holding its annual convention at the Pennsylvania Convention Center this week, attracting 15,000 people.
For his troubles he was apparently paid, however
his foundation did not respond to a request for information about Monday's speaking fee. Hillary Clinton's campaign also did not respond to a similar request. A spokeswoman for Klick Health declined to provide Clinton's fee.
It is likely he was well paid, since his going rate is very high:
disclosure forms indicated Bill Clinton received between $225,000 and $275,000 for each of eight speaches delivered between March 31 and May 14 of this year.
Clinton Endorses the Miraculous $1000 Pill
So what would a former president say to a bunch of pharmaceutical and biotechnology executives and their friends? He chose to talk about the prices of new drugs:
Former president Bill Clinton said Monday in Philadelphia that high prices for some medicines are hard to justify, and the biotech and pharmaceutical industries should try full explanation and disclosure to make their case.
'Explain, explain, explain and disclose, disclose, disclose,' Clinton said in a speech and question-and-answer session before about 200 biotech and health-care executives at the National Museum of American Jewish History. 'Don't expect everybody to love you, but at least they will hear your side of the story.'
Who could quarrel with more explanations and disclosures? President Clinton did not stop there, and went on to opine about prices versus drugs' purported value to patients, with a focus on new drugs for hepatitis C.
Clinton pointed to new hepatitis C drugs, Sovaldi and Harvoni, which are sold by Gilead Sciences for more than $80,000 for a 12-week program of treatment. Those medications often cure a disease that can cause liver disease and eventually lead to transplants or death, which are expensive, too. But the sticker price on the drug has caused a backlash by payers and patients.
'Who wants to let somebody's liver rot? Nobody,' Clinton said. 'Who's got $80,000 to spend? Not many. And if you're a small businessperson and you're in a small pool [of employer-based insurers], are you going to fire somebody who needs that treatment? These are all practical problems, and we can solve them.'
So the implications are clearly - President Clinton thinks it is reasonable to charge $80,000 for a course of treatment with Sovaldi, but society needs to figure out who will pay - Apparently he thinks it is reasonable because without treatment, patients with hepatitis C will get "liver rot," but the drugs will prevent that.
The Evidence Fails to Support the President
President Clinton's preparation for this talk apparently did not include speaking with someone who had critically reviewed the best evidence from clinical studies about hepatitis C, and the effects of new drugs on it, particularly, the effects of sofosbuvir (Sovaldi.) Neither did President Clinton read Health Care Renewal.
If he did, he would have found out starting in March, 2014, we have posted about the lack of good evidence from clinical research suggesting these drugs are in fact so wondrous. The drugs are now touted as "cures," at least by the drug companies, (look here), and physicians are urged to do widespread screening to find patients with asymptomatic hepatitis C so they can benefit from early, albeit expensive treatment.
However, as we pointed out (e.g., here and here) - The best evidence available suggests that most patients with hepatitis C will not go on to have severe complications of the disease (cirrhosis, liver failure, liver cancer), and hence could not benefit much from treatment. - There is no evidence from randomized controlled trials that treatment prevents most of these severe complications - There is no clear evidence that "sustained virologic response," (SVR), the surrogate outcome measure promoted by the pharmaceutical industry, means cure. - While the new drugs are advertised as having fewer adverse effects than older drugs, it is not clear that their benefits, whatever they may be, outweigh their harms.
Furthermore, health care professionals and researchers with heftier credentials in clinical epidemiology and evidence based medicine than mine have since published similar concerns. These included - a report from the German Institute for Quality and Efficiency in Health Care (the English summary is here) - an article in JAMA from the Institute for Clinical and Economic Review (1) - a report from the Center for Evidence-Based Policy (link here) - an article in Prescrire International (2)
These publications and your humble scribe noted that the clinical trials or other types of clinical research about new hepatitis C treatment published in the most prominent journals had numerous methodologic problems that all seemed likely to make the new drugs look better, perhaps intentionally. (See posts here, here, and here.)
But because, as we noted here, concerns about the lack of evidence in support of Sovaldi and its new competitors have been anechoic, it might not have been so easy for President Clinton to quickly determine if hepatits C usually causes "liver rot," and whether Sovaldi almost always prevents "liver rot," and hence might just be worth $1000 a pill.
Hype Wins, Logic and Reason Lose
Unfortunately, the problem is not merely that the BIO folks hired a celebrity to tell them what they wanted to hear. President Clinton has a lot more gravitas than a Hollywood star, even given his famous equivocation about the meaning of the word "is."
More unfortunately in this context, President Clinton is also the husband of the current front running Democratic candidate for President. Should former Senator and Secretary of State Hilary Clinton win the election, would her health policy choices be influenced by the (probably erroneous) belief that the current extremely high prices of medical treatments, particularly new drugs, are reasonable because of their magical curative properties? Furthermore, President Clinton is also the Founder and presumed current leader of the the Bill, Hilary and Chelsea Clinton Foundation whose goals include working "to improve global health and wellness,..." Is this work based also based on the assumption that the astronomical prices of new drugs are justified by their miraculous powers?
Thus President Clinton's apparent endorsement of the wonderful powers of Sovaldi, despite the lack of good evidence underlying them, may carry a lot of weight.
Conclusion
How distorted is health care these days. Misinformation, even disinformation seems to dominate evidence and logic. Concerns about health care dysfunction are suppressed by the anechoic effect. Perhaps inspired by the generic managers who now run health care organizations, everyone seems to have become a health care expert, and so the reach of viewpoints on health care seems to be more about the celebrity of their proponents rather than their knowledge, or the logic and evidence underlying their views.
As a start, true health care reform has to somehow liberate good clinical evidence from where it has been hidden, and encourage logical discourse over marketing, public relations, hype, propaganda, and disinformation.
If only someone who knows something about health care, logic and evidence could get their views heard by ex Presidents and others who dominate our 24/7 conversation.
References 1. Ollendorf DA, Tice JA et al. The comparative clinical effectiveness and value of simeprevir and sofosbuvir in chronic hepatitis C viral infection. JAMA Intern Med 2014. Link here. 2. Sofosbuvir (Sovaldi), active against hepatitis C virus, but evaluation is incomplete. Prescrire Int 2015; 24: 5- 10. Link here.
Monday, May 18, 2015
Why is the New England Journal of Medicine Scolding "Pharmascolds"?
I, a normally quiet blogger on this site, was disquieted by what may be a backlash aimed at quashing the anti-conflict-of-interest movement.
Lisa Rosenbaum just published her second of three treatises in the highly prestigious New England Journal of Medine, scolding "pharmascolds" (see Conflicts of Interest: Understanding Bias — The Case for Careful Study). "Pharmascolds" is the term Rosenbaum and others use for those of us at Health Care Renewal, the Institute of Medicine, and countless medical journals and institutions. Why? Because we dare assert there is great danger when providers practice though saddled by (potential) conflicts of interests in medicine. Such conflicts are created when physicians (up to 94% of us, according to Rosenbaum's research), other health care providers in practice, and health care organizations accept, not only gifts and trinkets, but also large, sometimes clandestine consulting fees and other arrangements from pharma and device companies, all the while providing direct patient care using the companies' products.
Rosenbaum and others say we pharmascolds are essentially self-righteous and obstructionist, holding back the progress of medical science. In this article, she seems to claim that not proving direct patient harm from a specific questionable financial arrangement with a company whose product we may therefore more likely prescribe, speak well of, or publish (pseudo)evidence supporting the use of, is enough of a reason to justify the arrangement.
Wouldn't that be the same as saying, "Until you actually crash into another car while texting, it's ok to text while driving, even if it's distracting."?
Rosenbaum uses mainly anecdote to prove her point, and appeals to a little-quoted, but still important, heuristic/bias called "moral liscensing." Rosenbaum describes the phenomenon correctly: "once disclosure [of a conflict of interest] gets the weight [of guilt] off your chest, you feel liberated and may feel licensed to behave immorally." True. But then Rosenbaum seems to support non-disclosure of acts that create conflicts of interest, because disclosure doesn't decrease the acts themselves.
Rosenbaum goes further. At the same time as she supports non-disclosure of conflicts, she attempts to paint those who accept conflict-generating arrangements and keep them clandestine as victims--afraid to "come out of the closet" because doing so is socially taboo, though the activity is not wrong.
I beg to differ. For certain acts, potential conflicts, and actual conflicts, it seems to me that mere disclosure of the act or conflict shouldn't relieve one of the guilt associated with the act or conflict. It also seems disclosure of a conflict should not make a speaker seem more credible to his/her audience because of its disclosure, though some research Rosenbaum quotes seems to show that disclosure improves credibility.
Perhaps the stronger argument for disclosure is to disqualify people from activities that should be prohibited for people in conflict, as well as to warn people away from engaging in questionable activities that would result in conflicts.
In an unbelievable twist of logic, Rosenbaum seems to be arguing in this article for more, not less of these questionable activities, in the interest of advancing science, until we prove patients are directly hurt by them, i.e., we have a "wreck." Heck, let's get rid of traffic lights too, while we're at it. People have eyes. We should trust them. They should be able to avoid accidents voluntarily, on their own.
In short, how could Dr. Rosenbaum not see that the best solution for the "problem" of conflicts of interests is avoidance when possible? One can't help but wonder if she and the Journal aren't blinded by the shimmer and pull of powerful, influential organizations, ones so shiny, so strong, and so ubiquitous that resistance is just too hard for her, the Journal, and for 94% of us.
Conflicts of interest should be avoided. Society has accepted that improved health will result not just from secondary prevention (e.g., not texting while driving after one has had an accident from the activity), but also from primary prevention (not texting while driving, even before an accident occurs).
Every day seems to bring the latest breathlessly touted innovation in modern health care. The endless hawking of new health care wonders is beginning to inspire some skepticism, but maybe not enough.
The Promotion of Vyvanse for Binge Eating Disorder
For example, at the end of January, 2015, reports of the first ever drug therapy for binge eating disorder appeared. For example, see Jonathan Rockoff writing in the Wall Street Journal
Shire PLC’s drug Vyvanse became the first drug approved for sale in the U.S. to treat some of the estimated 2.8 million adults who have a binge-eating disorder.
Rather ominously, the article described this disorder thus,
Patients regularly eat more food than they need, often when they aren’t hungry and until they feel uncomfortably full, the FDA said. The condition can lead to weight gain, obesity and related health problems.
Furthermore, it appears to be common,
An estimated 2.8 million adults in the U.S. are binge eaters, two times more than those who have the eating disorders anorexia and bulimia combined, according to Shire.
However, now there is a pharmaceutical solution!
In two pivotal studies, binge eating episodes declined to an average of one day a week among patients taking Vyvanse capsules for 12 weeks, down from an average of five days a week, Phil Vickers, Shire’s head of research and development, said in an interview.
'The approval of Vyvanse provides physicians and patients with an effective option to help curb episodes of binge eating,' Mitchell Mathis, director of the FDA’s division of psychiatry drug products, said in a statement.
Because the disease is common, that may mean a lot of money for Shire
For Shire, the approval could eventually add 'several hundred million' dollars in sales, and help the company reach its goal of $10 billion in yearly sales by 2020, said Flemming Ornskov, the company’s chief executive. Vyvanse is the company’s top-selling drug, notching $1.1 billion of the company’s $4.3 billion in total sales during the first nine months of last year.
The only hitch is that all those long suffering victims of binge eating disorder have to be found, and presented with this wonderful new alternative:
One challenge: increasing the numbers of patients diagnosed as binge eaters. Shire estimates that just 3% of Americans with the disease have been diagnosed under the mental-disorder criteria, Dr. Ornskov said.
Brief coverage of the initial approval of Vyvanse appeared in the NY Times. Bloomberg also weighed in, adding to the urgency by underlining how seriously the FDA had handled this:
'Binge eating can cause serious health problems and difficulties with work, home and social life,' Mitchell Mathis, director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, said in a statement.
The FDA gave Vyvanse priority review, a designation for drugs with promise to 'provide a significant improvement over available therapies,' the agency said.
Among the major media covering the rollout, only Reuters noted a potential fly in the ointment in this article,
Vyvanse is an amphetamine which, like other amphetamines, carries the potential for abuse and addiction. They also have been associated with increase blood press sure and heart rate, sudden death, stroke, heart attack, insomnia and psychiatric side effects such as hallucinations and mania.
What Really is the Clinical Evidence Supporting Vyvanse for Binge Eating Disorder?
So Vyvanse is actually lisdexamfetamine, and having been a child when the slogan "speed kills" referred to methamphetamine, not driving automobiles fast, I thought it might be worth looking into the evidence that this somewhat new amphetamine, a relative of that infamous "speed," was now deemed a wondrous treatment for eating too much.
In particular, a recent article in JAMA Psychiatry reported results of one of the two trials Shire did of Vyvanse for binge eating disorder.(1) The study by McElroy et al randomized patients with binge eating disorder to one of four groups, to receive the drug at dosages of 30, 50, or 70 mg/ day or placebo. The investigators followed patients for 11 weeks. The main outcome variable was the number of binge eating days per week reported by the patients.
Patients in all groups were binge eating during approximately 4.5 days/ week at the beginning of the study. At 11 weeks, the average number of binge eating days/ week declined in all groups, dropping 3.3 days/ week for the placebo group, 3.5 for the 30 mg group, 4.1 for the 50 mg group, and 4.1 for the 70 mg group. Thus, by this measure, the difference between patients given placebo versus patients given maximum dosage of the drug was an average decrease of 0.8 binge eating days a week. That does not seem like a very big effect size, or in other words, it seems that the drug had only a small effect on binge eating compared to placebo.
That impression was reinforced by looking at some other study outcomes. The average numbers of binge eating episodes per week at 11 weeks were 1.1 for placebo, 1.2 for the 30 mg group, 0.5 for the 50 mg group, and 0.5 for the 70 mg group. Again, patients given the maximum dose of the drug had only a slightly smaller number of binge eating episodes than those given placebo, reinforcing the impression that the drug is not very effective.
A graph of binge eating days/ week measured over time makes things clearer. It showed that all groups, including patients given placebo, markedly reduced their reported binge eating over the 11 week period. Since the study did not allow any patients to get any other treatment for binge eating other than placebo or the study drug, this again suggests that the drug was not much better than placebo. Further, the apparent reduction in binge eating by patients given placebo suggests a number of possibilities: - Just paying more attention to patients by putting them in a trial could lead to marked decreases in binge eating, or - People in binge eating trials could tend to report they are improving, whatever treatment they get, or - Binge eating may not be a stable phenomenon, and its intensity could vary over time, or - It may be difficult to make a reliable diagnosis of binge eating disorder.
In summary, at best, the trial showed that Vyvanse only caused small reductions in binge eating, and that binge eating may decrease spontaneously, or at least when patients are given more attention or scrutiny. Thus, even putting the best face on the evidence from a trial done by the maker of Vyvanse does not greatly support the benefits of this drug.
In addition, according to evidence-based medicine advocates, the benefits of a treatment must be balanced with its potential harms. In this study, about 5% of patients given any dosage of Vyvanse had to discontinue its use because of adverse effects. 3/196 patients initially randomized to Vyvanse had serious adverse effects, and one patient died, apparently of an amphetamine overdose. Oddly, the article declared that the one death, due to methamphetamine overdose, was thought by a study investigator not to be related to treatment with another amphetamine, lisdexamfetamine. That makes little sense, given that in a randomized controlled trial, the presumption is that differences in groups given different treatments were caused by these treatments.
In addition, patients given Vyvanse (lisdexamfetamine) had higher rates of various symptoms that are commonly associated with amphetamines, including insomnia, nausea, constipation or diarrhea, anxiety, feeling jittery, palpitations, and sleep disorder.
This suggests that the relatively small apparent benefits of the drug must be weighed against rates of adverse events that are not negligible, especially given the short amounts of time patients were followed. So this study did not show that the benefits of Vyvanse clearly outweigh its harms.
Finally, there were many problems with this trial that further cloud its validity, or applicability to patients (generalizability): - Patients were diagnosed using DSM-4 criteria, rather than the new DSM-5 criteria - Patients with any other psychiatric illness were excluded, limiting the applicability of its results. - Patients with an ostensibly chronic disease were only followed for 11 weeks, so the effects of this drug given for the treatment duration that might be needed to treat a chronic problem are unknown - The loss to follow-up rate, about 5% for treated patients decreases precision of the results given the relatively small effect size - The study was done at a large number of sites, initially 32, given the size of the patient population (starting at 260), and one site was dropped because of an "investigation," raising questions about the quality of the study implementation and data collection
So, in my humble opinion, even this Shire sponsored study, which was responsible for half the evidence used to support the approval of Vyvanse for binge eating disorder, provided only weak and questionable evidence that the benefits of the drug outweigh its harms in the short term, and no evidence about long-term use of the drug.
However, no media coverage so far has addressed the weakness of the clinical evidence supporting the use of Vyvanse. I have yet to see any other attempts at a rigorous, skeptical review of the clinical trial evidence supporting Vyvanse in this application. Instead, the media reporting so far seems to have accepted the word of the manufacturer's executives, who obviously have an interest in promoting the drug. (See the WSJ article above which just repeats assertions by a Shire executive.
Why So Much Enthusiasm about a Type of Drug with Such a Bleak Past?
This lack of skepticism was particularly baffling given the nature of the drug that was being promoted, and its long and unfortunate history. As I noted, the amphetamines have proved to be dangerous drugs when abused, and they are abused frequently.
The beginnings of widespread amphetamine abuse grew out of previous efforts to promote these drugs for obesity (which can be, of course, a consequence of eating too much). As documented by Cohen and colleagues(2),
The discovery of amphetamine energized the weight loss industry. Introduced as the Benzedrine inhaler in 1932 by venerable Philadelphia firm Smith, Kline, and French, the American Medical Association (AMA) soon recognized Benzedrine as a treatment of narcolepsy, postencephaletic Parkinsonism, and certain depressive psychopathic conditions. Several clinical studies first published in the late 1930s demonstrated amphetamine’s anorectic effect. The Clark & Clark Company of Camden, NJ, established in 1941, was one of the earliest manufacturers of diet pills combining amphetamine sulfate and thyroid along with phenobarbital, aloin, and atropine sulfate to counteract untoward effects.
These rainbow pills were used with great enthusiasm, however,
adverse events, including deaths, began to be reported to the FDA as early as the 1940s. In the early 1950s, additional adverse reactions including deaths prompted a detailed investigation by the agency.
By the 1960s, the problem was acute,
Efforts had been in place at least since the 1965 Drug Abuse Control Amendments to increase accountability of the use of amphetamine in medical practice. Diversion of the drug for recreational use and the concomitant public health concerns had been recognized as a serious problem by the 1950s, but prescribing amphetamine— whether alone, as part of the rainbow regime, or for indications other than weight loss—continued to rise in the 1960s. Under the Comprehensive Drug Abuse Prevention and Control Act of 1970, which established different schedules for certain drugs based on their medical value vis-รก-vis their abuse potential, amphetamine was relegated to Schedule II. This status mandated even greater hurdles for the prescribing and dispensing of the drug as well as production ceilings. In the 1970s, FDA also reconsidered obesity as a safe and effective use of amphetamine and its congeners, ruling that amphetamines were effective but only safe for short-term use, which essentially 'marginalized the anorectics and contributed to the eventual decline in their use.'
That is, until they were resurrected as a treatment for attention deficit disorder in children, and then their use was extended to adult patients with so-called adult ADHD, and now to patients with binge eating disorder.
Given this history, the rapid approval of Vyvanse by the FDA, without the benefit of an expert panel, especially given that it was for a supposedly common disorder of adults, is very curious, and worrisome. As Dr Daniel Carlat said (quoted on the WBUR CommonHealth blog),
'I’m concerned that the FDA’s approval of Vyvanse for binge eating disorder is going to worsen our problems with stimulant abuse,' Carlat says.
'Vyvanse is a derivative of Dexedrine. We’ve seen epidemics of Dexedrine abuse in the past when it was used to help people diet. I predict that the FDA has just opened the gates to another similar epidemic – after all, binge eating disorder is a subjective diagnosis that could be potentially expanded to cover many millions of people.'
Why So Much Enthusiasm about Treating Such a Doubtful Diagnosis?
As Dr Carlat noted above, it is not so obvious that binge eating disorder should be considered to be a disease. Starting with first principles, its definition is very vague and subjective. According to the Alliance for Eating Disorders, the DSM-5 criteria for it are:
Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following:
eating, in a discrete period of time (for example, within any 2-hour period), an amount of food that is definitely larger than most people would eat in a similar period of time under similar circumstances
a sense of lack of control over eating during the episode (for example, a feeling that one cannot stop eating or control what or how much one is eating)
The binge-eating episodes are associated with three (or more) of the following:
eating much more rapidly than normal
eating until feeling uncomfortably full
eating large amounts of food when not feeling physically hungry
eating alone because of feeling embarrassed by how much one is eating
feeling disgusted with oneself, depressed, or very guilty afterwards
Marked distress regarding binge eating is present.
The binge eating occurs, on average, at least once a week for three months.
The binge eating is not associated with the recurrent use of inappropriate compensatory behavior (for example, purging) and does not occur exclusively during the course Anorexia Nervosa, Bulimia Nervosa, or Avoidant/Restrictive Food Intake Disorder.
"An amount of food that is definitely larger than most people would eat in a similar period of time under similar circumstances?" In this case, how are "larger," "most people," and "similar circumstances" defined, and by whom? If I go out to eat with friends, and am the only one who has desert, or soup, for that matter, does that qualify? Similarly subjective are "a sense of lack of control," and "eating more rapidly than normal."
In fact, the DSM-5 which ordained the new binge eating disorder diagnosis has been roundly criticized for embodying "diagnostic hyperinflation," turning aspects of the human condition, symptoms, and behavioral variants into disease. Dr Allen Frances, who has been one of its prime critics, described "binge eating disorder" thus,
Excessive eating 12 times in 3 months is no longer just a manifestation of gluttony and the easy availability of really great tasting food. DSM-5 has instead turned it into a psychiatric illness called Binge Eating Disorder.
Perhaps the enthusiasm to make binge eating disorder a disease had to do more with the financial relationships among the authors of DSM-5 and pharmaceutical companies that wanted to market drugs for the problem. An article by Cosgrove and colleagues(3) noted that members of the DSM-5 work group that approved binge eating disorder as a disease included three people with financial relationships with Eli Lilly, maker of Cymbalta, three people with relationships with GlaxoSmithKline, maker of Lamictal, and one person with a relationship to Shire, maker of Vyvanse.
Yet the discussion of Vyvanse in the big media outlets did not address these past questions about the validity of the binge eating diagnosis for which it is now being promoted.
The Over-Marketing of Binge Eating Disorder to Promote Vyvanse
This week, however, at least some skepticism about other aspects of Vyvanse's promotion appeared in a major media outlet. Just a few weeks after that initial coverage, the NY Times published a somewhat more skeptical take on the promotion of Vyvanse. It noted that Shire was underwriting celebrity endorsements without disclosing its financial backing of them,
The retired tennis player Monica Seles spent this month making the rounds of television talk shows, appearing on everything from 'Good Morning America' to 'The Dr. Oz Show' to share her personal struggle with binge eating.
'It took a while until I felt comfortable talking about it,' she said in a People magazine interview, explaining that she secretly devoured food for years while she was a professional athlete. 'That’s one of the reasons I decided to do this campaign: to raise awareness that binge eating is a real medical condition.'
But that is not the only reason. Ms. Seles is a paid spokeswoman for Shire, which late last month won approval to market its top-selling drug, Vyvanse, to treat binge-eating disorder,...
Shire also was funding patient groups as part of its promotional efforts,
And patient advocacy groups — freshly infused with donations from Shire — began driving social media traffic to a company website that provides advice on how to raise the issue of binge eating with a doctor.
Furthermore, Shire has been trying to raise awareness of the new binge eating disorder diagnosis in ways that obfuscate its promotional interests,
Shire appeared to be following a familiar drug industry playbook by promoting awareness of a disorder, in this case binge eating, before more directly marketing its treatment. A company website, BingeEatingDisorder.com, makes no mention of Vyvanse but provides detailed information about how to talk about the disorder with a doctor, including a printable symptom checklist and sample opening lines to start the conversation. The site also tells patients 'don’t give up' if a doctor initially resists.
Some experts in prescription-drug abuse said the content was troubling because it appeared to coach patients about how to receive a diagnosis for a relatively uncommon condition, or shop for a new doctor if they were not successful.
Note Shire's use of undisclosed payments to celebrity spokespeople and patient advocacy groups and a disease awareness website whose connection to the company's drug was obscured suggests the operation of a stealth marketing campaign. Furthermore, the article noted that Shire has been accused of deceptive marketing in the past, and specifically for its marketing of Vyvanse and another stimulant.
In 2011, the F.D.A. cited Shire, which is based in Dublin, for misleading advertising, and last fall the company paid $56.5 million to settle federal charges that it improperly promoted Vyvanse, Adderall and other drugs. Among the allegations, which Shire denied, was that the company played down Vyvanse’s addiction potential and said it would prevent car accidents, divorce, arrests and unemployment.
The article also emphasized concerns about this new pushing of amphetamines,
With the approval of Vyvanse for binge eating, 'now we have another reason for the public to learn about the glories of amphetamine — it’s very worrisome,' said Dr. Lawrence H. Diller, a behavioral pediatrician in Walnut Creek, Calif., who has written about A.D.H.D. drugs. 'My hat’s off to Shire. They’ve done it again.'
Also,
Several drug safety and addiction experts said the approval was of particular concern because of amphetamines’ troubled history as a treatment for weight loss. Vyvanse is converted by the body into an amphetamine when it is swallowed.
From the 1940s through the 1970s, the drugs were commonly prescribed to overweight people who then became addicted. After public outcry and tighter government controls, companies stopped selling amphetamines as obesity treatments and their use is now tightly restricted. In 2012, the F.D.A. approved Qsymia, a drug combination that treats obesity and contains the amphetamine phentermine, although unlike Vyvanse, it is classified by the federal government as having a low potential for abuse.
The F.D.A. expressly forbade Shire from promoting Vyvanse as an obesity drug, but some drug safety experts said they worried its weight-loss attributes could be attractive to people who habitually overeat. The company says about 80 percent of people with the disorder are overweight or obese. Weight loss and appetite suppression are a common side effect of amphetamines.
'There’s so many reasons to be concerned about this,' said Dr. Andrew Kolodny, the chief medical officer of Phoenix House, a drug treatment organization.
He questioned why the F.D.A. approved the new use of Vyvanse so swiftly and said that given amphetamines’ troubled past, more caution was necessary. 'We had a horrible experience with amphetamines in this country, so the fact that this would just get rushed through without even bringing it before an advisory committee is especially concerning,' he said.
However, the NY Times article still did not address the lack of good evidence that the drug provided a substantial benefit even in terms of just reducing binge eating, and questions raised whether binge eating disorder is a valid diagnosis.
Summary
Once again we see the overenthusiastic promotion of the latest wonder drug, starting with uncritical media reports that parroted drug company executives. At least this time some skepticism appeared about how an apparent stealth marketing campaign was organized, and about how the drug's riskiness was soft-pedaled.
However, so far there has been little skepticism about the efficacy of the drug. In fact, close reading of the report of one major trial showed that at best it has minimal efficacy, and even the evidence for that is weak and sketchy. Furthermore, major news media have been hesitant to cite the real questions that have been raised about the nature of the disease for which the drug was advocated.
Most concerning is that this promotion was of an amphetamine, a type of drug with a very dark past, a type of "hard drug" responsible for major abuse problems, and known to cause particularly bad side effects, a type of drug whose illicit use has been previously sparked by over-enthusiastic marketing for dubious indications.
So once again I get to say that physicians need to be much more skeptical about the new "innovations," often promoted as miracle cures, that seem to appear weekly. Attempts to educate physicians about clinical epidemiology, the principles of evidence based medicine, and just simply how to read a clinical research article with an appropriately skeptical and critical eye seem to have fallen by the wayside. Furthermore, the diminishing number of health care journalists with diminishing resources may not be able to sufficiently skeptical of the marketing and public relations hype surrounding new drugs and devices. Physicians and journalists need to have the courage to be more skeptical, and the public, who may trust journalists and physicians to cut through the bloviation, need to advocate for better training of physicians and journalists.
Finally, health care professionals and the public at large have been told to trust government regulators to only approve medicines that are safe and effective. Yet the US Food and Drug Administration increasingly seems too cowed to challenge the pharmaceutical industry, and did not seem to exert much critical thinking before approving an amphetamine for over-eating. The public and health care professionals ought to be advocating intensely for regulators that are less captured by the industry they are supposed to oversee.
As we have said until blue in the face, true health care reform would bring some skeptical thinking and regard for evidence and logic into the health policy discussion.
For our closing musical inspiration, or warning, note the chorus in "Amphetamine Annie" by Canned Heat...
"Speed Kills"
References
1. McElroy SL, Hudson JI, Mitchell JE et al. Efficacy and safety of lisdesamfetamine for treatment of adults with moderate to severe binge eating disoder: a randomized clinical trial. JAMA Psychiatry 2015; Link here. 2. Cohen PA, Goday A, Swann JP. The return of rainbow diet pills. Am J Pub Health 2012; 102: 1676-1686. Link here.
3. Cosgrove L, Krimsky S, Wheeler EE et al. Tripartite conflicts of interest and high stakes patent extensions in the DSM-5. Psychother Psychosom 2014; 83: 106-113. Link here.
