Health Science

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.

Per the NY Times,

'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.

Per the Wall Street Journal,

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.'

Per a Medscape news post, Dr Clyde Yancy also said,

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.

In Reuters,

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.

Years after his death, there is now a little more clarity about the clinical trial in which Dan Markingson was enrolled when he died.  Whether this clarity will have any impact remains to be seen.

We most recently posted about the aftermath of Mr Markingson's death here, (and see posts in 2013 here, and in 2011 here.)  Very briefly, Mr Markingson was an acutely psychotic patient enrolled in a drug trial sponsored by Astra Zeneca at the University of Minnesota.  His enrollment was said to be voluntary although at the time he enrolled he had been under a stayed order that could have involuntarily committed him to care.  Despite his mother's ongoing and vocal concerns that he was not doing well on the study drug and under the care of trial investigators, he continued in the trial until he died violently by his own hand.  After his death, his mother Mary Weiss, friend Mike Howard, and University of Minnesota bioethics professor Carl Elliott campaigned for a fair review of what actually happened.  University managers not only rebuffed their concerns, but harshly criticized Professor Elliott, and ended up reprimanding him for "unprofessional conduct."

Two New Reports

In the last few weeks, two new independent reports on the case appeared.  Both vindicated the concerns and questions raised by Mary Weiss, Mike Howard, and Prof Elliott.

Association for Accreditation of Human Research Protection

One, called for by the University of Minnesota faculty senate, was by the Association for Accreditation of Human Research Protection,  and said that the university left research subjects "susceptible to risks that otherwise would be avoidable" (see this Minneapolis Star-Tribune article.)  Furthermore, according to a post in the Science Insider blog from the American Association for the Advancement of Science, it said,

[T]he external review team believes the University has not taken an appropriately aggressive and informed approach to protecting subjects and regaining lost trust,

Also, it said the university has been

assuming a defensive posture. In other words, in the context of nearly continuous negative attention, the University has not persuaded its critics (from within and outside the University) that it is interested in more than protecting its reputation and that it is instead open to feedback, able to acknowledge its errors, and will take responsibility for deficiencies and their consequences.

Finally, it noted a "climate of fear" in the Department of Psychiatry.

Office of the Legislative Auditor for the State of Minnesota

The second report, available in full here,was from the Office of the Legislative Auditor for Minnesota.  If anything, it was more damning. Its summary included,

the Markingson case raises serious ethical issues and numerous conflicts of interest, which University leaders have been consistently unwilling to acknowledge. They have repeatedly claimed that clinical research at the University meets the highest ethical standards and dismissed the need for further consideration of the Markingson case by making misleading statements about past reviews. This insular and inaccurate response has seriously harmed the University of Minnesota’s credibility and reputation.

It seemed to affirm in detail nearly all of Weiss', Howard's and Elliott's concerns.  It recommended that the University should suspend new psychiatric drug trials until the problems it identified were remedied (see Star-Tribune article here.)

Vindication, but Will It Lead to Progress?  

Taken together, these reports vindicate the work of Mr Markingson's mother, friend, and academic watchdog Professor Elliott and their supporters.  As the Star-Tribune reported,

'Over the past eleven years the University of Minnesota has made us feel as if we have no voice, no rights and absolutely nothing remotely called justice,' wrote Mike Howard, a close friend to Markingson’s mother, in a letter in the audit. 'This report is the first step toward accountability.'

The Minnesota Post added the response of Professor Elliott and a colleague,

'It’s nice to have an independent confirmation of what we’ve been telling the university for five years, but which they have refused to listen to,' he told MinnPost on Thursday.

Elliott said he is not convinced, however, that Kaler and other university leaders are going to take responsibility for what happened in the Markingson case — or take the necessary steps to fix the problem going forward.

'One of the most worrying findings in the report was the widespread belief on campus that the university leadership doesn’t care about human study subjects,' he said.

Leigh Turner, another U bioethicist who has also been outspoken about the issues raised by the Markingson case, expressed similar concerns. 'Can we expect reform from the very people who have done nothing for the past several years?' he said in a phone interview.

'I hope there’s some change,' he added. 'But the fact that [Markingson died in 2004] and it’s now 2015, I think hope has to be tempered with a dose of realism. There are some very powerful forces interested in minimizing the findings and suggesting that there are only minor things that need to be done.'

It appears there a several major remaining questions.

What Were the Underlying Causes?

Although both reports went into some detail about what happened to Mr Markingson, they seemed not to dwell on why it happened.  They did not seem to address relevant contextual factors, policies, and decisions.  For example, the report by the Office of the Legislative Auditor included,

We understand that the University of Minnesota has been and should continue to be an institution that delivers not only high quality medical care but also engages in cutting edge medical research— research that does pose risks to human subjects. In addition, we do not question the appropriateness of the University obtaining money from pharmaceutical and other medical companies to support that research. However, in every medical research study—whether supported with public or private money—the University must always make the protection of human subjects its paramount responsibility.

However, as we and many others more erudite have discussed frequently, clinical research that evaluates products or services made by the commercial sponsors of the research has proven to be highly susceptible to manipulation by these sponsors to increase the likelihood that the results will serve marketing purposes, and suppression if the manipulation fails to produce the wanted results.  Commercial sponsors often strongly influence the design, implementation, analysis and dissemination of clinical research.  Often their influence is mediated by financial relationships with individual researchers and with academic institutions who seem more and more beholden to outside sponsors, that is, by conflicts of interest.  The report by the Auditor noted pressures, including financial pressures on the physician who ran the study in which Mr Markingson was a subject to enroll more patients and keep them enrolled.  To protect patients better in the future, in my humble opinion the relationships among commercial sponsors, academic medical institutions, and individual researchers need further consideration.  Is the easy money supporting research coming from commercial firms with vested interests in the outcome of that research really worth the risks of biased results, hidden results, and to research subjects?   

Will Anything Change and Will Anyone be Held Accountable?

Once these two reports were delivered, it now seems to be up to university managers to make needed changes.  In general, these are the same managers who are described above as so "defensive," who not only ignored complaints, but appeared to try to silence those who complained.  If they are left in charge, why should we expect them to make any meaningful changes?  Instead, should they  not be held accountable for their actions?  

Will the University Cease Hostilities Against Dr Elliott?

Again, as noted above, university managers did not merely disagree with Professor Elliott.  They disparaged him, appeared to try to intimidate him, and reprimanded him.  It seems at the very least he is owed an apology.  So far, nothing in the news coverage suggests he has or will receive one.

Will Anyone Notice? 

So far, this case has gotten good coverage in Minnesota media.  However, it has largely been ignored in the national media.  Beyond Minnesota, I could only find mention in some blogs, e.g., in PharmaLot by Ed Silverman, and in Forbes by Judy Stone.  I have seen nothing in any US medical or health care journal, although the British Medical Journal did cover it in a news feature.  This case clearly has global implications, and ought to be considered one of the most important cases illustrating the perils of commercially sponsored human research, but it remains proportionately anechoic.

Summary

The latest reports seem only to confirm that clinical research at major academic institutions has gone way off track.  It now seems that in their haste to bring in external funding, university administrators and the academic researchers who are beholden to them have sadly neglected the protection of their own patients.  As we have said ad infinitum, true health care reform would turn leadership of health care organizations over the people who understand and are willing to uphold the mission of health care, and particularly willing to put patients' and the public's health, and the integrity of medical education and research when applicable, ahead of the leaders' personal interests and financial gain.

ADDENDUM (25 March, 2015) - See also numerous posts by Professor Elliott on the Fear and Loathing in Bioethics blog,  by Bill Gleason in the Periodic Table blog,  and by Mickey Nardo on the 1BoringOldMan blog. 

ADDENDUM (30 March, 2015) - Note that after receiving offline comments, I changed the first paragraph to emphasize the clarity is about the trial, rather than the patient's death, and second paragraph to clarify that the order to commit was stayed.

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-á-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.

 We posted about that settlement here. 

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.

As we wrote, most recently last week, the hepatitis C screening and treatment bandwagon keeps rolling along.  There is constant public argument about the prices of treatment regimens, which approach $100,000 per patient in the US.  However, nearly all the public chatter, which seems mostly to come from corporate public relations people and marketers, investors and investment advisers, physicians with financial conflicts of interest, and pundits with little background in clinical epidemiology, seems never to question the assumption that the new drugs for hepatitis C are miraculous cures, which, of course, makes it hard to argue that they should not cost royal amounts.

The Lack of Good Evidence for the New Hepatitis C Treatments

However, 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.)

The British Medical Journal Publishes a Skeptical Review of Hepatitis C Screening  

Now an article in the British Medical Journal again raises questions about whether the emperor of hepatitis C treatment has some missing garments.(3)  To date, this article has received minimal attention from large media outlets.  I could only find stories in Bloomberg, and by the San Francisco Chronicle to date.

The article by Koretz et al focused on the evidence, or lack thereof in favor of screening for hepatitis C, but affirmed the following points

Most Patients with Hepatitis C Will Not Go On to Have Severe Complications of the Disease

To wit,

At least 2.7 million people are infected with hepatitis C virus in the US, and around 16 000 people each year die or have liver transplantations because of the disease. This suggests that less than 0.6% of infected patients will die of liver disease or be transplanted each year.

Also,

Retrospective studies of the natural course of hepatitis suggest that end stage liver disease is common and that it takes about 20 years to develop cirrhosis and 30 years to develop liver cancer. However, such series are usually composed of people who have a medical problem and are thus a sicker subpopulation of the people with chronic hepatitis C infection (referral bias). Furthermore, the total number of infected patients from which they are drawn is unknown.

Finally,

The risk of developing end stage liver disease is low for the first three decades of infection. Unfortunately, data on the risk beyond that point are limited. Only three studies provide data beyond 30 years, and the data are for children and women (both groups perhaps being at lower risk of progression) and for men in whom it was not clearly proved that the infections were chronic when diagnosed. Nonetheless, these data are consistent with previously cited epidemiological data from the general population, and it is likely that 80-85% of patients with chronic hepatitis C will die from non-hepatic causes

There is No Evidence from Randomized Controlled Trials that Treatment Prevents Most of these Complications

The most convincing way to establish efficacy of treatment is through well designed and conducted randomised, placebo controlled trials using clinical outcomes (morbidity and mortality). However, such trials are available only for interferon monotherapy. Ten randomised trials of interferon alfa have been conducted in patients with severe fibrosis or cirrhosis. The results were disappointing, even though at the time, expert opinion advocated interferon treatment for these patients.

There is No Clear Evidence that SVR Means Cure

Sustained virological response is not a cure. Viral RNA is sometimes found in body tissues even when the serum is clear; in some studies this has been found frequently. The virus also reappears in some patients with sustained response, and though this might be thought to be due to reinfection, at least sometimes these events represent the reappearance of the same virus. Moreover, a few patients with a sustained response develop end stage liver disease. In the largest observational study to assess this risk, 1001 patients with severe fibrosis (84% with cirrhosis) with sustained virological response were followed for up to eight years. During that time, 50 developed hepatocellular carcinomas, a 1% annual risk. Observational studies have suggested that the annual incidence of hepatocellular carcinoma in people with compensated cirrhosis secondary to hepatitis C infection is 1.4-3.3%.

There is No Evidence that the Benefits of Treatment Outweigh Its Harms

Claims of increased safety or tolerability of the newer treatment have been based on fewer and less severe side effects. However, the new drugs can still cause serious adverse events (resulting in persistent disability, hospital admission, or death).

Also,

Safety data are limited for the newest drugs. However, in a trial of sofosbuvir versus peginterferon plus ribavirin, 3% of participants taking sofosbuvir experienced serious adverse events compared with 1% in the peginterferon plus ribavirin arm (difference not significant). Combination therapy with sofosbuvir plus ledipasvir with or without ribavirin, was associated with a 0.5-2% rate of serious adverse events. According to a recent analysis of US Food and Drug Administration data, over one year telaprevir accounted for the single greatest number of reported severe and fatal skin reactions of any drug monitored. Unfortunately, we cannot weigh the risk versus the benefit at this time because we have no data on the precise benefit (if any).

Summary

Koretz et al supplied these conclusions:

If the treatment of hepatitis C is to be scaled up to cover a large portion of the 125-150 million infected people worldwide, regulatory agencies should ensure that drugs have been evaluated by long term follow-up of clinical outcomes (not just surrogate markers) in several thousands of patients. The financial cost of treatments have been discussed elsewhere, but given the uncertainty about the validity of the surrogate markers, the lack of evidence regarding clinical outcomes of treatment or of screening strategies, and the adverse events caused by the newer regimens, screening may be premature. 

By the same logic, it is not clear that treatment of asymptomatic patients found to have hepatitis C provides benefits that outweigh its harms.

Thus, more authoritative voices are saying that the hepatitis C treatment emperor is seriously fashion challenged.

If there is no good evidence that these drugs do more good than harm for asymptomatic patients, why should physicians prescribe them for these patients?  If use of these drugs in general has not been shown to do more good than harm, why should they be prescribed for any but the most desperate patients?  Finally, if these drugs have not been shown to do more good than harm, and the lack of evidence is clearly the responsibility of  the drugs' manufacturers who chose not to do very large and/or long-term randomized controlled trials and not to assess clinical outcomes, what justification is there for the gargantuan prices of these drugs?

A larger societal question is why the public discussion has been so dominated by enthusiasts for these drugs, and so little informed by the existing evidence, or lack thereof, from clinical research?  

To repeat,.. the Sovaldi (and now Harvoni, Viekira Pak, etc) case is a signal example of how our health care system is awash in marketing hype and public relations buzz that has swamped rational skeptical thinking about logic and evidence.  That marketing and PR is ever enriching managers while it will send the rest of us, health care professionals included, to the poor house.  And all the money we spend will likely not buy us the promised miracles and triumphs.

It is disappointing that so many physicians and other health professionals have been caught up in this hype and spin, probably abetted by their wishful thinking about cures of hepatitis C, and perhaps also abetted by financial conflicts of interest.  Yet to protect the best interests of their patients, they should be rigorously skeptical of illogical or evidence-free arguments made to further vested financial interests.

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.

ADDENDUM (19 January, 2015) - See also comments in the HealthNewsReview.org blog.

ADDENDUM (22 January, 2015) - See an analysis of logical fallacies found in comments arguing with this post, and employed by authors of rapid responses to the Kortetz et al article in the BMJ, in this post.

ADDENDUM (28 January, 2015) - This post was republished in OpenHealth News here. 

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 Inte Med 2014.  Link here.
2. Sofosbuvir (Sovaldi), active against hepatitis C virus, but evaluation is incomplete. Prescrire Int 2015; 24: 5- 10. Link here.
3. Koretz RL, Lin KW, Ioannidis JPA, Lenzer J.  Is widespread screening for hepatitis C justified? Br Med J 2015; 350: g7809. Link here.

The Hepatitis C Spin Cycle Continues

Since our last post in July, 2014, about sofosbuvir (Sovaldi, Gilead), the $1000 pill proclaimed to be a wonder drug for the treatment of hepatitis C, the marketing juggernaut for new antiviral drugs for this condition continues to roll along.

For example, I just got a notice to look at a Gilead website which proclaims 

HCV can be cured

In October, Gilead got permission so sell Harvoni, a new combination drug that includes sofosbuvir and ledipasvir, hailed as a once daily pill that can cure hepatitis C, for a mere $94,500 for a typical treatment course. (See this article in the Wall Street Journal.) Meanwhile, AbbeVie launched its own antiviral treatment for hepatitis C, Viekira Pak, (ombitasvir, paritaprevir, and ritonavir tablets plus dasabuvir tablets) priced just under sofosbuvir, but still very expensive.  (See this Bloomberg article.)

Media coverage of these developments suggests that there is no controversy about the curative, nay lifesaving properties of these new drugs.  For example, a Wall Street Journal article about how Express Scripts will only pay for the slightly less expensive Viekira Pak referred to Sovaldi, Harvoni, and the Viekira Pak as "lifesaving medicines," and later noted, "Both Gilead’s Harvoni and AbbVie’s Viekira Pak have been shown in clinical trials to cure as many as 90% of patients..."


Never Mind the Evidence from Clinical Research, or Lack Thereof

Nearly all cases of hepatitis C can be cured, and one of the best hopes for a cure is sofosbuvir, maybe plus ledipasvir?

Never mind that the prominent published studies of sofosbuvir plus ledipasvir(1-3) did not compare this combination to any other drugs.  They simply compared different durations of treatment with the combination, plus minus other drugs.  So whether this combination is better than any other treatment, and even whether the apparently high rate of "cure," really suppression of virus detectable in blood samples at 12 weeks, would apply to patients less highly selected than those in the study was unclear. 

Of course, like every other trial of antiviral drugs for hepatitis C, these studies only assessed whether the drugs causes a "sustained virological response," that is, made the virus undetectable in patients' blood for 12 weeks.  They did not assess whether the virus reappeared after that, and certainly did not assess whether the drugs affected the development of the dreaded complications of hepatitis C infection, that is cirrhosis, liver failure, liver cancer, and death.  In the absence of controlled trials that assessed these long term clinical outcomes, the assertions that these drugs are curative or lifesaving do not appear to be well substantiated.

It is not even obvious that the new sofosbuvir based regimens are better than the old peg-interferon based regimens.   As we noted here, there apparently has only been one published study that compared sofosbuvir to another antiviral drug, peg-interferon.  That study had multiple methodologic problems, most of which appeared likely to make sofosbuvir look better, but nonetheless did not show sofosbuvir to be clearly more effective or safer than this, or any other alternative. (See posts here and here.)

In October, a cost-effectiveness analysis appeared that was used to make the case that expensive drugs like sofosbuvir could nevertheless be cost-effective.(4)  It showed that the drugs increased quality adjusted life expectancy for a relatively modest cost.

Never mind that the analysis was based on the highly questionable assumption, that "treatment resulting in cure [presumably meaning sustained virological response] could leave patients with residual fibrosis consistent with their stage at the time but without additional progression." [Italics added.] This assumption was completely unsupported by randomized controlled trial data.  As Chavez-Tapia et al wrote in a December, 2014, letter to JAMA,(5) "SVR is poorly correalted with clinical outcomes in randomized controlled trials, and even though efforts have been made to correlate it with mortality, evidence to date is insufficient to assert that SVR will translate into improved quality of life or life expectancy."

Is the evidence supporting the Viekira Pak any better?

Not obviously.  The prominent November, 2014, New England Journal of Medicine study by Ferenci et al of the drugs within the Viekira Pak also equated 12 week SVR with cure, also failed to allow patients long-term, and also failed to assess clinically important complications of hepatitis C such as cirrhosis, liver failure, liver cancer, and death.  Furthermore, the study did not compare the Viekira Pak with any other treatment option, e.g., one containing sofosbuvir or peg-interferon, or to placebo.(6)   Thus, assertions that the Viekira Pak is curative or lifesaving also do not appear to be substantiated by evidence from well-designed long-term clinical trials.

However, the lack of evidence so far as not discouraged the breathless claims, and the acceptance of these claims in the media, and probably by many physicians.

Another Skeptical Review

However, one bit of common sense about all this just appeared in the form of a 2015 article in the French journal Prescrire International.(7)  The full article requires a subscription, but a summary is available on the web, and includes the following dry but telling language:

Sofosbuvir’s initial clinical evaluation includes several comparative trials. But these trials investigate its harm-benefit balance in a minimal way. Sofosbuvir has not been compared directly with a viral protease inhibitor in a randomised clinical trial. The evaluation of sofosbuvir in patients infected with a genotype 1 HCV and suffering from cirrhosis is very poor.

Clinical trials have shown that the addition of sofosbuvir to various drug combinations increases their virological efficacy, but there is no guarantee of success.

In practice, in patients with liver damage requiring antiviral drug therapy, sofosbuvir seems to be at least as effective and less harmful than viral protease inhibitors such as boceprevir. Its use makes it possible to reduce the duration of treatment by several months. But there is a great deal of uncertainty as to its adverse effects and its interactions. In genotype 1 cases, the addition of sofosbuvir to the peginterferon alfa + ribavirine combination is an option. In genotype 2 or 3 cases, sofosbuvir is an alternative to peginterferon alfa. However, given the slow progress of hepatitis C and the many unknowns surrounding sofosbuvir, it is a reasonable option to await further clinical evidence to be available.

Meanwhile, more skepticism about the sky high pricing of these new antiviral drugs appeared in the form of a lawsuit by the Southeastern Pennsylvania Transportation Authority (SEPTA) for price gouging that allegedly violates antitrust laws.

But even the coverage of this lawsuit, like nearly all the other coverage of Sovaldi, Harvoni, and competing drugs, assumed that these drugs are miracle cures, e.g., see this Wall Street Journal article.  As we discussed in detail before (look here, here, here, here, here and here)  there is no good evidence that any of these new treatments prevents cirrhosis, liver failure, liver cancer, or death due to hepatitis C, and their long-term safety is unclear.  Similar points have been made by rigorous reviews in Germany, in the US, and now in France.  Yet the antiviral spin continues without regard to evidence, or the lack thereof, from good clinical research.  I would like to hope that each new added bit of skepticism, now including the Prescrire International review, will have some effect.  But that may be wishful thinking, since most of what goes on in the health care "industry" now seems less than fully reality based.

Summary

As we said before,  the Sovaldi (and now Harvoni, Viekira Pak, etc) case is a signal example of how our health care system is awash in marketing hype and public relations buzz that has swamped rational skeptical thinking about logic and evidence.  That marketing and PR is ever enriching managers while it will send the rest of us, health care professionals included, to the poor house.  And all the money we spend will likely not buy us the promised miracles and triumphs.

It is disappointing that so many physicians and other health professionals have been caught up in this hype and spin, probably abetted by their wishful thinking about cures of hepatitis C, and perhaps also abetted by financial conflicts of interest.  Yet to protect the best interests of their patients, they should be rigorously skeptical of illogical or evidence-free arguments made to further vested financial interests.

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.

References

1.  Afdhal N, Reddy KR, Nelson DR et al.  Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.  N Engl J Med 2014; 370: 1483-98.  Link here.
2.  Afdhal N, Zeuzern S, Kwo P et al.  Lepipasvir and sofosbuvir for untreated HCV genotype 1 infection.  N Engl J Med 2014; 370: 1889-98.  Link here.
3.  Kowdley KV, Gordon SC, Reddy KR et al.  Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.  N Engl J Med 2014; 370: 1879 - 1888.  Link here.
4.  Liu S, Watcha A, Holodniy M et al.  Sofosbuvir-based treatment regimens for chronic genotype 1 hepatitis C virus infection in the U.S. incarcerated populations: a cost-effectiveness analysis.  Ann Intern Med 2014; 161: 546 - 553.  Link here.
5.  Chavez-Tapia NC, Barrientos-Gutierrez TB, Uribe M. Assessment of outcomes of hepatitis C treatment.  JAMA 2014; 312: 2570-2571.  Link here. 
6.  Ferenci P, Bernstein D, Lalezari J et al. ABT-450/r–Ombitasvir and Dasabuvir with or without Ribavirin for HCV. N Engl J Med 2014; 370:1983-1992. Link here.  
7.  Sofosbuvir (Sovaldi), active against hepatitis C virus, but evaluation is incomplete.  Prescrire Int 2015; 24: 5- 10.  Link here.

Summer must be over, because the next new blockbuster drug appears to be here.  At the end of August, the media heralded the results of a study of a new product for congestive heart failure (CHF) from Novartis.

Novartis' New "Game Changer"

The New York Times article was fairly restrained, simply saying it

has shown a striking efficacy in prolonging the lives of people with heart failure

The Reuters article's headline said

New Novartis drug may upend heart failure treatment

In Forbes, Matthew Herper called it a

Game Changer

The accompanying editorial in the New England Journal of Medicine (1) suggested the drug

may well represent a new threshold of hope for patients with heart failure

On the heels of the debate about the high price of Sovaldi, Gilead's drug similarly touted as a game changer for the also common disease, hepatitis C (look here), almost immediately the concerns about cost followed.  Another Reuters article quoted the past president of the European Society of Cardiology,

We are entering a new era of treatment and, of course, it will cost a lot of money, which is a problem

This blog was late to the party for Sovaldi, and did not get to examine the evidence used to support its ostensibly wondrous properties until a while after it was published, and after the drug was approved.  Therefore, I thought we should examine the new evidence about Novartis' new drug now, before the drug is reviewed for marketing approval.

Congestive Heart Failure

First, let me give a very informal review of congestive heart failure (CHF).  CHF is a syndrome that is the final common pathway for many patients with heart disease.  It can be commonly caused by prolonged hypertension, coronary artery disease (often after one or more myocardial infarctions, or heart attacks), cardiac valve disease, or various problems with the heart muscle (cardiomyopathies).  In CHF, the heart cannot pump sufficiently to meet the body's needs.  The body responds in various ways, not all advantageous.  There are two main types of heart failure.  In one, systolic dysfunction, the heart's pump function, measured by its ejection fraction, is directly reduced.  In the other, sometimes called diastolic dysfunction, the heart becomes stiff, and hence it may not fill with blood adequately.  In either case, a common response is accumulation of fluid.  Fluid can accumulate in the lungs, causing breathlessness.  CHF patients often are fatigued, breathless, find it hard to do physical activity, and may have swelling of the legs or abdomen (edema).

Starting more than 20 years ago, a series of landmark clinical trials found that various types of medication could be used to modify the often disadvantageous compensatory mechanisms evoked by CHF with systolic dysfunction.  Controlled trials showed these medications could reduce symptoms, reduce hospitalizations, and prolong life.  These medications included those that affected the renin-angiotensin system, used by the body to control blood flow and pressure, including angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs).  Also found to be efficacious were beta-blockers and mineralocorticoid blockers. At this point, all these medications are available in cheap, generic form in the US.

Review of the New Study of Sacubitril and Neprilysin Inhibtion

So let us examine the article just published online that reports a trial of Novartis' new drug.(2)

The new Novartis medication is sacubitril, which inhibits an enzyme called neprilysin, which degrades various active compounds in the body.  Inhibition of the enzyme and the resultant increase in the level of these compounds seems to favorably affect the disadvantageous compensation mechanisms found in CHF.

A previous effort to develop a neprilysin inhibitor found that it produced an unacceptable risk of a serious side-effect, angioedema, when combined with an ACE inhibitor.  So the current study involved another neprilysin inhibitor, sacubitril, combined with a angiotensin receptor blocker, valsartan, sold by Novartis under the trade name Diovan.

The trial had many good features.  It was large, including 8442 patients randomized.  It followed patients for longer than the short-term, a median of 27 months.  Most importantly, it assessed real clinical outcomes that might be important to patients (that is, "patient-centered outcomes,") including death, acute hospitalization, and a measure of health status and physical function, the Kansas City Cardiomyopathy Questionnaire (KCCQ).  

So far, so good.  However, a close read revealed some major and some minor problems.
  
Low Dose of Comparator 

This is a bit complex so bear with me.  

The study assessed a combination of sacubitril and valsartan versus a well-known ACE inhibitor, enalapril.  The target dose of the sacubitril and valsartan, rather confusingly called LCZ696, was 160 mg of valsartan twice daily, for a total of 320 mg/ day of valsartan.  The target dose of enalapril was 10 mg twice daily, for a total of 20 mg.

Note that both ACEIs like enalapril and ARBs like valsartan are considered appropriate first line treatment of CHF with systolic dysfunction.  In the most recent ACCF/ AHA guideline for heart failure, the maximum suggested dose of enalapril is 10-20 mg twice a day, and of valsartan, 160 mg twice a day.  Previous studies have suggested that pushing these doses as high as patients can tolerate improves outcomes.  

So the current study compared a targeted maximum dose of valsartan (plus sacubitril) to a less than maximum dose of enalapril.  The article did not explain why the study did not call for a maximum dose of enalapril, or indeed why valsartan plus sacubitril was not compared to valsartan alone. 

Thus the advantages of valsartan plus sacubitril found in the study could be entirely due to the superiority of maximum doses of valsartan versus moderate doses of enalapril.  I do not believe the study design can allow conclusions to be drawn about the efficacy of sacubitril.

 Note that this problem was noted in an online comment on the article by Dr Martin Nitschke.   

Choosing to compare the new drug to a less than maximally efficacious dose of the comparator medicine could make the new drug appear to be more efficacious than it actually is.  This apparent major design problem has been listed as one of the ways commercially sponsored studies may be manipulated to make the sponsors' products appear better.  The particular tactic of conducting a trial "against a treatment known to be inferior" was listed in a 2005 article on clinical research manipulation by Richard Smith.(3)


Active Run-In Period

Before patients were enrolled in the trial, they went through two "run-in" periods.  In the first, they were switched from their previous doses of ACEIs or ARBs to enalapril, up to 10 mg twice daily.  Patients unable to tolerate this were not randomized.  

Then the patients were switched from enalapril to valsartan 160 mg plus sacubitril up to .  Again, if they failed to tolerate this, they were also not randomized.  

The article noted that substantial patients were disqualified during these active run-in periods.  During the enalapril period, of 10,513 patients, 1102 were dropped from the study, including 591 (5.6%) due to an adverse effect, 66 (0.6%) due to an abnormal test results, and 49 (0.5%) who died.  During the valsartan plus sacubitril period, of 9419 patients, 977 were dropped, including 547 (5.8%) for adverse effects, 58 (0.6%) for abnormal test results, and 47 (0.5%) who died.  

There are major problems with such active run-in periods.  First, by eliminating patients who had adverse effects from the main results, they make the adverse effect rate appear smaller.  

Second, they raise questions about the patient population to whom the study results apply.  The study results only clearly apply to patients who are known to be able to tolerate valsartan and sacubitril.  In practice, should the drug be approved, at that time the only such patients would be those who already participated in trials.  (Of course, the results only apply to patients known to be able to tolerate enalapril.  This drug, however, has been on the market for years, and is widely used for problems, like hypertension, other than CHF.  So there are already quite a few patients known to tolerate it.)

The problems with interpreting studies that included active run-in periods were clearly described in an article by Pablos-Mendez et al in 1998.(4) 

Failure to Consider Adverse Effects Specific to Sacubitril

Valsartan and enalapril are now old drugs.  Their adverse effects are well known.

Sacubitril is a new drug in a new class.  It inhibits an enzyme that in turn affects the metabolism of many substances.  Thus, it is possible it has widespread effects, and may have multiple, and possibly unusual side-effects.

Yet the current study did not apparently include any efforts to anticipate and attempt to assess such side effects.  This problem was pointed out in a comment by Dr Ivan Boyadzhiev.

Failure to consider specific adverse effects may mean these effects are overlooked.  Thus, it is possible that the new drug has adverse effects that go beyond what are addressed in the article. 

Large Numbers of Sites and Quality Control

The study was done in 1043 centers in 47 countries.  The list of investigators took up six pages of the supplementary documentation.  Thus the average number of patients recruited per center was less than nine.

It seems improbable that a study involving so many investigators and centers, most of whom must have devoted little of their time and effort to this particular study, would have adequate quality control.  One indicator that quality control may have been a problem was that although the study inclusion criteria included patients with class II-IV heart failure, about 5% of study patients had class I heart failure.

The article and the supplementary material did not discuss study coordination or quality control.  It is not possible to tell whether any such problems with quality control may have distorted the study's results.

Lack of Generalizability in the Patient Population

The complete list of exclusion criteria, only appearing in the supplementary material, was extensive.  Patients with many common problems were supposed to be excluded, and the definition of the some exclusion criteria were vague and subjective.  These problems included coronary or carotid artery disease "likely to require" surgical or percutaneous intervention within 6 months, "history of severe pulmonary disease," "any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of study drugs," including inflammatory bowel disease, duodenal or gastric ulcers, evidence of liver disease, and "presence of any other disease with a life expectancy of less than 5  years."

CHF patients are commonly elderly and have other medical problems.  Thus the study's results may not generalize to many patients with CHF in real-life. 

 Summary

It would certainly be nice to have a new medicine to improve the management of chronic CHF.  Sacubitril may have promise to do so.  Unfortunately, the clinical trial that just generated much favorable publicity ahead of regulatory consideration of this drug had major, possibly fatal flaws.  Use of a probably non-comparable and inferior "comparator" medication made it impossible to tell whether sacubitril actually is efficacious.  Use of an active run-in period, and failure to consider whether this new drug may have unexpected side-effects made it likely that the study underestimated its adverse effects.  Study results may not generalize to many real-life patients.  There are reasons to be concerned about whether the quality of study implementation was adequate.

Therefore, all the enthusiasm about this drug may be premature, and does not appear to be evidence-based.  That clinical research sponsored by organizations that sell health care goods and services may be manipulated to make the sponsors' products look better than they really are is now an old story.  We have seen multiple instances in which drugs and devices turned out to be less efficacious and/or more dangerous than originally advertised.  Excess enthusiasm about such new innovations may drive up costs, and worse, hurt patients.  Physicians, other health care professionals, and those concerned about health policy ought to be much more skeptical about every new instance of a purportedly wondrous innovation. 

 Evidence-based medicine rigorously applied suggests that individual health care and health policy decisions should be driven by the best available evidence, mostly from clinical research, about the benefits and harms of tests, treatments, programs, and so on, in the context of what outcomes matter to patients.  The skepticism EBM should engender lead to health care that is more about patients and their outcomes, and less about ideology, hype, and hucksterism.

ADDENDUM (3 September, 2014) - See also post by Dr Vinay Prasad on the CardioExchange site.  He drew similar conclusions about the choice of comparator, and the active run-in period, and added a new concern about the early stopping of the trial.  The comments include a - ahem - vigorous exchange between Dr Prasad and Dr Milton Packer, the Principal Investigator of the trial.  IMHO, Dr Packer did not completely understand or appreciate the points made by Dr Prasad.  Also, see our later blog post on this exchange here.

ADDENDUM (9 September, 2014) - See also a post by Gary Schwitzer on the HealthNewsReview.org blog that summarizes other critical online comments about the PARADIGM - HF study.  In particular, Dr Richard Lehman on his Journal Review blog on the British Medical Journal website wrote this scathing paragraph:

 And now, alas, to the much-vaunted PARADIGM-HF trial. This has been hyped as the biggest breakthrough in heart failure for at least 20 years.  A fixed dose of enalapril was compared with a substance called LCZ696. This turns out to have been a mixture of valsartan and sacubitril, a neutral endopeptidase inhibitor, and most participants ended up receiving a daily dose of 320mg of valsartan, versus 20mg of enalapril. A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died after a median follow-up of 27 months, at which point the trial was stopped prematurely. So just what are we looking at here? How can we distinguish the effect of the sacubitril from the effect of the high dose of valsartan? Well, we can’t. And this trial is a perfect example of everything that is wrong with heart failure trials. The mean age of the 8442 patients was 63.8, nearly  80% were male, and they were selected by reduced ejection fraction in 1043 centres across 47 countries. A logistic nightmare, but a great way for Novartis to spread influence. And Novartis then collected, managed and analyzed all the data itself. As I have said, a submaximal dose of one drug was compared with a maximal dose of another plus an extra ingredient. There was a run-in period, in which patients who were intolerant to the new treatment (12%) dropped out. Adding bias to bias, the trial was terminated prematurely. One of the primary end-points was hospitalization, which was ably demolished in a JAMA article I pointed out last week. And yes, there was a mortality benefit, but the number-needed-to-treat was about 35 to prevent one death in 2 and half years, in a population far removed from the elderly co-morbid patients we see in real life. As I draw to the end of a clinical career in which I’ve tried to help people with heart failure, I stand bemused. This is just how things have been done for the last 30 years, and it’s not good enough. At the very least, Novartis must make its full data set available for independent analysis. And before sacubitril is licensed, we need a properly designed trial, say between valsartan 160mg b.d. alone and valsartan plus sacubitril, in a typical population with heart failure. It will be very interesting to see what the FDA, the EMA and NICE decide.

 
References
1.  Jessup M. Neprilysin inhibition - a novel therapy for heart failure.  N Engl J Med 2014;  DOI: 10.1056/NEJMe1409898.  Link here.
2.  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.
3.  Smith R. Medical journals are an extension of them marketing arms of pharmaceutical companies.  PLoS Medicine 2005;  DOI: 10.1371/journal.pmed.0020138.  Link here.
4.  Pablos-Mendez A, Barr G, Shea S. Run-in periods in randomized trials: implications for the application of results in clinical practice.  JAMA 1998;  279(3): 222-225. doi:10.1001/jama.279.3.222.  Link here.