Not So Wondrous Drugs? – New Warnings about Severe Adverse Effects of New, Heavily Marketed Drugs for Hepatitis C

Yves here. Even though this post is about a hepatitis C treatment, it also serves as a cautionary tale about new, heavily promoted drugs in general.

By Roy Poses, MD, Clinical Associate Professor of Medicine at Brown University, and the President of FIRM – the Foundation for Integrity and Responsibility in Medicine. Cross posted from the Health Care Renewal website

Background – Wonder Drugs for Hepatitis C

In our April, 2014, post we noted how Sovaldi (sofosbuvir), the new antiviral drug made by Gilead for hepatitis C was touted as a “triumph of of medical technology.”  In that, and subsequent posts we discussed how such claims were not buttressed by much good data from clinical research.

We could find only one published randomized clinical trial of sofosbuvir (and ribavirin), which compared it to the older drug used to treat hepatitis C, peg-interferon (and ribavirin).  At best, the new drug showed about the same ability to eliminate detectable virus from the patients’ blood in the short-term as did the older drug.  The new drug also produced fewer unpleasant side effects, but possibly more severe adverse effects.  Just like all previous known published trials of hepatitis C treatments, this trial of sofosbuvir did not follow patients long enough to determine if the drug had any effect on the serious, but not inevitable long-term complications of hepatitis C infection, severe hepatitis, cirrhosis, liver failure, liver cancer, and premature death.

I could find no other published trials of sofosbuvir versus either older drugs or placebo.  Most of the subsequently published, and loudly hyped studies of the drug were of highly selected patients, and did not include control groups which did not receive sofosbuvir.  So the very high short term “cure” rates – which were really rates of elimination of detectable virus from the blood, could have been mainly a function of these studies’ highly selected patient populations.

Yet the lack of strong evidence that sofosbuvir, and subsequent competing drugs actually made patients better, i.e., feel better, function better, avoid serious subsequent medical problems, or live longer, did not stop tremendous enthusiasm in the media for the new drug.  Much of it doubtless stemmed from huge marketing and public relations expenditures.  Nor did did the lack of evidence stop Gilead and other drug makers from pricing the new drugs in the stratosphere.  Initially a 12 week course of of Sovaldi cost $84,000.

Since then, there has been tremendous buzz about the price of these new antiviral drugs for hepatitis C, and tremendous anxiety about the consequent difficult access to these presumptively “life saving” therapies.  However, my and others’ questions about whether these drugs actually benefit patients, and whether any benefits might be worth their harms, remained anechoic (See appendix below.)

The Harms of the “Wonder Drugs” Begin to Appear

Nowadays new drugs, devices, and other health care technologies are often touted based on little evidence.  What evidence is produced mainly comes from commercially sponsored clinical trials.  Commercial sponsors may manipulate the design, implementation, analysis and dissemination of these studies to increase the likelihood that they will make their products look good.

In particular, such trials may fail to detect adverse effects of the new products to be hyped.  The trials  often enroll only small numbers of patients, decreasing the likelihood of finding rare but serious problems.  Often patients who have any health problems other than the disease of interest are excluded from trials, decreasing the likelihood of detecting adverse events that might affect patients with multiple morbidities or on other treatments.  Trials may fail to follow patients long-term, so they may fail to detect adverse effects that appear only after prolonged therapy.  These sorts of problems certainly afflicted the very few real clinical trials of sofosbuvir, and other new antiviral drugs for hepatitis C.

So it should not have been surprising that sofosbuvir has now been found to produce two kinds of severe adverse events that were undetected, or at least undisclosed when it was launched.  The second kind of adverse event was just announced, and also seems to occur after administration of other new anti-hepatitis C drugs.

Severe Heart Rhythm Abnormalities

In March, 2015, as discussed by Dr John Mandrola in Medscape,

As reported by heartwire , the US FDA recently announced a change in labeling for the hepatitis-C antivirals ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) and sofosbuvir (Sovaldi, Gilead Sciences) after their manufacturers reported bradycardia, pacemaker intervention, and even death in patients who took the medications along with amiodarone. Notably, six of these nine cases occurred within 24 hours of sofosbuvir dosing.

While Dr Mandrola was concerned about this adverse effect, the news media put more emphasis on the Wall Street analysts who thought the problem would have “zero impact” on sales of the fabulously expensive antiviral drugs. (See this post by Ed Silverman on PharmaLot.)

So all remained serene, until this week.

Reactivation of Hepatitis B Infection

On October 4, 2016, Medscape reported

Patients with a past or current hepatitis B virus (HBV) infection can experience sometimes fatal HBV reactivation if they take any of nine direct-acting antivirals for hepatitis virus C (HCV) infection, the US Food and Drug Administration (FDA) announced today.

The agency will require a boxed warning for the drugs advising clinicians to screen patients for evidence of a past or current HBV infection before ordering antiviral treatment for HCV.

Also,

The FDA said in a news release that it had identified 24 cases of HBV reactivation in coinfected patients treated with these antivirals from November 22, 2013, to July 18, 2016, in reports to the agency and published literature. Two patients died, and one needed a liver transplant.

Why were we not made aware of this before?  Failure to detect this adverse effect was apparently due to the exclusion of patients with a history of hepatitis B from previous studies of the new drugs.  As we mentioned above, commercially sponsored trials often exclude patients with nearly any medical conditions other than the one of interest.  Yet hepatitis C patients often have comorbidities.  I

clinical trials for the HCV drugs in question did not report HBV reactivation because they excluded patients infected with HBV.

Will this prompt a reexamination of our enthusiasm for new antiviral hepatitis C treatments? I suspect not. Even FDA officials suggested we should not be too alarmed. In particular, Dr. John Farley, deputy director of FDA’s Office of Antimicrobial Products, said according to NBC News,

I think it is important to recognize that these hepatitis C drugs are lifesaving medications. What we don’t want to do is discourage patients with hepatitis C from getting treatment,…

But remember, there has never been a controlled trial that showed that treatment of hepatitis C with anything actually reduced the risk of later severe hepatitis, cirrhosis, liver failure, liver cancer, or premature death. And there may be other adverse effects of this new treatment that remain unknown.

Even government regulators, who are supposed to put the public health ahead of the profits of the pharmaceutical industry, seem to have fallen for the life saving miracle drug meme in this case.

Summary

The ongoing story of hepatitis C treatment demonstrates how hype and buzz, largely generated by marketing and public relations, and likely fueled by financial relationships among commercial health care firms and health care professionals and academics, has triumphed over rigorous skeptical evaluation of the best available evidence from clinical research.

There has never been good evidence that hepatits C treatments prolong life, or prevent severe liver disease in the long run.  There has never been good evidence that these drugs’ clinical benefits outweigh their harms.  Yet they have been relentlessly promoted as game changers, miraculous, triumphant lifesaving medicines.

One obvious lesson is that health care professionals, policy makers, and the public at large have to be much more skeptical about commercial claims for drugs, devices, tests, etc.  We need to figure out when claims are coming from marketing departments and public relations hacks.  We need to figure out when researchers and professionals who are supporting these claims could be influenced by financial relationships with the firms benefiting from the claims.

Furthermore, it is high time to revisit all the regulatory and policy changes over the last 30 years that have put manufacturers in charge of the research meant to test their own health care products.

In conclusion, 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.

…….
APPENDIX – Clinical Research about Hepatitis C Treatments

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 Internal Medicine 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 herehere, and 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 Intern Med 2014;174(7):1170-1171. Link here.
2. Sofosbuvir (Sovaldi), active against hepatitis C virus, but evaluation is incomplete. Prescrire Int 2015; 24: 5- 10. Link here.

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23 comments

  1. paul

    The moment you see the phrase ‘surrogate outcome’ you know they aren’t looking at the disease anymore.

  2. Todd

    Not on the drug mentioned in the post,
    but 3 different doctors, tried to put
    on biologics, Humira or Enbrel!
    You should read the warning labels,
    Enbrel, Humira, or any other biologic
    very similar to rat poison!
    What a joke!
    Is the FDA worse than the SEC,
    you bet!

  3. LVuoto

    My own experience with hepatitis C, a support group for people with hepatitis C, and the number of people I know whose lives have been made better by treatment with these new antiviral drugs tells me that the person who wrote this article does not have much experience treating (or knowing) patients with hepatitis C.

    He says there are no good studies showing their effectiveness. I would suggest spending a little time searching for (and actually reading) the published research (google “Daklinza” or “Epclusa” and “clinical trials”), Also, by the way, one of the reason the most recent clinical trials don’t include control groups is because the drugs were so effective and had such high cure rates that it was deemed unethical to withhold it from control patients who are sick with hepatitis C.

  4. JustAnObserver

    Is it any coincidence that the US is one of the few developed countries that allows drug advertising on television ? I’ve lost count of the number of times I’ve wanted to throw something at the TV when I hear the phrase “ … ask your doctor whether Drug X is right for you !”.

    OTOH maybe that’s a plus. If its being promoted on TV then avoid it at all costs until you’ve read the independent trial evidence.

    1. Anonymouse

      Better yet, just avoid the TV at all costs. You are simply being manipulated.

      If you did not choose to put something in front of your eyeballs, you can be highly confident that somewhere, there’s a serious conflict between the message being delivered and your best interests.

      And even if you did choose it, be careful what the producer’s motives were…

    2. John Zelnicker

      @JustAnObserver – New Zealand is the only other country that allows direct-to-consumer advertising.

  5. likbez

    We are talking about “medical industrial complex” here. So this is a systemic problem
    Dangerous drugs, “blockbuster drugs” are just the tip of an iceberg.

    When profit motive replaces Hippocratic oath terrible things happen. And this is what happened under neoliberalism. “Greed is good” is the new morality.

    That include useless surgeries, such as cardiac stenting (which is a mass practice in the USA).

    See

    https://www.zevandavidson.com/doctor-performs-unnecessary-surgery-for-profit/

    http://www.softpanorama.org/Skeptics/Health/Heart_diseases/Arteriosclerosis/Angioplasty/Abuse_of_cardiatic_stents/index.shtml

    http://www.nytimes.com/2016/08/04/upshot/the-right-to-know-that-an-operation-is-next-to-useless.html?_r=0

    Actually any area where control is difficult and the same doctor recommends the procedure and later does the surgery is suspect.

    When you’re a hammer everything looks like a nail.

    Hospitals became more of a money making machines and the duration of your stay in hospital often is determined by the insurance you have and doctors financial motives, not by your disease.

  6. Denis Drew

    First step of the government take over all pharmaceutical research could be government paying for all clinical trials. What could the industry object? It would mean much less financial risk for the firms — an incentive.

    No matter who pays for the research it is the same university researchers doing the work — as far as I know. Government could fund the whole thing without any need for greed.
    * * * * * *
    Right now, 10,000 Americans die weekly (!) of heart failure. Formerly there was no improvement and certainly no cure. In 2012 a small clinical trial or a balloon inserted around the heart to assist pumping ended with 5 actual cures, most improved and a few held steady. A much larger trial of 200 is being attempted to get FDA approval …

    … but is in Limbo (from my reading) by inability to get investors to pony up for more than 100 of the 200 — $30 million short being the reason. The flip side of profit based research ripoff.

    I’m sure today’s 5 million heart failure sufferers in the US would gladly pony up $6 apiece. Maybe one of them should start a go-fund-me for $30 million. Maybe investors would not want them to.

    Read more about this for profit fantastic here — I think I’ve got it right: http://ontodayspage.blogspot.com/2016/06/will-500000-americans-year-die-for-lack.html
    * * * * * *
    Gilead — the same company that brought us Sovaldi — now has developed a drug that claims to be 95% effective against all versions of hepatitis: Epclusa. At $75,000 a treatment (that may only cost them $150 to manufacture) X 300 million worldwide sufferers, that comes to $22.5 trillion (with a “t”) to treat all. I’m sure they need most of that for future research (or divert it to pay for the living and business expenses for every man, woman and child in the US, Canada and Mexico for one year).
    http://www.marinij.com/article/NO/20160710/FEATURES/160719994

    1. Wisdom Seeker

      Ahem. We need to eliminate monopolistic practices and pricing, not create a new monopoly.

      “government paying for all clinical trials”

      That would not eliminate the conflicts of interest faced by government researchers, the revolving-door cronyism between government and private industry (already rampant in the healthcare sector), or the fact that researchers capable of winning government grants and producing profit-making data won’t be constrained by your attempt to limit their intellectual or entrepreneurial freedom by mandating that “only” government can “fund” research.

      “No matter who pays for the research it is the same university researchers doing the work — as far as I know”
      You don’t know. And once you change who pays, you will change the incentives and end up with different (most likely less effective) researchers, as the highly motivated ones will do something different than what you naively expected when you changed their business model.

      “Government could fund the whole thing without any need for greed.”

      Where there are potential profits, greed will be there. Who funds the research is not as relevant as who reaps the rewards from the intellectual property. If you take away the potential rewards entirely, nothing will get done.

      What is needed is rigorous enforcement of the Sherman-Clayton antitrust acts, to prevent price gouging. Add in the elimination of illegal constraints on international trade leading to order-of-magnitude pricing differences between U.S. and rest of world on what should be commodity items, to ensure that everyone pays the same price, and the cost of drugs will drop. If that means less funding for “research”, so be it. The increase in competition and affordability will still lead to better healthcare outcomes. And there will still be plenty of money for research as long as Congress is disproportionately elderly and the electorate is as well.

  7. Elizabeth

    A pharmacist friend of mine told me never to take any drug that hasn’t been on the market for at least 5 years. The FDA is toothless and is corrupt just like every other regulatory agency in this country. Big pharma is primarily concerned with huge profits like “blockbuster” (expensive) and drugs that you have to take over a long period of time and this is probably one reason why a lot of research on superbugs isn’t being done. There’s no money in it.

  8. Perdu

    It is indeed a cautionary tale, and certainly not unique. One of my personal favorites is Xarelto (rivaroxaban). This is currently the most widely prescribed of the new and expensive oral anticoagulant drugs collectively known as NOACs (novel oral anticoagulant drugs; now there’s a “novel” acronym. Ugh) used for the prevention of stroke and embolism. The gold standard for the prevention of stroke is warfarin, which is somewhat difficult to control, but inexpensive and effective.

    What’s striking about this particular medication is that the clinical trials supporting its use in the treatment of atrial fibrillation were notably deficient. The only reason the drug was superior to warfarin was that the physicians performing the study horribly bungled the warfarin control. The FDA’s analysis of the results suggested that the drug was inferior to Pradaxa (dabigatran), although there was no direct comparison in that trial. In fact, the FDA reviewers suggested that it be used as a third line drug, behind warfarin and Pradaxa.

    To make it worse, one of the early concerns about the NOACs was the lack of treatments to reverse the effects of the drug in patients with poorly controlled bleeding. An antidote to Pradaxa was developed and approved last year. Not so much for Xarelto, although manufacturers have certainly tried. The FDA just rejected an effort to do so in August of this year.

    So why is Xarelto the most widely prescribed of these medications despite inferior evidence for effectiveness and lack of an antidote? In the absence of a definitive market analysis, my first, second and third guesses would be advertising/marketing. Great way to run a health care system. Not.

  9. sleepy

    I was treated for hepatitis C ten years ago with weekly pegalated interferon shots and daily ribavirin pills. The 24 week treatment (I was lucky to have genotype 2–the 3 or 4 other genotypes have a 48 week treatment period) resulted in no detectable virus after 12 weeks, but continued treatment for the full 24 weeks. Prior to treatment my liver enzymes were sky high, the liver imaging (CAT scan?), and the liver biopsy diagnosed moderate liver damage but no cirrhosis–not particularly serious since the liver at that point can repair itself if treated.

    The referenced SVR means of course that the virus is undetectable. It doesn’t mean the virus isn’t there, just that the test can only detect it down to a point, i.e., 5 viral parts per milliliter of blood. When I began treatment it was 4 million viral parts per milliliter of blood.

    A year after treatment, I was tested again and there was no evidence of the virus. I was given the same liver imaging and my liver had repaired itself up to a normal level. Since then, I have had several physicals and my liver enzymes have always been normal.

    I was treated at Mayo Clinic, not because I required elite medical care, but because Mayo is 80 miles away and the main medical center for my area of rural northern Iowa. The Mayo gastroenterologist used the term “cured” after my final test–a year after ending treatment. The rationale was that a year after ending treatment, if the virus had been present below the detectable levels it would have come back to detectable levels after a year of no treatment.

    Given the fact that my liver and the liver enzymes all returned to normal, I would agree with the doctor. And yes, I know my anecdote is not evidence. Was treatment warranted? I don’t know, but I no longer have any observable liver disease caused by the hep c virus, and haven’t for 10 yrs.

    My point is that my treatment for 24 weeks, including the biopsy, imaging, doctor visits, numerous lab tests, the drugs, the psychiatrist and his scripts (interferon makes you crazy) and the follow ups to all of that cost a grand total of a hair over $30,000. I had great insurance which paid for it all, except for c. $175 (I showed up at Mayo for an appointment and they were close to not seeing me over the $175 bill which I’d forgotten about, after they had already been paid over $25,000 by my insurer). Expensive enough but a far cry from what the new stuff costs.

    I also have a bone to pick with the pharma ads about this new treatment–they claim a high SVR rate, but that is only for those who have not failed in earlier treatment. And the older drug treatment for most genotypes had just a 50% SVR rate. So, for many, the drugs do nothing.

    Sorry for my long story.

    1. sleepy

      I should add that aside from the tests, my hep c was always completely asymptomatic. I felt fine and the virus was only discovered as a result of my high liver enzymes during a routine physical with blood tests.

    2. Yeti58

      I too was diagnosed with hep C in mid 2001, started treatment with 3x a week shots of interferon and oral ribavarin. Can’t remember which genotype I had but was on a 24-26 week regimen. My ALT/AST readings were very high at start of treatment and went down to normal early on in treatment. Treatment was brutal and I was only able to work 3 days a week at first than after about 3 months had to stay off work until about 3-4 weeks after treatment ended. Just had a viral load check this summer and still show no detectable virus 14 years later. Now whether or not I will live longer due to treatment I have no idea, and would love to find out but as has been noted no proper study has been performed. Now almost 58 years old and feel pretty good. Hope this may help someone thinking about taking the treatment that maybe the older treatments are a better option.

  10. robnume

    As this article points out, these are only some of the many problems with a for profit health care system. When my doctor wants to prescribe any meds for me I always insist on meds which have been around for a long time and have proven their efficacy and safety. DTC advertising is a terrible idea and we ought not allow it. Single payer, now. Support PNHP. They do great work.

  11. TODD

    Humira, the top selling drug in the world,
    USED BY ONLY 1 PERCENT OF THE POPULATION,
    A BLACK LABEL DRUG BY THE FDA,
    SPENT OF 203 MILLION DOLLARS IN ADVERTISING.
    AGAIN, A BLACK LABEL DRUG USED BY 1 PERCENT OF THE POPULATION.

  12. m duncan

    this article is highly misleading regaurding the effectiveness of new hcv regimens and the social costs of hcv infection. hcv infection is now the leading cause of infectious disease death in the u.s.
    while real world results don’t mach some of the initial hype, anybody familiar with previous treatments (the original interferon/ribavirin treatment or first generation antivirals) without an axe to grind will acknowledge the greatly improved effectiveness of the new drug regimens. that is exactly why their makers can get away (so far) with the criminal prices they are charging. the author is approaching aids-denialism levels of misinformation in this article.
    google “sovaldi real world svr rates” to see for yourself. example

  13. TheCatSaid

    In addition to the many weaknesses of the mainstream medical/pharmaceutical (MSMP) industry, there are other weaknesses of our “advanced” society’s basic concepts of illness, injury and the healing process.

    Our societal paradigm of “health” and “disease” is itself a kind of disease. Many know this–including many health professionals–but the tool boxes they are familiar with are often limited.

    Fortunately there are many ways to address our health that do not require buying into the MSMP paradigm. There is no one right way. We all have different paths. Sometimes illnesses serve an important purpose (e.g., learning something that was of vital importance for our evolution, or providing the doorway for the death transition process).

    For example, here is an interview with Dr. Mary Helen Hensley just posted. In it she shares a lot of information about illness, other painful life events, and the healing process–but coming from a much larger perspective.

    I’ve learned a lot from Machaelle Small Wright’s books as well, for example The Medical Assistance Program. Dr. Jjill Bolte Taylor and My Stroke of Insight is another. Anita Moorjani’s is yet another.

    The existing MSMP system is not the only possibility.

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