Sacubitril - Valsartan, a "New Threshold of Hope" or Hype for Heart Failure?

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.

Sovaldi, a Quantum Leap... Backwards to the Days Before Randomized Controlled Trials?

The Sovaldi (sofosbuvir - Gilead) media circus is continuing.  The New York Times just reported that sales of the new drug for hepatitis C were about $3.5 billion for the last quarter, which should intensify the kerfuffle over its US price ($1000 per pill, $84,000 for a 12 week course of medication).

Meanwhile, reports of its wondrous properties continue to appear in medical journals.

The latest was announced this way in Bloomberg,

Gilead Science Inc Solvadi, controversial because of its price, helps cure hepatitis C in people with HIV, according to researchers who say the drug has the potential to limit a top cause of death in these patients.

In a study of 223 HIV-infected patients, Solvadi combined with ribavirin cleared the most common US strain of hepatitis C in 76 percent of newly treated patients over 24 weeks. Only seven participants stopped treatment because of side effects and there were no adverse effects on HIV treatment, according to a report in the Journal of the American Medical Association.

Not unexpectedly, the study investigators were thrilled,

This is 'the first clinical trial to demonstrate that we can cure hepatitis C in patients with HIV co-infection without the use of interferon,' said Mark Sulkowski, the study author and medical director of the John Hopkins Infectious Disease Center for Viral Hepatitis in Baltimore. 'It represents a transformative step in our approach to this therapeutic area.'

Furthermore, as noted in a Medscape report,

In an accompanying editorial,(1) Michael Saag, MD, also of the University of Alabama at Birmingham, said the finding is a 'quantum leap' forward for people coping with both viruses.

What Clinical Trial?

I have posted previously about the controversy over the high price of Sovaldi.  I noted that most of the arguments, even from people most incensed about paying $1000 per pill, assumed that the drug was nearly miraculous, e.g., "a triumph," or "a revolution" in medicine.  Yet my reading suggested that the published evidence from clinical studies of the drug was in fact weak.  Critical reviews of the evidence from groups in the US, the UK, and Germany (look here, here, and here) also questioned the evidence backing Sovaldi.  Yet doubts about the drug's benefits versus harms have yet to influence the public discussion, which is focused on whether $1000 a pill is too much to charge for a miracle drug.

So I thought that "quantum leap" demonstrated in the latest trial(2) would bear further scrutiny.

The most important feature of the "trial" is how its design is described,

In this multicenter, open-label, nonrandomized, uncontrolled phase 3 trial, all patients received 400 mg of sofosbuvir (Gilead Sciences) administered orally once daily along with ribavirin (Ribasphere, Kadmon) administered orally twice daily, with doses determined according to body weight....

Let me make very clear, in this "trial," all patients got the same therapy.  There was no comparison group.  The study description is therefore inherently self-contradictory.  In fact, this study was a case-series, not a clinical trial.  It had no control group.

The classic Users Guides to the Medical Literature suggests that the first question a critical reviewer should ask about a study to assess a treatment is "was the assignment of patients to treatment randomized?"(3) The rationale was that studies of patients for whom clinicians made treatment decisions could easily be confounded by the reasons clinicians used to make these decisions.  Clinicians are trained to individual treatment decisions, and thus patients prescribed a treatment are likely to greatly differ from those not assigned that treatment.  The ways they differ could have as much, or more effect on their outcomes than the treatments themselves.  Although complex statistical adjustment methods could be used to try to compensate for these differences, it is rarely possible to be assured that all important differences have been taken into account. 

However, this still assumes a comparison between patients getting different treatments, or treatment versus no treatment.  In the case-series of sofosbuvir, there were no patients getting alternative treatments.  Thus the study itself could not be used to make comparative assessments of sofosbuvir.  

Of course, one could imply comparisons with the results of other studies.  However, such comparisons would not only be susceptible to confounding by reasons for treatment decisions as above, but to bias due to  differences between the current case series and previous studies, e.g., in characteristics of patients recruited, details of treatments given, study settings, and changes in patients, diseases, and treatments over time.   

Thus, a very basic rule in critical review is thou shalt not draw any conclusions about therapy from case-series unless the results are truly extraordinary, i.e., patients clearly doomed to die suddenly become completely well.  There were no such extraordinary results in the case-series of patients with HIV treated with Sovaldi for hepatitis C. 

The latest study of Sovaldi for patients with HIV and hepatitis C is virtually useless to assess whether Sovaldi might be the preferred therapy for such patients.   

Comparable Results?

Yet in an accompanying editorial(1), Dr Michael S Saag asserted that this non-trial 

demonstrates the efficacy of the all-oral regiment of the directly acting agent sofosbuvir plus ribavirin in patients with HCV who are coninfected with HIV

To demonstrate efficacy means to show that the treatment caused good effects.  But without a control group, it is not possible to assess causation.

Also,

The PHOTON-1 trial demonstrates that the all-oral combination of sofosbuvir plus ribavirin yielded results comparable with those of standard pegylated-interferon-ribavirin-vased regimens for each of the genotypic groups, thereby demonstrating that an all-oral combination could achieve similar outcomes as those derived from an injectable therapy.

However, this case-series could not assess comparability, because it included no comparison.


There Goes the Neighborhood - Throwing Out Skeptical Evaluation in the Rush to Promote "Innovation"

For years, the randomized, and usually double-blind, controlled trial has been considered the scientific cornerstone of the evaluation of new treatments.  Yet in the rush to bring new "innovative" treatments to market, presaging often tremendous revenues for their manufacturers, suddenly the randomized controlled trial does not seem so necessary.  In the US, the Food and Drug Administration (FDA) no longer seems to require randomized controlled trials to demonstrate efficacy of new drugs deemed to be "breakthroughs."   As noted by Steinbrook and Redberg in the July, 2014, issue of JAMA Internal Medicine(4)

these drugs [for hepatitis C] were approved quickly based on the surrogate endpoint of sustained viral response rate; they were studied in limited populations without long-term follow-up.  Under the US Food and Drug Administration's breakthrough therapy designation, the marketing for sofosbuvir did not include requirements for randomized clinical trials.

Yet without such trials, how could one ever determine if the drug is really so efficacious as to constitute a "breakthrough?"  


As we noted earlier, the two real randomized controlled trials of sofosbuvir did not assess its effects long term, even though it is a drug meant to treat a chronic disease, and particularly did not assess whether it affect clinical outcomes, that is, reduce rates of cirrhosis, liver failure, or liver cancer.  In fact, there has never been a controlled trial meant to assess whether any treatment of hepatitis C affects these outcomes.  Furthermore, while the first author of the case-series above, and many others have claimed the Sovaldi cures hepatitis C, it has never been shown that SVR equals cure.  As Gluud et al wrote in a letter to Lancet,(5)

The claim of cure rests solely on sustained virological response (SVR).  Since some patients who achieve SVRs still go on to develop end-stage liver disease and might die from the interventions, this concept is not correct and might even be wrong in principle.

However, despite all the words written, the concernthat Sovaldi (and possibly other new drugs for hepatitis C) might not be wondrous quantum leaps, because there is really no good evidence to that effect, has remained anechoic.  Not only does the evidence about the benefits and harms of this new drug need to be part of the discussion whether its price is excessive, there needs to be a larger discussion of whether in our rush for "innovation," we will throw out the baby of scientifically valid assessment of new therapies with the bathwater.

Finally,  the Sovaldi 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 not buy us the promised miracles and triumphs.

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. Saag MS. Quantum leaps, microeconomics, and the treatment of patients with hepatitis C and HIV coinfection. JAMA 2014; 312: 347. doi:10.1001/jama.2014.7735.  Link here.

2. Sulkowski MS et al.  Sofosbuvir and ribavirin for hepatitis C for patients with HIV coninfection.  JAMA 2014; 312: 353.  doi:10.1001/jama.2014.7734.  Link here.
3. Guyatt GH, Sackett DL, Cook DJ et al. Users' Guides to the Medical Literature: II. How to Use an Article About Therapy or Prevention A. Are the Results of the Study Valid? JAMA. 1993; 270(21): 2598-2601. doi:10.1001/jama.1993.03510210084032. Link here.
4.  Steinbrook R, Redberg R. The high price of the new hepatitis c virus drugs.  JAMA Int Med 2014; 174: 1172.  Link here. 
5.  Gluud C, Koretz R, Gurusamy K. Hepatitis C: a new direction, but an old story? Lancet 2014; 383: 2122-2123.  Link here.

Fourth Time is the (Anti)Charm? - UK NICE Highlights "Uncertainties in the Evidence Base" About Sovaldi

As we have discussed, (here, here and here), while anger continues to build about the $1000/ pill price sought by Gilead for its new antiviral drug for hepatitis C, Sovaldi (sofosbuvir), almost all public discussion still treats the drug as miraculous.  However, my reading of some key trials, and reviews by three groups of evidence-based medicine experts, suggested that the evidence supporting the drug is actually weak and unclear, and hardly suggests it is miraculous.

NICE Weighs In

Now, as first noted by the indomitable Ed Silverman in his revived PharmaLot blog, the National Institute for Health and Care Excellence in the UK is also skeptical.   

the U.K.’s National Institute for Health and Care Excellence, otherwise known as NICE, has declined to endorse the use of Sovaldi, at least for now, until Gilead supplies further evidence of the medication works in certain subgroups of patients. In announcing the move, NICE officials wrote there are 'substantial uncertainties' in the evidence from the drug maker. In a statement issued about a draft guidance, NICE wrote that the agency 'is minded not to recommend' that the U.K.’s National Health Service cover the cost of Sovaldi,

The actual statement said,

 The available evidence shows that sofosbuvir is an effective treatment for chronic hepatitis C in certain patients. However, evidence is lacking for some subgroups of patients with chronic hepatitis C, and there are also substantial uncertainties in the evidence base presented by the manufacturer. The Committee has therefore requested further information from the manufacturer before it can decide whether sofosbuvir is a cost-effective use of NHS resources.

In the US, the only other news source that covered the NICE statement was Bloomberg.

The Problems with the Evidence

As we discussed in our previous posts, the problems with the evidence underlying Sovaldi include:
- Lack of a randomized controlled trial comparing Sovaldi to the previously most recommended treatment regimen
- The only trial trial to compare an antiviral regimen containing Sovaldi to one without it  (Sovaldi plus ribavirn versus peg-interferon plus ribavirin) used a lower dose of ribavirin in the comparator regimen, seemingly handicapping it; had a highly selected patient population whose results would be unlikely to generalize to many patients in the real world; had issues with randomization of patients; only assessed short-term "sustained" virologic response, but not any clinical outcomes; even so, did not show that the sofosbuvir containing regimen produced a better SVR than did the comparator; and appeared to show that the sofosbuvir containing regimen produced more severe adverse effects, and perhaps a higher death rate than the comparator regimen
-  So far, the other published trials included one versus placebo, and multiple trials that compared only sofosbuvir containing regimens to each other, and hence were effectively just case series of patients receiving sofosbuvir.  These case-series all had highly selected patient populations results from whom would be unlikely to generalize to real world patients.

The severe problems with the evidence have now also been noted by
-  the German Institute for Quality and Efficiency in Healthcare (IQWiG)
-  the US Institute for Clinical and Economic Review (look here)
-  the US Center for Evidence-Based Policy (look here)
-  the UK National Institute for Health and Care Excellence (NICE)

Summary - Why Does the Evidence, or Lack Thereof, Remain Anechoic?

Yet none of these reviews have gotten any significant attention in the US media or medical and health care literature, and the idea that Sovaldi has hardly been proven to be a miracle drug, or even better than older drugs for hepatitis C has not informed the US debate and the US outrage about its price.  Examples of the most recent outrage include this in Forbes,

A cure for hepatitis C is within reach for 170 million people around the world — thanks to the charitable efforts of poor and sick Americans who are picking up the tab by paying outrageous prices for their own treatment. It’s like Robin Hood in reverse.

Also,

It also took a complete lack of self-awareness — and unmitigated gall — to price Sovaldi the way Gilead has.

Furthermore, Democrats in the US House of Representatives are calling for an investigation (which their Republican "colleagues" will doubtless block), according to Bloomberg,

The company 'did not provide a compelling justification for the high price they are charging for most patients,' Waxman and DeGette wrote 

If the price is outrageous for a miracle drug, it would be even more outrageous for a drug that has not been proven to be better than previously available treatments.

The fact that skepticism about all the hype for Sovaldi has hardly touched the public discussion in the US is a prime example that the anechoic effect lives.  (The only skepticism from an expert could [probably only] be found again in PharmaLot, and came from one of the authors of the Center for Evidence Based Policy report [see above]). 

'For most patients with hepatitis C, they have time to make those decisions,' Valerie King, one of the physicians at the center who worked on the Sovaldi review, tells OregonLive. 'I’m certainly not saying that this is a bad drug. I’m just saying that we don’t know that it is a good drug.' [UPDATE: King later called us to say that 'the research hasn't been extensive enough or transparent enough to tell us it is a good drug or bad drug, or has limited application.' This was based solely on assessing clinical research, not cost issue.]

We have endlessly discussed the anechoic effect, that information and ideas that challenge the powers that be in health care, and particularly that challenge the ability of health care leaders and well-connected insiders to personally profit, often to a tremendous extent - the CEO of Gilead, John Martin, was listed by FiercePharma as the eighth highest paid biotech CEO in 2013, with total compensation of $15.45 million, before sales of Sovaldi really increased -  are considered recent unpleasantness that are just not to be discussed.  However, without open honest discussion of truths, however inconvenient or unpleasant, and the ideas that they suggest, health care will continue to degenerate into a plutocratically run, often corrupt swamp with ever increasing costs, and ever worsening access and quality, causing increasing suffering of patients and worsening of public health.

A good place to start true health care reform might be honest discussion of the evidence about sofosbuvir.   

Sovaldi - a "Revolution" in Clinical Care, or in Marketing and Public Relations?

The continuing public discussion of the sky high price Gilead has set for Sovaldi (sofosbuvir,) its new antiviral drug for hepatitis C, continues to avoid considering the lack of good evidence that the drug is as safe and effective as its proponents claim.

We first posted about the Sovaldi debate on March 27, 2014, and its focus on price rather than the quality of the evidence underlying loud claims about the miraculous qualities of the drug.  We suggested that there is no good evidence supporting claims that most hepatitis C patients have very bad outcomes if untreated, treatment prevents most bad outcomes, Sovaldi cures nearly all patients, and Sovaldi has very few side effects.

In a subsequent post we wrote that initially, "no one but your humble blogger seemed to be publicly skeptical about published assertions that the drug was some sort of modern miracle, and a triumph of medical science."

On May 7, we noted an assessment by the German Institute for Quality and Efficiency in Health Care (IQWiG) of information submitted by "industry" (presumably Gilead) to the German government.  This assessment found multiple problems with the evidence, including limited generalizability, problems with randomization, lack of information about important outcomes, and lack of ability to quantify benefit.   Also  the US based Institute for Clinical and Economic Review noted that there was little evidence that compared to previous treatments, Sovaldi is better, and no evidence that Sovaldi produces cures in the long term.

Nonetheless, the notions that the evidence supporting Sovaldi (and perhaps other similar drugs) is weak, and that the drugs therefore should not yet be considered miracle cures have not seemingly affected the public discussion. 

Examples of the Latest Discussion

Washington Post/ Kaiser Health News


On May 12, 2014, in an article on the dilemma the drug's US price of $1000/ pill presents to Medicare, Richard Knox wrote this about a patient with the infection:

Previous drug treatments didn't clear the virus from Bianco's system. But it's almost certain that potent new drugs for hep-C could cure him.

In other words, the article asserted that Sovaldi and similar drugs cure nearly everyone with hepatitis C, even those not cured by previous treatment.

 Reuters

On May 20, 2014, in an article about how US health insurers are balking at the price of Sovaldi, was this statement by the main trade organization for US for-profit health care insurers, America's Health Insurance Plans (AHIP),

Sovaldi has shown tremendous results, and it's the kind of medical innovation we need to sustain. 

In the article's text was the assertion,

The new drug has demonstrated an ability to cure well over 90 percent of patients in just 12 weeks or less with few side effects.

Prior to the Sovaldi approval, hepatitis C treatments took 24 or 48 weeks, cured about 75 percent of patients and involved many more pills as well as injectable interferon that causes flu-like symptoms and other side effects that led many people to avoid or discontinue treatment.

In other words, the article asserted that Sovaldi can cure over 90% of patients compared to the cure rate of 75% provided by previously available treatments, and implied Sovaldi has fewer side effects.

CNBC

On May 22, 2014, in an article on the high costs of new drugs, a quote from Dr Douglas Dieterich, "a liver disease specialist at Mount Sinai Hospital," who "has consulted for pharmaceutical companies, including Gilead," appeared,

I don’t think there’s any question that treating patients with hepatitis C will lower overall health-care costs in the coming 20 years,...

If we could get rid of the liver disease in these patients with hepatitis C, prevent them from dying of liver cancer, cirrhosis and liver failure, then there’s no question the cost will be less.

The implication was that the new drugs can get rid of the disease, that is, cure it, and in doing so prevent early mortality, cirrhosis, and liver failure.

CTV

The discussion of Sovaldi in Canada seems similar. On May 25, 2014, an article on the high cost of hepatitis C drugs in Canada from CTV, "Canada's largest private broadcaster," (look here) quoted a Canadian physician,

 Dr. Curtis Cooper, director of the viral hepatitis program at the Ottawa Hospital, said the drugs Sovaldi and Galexos offer a revolution for patients with the hepatitis C virus (HCV).

'It only requires 12 weeks of treatment and (they) are producing cure rates of 90 to even 100 per cent,' he told CTV News.

And later, addressing the treatment of a particular patient,

We're talking about curative therapies, which could potentially save her from liver failure, save her from liver cancer

Again, the assertions were that the drug cures 90%, maybe 100% if patients, and that cure will prevent liver failure and cancer.

Is There Any Good Evidence?

Again, while there is much discussion, and some outrage over the $1000 per pill price of Sovaldi in the US (in Canada, a bargain at Canadian $650 per pill), all the discussion seems to assume that the pill is really a "revolution" (as per CTV), that provides

- cure rates of 90 - 100%, much better than previously available treatments

- lower adverse effect rates than than those caused by previously available treatments

-  prevention of complications of hepatitis C, including cirrhosis, liver failure, liver cancer, and early death.

I have found just one recent media article that throws a bit of evidence-based cold water on these claims, and refers to a new systematic review that should be generating a lot of interest, and provoking much more skepticism about the drug, but so far is not.

The Single Skeptical Article

On May 22, 2014, a MedPage Today article noted a new systematic review of sofosbuvir (Sovaldi) that had a very different message from the articles above.  In summary,

The evidence base for one of the star hepatitis C drugs is poor and the guidelines for its use are flawed, according to a report obtained by the National Association of Medicaid Directors.

According to the report, studies of sofosbuvir (Sovaldi) are generally of poor quality, mostly directed by the drug's maker, and don't answer key questions, including whether the drug is better and safer than the current standard of care.

The only available guidelines for its use -- guidelines created by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America -- are 'methodologically flawed,' according to the report, which was prepared by the Center for Evidence-Based Policy at Oregon Health and Science University in Portland (OHSU).

In addition, their authors and sponsors had 'multiple and significant conflicts of interest,' the report argued.

The Report from the Center for Evidence-Based Policy

The report is now public, and directly addresses all four of the major claims made about Sovaldi that we discussed in our first post n the topic.

- Most hepatitis C patients have very bad outcomes if untreated


The report cited the best data about outcome prevalence,

approximately 15% to 25% of people infected with HCV will clear the virus during the acute stage without treatment.  Seventy-five to 85% of infected individuals will develop a chronic HCV infection, and 60% to 70% of patients with chronic infection will develop chronic liver disease.  Over 20 to 30 years, 5% to 20% of infected patients will develop cirrhosis and 1% to 5% will die of cirrhosis or liver cancer.

Although a majority of chronically infected patients will develop some liver disease, only a minority will develop cirrhosis or liver cancer.

- Treatment prevents most bad outcomes


The report stated,

Because of the slow progression of the disease, clinical trials have not evaluated these patient-important conditions [cirrhosis, hepatocellular carcinoma, decompensated liver disease, liver transplant, or death] as trial outcomes.  Instead a surrogate endpoint of sustained virologic response (SVR) has been used to measure success of treatment.  The SVR is defined as undetectable HCV-ribonucleic acid (RNA) levels.  The standard measure of treatment success has been SVR at 24 weeks post treatment (SVR24).

Several long-term studies of patients with chronic HCV infection have shown an association between achieving SVR24 and patient-important clinical outcomes.

So there is no direct evidence that treatment prevents any of the bad outcomes.  There is only indirect evidence that treatment may reduce the rate of some bad outcomes.  For example,

A 2014 observational study of a VA population found that ... the 5180 (4%) of patients who were able to achieve an undetectable viral load with interferon-based treatment had a 45% reduction in the risk of death ... and 27% reduction in the composite clinical endpoint ... of newly diagnosed cirrhosis, HCC [hepatocellular carcinoma], or liver related hospitalization.

However, at best, based on an observational analysis that could have been biased, treatment only may have prevented a minority of bad outcomes.

- Sovaldi cures nearly all patients

As we noted earlier, there have been only two randomized controlled trials published that compared sofosbuvir with anything else.  One compared it to placebo, and one was the trial we discussed earlier that compared it sofosbuvir with ribavirin to pegylated interferon with ribavirin.  (Look here.)  

All other studies were designed to refine drug dose, drug combination or duration of treatment.

Also,

All studies were rated as having a high risk of bias.  No study was judged to have good applicability....  The overall summary judgement for each of the published studies yielded a rating of poor.

Furthermore, the review found even more problems with the only study that compared sofosbuvir to active treatment (peg-interferon) than we did.  In particular, that study did not compare sofosbuvir with ribavirin to the current standard regimen of PEG plus weight-based ribavirin.  Instead, it compared it to a regimen that included low dose ribavirin.  By comparing sofosbuvir plus a higher dose or ribavirin, an active drug, to a peg-interferon plus a lower dose of ribavirin, the study design seemed designed to artificially enhance the efficacy of the sofosbuvir containing regimen.   Furthermore, the study did not assess the measure of sustained viral response at 24 weeks currently accepted as the best surrogate variable.  Instead it used SVR at 12 weeks, which may be correlated with SVR24 but is often higher. Thus this choice of endpoint seemed designed to increase the apparent efficacy of the regimens it evaluated. 

So sofosbuvir has so far been compared to another active anti-viral regimen against hepatitis C in only one study.  That study was poorly designed and implemented, and its problems seemed likely to enhance the apparent efficacy of sofosbuvir.  Nonetheless, that one study did not show that sofosbuvir was more efficiacious, or safer than peg-interferon.

- Sovaldi has very few side effects.

The review had this summary,

The FDA compiled reports of adverse events from four trials....  There were no treatment-related deaths reported [note that we found there were deaths in the one trial that compared sofosbuvir to PEG, look here].

Approximately 78% of patients receiving placebo, 88% of patients on SOF + RBV treatment and 95% of patients receiving PEG + SOF +RBV reported a side effect from treatment.  The most common side effects were fatigue, anemia, nausea, rash, headache, insomnia and pain....

Thus it seems likely that Sovaldi has a lot of side effects, and whether it has fewer than standard treatment is unclear.  Furthermore,

studies on sofosbuvir were small, included populations that were healthier than the general hepatitis C population, were of short duration and had limited follow-up.  In many of the studies, the manufacturer was responsible for recording and reporting adverse events.  In general, reporting of adverse events is often incomplete and discrepancies between clinical trial reports and publications are common....  All of these factors would lead to a bias in under-reporting the true nature of adverse events.

Thus there is no good evidence that sofosbuvir has few side effects, or is dramatically safer than older treatments.

Summary

While there continues to be concern, if not outrage, that the latest treatment for hepatitis C is priced at $1000 per pill, most of those expressing concern seem to assume that the pill is a wonder drug, promising nearly everyone a cure without major side effects.  However, as we first noted in March, 2014, there is no strong evidence to that effect.  In fact, now three skeptical looks at the evidence by people with more resources and perhaps more expertise than we possess have shown similar conclusions.

It is a tribute to the power of the anechoic effect that there has been almost no recognition by physicians and other health professionals, journalists, and most amazingly, insurance companies who stand to lose billions paying for Sovaldi, that there is little good evidence that Sovaldi works, much less is superior to previous treatments.  Instead, even America's Health Insurance Plans thought the drug had "tremendous results," not very different from the assertion by the drug's manufacturer that the drug provides "a finite cure," (as reported by Reuters).  One might think that the insurance companies have enough money to invest in some real evidence-based medicine experts who could provide a skeptical assessment of the pricy new drugs and devices for which these companies may pay.  Is it that the commercial insurers are so now so dominated by generic managers who know nothing about health care, medicine, or biomedical science, much less evidence-based medicine that they are unable to resist the marketing and public relations hype?

The Sovaldi 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 not buy us the promised miracles and triumphs.

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 (25 July, 2014) - Web link added for CEBP report. 

Some Authoritative Skepticism about the "Triumph" of Sovaldi to Add to Outrage about "Blood Money"

Three weeks ago we posted about the continuing controversy over the stratospheric price of the new antiviral drug for hepatitis C (HCV), sofosbuvir (Sovaldi, by Gilead).  While the amazing $1000 per pill price got deserved attention, at that time no one but your humble blogger seemed to be publicly skeptical about published assertions that the drug was some sort of modern miracle, and a triumph of medical science.  At that time, we noted that there is no "strong clear evidence that this drug is extremely effective and remarkably safe, i.e., that the drug is a 'triumph' that will cure nearly everyone without risk or harm to them, and therefore warrants a princely price."


Since then, two other skeptical opinions have become public.

The German Institute for Quality and Efficiency in Health Care (IQWiG) Early Benefit Assessment

The German agency performed this assessment based on a dossier submitted by the drug manufacturer (presumably Gilead).  The assessment found some reason to think the drug beneficial, but that the evidence was sparse, left many questions unanswered, and was inadequate to assess the drug for some important patient populations.  At this point, only a summary is available in English.  It includes links to further information in German.

The overall assessment was,

The dossier submitted by the drug manufacturer provides indications of added benefit for non-pretreated patients infected with the virus of genotype 2. However, the extent cannot be quantified. There were no suitable data in the dossier for patients who are infected with other virus types (genotype 1 and 3 to 6) or who are coinfected with HIV.

Limited Generalizability


Particular problems with data about genotypes other than 2 were:

The manufacturer presented no adequate analyses for infection with type 1 and type 3 to 6 viruses and for HIV coinfection. It analysed results from studies in which the respective comparator therapy was tested in at least one study arm and compared these in a 'historical' comparison.

It included both randomized controlled trials (RCTs) and one-arm studies on the sofosbuvir side, but only RCTs on the comparator side. It justified this by claiming that it wanted to reduce the number of hits of its literature search. However, the database for the comparison was different because of this and the comparison itself was therefore unsuitable. A first literature search by IQWiG showed that a number of studies were not considered in the dossier.

Thus the assessment concluded that the drug company dossier included at best irrelevant data that it tried to pass off  as important, and inexplicably left out other data that might have been relevant.

Problem with Random Allocation

The German assessment focused on the single randomized controlled trial which compared sofosbuvir and ribavirin to peg-interferon and ribavirin whose results were published in the New England Journal and discussed in our previous posts (here and here).   However, the German assessment analyzed what was submitted in the company's dossier about this trial, rather than the published results in the NEJM.  It found problems in addition to those we found, starting with problems with the randomization,

Overall, IQWiG assessed the risk of bias of the FISSION study as high. The main reason was that the manufacturer only included those participants in the analysis who had received at least one dose of the medication they were randomized to. However, particularly in the control arm, where not the new drug, but conventional drugs were administered, some patients refused to have their planned treatment.

This is a general problem of open-label studies, where it is known who receives which treatment. This poses the risk that patients discontinue the study prematurely depending on which treatment they were randomized to. This compromises the aim of randomization: the comparability of the treatment groups.  This is exactly what happened in the FISSION study, which may lead to (highly) biased results.

Thus, the assessment concluded that the study had a major problem with randomized allocation.  This should be added to the other problems we found: unblinded ascertainment of adverse effects potentially leading to bias, apparently deliberate obfuscation of adverse effects, especially deaths occurring during the trial, and lack of long term followup.  This suggests that the study was manipulated to increase the likelihood of favorable results

Failure to Consider Important Outcomes

The German assessment also concluded that the trial provided no information about mortality or quality of life benefits,

 As no deaths occurred in the FISSION study in the therapeutic indication genotype 2, there could be no differences between the treatment groups, and therefore no proof of added benefit, in the outcome 'mortality'. This also applies to health-related quality of life, but in this case because the dossier contained no evaluable data for this outcome.

Note, however, that this suggests that the data submitted in the dossier was different than that reported in the New England Journal of Medicine.  We noted that in the supplemental data from the trial available on the web appeared data on mortality.  However, it showed higher (albeit still very minimal) mortality in the sofosbuvir group than in the peg-interferon group. The fact that the dossier submitted in Germany omitted all mortality results should be added to the fact that the NEJM report buried the mortality data in the on-line supplement, increasing the likelihood that the dissemination of this part of the results was manipulated to forestall the questions that it ought to provoke.

The German assessment further noted that the dossier included no good data about possible harms or adverse effects of the new drug,

The data on side effects contained in the dossier could only be assessed to a limited extent. The manufacturer presented these data on the basis of the proportions of patients with at least one event. However, this type of analysis is only suitable to a limited extent because the observation period of the patients was different in the two study arms.

Note that is suggests another type of study manipulation, unequal assessment of harms in the study arms perhaps meant to minimize the apparent harms of the new drug.  

Furthermore, again the data in the dossier appeared discrepant from that in the NEJM article (which we discussed here),

 Severe adverse events only occurred once in each of the two study arms. A statistically significant difference in the outcome 'treatment discontinuation due to adverse events' in favour of sofosbuvir was not robust in the sensitivity analyses performed by IQWiG. With regard to side effects, IQWiG therefore considers the added benefit as not proven.

The severe adverse event rates reported in the New England Journal article were higher, and the reason for this discrepancy is unclear.  

A Non-Quantifiable Benefit?

So ultimately only a qualitative assessment of the drug's benefits for genotype 2 patients was possible,

 For treatment-naive patients with genotype 2 chronic hepatitis C, an overall positive effect of sofosbuvir in comparison with the appropriate comparator therapy remains with regard to serious secondary diseases. The extent of this added benefit – which was determined with the surrogate 'SVR' – is non-quantifiable, however, because it is unclear how often the development of liver cancer can in fact be prevented. 

Note that mention of the IQWiG assessment has been made so far in only one major US media outlet, Bloomberg.  

 The Institute for Clinical and Economic Review Evidence Report

This report just appeared online in JAMA Internal Medicine [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.] 

The review found again that there were major limitations in the available data, and so much of it was based on a network meta-analysis and simulation studies,

The review was limited to patients with genotype 1, 2, and 3 infections, which account for most HCV cases in the United States. At the time of the review, no head-to-head trials of the direct-acting antiviral drugs had been performed, and most of the data on sofosbuvir came from uncontrolled studies We therefore used network meta-analytic techniques to perform indirect comparisons of sustained virologic response outcomes across treatment options and used these results as the input to a simulation model that compared the estimated clinical and economic outcomes of treatment after 1 and 20 years.

It is very hard for me to independently evaluate the credibility of these indirect methods of analysis of what amounts to sketchy data.  However, I should note that Ollendorf et al did not some other specific problems with the available data on sofosbuvir:

Yet at the time of this review there were several reasons for caution. First, the evidence base on the comparative clinical effectiveness of these 2 new drugs remained thin in most areas and notably incomplete in others. For example, in some subgroups, such as patients who have failed earlier treatments, there were little or no data available. There were no long-term data demonstrating the durability of short-term sustained virologic response rates for either drug; nor had either drug been compared head-to-head in a randomized clinical trial with each other or with a first-generation direct-acting antiviral drug. Finally, the evidence necessary for sofosbuvir to gain marketing approval through the FDA’s breakthrough designation was particularly sparse and did not include requirements for controlled trials.

Furthermore, it suggested reduced enthusiasm for treatment since most patients with hepatitis C will not develop severe complications, limiting the potential benefits of treatment,

 HCV is an indolent infection, and most adults with this infection will never develop negative health effects during their lifetime. Many people with HCV infection have no evident liver dysfunction. For such patients, the decision about whether and when to initiate treatment should involve careful consideration of the balance of risks and benefits and shared decision-making with experienced clinicians.

Note that at least to date, I have seen no discussion of the Ollendorf report in the media.

Pricing Unrelated to Production or Research and Development Costs

Meanwhile, there has been continued outrage in the media over the pricing of this probably not so miraculous drug.  Some has focused on the likelihood that most of the price represents pure profit, excess marketing (and perhaps huge payments to corporate insiders), rather than production or research and development costs.  For example, Bernard Munos wrote in Forbes

To compound the outrage, there is hardly a relationship between drug prices and their actual costs, which makes many patients feel as if they were held to ransom. Gilead, to its credit, has negotiated a deal that makes Sovaldi available to Egyptian patients at a 99% discount, but it may have also bolstered suspicions of profiteering.

Similarly, Julian Urrutia wrote in the Bill of Health blog from the Harvard Law School Petrie-Flom Center,

Gilead is working to offer lower prices in dozens of developing countries (of the 150 million patients with HCV, only about 1% are in the USA).

To me, this implies one of two things. Either Gilead will be selling the drug in developing countries at a price that allows it to make normal profits (in which case Gilead is capturing enormous rents in the USA market from $84K price tag), or whoever pays for the treatment of patients with HCV in developed countries will be subsidizing the treatment of patients in the developing world.

 The Editor of Modern Healthcare, Merrill Goozner wrote, an analysis of how Gilead's immense revenue was built on US government funded research, and academics who could privatize the research they did with such funding on university time,

 The National Institutes of Health invested heavily in university-based scientists to understand the genetic weak points of hepatitis C, just as it did for HIV. It gave grants to build virology labs, come up with potential drugs and conduct clinical trials.

One of those scientists was Raymond Schinazi, director of the Laboratory of Biochemical Pharmacology at the Emory School of Medicine in Atlanta. During the past 20 years, Schinazi's laboratory received at least $7.7 million from the National Institute of Allergy and Infectious Diseases. He wasn't alone. Some, like Kevin Raney, chair of the biochemistry and molecular biology department at the University of Arkansas for Medical Sciences, even developed drugs on their government grants, although his never made it into clinical trials.

Schinazi, a serial entrepreneur, took a different path. In the late 1990s, he formed the pharmaceutical company Pharmasset, to develop an antiviral drug invented at Emory. The company also worked on cures for HIV and hepatitis B. The original drug candidate went nowhere, he told me in a telephone interview. But chemists working inside Pharmasset—at the time of its sale to Gilead in 2011 it had only 82 employees—developed several novel therapeutics for the diseases, including one that eventually became Sovaldi.

Securities and Exchange Commission filings for Pharmasset during its years as a stand-alone research and development company revealed it spent under $7 million on R&D in 2003. In its early years, it received $1 million in government grants. Its total losses through 2011 came to $314.8 million. It was also investigating drugs for HIV and hepatitis B throughout that period.

The company hit the jackpot with hepatitis C and Sovaldi though, which led Gilead, whose initial success came from HIV drugs, to pay $11 billion for the company. Schinazi, who had retained a sizable stake in the firm after cutting his ties in 2006, walked away with over $400 million, according to a published report.

Gilead spent tens of millions of dollars to complete Sovaldi's clinical trials. Yet last August, the NIAID issued a news release touting its role in running one of those trials when positive results were reported in JAMA. The government, it turns out, had kept its hand in the development of Sovaldi.

So it appears that the pricing of Sovaldi has almost nothing to do with production or research and development costs.  Much of the initial research needed to develop Sovaldi was underwritten by the government.  Gilead paid royally for the results of the research, but most of the money went to investors and executives, including the former academic who did some early development work on government money and became tremendously rich from Gilead's largesse.

Growing Outrage over Extortionate Behavior


Some has focused on how the price represents unethical, if not extortionate behavior by corporate executives.  For example, Munos also wrote,

What has changed is perhaps the fact that the industry no longer realizes – or accepts – that it has a covenant with society. This is no ordinary business as it can only operate by the will of the people. Drug makers get intellectual property rights, which are essentially a license to print money, but in exchange society expects affordable innovation. For most of the past century, that bargain has worked remarkably well. But, if drug companies fail to live up to it, society can also revisit its part, and scale back patent rights, or deny reimbursement. And this is happening in a rapidly-growing list of countries – not just India and China, but Germany, the UK, France, Canada, and soon… coming to a drugstore near you.

The legendary leaders who built the pharmaceutical industry as one of the most respected understood that bargain. One remembers George Merck's admonition ('Medicine is for the people. It is not for the profits'), Jonas Salk’s quaint remark about the polio vaccine patent, Robert Wood Johnson’s Credo, and Roy Vagelos’ more recent warning about the industry’s ill-conceived pricing policies.  They understood that self-policy is always better than regulation, and such moderation served them well. But their successors’ failure to uphold their advice has led to an onslaught of regulations and policy changes that threatens to permanently remake the industry.

Elisabeth Rosenthal wrote in the NY Times, quoting Steve Francesco, a pharmaceutical consultant,

'To understand drug pricing you have to shed your sense of value as a consumer and as a noble human being,' Mr. Francesco said. 'You have to put on the lens of the health care industry, where what you’re doing is looking for opportunities to maximize return.'

Also in Forbes, Dr Robert Pearl wrote this about Sovaldi pricing,

 But at $1000 a pill, its pricing is exorbitant, monopolistic, and disrespectful to the purchasers and patients who will bear the brunt of the massive cost.

Dr Frank Huyler wrote in the New York Daily News about blood money,

This sort of blood money is nothing new. But it is among the worst of recent examples; yet another evil act, yet another predation on mostly poor, mostly desperate people, who inevitably will ask taxpayers to save them.

Summary

It is even bloodier money if the assumption that the drug is a "well-tolerated and effective cure," which  Dr Huyler held, proves not to be true.  It is clear that most of the money that Gilead is now scooping up in the US is not to pay retrospectively for research and development or drug production. Instead, it seems likely to be supporting marketing, public relations, some investors' profits, and huge executive compensation.  When the public realizes that the money may not be buying miracles, the outrage should increase.  

The Sovaldi 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 not buy us the promised miracles and triumphs.  

True health care reform would revisit the pact society once made with drug, biotechnology and device companies meant to promote reasonably priced innovation, but now promoting oligarchy; support transparency and honesty in clinical research; and challenge how health care managers can make millions or billions from unproven, and sometimes worthless or dangerous products.

Knee Deep in the Hoopla - "A Triumph of Medical Technology" Sans Evidence of Superiority from Published Randomized Double Blind Controlled Trials

With the publication of several new articles in the prestigious New England Journal of Medicine, the buzz about Sovaldi (sofosbuvir - Gilead), a new oral treatment of hepatitis C, has become feverish.  The drug had been hailed as near miraculous, and the only debate has been about its near stratospheric cost (look here). 

This week, of all weeks, however we should be extremely skeptical about expensive drugs promoted as the cures of our most feared ills.  This week a series of articles appeared in the British Medical Journal showing that there was no evidence to support the clinical value of the  antiviral drugs stockpiled for governments as proof against dreaded influenza epidemics (look here to start).  

The Latest Buzz

As we posted earlier, the discussions contrast the ostensibly near miraculous aspects of the drug's performance with its extremely high price.  For example, a few days ago the Los Angeles Times reported,

In a series of clinical trial results, a new generation of antiviral medications was able to clear the liver-ravaging virus from virtually all patients' bloodstreams in as little as eight weeks. Even in patients with the most stubborn infections, the new drugs were capable of suppressing the virus completely at rates well over 90%. The treatments, however, come with a steep price tag.

So,

The new medications are 'a triumph of modern medical technology,' said Dr. Jeffrey Tice, a UC San Francisco physician who was not involved in any of the clinical trials.

Accompanying the research reports in the New England Journal was a commentary by Dr Raymond T Chung and Dr Thomas F Baumert.  Its title proclaimed Sovaldi and similar drugs also to be part of "The Arc of Medical Triumph."(1)  Buried in the commentary's supplementary material was a link to disclosure forms that showed that:

Dr Chung reports grant support from Gilead Sciences [the manufacturer of Sovaldi], Mass Biologics, Vertex and Merck, and personal fees from Abbvie, Enanta and Idenix.

Note that Abbvie and Merck are also at work on antiviral treatments for hepatitis C.

and

Dr Baumert reports several patents ... and pending patents [apparently that could be conflicts of interest]

It is clear that there have been major scientific advances in the characterization of the hepatitis C virus, and development of multiple new antiviral agents which promise to treat that infection.  Furthermore, clearly there is reason for hope for treatment of hepatitis C that prevents its long-term complications and averts premature death. (Of course, that hope could be a bit stronger in the hearts of those who have financial relationships with the corporations that stand to profit from sales of these drugs.)

But it is not obvious that there is sufficient clear evidence from clinical research, particularly from double-blind randomized controlled trials (RCTs), that shows the newest treatments will provide triumphal benefits to patients that outweigh their possible harms.

One Published Unblinded RCT Compared Sovaldi to Peg-Interferon


In our previous post, written after the immense price of the new drug in the US became apparent, we questioned whether the evidence from controlled trials then available would justify the hype, and the high price.

We looked at what appeared to be the then single best available study. The most prominent randomized controlled trial of Sovaldi for patients who had not had previous therapy for hepatitis C that had been published by March, 2014, appeared in the New England Journal of Medicine in May, 2013.(2)   While it provided some reason for hope, it did not provide clear evidence that Sovaldi was a miracle drug.

The study showed that Sovaldi plus ribavirin produced the same rate of sustained virologic response (SVR), 67%, as did the previously accepted standard treatment, peg-interferon plus ribavirin, again 67%.  (SVR means that the hepatitis C virus has become undetectable in the patient's blood, and is believed, but not proven to represent a cure.)

While Sovaldi had lower rates of unpleasant side effects than did peg-interferon, these rates were not negligible. For example, the rate of nausea after peg-interferon was reported to be 29%, but after Sovaldi it was still 18%.  Given that the trial was unblinded, and that some of these side effects have a subjective element, these figures could have been biased due to patient expectations that the new drug would have fewer side effects.

Furthermore, Sovaldi appeared to produce higher rates of severe adverse effects (3%) than peg-interferon (1%).  However, the article did not mention any deaths in either treatment group.  When I later reviewed the  supplemental data available on the web from the May, 2013 article, I found that buried within this information were the facts that two people died during treatment with Sovaldi, and one after treatment with peg-interferon.  So, the rate of  severe adverse effects or death after Sovaldi treatment was more than double (9/256 ) than that after peg-interferon (4/243).  It is very curious and concerning that the authors chose not to mention deaths of study subjects in the paper that reported their trial results.   

Finally, the trial, like just about all previous trials of treatment of hepatitis C, did not follow patients long-term, and hence could not show whether treatment actually resulted in better clinical outcomes, for example, longer survival, decreased rates of severe liver disease, etc.  We thus concluded that there really was no clear evidence that Sovaldi was really a miracle drug, which could cure more people, in fact, nearly everyone, compared to standard therapy, yet with fewer side effects and more safety.

Any Evidence from Other Controlled Trials?

We looked through the newly published articles, the articles they cited, and the official US label for sofosbuvir to see if there is any other evidence from controlled trials to support the triumphant claims about sofosbuvir.  To simplify this casual, not systematic review, we only looked at articles about patients who had not been previously treated for hepatitis C.

The drug label mentioned a controlled trial that compared sofosbuvir to placebo.  The POSITRON study (study 107) was a trail that compared Sovaldi and ribavirin to placebo in patients who are "interferon intolerant, ineligible or unwilling."  The overall SVR in the treated group was 78%.  The label did not mention adverse effects rates in this trial, and as far as I can tell, it was not published.  Again, while the SVR was good, it was NOT over 90%.  As far as I could tell, the results of this study have not otherwise been published. 

The new studies in the New England Journal, and the studies cited by one of them were NOT double-blind randomized controlled trials of sofosbuvir versus some other treatment, or versus placebo for that matter.

For example, the study by Afdhal et al in the New England Journal considered sofosbuvir in combination with another new drug from Gilead, ledipasvir.  However, this was an open label (unblinded) study that compared patients given different durations of treatment with both sofosbuvir and ledipasvir with or without ribavirin.  It did NOT directly compare sofosbuvir (or ledipasvir) to any other treatment, or to placebo.(3) Another study by Sulkowski et al in the NEJM focused on previously treated patients.

Cited by Afdhal et al were studies by Osinusi et al (an unblinded study that compared different doses of ribavirin given to patients also who all received sofosbuvir)(4); Lawitz et al (an unblinded study that compared different durations of treatment for both sofosbuvir and ledipavir with or without ribavirin)(5); and Gane et al (a study that compared various drugs again all added to sofosbuvir)(6).  Again, NO study compared sofosbuvir to any other treatment, or to placebo.

Thus so far I have been unable to find any additional studies that compared Sovaldi (sofosbuvir) to any other potential treatments for hepatitis C.  Without a comparison to another treatment, it is not possible to tell whether the high rates of patients whose blood tests show no detectable hepatitis C virus in the short-term after treatment were due to the excellence of the treatment, or due to selection of patients with particularly good prognoses.   Recall that there is evidence that some patients with hepatitis C spontaneously clear their blood of hepatitis C, and become spontaneously cured (see our previous discussion, and particularly the study by Seeff et al[7]). 

There is evidence that the studies above may have been designed to only include patients with the best prognoses.  They generally were designed with very complicated, restrictive and subjective inclusion and exclusion criteria that could have eliminated all but the healthiest patients.  For example, according to the study protocol found in the supplementary material for the study by Afdhal et al, patients with "clinically-significant illness (other than HCV) or any other major medical disorder that may interfere with subject treatment, assessment or compliance with the protocol" would have been excluded, as would have "subjects currently under evaluation for a potentially clinically-significant illness (other than HCV)...."

So, while many articles about sofosbuvir (Sovaldi) have appeared recently, in my humble opinion they do not provide strong clear evidence that this drug is extremely effective and remarkably safe, i.e., that the drug is a "triumph" that will cure nearly everyone without risk or harm to them, and therefore warrants a princely price.

Summary

While the buzz about Sovaldi intensifies, there still seems to be little clear evidence to justify extravagant claims made for it, or the extravagant price demanded for it.  Yet there seems to be a bandwagon building to somehow pay whatever it takes to provide the "triumph" of medical science to every patient who needs it.  At the current price, that should make the CEO of Gilead even richer (increases in the stock price after the $84,000/ course drug price was announced already turned him into a billionaire on paper, look here.)  As noted above, it is not clear what benefits such a costly policy would bring to patients, and at what risks.

We have discussed how our current policy of letting corporations sponsor and run the clinical research meant to assess their own products has lead to widespread manipulation of research to make their products look better, and sometimes suppression of research that cannot be manipulated into making their products look good.  This should make health care professionals, policy makers, and the public extremely skeptical of every over-hyped new "innovation."  So far, there seems to be no public skepticism about this latest, and seemingly most expensive pharmaceutical "triumph."

The US health care system, and to some extent the health care systems in most developed countries are experiencing ever higher prices.  Much of these prices' effects seem to drive up remuneration of health care executives and managers, but whether they buy better care or outcomes for most people is not so clear.  The ever rising prices seem to be buoyed by endless enthusiasm for new tests, treatments, programs, and unbridled faith in the benefits of all new technology.  It is not clear how much of that is due to evidence, how much is based on ideology and unquestioning faith in technological progress, and how much is driven by marketing and public relations, which not always may be entirely honest and free from deception.

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 could lead to health care that is more about patients and their outcomes, and less about ideology, hype, and hucksterism. If only such skepticism were easier to find.


References
1.  Chung RT, Baumert TF.  Curing chronic hepatitis C - the arc of medical triumph.  N Engl J Med 2014:  Link here.
2.   Lawitz E, Mangia A, Wyles D et al.  Sofosbuvir for previously untreated chronic hepatitis C infection.  N Engl J Med 2013; 368: 1878-1887.  Link here.
3.  Afdhal N et al.  Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.  N Engl J Med 2014: Link here.
4.  Orinusi A Meissner EG, Lee YJ et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial.  JAMA 2013; 310: 804.  Link here.
5.  Lawitz E, Poordad FF, Hyland RH et al.  Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised phase 2 trial.  Lancet 2013; 383: 515.  Link here.
6.  Gane EJ, Stedman CA, Hyland RH et al.  Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection.  Gastroenterology 2013.  Link here.
7.  Seeff LB, Hollilnger B, Alter HJ et al.  Long-term mortality and morbidity of transfusion- associated non-A, non-B, and type C hepatitis: a National Heart Lung and Blood Institute Collaborative Study.  Hepatology 2001; 33: 455-463.  Link here.

ADDENDUM (21 April, 2014) - Also see the post on "breakthrough cures?" by Dr Howard Brody on the Hooked: Ethics, Medicine and Pharma blog.