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Drug companies

Primary Care with Geoffrey Modest MD: Diabetic peripheral neuropathy, and more drug company shenanigans

4 Apr, 17 | by gmodest

By Dr Geoffrey Modest

There was a recent systematic review in the journal Neurology on pharmacotherapy for diabetic peripheral neuropathy pain and its effect on quality of life (see doi. org/ 10. 1212/ WNL. 0000000000003882). This appeared right after the recent guidelines from the American Diabetes Association (see link below), but had several eye-opening differences.

Details:

— the researchers updated a 2014 systematic review of 57 studies (see  Griebeler ML. Ann Intern Med 2014; 161:639, and prior blog on this  here) with 24 additional published studies and 25 unpublished studies. All trials were published between 1990 and 2015. The number of participants range from 20 to 804. They referenced the website clinical trials.gov on March 9, 2016 to get data on unpublished studies.

 

Results, from placebo-controlled RCTs (those with moderate or large effect are highlighted):

— for anticonvulsants:

   — pregabalin, 16 RCTs, small effect, with low strength of evidence (SOE)

   — gabapentin, 5 RCTs, not effective, low SOE

— serotonin-norepinephrine reuptake inhibitors/antidepressants:

   — duloxetine, 7 RCTs, large effect, moderate SOE

   — venlafaxine, 2 RCTs, large effect, moderate SOE

   — tricyclic antidepressants, 4 RCTs, moderate effect, low SOE

— opioids

   — typical opioids (eg, oxycodone), 4 RCTs, not effective, low SOE

   — atypical opioids (tramadol, tapentadol), 5 RCTs, moderate effect, low SOE

— topical agents

   — capsaicin cream 0.075%, 5 RCTs, not effective, low SOE

— other agents

   — dextromethorphan, 3 RCTs, not effective, low SOE

   — mexiletine, 5 RCTs, not effective, low SOE

   — botulinum toxin, 2 RCTs, moderate to large effect, low SOE

–there were not enough data to evaluate the effect of these medications on quality-of-life.

–adverse effects: varied by agent. Dropout rates in the studies varied from 2.5% to 70% for oral agents, very low for topicals

 

Commentary:

— Unfortunately, few of the studies extended beyond 3 months (mean follow-up was 8.8 weeks with a maximum of 22 weeks), limiting their clinical utility some.

— The presumptive difference between the typical and atypical opioids as above is that the atypical ones have activity as norepinephrine reuptake inhibitors as well as mu agonists, with moderate effectiveness (vs oxycodone, a mu agonist, which was no more effective than placebo)

— I was a little surprised that capsaicin cream had no benefit, given the initial studies. And I have had patients do pretty well, with essentially no adverse effects. But, even if this is mostly a placebo effect, it is a pretty harmless med and if it works…

— The American Diabetes Association review  gave primary billing to pregabalin and duloxetine (see here  )

— The ADA review also did find a small benefit for oxcarbazepine, with low SOE, but not for other anticonvulsants such as topiramate, valproic acid, or lamotrigine.

— So, why are the above conclusions so different from those of the American Diabetes Association?  Of the 25 additional studies in clinicaltrials.gov which were unpublished, 18 were actually completed. The researchers were able to include 7 of these 18 completed studies. Of note, though pregabalin seemed to be effective, with a moderate reported effect size, when the 6 additional unpublished studies were included (all with negative results), the effect size decreased to “small”. In fact an analysis which included these negative clinicaltrials.gov studies found that the number of patients who would need to be treated with pregabalin for one patient to achieve a 50% pain relief was 7.7, so pretty few patients seem to benefit from pregabalin (Finnerup NB. Lancet Neurol 2015; 14:162)

–I suspect that the reason that gabapentin was considered ineffective but pregabalin not is mostly related to the serendipity of the studies done. Their anticipated physiologic effect is essentially the same, though gabapentin may be more slowly and erratically absorbed. In both cases there have been published studies suggesting positive efficacy of the medications, but on digging a tad under the surface, there are several large unpublished studies for each finding no benefit.  My guess is that they really do have similar and probably low levels of effectiveness. As with most drugs, some patients may benefit more than others. Is this from genetic differences in receptors or other drug mechanism?  Or maybe placebos work better in some people when they have mild to moderate adverse effects, and these meds both certainly do…(I have never seen anything written on this, but I suspect that meds with more systemic adverse effects may have more placebo effect as well, since some patients may internalize that meds with adverse effects must be stronger meds???…).The recent negative study of pregabalin in sciatica does also raise the question of its overall utility (see here  ). So, I’m not convinced that we should use pregabalin (only available as an expensive brand-name drug) over gabapentin (widely available generic), if we decide to use one of these types of drugs.

— One important finding in the current Neurology review was that venlafaxine, available as an inexpensive generic, was found to have a large effect size, with moderate SOE. This was also found for tricyclic antidepressants, though with moderate effect size. I am a bit hesitant to endorse venlafaxine as the single best agent (largest effect size of meds, somewhat larger than duloxetine which has no generic), since there were only 2 studies published on it. But I will add it to my short list of initial meds to try, along with tricyclics.

–so, bottom line here: the American Diabetes Association’s top 2 drugs, pregabalin and duloxetine, have both been knocked down by this more extensive Neurology review….. and, I think all systematic reviews should include looking at clinicaltrials.gov to find potentially pivotal negative studies which have not been published.

 

But, I think there are a few pervasive generic issues that this systematic review brings up:

–one of the biggest issues raised by this systematic review is: what should we trust in the medical literature? Clearly meta-analyses and systematic reviews can come to different conclusions based on their study inclusion criteria (see here for some of my thoughts on this). But additionally, we have moved to a place where the majority of large-scale medical studies are industry-funded. And they have a very clear bias to publishing the most positive results and putting the most positive spin on their results. And negative results are often not reported (this was the reason the feds required new studies to be logged into clinicaltrials.gov when they are initially approved, a law enacted in 1997). And the finding above about pregabalin is a case in point (a similar issue prevailed in the initial gabapentin studies, where there were also large, unpublished negative studies).  So, though pregabalin was highlighted in the recent Am Diabetic Assn recommendations 2 weeks ago, when the unreported negative studies are included, it really does not look so good…

–And,  as per here  companies often do not conform to government regulation/requirements, including rarely providing post-marketing data as required by the feds (their compliance rate was on  the order of 15%!!!!!). And, and, and, this whole situation is very likely to get whole lots worse with Trump, as the FDA moves to earlier licensing of drugs and medical devices, with less rigorous attention paid to their actual clinical benefit. So, the really difficult challenge is “what should I believe in the medical literature??”  I’m not sure how to answer that. But we need to be diligent, skeptical, and even less ready to jump on the bandwagon for new meds and medical devices. (One of my real purposes in writing these blogs is to critique studies or guidelines, and to assess their real generalizability and utility in the context of primary care clinical practice. And I hope they provide some context to help assess applicability of the studies/guidelines…..)

 

Primary Care Corner with Geoffrey Modest MD: Drug shenanigans come home to roost (finally, at least a beginning)

19 Dec, 16 | by EBM

By Dr. Geoffrey Modest

There was a timely article in STATnews (in particular their Pharmalot series by Ed Silverman which regularly exposes drug company malfeasance) about price-fixing among generic drug makers. And, 2 generic pharmaceutical executives have finally been accused by the feds (see https://www.statnews.com/pharmalot/2016/12/14/heritage-generics-antitrust-price-fixing/?s_campaign=trendmd ). Hopefully more to come…

Jeffrey Glazer and Jason Malek of Heritage Pharmaceuticals, the former chief executive officer and president respectively, were accused by federal authorities of conspiring with rivals to fix prices for doxycycline hyclate and glyburide. This is the first criminal charges of a two-year federal investigation into such price-fixing among generic pharmaceuticals. At this point no other companies have been named, though Mylan Pharmaceuticals, Teva Pharmaceuticals, Actavis, Lannett Co, Impax Laboratories, Sun Pharmaceuticals, Endo International’s Par subsidiary, and Taro Pharmaceuticals have disclosed receding subpoenas in this investigation. These two executives had been fired from Heritage in August 2016 for a seven-year long “running criminal conspiracy that severely damaged Heritage”, noting that they had “looted tens of millions of dollars from Heritage by misappropriating its business opportunities, fraudulently obtaining compensation for themselves, and embezzling its intellectual property”, per the court documents. Heritage Pharmaceuticals claimed that these two had redirected more than $9 million to a dummy company between 2012 and 2015.

Prior findings have found that half of all generics had become more expensive during the prior 12 months, with 11 at least doubling the price, and one medication increasing 17,000%. This led to an investigation by Sen. Bernie Sanders of Vermont and Representative Elijah Cummings from Maryland, but the manufacturers have refused to testify (including Heritage), stifling the investigation. At that point Sanders had his formidable quote: “pharmaceutical executives must be held accountable for ripping off the American people by charging them the highest prices in the world for prescription drugs… At a time when one out of five Americans cannot afford the medication they need, we must do everything we can to end the greed and illegal behavior of the drugmakers. Fraud can no longer be an acceptable business model for the pharmaceutical industry.”

Also as reported by a prior issue of STAT and on a PBS news-hour blog on November 4, 2016 (http://www.pbs.org/newshour/rundown/bernie-sanders-requests-federal-investigation-insulin-makers-price-collusion/ ) Sanders and Cummings want an FTC investigation into Eli Lilly, Sanofi, and Novo Nordisk, since their price for insulin has been going up in tandem over several years. The cost of insulin more than tripled from 2000 to 2013, from $231 to $736 a year per patient, despite the fact that the original insulin patent had expired 75 years ago.

There have been many blogs in the past on drug company shenanigans (see http://blogs.bmj.com/ebm/category/pharmacy/ ). One (http://blogs.bmj.com/ebm/2015/09/30/primary-care-corner-with-geoffrey-modest-md-and-the-drug-company-shenanigans-continue/ ) commented on pyrimethamine but also mentioned the above Heritage increase in price of doxycycline from $20 for 50 tablets in October 2013 to $1849 in April 2014, an increase of  >8000%, leading many of us (including myself) scouring around for substitutes….

Primary Care Corner with Geoffrey Modest MD: HIV Drug Costs and Effectiveness. Are We Going in the Wrong Direction?

8 Nov, 16 | by EBM

By Dr. Geoffrey Modest

An observational cohort study looked at patients on antiretroviral therapy (ART) for HIV, finding that some of the most effective yet cheapest regimens are not being recommended for use today (see Eaton EF. AIDS 2016; 30: 2215). I have included the 340b pharmacy pricing, which is the reduced federal pricing available since 1992 to eligible health care organizations (mostly Federally-funded clinics and public hospitals) vs the AWP, average wholesale price, used in private pharmacies.

Details:

  • 491 patients (mean age 36, 83% men, 61% African-American) initiating anti-retroviral therapy (ART) between 2007-2013, at the University of Alabama at Birmingham
  • Durability (time from regimen initiation to discontinuation), used as a surrogate for the combo of effectiveness and tolerability.
  • Results for the 5 most common ART regimens used during that time:
    • TDF/FTC (tenofovir disoproxil fumarate/emtricitabine) with efavirenz (atripla): durability 40.1 months; 340b price $726.26
    • TDF/FTC with raltegravir: durability 47.8 months (longest); 340b price $1080.60
    • TDF/FTC with darunavir/ritonavir: durability 47.8 months (longest); 340b price $1153.00
    • TDF/FTC with atazanavir/ritonavir: durability 31.9 months (shortest); 340b price $1070.88
    • TDF/FTC with rilpivirine: durability 3 months; 340b price $917.50
  • Overall, combining durability with price, the efavirenz (atripla) regimen dominated, with the rilpivirine one following closely behind

Commentary:

  • Several of the older treatments have been downgraded in recent guidelines, including atripla (TDF/FTC/EFV) for neuropsych effects of dizziness, anxiety, lack of concentration, vivid dreams and suicidality (though large observational studies have not found increased suicidality) and complera (TDF/FTC/rilpivirine) since it is less effective in those with high HIV viral loads.
  • The new guidelines do attach a comment that we should consider cost in determining the regimen, but they formally downgraded the cheapest regimens. For a review of the guidelines, see http://blogs.bmj.com/ebm/2016/07/29/primary-care-corner-with-geoffrey-modest-md-2016-hiv-treatment-guidelines/ for the Intl Antiviral Society–USA guidelines, or go to https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf for the DHHS updated guidelines (these 2 do differ slightly, with the first one suggesting the TAF (tenofovir alafenamide) regimens only, but the first-line regimens are basically the most expensive of the list below)
  • I did get today’s 340b pharmacy costs for common HIV meds, for a 30-day supply (note: the 340b cost is much lower and does not track well with the AWP)
    • Atripla (TDF/FTC/EFV): $688.93 (generic is still not available, but should be soon, which should drive down this cost)
    • Truvada (TDF/FTC): $428.61 (generic is still not available, but should be soon, which should drive down this cost)
    • Raltegravir: $591.58
    • Descovy (TAF/FTC): $428.61 (ie, same price as brand-name truvada, and probably because the drug company wants us to continue with this product instead of the switching to the generic truvada when available. And though TAF does not have the long clinical trials of TDF, it does offer some real potential advantages in terms of decreasing the renal and bone toxicities of TDF)
    • Tivicay (dolutegravir): $832.44
    • Odefsey (TAF/FTC/rilpivirine): $1716.13
    • Genvoya (elvitegravir/cobicistat/TAF/FTC): $1893.68
    • Stribild (elvitegravir/cobicistat/TDF/FTC): $1638.87 (though here, substituting TAF for TDF does seem to increase the cost….)
    • Prezcobix (darunivir/cobicistat): $759.39
    • Evotaz (atazanavir/cobicistat): $700.70
    • Triumeq (dolutegravir/abacavir/3TC): $1580.35
  • Just to put all of this in perspective:
    • The new drugs are really great, with excellent acceptability (I have had to stop dolutegravir only once for GI effects), along with remarkable efficacy, combined with much more “leniency” than the older drugs such as efavirenz (one can miss more doses but maintain continued viral suppression, without developing resistance so easily)
    • But the old drugs (especially atripla) were the ones which were able to turn the AIDS from almost uniformly fatal to almost uniformly a chronic disease
    • And, the vast majority of patients tolerated these drugs well. The +/- 90%  who were able to continue on them had the same remarkable great outcomes as with the new drugs (I have rarely had to change my old patients on atripla to one of the newer formulations)
    • And, these old regimens are likely to get much cheaper when generics become available
  • So, what does this all mean? We live in an extremely expensive health care system (1/3 of Massachusetts spending is for healthcare/Medicaid), yet we have the remarkably opaque system where clinicians providing the care are “shielded” from its cost. Hospitals do not provide us with the cost of MRIs or colonoscopies, or the fact that at one hospital it is 2-3x the price of another. It is not easy to find the actual costs of medications, and this cost can vary considerably from one pharmacy to another (again, it is a lot of work for us to find out the actual costs). Drug companies and hospitals, in these cases, have no interest in advertising costs — drug companies promote the “newest and best” to us through sponsoring the studies and advertising aggressively (and expensively) to us and directly to consumers, highlighting their new cancer drug which increases life expectancy a couple of months at $100,000 per injection, etc etc. Ironically, we clinicians as consumers would (mostly, I assume) never tolerate buying other consumer products without knowing their price and their relative value compared to other items of the same class. so, though I have been prescribing these new HIV drugs to my newly diagnosed patients, I think this article really does give pause and highlights the strange situation we are in in our increasingly expensive, increasingly unaffordable, intentionally cost-opaque health care system, which in many ways does not lead to major improvements in community health or health care outcomes, yet with us as clinicians inadvertently being put in the position of how $$ is spent: a perfectly devised system to maximize the profits of the drug companies, hospitals, etc. And many of the people sitting on the committees writing the new guidelines in medicine are financially supported by drug companies, etc, both for their research and personal financial gain, which really should be seen as an unacceptable conflict-of-interest.

See http://blogs.bmj.com/ebm/2016/04/26/primary-care-corner-with-geoffrey-modest-md-life-expectancy-and-income/ , a recent blog which includes reference to the book The Health Care Paradox, which argues well that we in the US spend huge amounts of money per capita on medical care but reap really poor-to-mediocre improvements in health outcomes (e.g., infant mortality or life expectancy being lower than almost any other industrialized country), because we devote the vast majority of the medical care $$ specifically to health care and such a low percentage to public health/social programs that promote the prerequisites for good health: good employment, housing, food, supportive social environments, exercise programs, day care/elder care……)

Primary Care Corner with Geoffrey Modest MD: No End to Pharma Shenanigans

1 Nov, 16 | by EBM

By Dr. Geoffrey Modest

I have held back from writing about drug company shenanigans, mostly because their daily outrageous acts could totally fill up my blogs (witness the Mylan epi-pen example). But, I just couldn’t resist. I will not repeat what is quite well-researched and written in STAT, but refer you to the URL: https://www.statnews.com/pharmalot/2016/09/23/drug-price-skin-gel/ for details.

But the bottom line: yet again, pretty sleazy business types, moving from one small drug company to another to repeat their predatory practices, are buying out old drugs and dramatically raising their prices. In this case, one of their 3 gels is composed of aloe and iodoquinol, the latter when taken orally being an antiprotozoal/an amebicide!!! , and is being promoted as preventing growth of fungus/bacteria topically to treat dermatitis and eczema. Their own prescribing information states it is only “possibly effective”, as per the FDA. Another of their gels throws in some hydrocortisone to this mix. And they raised the price to $9,561 for a tube (had been around $200). Just think what they would charge if it truly were “effective”….

See http://blogs.bmj.com/ebm/category/pharmacy/ for some of the prior blogs.

Primary Care Corner with Geoffrey Modest MD: Sugar Industry’s Role in Creating Policy

7 Oct, 16 | by EBM

By Dr. Geoffrey Modest

The NY Times ran a recent story on the historic role of the sugar industry, in close relationship with academia, in promoting the role of fats/undercutting the role of sugar in the development of coronary artery disease (CAD)

The Details:

  • In 1954, the Sugar Research Foundation (SRF) president stated that there was a chemical connection between fats and atherosclerosis, and that the carbohydrate industries could dramatically increase their market share by getting people to eat less fat. The industry spent $5.3 million (in 2016 dollars) to promote this, along with “that sugar is what keeps every human being alive and with energy to face our daily problems”
  • Since 1957, the British physiologist John Yudkin reported several studies finding that sugar was at least as important as fats in promoting CAD
  • The SRF in 1964 decided to pursue CAD research to see “the weak points there are in the experimentation [of the anti-sugar reports], and replicate the studies with appropriate corrections. Then we can publish the data and refute our detractors”
  • The SRF recruited Frederick Stare, chair of Harvard School of Public Health (HSPH), to join the SRF Advisory Board as an ad-hoc member.
  • There were a few articles in the Annals of Internal Medicine by D Mark Hegsted from HSPH linking sucrose to CAD, corroborating Yudkin, finding that “sucrose must be atherogenic”
  • In 1965, the SRF paid that same Hegsted and another person $48,900 (in 2016 dollars) to write a review article on sugar’s role, under the supervision of Stare, with a goal of undercutting the increasing scientific and public concerns about the role of sugar (the New York Herald Tribune had just run a full-page article about the Annals’ articles by Hegsted and others, highlighting the adverse role of sugar). This review article was delayed by ongoing evidence in the medical literature of sugar’s negative role in development CAD, but ultimately led to a 2-part NEJM review article, including both Hegsted and Stare as authors, which concluded that there was “no doubt” but that the only intervention to decrease CAD was to substitute polyunsaturated fat for saturated fat. The review article did comment on the sugar link but then discounted its role in CAD, through very inconsistent arguments. Although this review did disclose industry funding, it did not mention the SRF funding (it was not till 1984 that NEJM required authors to report financial disclosures/conflicts-of-interest).
  • One point that the review article highlighted and promoted was that it was okay to look just at serum cholesterol levels as a surrogate marker for CAD (at that time, we could only measure the total cholesterol levels), and ignore the often documented role of sugars in raising triglyceride levels.
  • The Sugar Association (the current name for SRF) then went on to undercut the role of sugar in dental caries, ultimately involved in shifting the 1971 emphasis of the National Institute of Dental Research’s National Caries Program to interventions other than restricting sucrose consumption.

Commentary:

  • As we know, as a result of reducing fat consumption as the target of the American Heart Association, various Nutrition societies etc; sugar/carbohydrate consumption has increased dramatically over the past many decades (e.g., witness the proliferation of low-fat foods, which basically substitute carbs for fats), as has the prevalence of obesity and its many unfortunate sequelae (diabetes, etc.). And there are pretty clear connections between sugar intake and CAD, as above, which date back to the 1950s. I did take a course on nutrition and health in the 1970s at the Harvard School of Public Health, when I read a book written by a decorated British military physician using cross-cultural epidemiologic studies to demonstrate a strong association between refined sugars and most chronic diseases at that time, though i cannot remember the author’s name. At that time Frederick Stare was still the head of HSPF, but retired in 1976 at least in part because of his role in the sugar industry: the nutrition dept at that time was openly up-in-arms against him). Hegsted later became the head of nutrition at the US Dept of Agriculture and played a key role in writing the government’s nutrition guidelines. It is pretty striking how the sugar industry was able to take the author of several anti-sugar articles in the Annals and (?? through $$, ??other political influences) was able to get him to write the 2-part NEJM review undercutting the role of sugar in CAD. And I do remember those reviews as being very well-read and oft-cited at the time.
  • The current article also brings up the concerns about using surrogate markers for clinical disease (as many of you know, I have very real concerns about using A1C levels instead of actual clinical outcomes as the measure of the benefit of new diabetes drugs: witness rosiglitazone, and the increasing reports of problems with most of the new meds. see many blogs in  http://blogs.bmj.com/ebm/category/diabetes/). In the CAD case above, we did not measure LDL or HDL levels at the time, and we now know that increasing triglyceride levels physiologically track with decreasing HDL levels, and conversely, a low glycemic index diet is pretty consistently associated with increasing HDL and decreasing triglyceride levels. Another faulty surrogate marker…
  • And this article does reinforce the disproportionate role of the most prestigious journals (e.g. NEJM) in informing general clinical practice (and, i wouldn’t be surprised if these types of articles also influence future research done as well)
  • Of course, the above article is limited by what was available in the archives they searched, so the above findings should be interpreted not as “rock solid”, but pretty suggestive
  • But it really does reinforce the concern about the increasing role of industry in designing and performing clinical trials — there has been a dramatic shift from the 1970s, effected by President Reagan, where funding for research began to shift from the public to the private sectors, researchers shifting their affiliations from the largelyscientifically-independent medical schools to private companies (with the often attendant shift in their incomes), to the point that most clinical studies now reported in the literature are industry-funded. Although the disclosure requirements are much better defined, if company-sponsored studies are the only source of data available to clinicians, it is hard to ignore them (and this is reinforced by drug company detailing and direct-to-consumer advertising, etc.). See http://blogs.bmj.com/ebm/category/pharmacy/ as well as http://blogs.bmj.com/ebm/2015/08/31/primary-care-corner-with-geoffrey-modest-md-regulation-of-medical-devices/ for several blogs on drug company “shenanigans”, including covering up adverse information about the drugs they are making, the role of direct-to-consumer advertising, drug company unseemly profits, ghost-written scientific articles by drug companies, and drug companies/medical device makers marked inconsistency in reporting negative studies as required by law.

____________________________________________________________________________________________________________________________________

As an addendum, Karen Henley sent me an email about STAT, and its article on conflicts-of-interest: https://www.statnews.com/2016/09/09/ijme-journal/
My comments:

STAT has some great, daily, free emails dealing with Zika (a daily update on the medical, political and funding issues) as well as highlights of pharmaceutical shenanigans (of which there have been way too many over the past few years, most recently with Mylan and the epi-pens).

The STAT article commented on an article in the Indian Journal of Medical Ethics, which is actually an old journal which has been getting more attention over the past few years. They highlighted the rather profound conflicts-of-interest in the elite medical journals, highlighting the twists and turns of New England Journal of Medicine and their publishing an industry-sponsored article on Vioxx (rofecoxib), then refusing to publish the warning about the increasing numbers of patients (tens of thousands) who died from the drug (see the link in the STAT article). This was also exposed by Marcia Angell and others a few years ago in her very pointed concerns about the direction of NEJM, but I think the Indian journal also added a broad view of the issue of conflicts-of-interest –> which I think are a huge problem, pretty omnipresent, and make me very wary about being an early adopter of new medications.

Also, see prior blog http://blogs.bmj.com/ebm/2015/10/26/primary-care-corner-with-geoffrey-modest-md-academic-conflicts-of-interest/ , which highlights the huge conflicts of interest with the leaders of academic medical centers, including some near and dear highly-acclaimed academic medical centers (i.e., the Brigham), and with comments by Marcia Angell

Primary Care Corner with Geoffrey Modest MD: Rivaroxaban and Increased Intracranial Hemorrhage vs. Dabigatran

6 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A recent review compared the adverse effects of dabigatran and rivaroxaban, two of the NOACs (non-vitamin K antagonist oral anticoagulants) –see doi:10.1001/jamainternmed.2016.5954. This follows another report finding increased bleeding risks as well as MIs in post marketing case reports for dabigatran following its approval. This new report, funded by Medicare and the FDA, did find a significant increase in major bleeds from rivaroxaban over dabigatran.

Details:

  • Retrospective new-user cohort study of 118,891 patients with nonvalvular atrial fibrillation who were 65 years or older and enrolled in Medicare from 2011 to 2014. Patients were included if they had a diagnosis of atrial fibrillation or flutter and filled a first prescription for either drug in this time period. Excluded if they had less than six months of enrollment in Medicare, were younger than 65, were in a skilled nursing facility or nursing home.
  • 52,240 were on dabigatran and 66,651 were on rivaroxaban
  • 50% were 65 to 74-year-old/40% were 75 to 84-year-old, 47% female, 91% white/4% black, 33% with diabetes, 40% hyperlipidemia, 86% hypertension, 15% obese, 19% smoking, 15% with heart failure, 33% with CHADS2 score of 0 to 1, 40% with score of 2, 19% with score of 3; 10% with HAS-BLED score of 1, 54% score of 2, 29% score of 3.

Results:

  • 2537 had a primary outcome of thromboembolic stroke (n=306), intracranial hemorrhage (176), or major extracranial bleeding (1209) including major GI bleeding (1018) and mortality (846).
  • Rivaroxaban vs. dabigatran was associated with:
    • 19% reduction in thromboembolic stroke, HR= 0.81 (0.65 to 1.01). Nonsignificant. This translates to 1.8 fewer cases of thromboembolic stroke per 1000 person-years
    • 65% increase in intracranial hemorrhage, HR 1.65 (1.20 to 2.26).  AIRD (adjusted incidence rate difference): 2.3 excess cases per 1000 person-years
    • 48% increase in major extracranial bleeding, HR 1.48 (1.32 to 1.67). AIRD = 13.0 excess cases per 1000 person-years; including 40% increase in major gastrointestinal bleeding, HR 1.40 (1.23 to 1.59). AIRD of 9.4 excess cases per 1000 person-years
    • 15% increase in overall mortality, HR 1.15 (1.00 to 1.32), borderline significant at p=0.051, AIRD of 3.1 excess cases per 1000 person-years. In patients 75 years or older or with CHADS2 score greater than 2, the excess risk was significant (27% and 24% increases, respectively).
    • The excess rate of intracranial hemorrhage exceeded the attributed reduced rate of thromboembolic stroke (the latter actually didn’t reach statistical significance)

Commentary:

  • As I have mentioned in several prior blogs, I am very concerned about the widespread adoption and use of NOACs in non-valvular atrial fibrillation. I believe there was significant drug company malfeasance in both the design and presentation of the data. See blogs referenced at the end for more information. This is not to say that NOACs are decidedly bad, just that the studies on which their approval were based were seriously flawed, perhaps largely because of the drug company cover-ups.
  • As a point of reference, in a large meta-analysis of warfarin in patients with a fib, intracranial hemorrhage occurred in 6 patients on warfarin vs. 3 on control, with n= 2900); and extracranial hemorrhage with warfarin was less than 0.3% per year(see Hart RG. Ann Intern Med 2007; 146:857).
  • It was interesting that more cardiologists prescribed rivaroxaban than family practitioners. Not sure what this reflects. Sensitivity analysis did not show that the patients on rivaroxaban were sicker. Perhaps the cardiologists were aware of the post marketing studies on the harms of dabigatran. Perhaps they were more influenced by the ROCKET-AF study of rivaroxaban(which has been criticized for using defective INR machines, see blogs and NEWS FLASH below). It is important to note that there are no head-to-head comparisons of these different NOAC medications
  • It is perhaps significant that the curves for intracranial hemorrhage, major GI bleeding, and mortality diverged during the follow-up period, though there was convergence on the event rate for thromboembolic strokes (i.e.: increasing problems without increasing benefits).
  • One wonders if some of the increased incidence of bleeding with rivaroxaban is that it actually has the same half-life as dabigatran of about 12 hours, but is dosed at once a day, whereas dabigatran is dosed twice a day
  • The study is limited by several factors. It is a retrospective analysis, and cannot have the rigor of the conclusions of a well conducted randomized trial. Also the mean duration of on treatment follow-up was only four months, though they did have a reasonable representation of those on meds at least 6 to 8 months.
  • So, to me this huge acceptance of NOACs over warfarin (which certainly has its well-known drawbacks) seems more to reflect drug company shenanigans and heavy-duty marketing than clear benefit, and with attendant risks (though i have occasionally prescribed them, e.g. when patients were spending long periods of time in other countries without access to INR monitoring).

For blogs on NOACs, best to go to http://blogs.bmj.com/ebm/category/vte/, which has blogs on the rivaroxaban study (ROCKET-AF) using  defective INR machines in those patients on warfarin, a huge Swedish study showing safety and efficacy of warfarin when patients were mostly in the appropriate therapeutic range, and a slew of articles on drug company malfeasance in promoting dabigatran when internal drug company memos for example showed that they knew that drug levels actually should be monitored (though this went against their main selling point: that one would not have to  monitor levels vs warfarin), as well as the study mentioned above about post-marketing serious adverse events of dabigatran, with the comment that “the Institute for Safe Medication Practices reported that dabigatran was responsible for more serious adverse events than 98.7% of all medications” [and it seems to be better than rivaroxaban, at least by the above study!!!!!]. I also continue to be concerned about the lack of easy access to reversal agents for the NOACs, especially in smaller hospitals outside of large academic centers.

*********NEWS FLASH********

  • There was a new investigative report by Deborah Cohen in BMJ last week (she seems to have spear-headed many of the really great reports in BMJ about drug company malfeasance), stating that the drug company (Janssen) actually knew that the INR testing devices were faulty in the ROCKET AF study (which single-handedly propelled rivaroxaban into blockbuster status), yet withheld this information from the FDA. It turns out that the increased intracranial bleeding with warfarin might have been related to the fact that 33% of actual laboratory readings of INR were above 4, yet the defective point-of-care machines gave an INR on the same sample of between 2-3 (see doi: 10.1136/bmj.i5131)

Primary Care Corner with Geoffrey Modest MD: Drug Company Shenanigans, the Blogs Continue

8 Jul, 16 | by EBM

By Dr. Geoffrey Modest

As an addition to the long list of prior blogs on drug company malfeasance (see link at end), there were a couple of relevant articles recently (since I have not railed against drug companies for a while)

  1. The Office of the Inspector General of US Dept of Health and Human Services released a 13-page report on dramatic increases in Medicare spending on meds (see http://oig.hhs.gov/oei/reports/oei-02-16-00290.pdf ), with my commentary embedded in the major points:
  • Medicare spending for Part D increased at $10 billion/yr from $51 in 2006 to $137 billion in 2015 (and $16 billion just from 2014-15).
    • One issue to me is that though Part D is a great help to many people (over 40 million beneficiaries in 2014), it was constructed by Bush to funnel the drug benefits through commercial pharmacies. And this is despite the fact that the feds have access to really cheap drugs (the cost of many generics to the feds is often about 1/100 that at the local pharmacies) and these vastly cheaper drugs are what millions of veterans already get through the VA system. To make things worse, the excessive cost of Part D leads to the “donut hole”, where after a few thousand dollars are spent on drugs, the federal subsidy decreases dramatically and many impoverished seniors are unable to afford continuing necessary medications
    • And, as we know only too well, there is no effective regulation on the price that drug companies charge, even for drugs they have been making for many decades (witness the huge increase in the cost of even the old insulins over the past decade, when the cost-of-living increased marginally)
  • Spending on commonly abuse opioids was >$4 billion in 2015
  • Spending on compounded drugs has increased dramatically
    • Overall Part D spending increased from $70 million in 2006 to $509 million in 2015, with the largest jump from 2014-15 (increase of $182 million)
    • Medicare spending for compounded topical drugs increased 3,466 percent since 2006, e.g. for the likes of lidocaine-prilocaine (local anesthetic) and topical diclofenac (anti-inflammatory).
    • Spending for compounded oral drugs increased 855 percent, IV drugs (e.g. parenteral nutrition and antibiotics) 333%, and other injectables by 285%
    • The availability of compounded drugs is important in several situations: a patient may need a liquid preparation of a commercially-available pill (trouble swallowing, etc.), or to eliminate an ingredient they are allergic to, or the drug is not available in a required form (e.g. injectable progesterone, used to help sustain a pregnancy in women with a threatened miscarriage; this had been available since the pre-FDA 1950s by compounding, but a (sleazy) drug company got a quick patent and increased the cost many-fold, and threatened the prior compounders with major lawsuits if they continued compounding it. See http://healthland.time.com/2011/03/10/can-patients-get-around-the-exorbitant-new-cost-of-a-pregnancy-drug/ which details some of the issues: the drug went from “around $10 per dose to $1500”)
    • Though, as we know from the recent compounding pharmacy fiascos, there does need to be some regulation to ensure against contamination as well as ensuring the potency of the drugs, with a couple of caveats here:
      • Compounders have worked for many decades without issues I’ve heard of. Some of the egregious issues with contamination seem to be more recent. ??why. ??decreased regulation ??increased drive for profits??
      • The role the FDA plays is not so clear to me. They openly state that their mission “is to ensure that drugs marketed in this country are safe and effective”, but they “do not test drugs” themselves (see http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ )
      • A couple of years ago I was interested to see what the FDA allowed as acceptable variability, e.g. when a drug company said “100 mg”. Was it +/- 2%, 10%, 50%??? I could find nothing printed, so I called them in Washington and actually spoke to someone there who said there was no general standard for brand-name or generic drugs. So, though the issue of potency is a real one, it seems that there is no acceptable variability standard overall, the FDA accepts what the drug companies say, and they do not regularly check for the accuracy of what they say…
    • “These trends raise concerns about fraud and abuse and patient safety”
      • The feds are pursuing some pharmacies that were paying kickbacks to physicians or to marketers for prescriptions, or they were filling prescriptions that should not have been filled

 

  1. Another recent study looked at a different angle of drug company influence: how sponsoring meals for physicians is associated with preferential prescribing of brand name meds (see doi:10.1001/jamainternmed.2016.2765). Details:
  • Cross-sectional analysis of industry payment data to physicians in the Medicare Part D prescriber file and prescribing data for individual physicians who wrote Medicare prescriptions
  • Assessing 4 brand-name meds from 4 different classes:
    • Rosuvastatin (Crestor) vs other statins (rosuvastatin is the 3rd most costly drug in Medicare D, at $2.2 billion in 2013)
    • Nebivolol (Bystolic, Nebilet) vs other cardioselective b-blockers
    • Olmesartan (Benicar) vs other ACE/ARBs
    • Desvenlafaxine (Prestiq, Desfax) vs other SSRI/SNRI meds
  • 279,669 physicians received 63,524 payments associated with these 4 drugs
  • Physician characteristics: 70% male; 43% family or general practice/36% internal medicine/10% cardiology; 60% >20 years since graduation/38% 6-20 years; spread evenly through the US, but 85% urban; 22% of 2013 claims were written for brand-name drugs
  • 95% of the payments were meals, with mean value <$20 (rest were from speaking fees, honoraria, travel expenses, free textbooks/etc. These were not included in the analysis)
  • Those MDs accepting meals were less likely to have drug claims for low-income or Medicare Advantage beneficiaries
  • Results:
    • Rosuvastatin comprised 8.8% of statin prescriptions
    • Nebivolol comprised 3.3% of cardioselective b-blockers
    • Olmesartan comprised 1.6% of ACE/ARBs
    • Desvenlafaxine comprised 0.6% of SSRI/SNRI meds
    • But, for physicians who received a single meal promoting the drug of interest, controlling for prescribing volume, specialty, practice setting and demographics (all p<0.001):
      • 18% higher use of rosuvastatin over other statins (1.18, CI 1.17-1.18)
      • 70% higher use of nebivolol over other b-blockers (1.70, CI 1.69-1.72)
      • 52% higher use of olmesartan over other ACE/ARBs (1.52, CI 1.51-1.53)
      • 118% higher use of desvenlafaxine over other SSRI/SNRIs (2.18, CI 2.13-2.23)
    • And, having more than one meal or having meals valued >$20 were associated with higher prescribing rates (true for all but desvenlafaxine, though the number of desvenlafaxine scripts was much less than the other meds), varying from 2-13% more if the meals were >$20)

 

Commentary:

  • As a perspective, the amount of $$ paid by drug companies to MDs is huge (in last 5 months of 2013, 4.3 million drug company payments totaling $3.4 billion were made to more than 470,000 physicians and 1000 teaching hospitals)
  • (but, I’m sure it was worth it to them, given the amount of $$ they make from the huge costs of the drugs as well as the undoubted tax write-offs for the expenses, if they deign to pay any taxes in the US)
  • One confounder may be that MDs attending meals may be more open to writing for brand-name drugs (selection bias), though the researchers did look at those receiving a rosuvastatin-related meal, and those MDs did prescribe more brand-name desvenlafaxine, though with much smaller effect size than those getting a dexvenlafaxine-related meal; but not vice versa (getting a desvenlafaxine-related meal did not increase rosuvastatin scripts); however it would have been good to compare rosuvastatin scripts with b-blocker or ACE/ARB scripts, since they are both in the cardiologic realm. Another potential confounder is that MDs may preferentially attend meals for drugs they prefer.
  • One old study that I remember (though do not have reference) asked doctors if they thought they were influenced by drug company “information”, with a pretty resounding response of “no”. Then the investigators asked the doctors what they knew about some of the newer drugs. And there was a pretty remarkable concordance between what the doctors said and what the drug company representatives said (as I remember, sometimes pretty much word-for-word). Rather striking how well we humans are able to rationalize almost anything…
  • And, from the recent JAMA article, it was interesting that MDs could potentially have their prescribing patterns altered for a meal valued at $12-18….

For trove of drug company shenanigan articles, see http://blogs.bmj.com/ebm/category/pharmacy/ , which reviews several different aspects of drug company malfeasance, from ghost-writing scientific articles (paroxetine), to suing the FDA to allow marketing of a triglyceride-lowering drug without an approved indication, to rebranding generics and dramatically increasing prices, to concealing adverse events from drugs and not revealing negative studies, to promoting a drug (dabigatran) but concealing important information which would undercut the “no need for blood monitoring” promotion, to huge profits from cancer drugs, to …..

Primary Care Corner with Geoffrey Modest MD: Warfarin in Nonvalvular Atrial Fibrillation

13 May, 16 | by EBM

By Dr. Geoffrey Modest

Over the years, I have sent out several blogs about the drug company shenanigans/malfeasance in studies promoting NOACs (non-vitamin K antagonist oral anticoagulants) — See link at bottom. Here is a large study suggesting the benefits of warfarin (See doi:10.1001/jamacardio.2016.0199 ). The authors note that studies finding NOAC superiority were in comparison to warfarin where the times-in-therapeutic range (TTR) varied from 55.2% to 64.9%. In the current study researchers looked at the relative effectiveness of warfarin for patients with atrial fibrillation (AF) as it varied with TTR. Data are from a large Swedish registry.

Details:

  • Retrospective, multicenter cohort study of 40,449 patients
  • 40% women, mean age 73, mean CHA2DS2-VASc (see below) score 3.3, TTR<70% in 43%, hypertension 60%, heart failure 30%, renal failure 4%, excessive alcohol use 2%, history of falls 8%, prior major bleed 6%, MI 21%, diabetes 18%, stroke 19%, TIA 8%
  • 4311 patients also on aspirin with the warfarin, with the concomitant diseases/risk factors about the same as the overall cohort except that 43% had a prior MI (vs 17% just on warfarin)

Results:

  • Annual all-cause mortality 2.19% (2.07-2.31), intracranial bleed 0.44% (0.39-0.49)
  • Comparing those with TTR <70% vs >70% (all are annual rates)
    • All-cause mortality was 4.35% vs 1.29%
    • Any major bleed was 3.81 vs 1.61%, with intracranial bleed 0.72 vs 0.34%; GI bleed 1.26 vs 0.56%
    • Any thromboembolism was 4.41 vs 2.37%, MI 1.90 vs 0.98%, venous thromboembolism (VTE) 0.24 vs 0.09%, and arterial embolism 2.52 vs 1.41% [thromboembolism defined as: stroke, TIA, peripheral arterial emboli, venous thromboembolism, MI]
  • The role of INR variability (dividing those around the median of higher vs lower variability in their cohort): comparing high vs low
    • All-cause mortality was 2.94% vs 1.50%
    • Any major bleed was 3.04 vs 1.47%, with intracranial bleed 0.51 vs 0.38%; GI bleed 1.05 vs 0.50%
    • Any thromboembolism was 3.48 vs 2.46%, with MI 1.53 vs 0.96%, VTE 0.16 vs 0.11%, and arterial embolism 1.98 vs 1.51%
  • For those with TTR >70%, INR variability did not matter
  • For those on aspirin
    • All-cause mortality was 2.57% vs 2.13%
    • Any major bleed was 3.07 vs 2.04%, with intracranial bleed 0.62 vs 0.41%; GI bleed 1.16 vs 0.67%
    • Any thromboembolism was 4.90 vs 2.12%, with MI 1.53 vs 0.96%, VTE 0.19 vs 0.12%, and arterial embolism 2.72 vs 1.54%
  • For those with renal failure, intracranial bleed more than twice as common, with HR 2.25 (1.32-3.82)
  • The strongest predictor of intracranial bleeding was renal failure

So, a few issues:

  • These data, though not from a prospective, randomized study, do reflect more of a real-world community setting.
  • The results for patients in good control (TTR>70%) is actually better than in the “pivotal NOAC studies”.
  • In terms of the issue of using the combo of warfarin and aspirin:
    • I am very concerned about the increased serious adverse events with this combination (see http://blogs.bmj.com/ebm/2014/11/20/primary-care-corner-with-geoffrey-modest-md-aspirin-plus-warfarin-for-afib-and-cad/ , which looks at several observational studies on aspirin plus warfarin for patients with AF and CAD, all showing much higher risks (e.g., bleeding) without any clear benefit. The PREFER trial (see De Caterina, R. Heart 2014; 100: 1625) looked at a large European registry of patients with AF and found that 95% of those on dual antiplatelet and anticoagulation therapy did NOT have an “accepted indication” (i.e.: acute coronary syndrome or stenting –and, this is the current recommendation of the European Society of Cardiology guidelines in AF: anticoagulant therapy only except in these indications).
    • In the above Swedish study, only 2.6% of those on additional aspirin had a clear indication for this therapy. And this study really supported NOT using aspirin, given the higher mortality, higher MI/VTE/arterial embolism, and much higher bleeding risk (though, as noted, this was not an RCT, had many more patients with prior MI, so it is not so surprising that there was an increase in these thrombotic events. But twice the level of major bleeds???  And 50% more thrombotic events??? Is aspirin really useful?? I personally have stopped aspirin in my patients on warfarin, based on the prior blog)
  • So, my bottom line: this Swedish study confirms the utility of warfarin in patients with nonvalvular AF, though clearly differentiates its advantages in those in good control (INR in range >70% of the time) vs not. I do have trouble with the NOACs overall, given the noted drug company issues in my prior blogs and the lingering concern that if they are in an accident, reversal agents are not widely available. But I have occasionally used NOACs in patients who are leaving the country and cannot get their INR checked, or it is just too difficult to get the INR in range despite best efforts all around, often including home-based nursing care/checking the INR at home. That being said, the clear majority of my patients on warfarin are definitely in the >70% TTR category and seem to be doing just fine…. (though I do need to monitor them frequently, but, then again, most of them have significant cardiac and other morbidities, and my guess is that the increased monitoring/health system contact is actually a positive thing)

CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 75 years [doubled], diabetes mellitus, stroke [doubled]–vascular disease, age 65-74 years, and sex category [female])

For older blogs, see: http://blogs.bmj.com/ebm/2016/01/19/primary-care-corner-with-geoffrey-modest-md-antithrombotic-therapy-guidelines/ goes through the antithrombotic therapy guidelines but also reviews the history of drug company malfeasance with the NOACs, which really make me uneasy about using them…

Primary Care Corner with Geoffrey Modest MD: Further Drug Maker Shenanigans, and Direct-to-Consumer Advertising

16 Mar, 16 | by EBM

By Dr. Geoffrey Modest

The NY Times had yet another expose on drug companies, this time perhaps setting a really bad precedent for the FDA (see http://www.nytimes.com/2016/03/09/business/fda-deal-allows-amarin-to-promote-drug-for-off-label-use.html?_r=0​ ). In this case a drug company sued the FDA to be able to market a triglyceride lowering agent without an approved indication. Details:

  • Background: the FDA has a long-standing policy that drug companies cannot market drugs for off-label indications, and in recent years drug companies have paid billions of dollars in fines for doing so.
  • The drug company (Amarin, which has only this product) had FDA approval in 2012 to market its fish oil variant Vascepa [icosapent ethyl, an ethyl ester of eicosapentaenoic acid (EPA)]​, to patients with triglycerides > 500 mg/dL. They subsequently wanted the right to market this drug to a much broader range of patients with lower triglyceride levels, without clinical trials showing documented benefit, stating that it was their first amendment right to advertise “truthful information to promote its drug”, and a district judge in Manhattan agreed. the FDA backed off and agreed to let Amarin use their “free speech” to promote this drug
  • The FDA downplayed the implications of this action, stating that this was a narrow ruling, applying only to this case, and that their general approach has not changed.
  • But, as quoted, Dr Michael Carome, director of health research at Public Citizen, a consumer advocacy group: “This really sends a signal to other companies that if you want to engage in off-label promotion, you can negotiate with the FDA”

So, this brings up a few issues:

  • Clearly, this type of lawsuit is quite troubling, allowing the drug company to promote a drug without FDA-approval but based on a judge stating this is “free speech”. Drug companies naturally see it as in their financial interest to broaden marketing by adding on indications for drugs as much as they can. And they are likely to use their own sponsored studies to document benefit as “truthful information” for the clinicians and patients to go on. As noted in a myriad of blogs over the past 5 years (see below), there are many drug companies that will do pretty much anything to increase their markets. so, one issue is the legitimacy of all of these drug-company sponsored studies (clearly, there are many important studies sponsored by drug companies that appropriately influence medical practice. but there are also many documented sleazy studies, where drug companies have not allowed access to the data, where negative studies have been squelched and not published, etc. again, lots of examples in the blogs.)
  • The Vascepa case, on my review, shows that the FDA based its original approval on a 12-week study in patients with fasting triglycerides between 500-2000 mg/dL, only showing a decrease in triglycerides. The FDA accepted this use of a surrogate endpoint (lowering triglycerides when they are very high) because of the known bad effects of very high triglycerides and with current guidelines suggesting treatment of such high levels [the best data are for the association of high triglycerides (>500, and esp >1000 mg/dL) and pancreatitis. the data on the relationship with coronary artery disease is pretty complicated and uncertain, to my reading]. So, extending the recommendation to those with lower levels of hypertriglyceridemia is a bit of a stretch. Of note, even for the higher levels of hypertriglyceridemia, there is a disclaimer in the drug labeling noting “the lack of evidence that treatment with Vascepa reduces the risk for pancreatitis in patients with severe hypertriglyceridemia”.
  • So, the real concern is the slippery slope. The ability of this drug company to get the FDA to bend, based on the rather spurious argument (to me) that it is free speech (though there is really ZERO scientific evidence showing that there are improved clinical outcomes, only drug-company innuendo), really does open the door for the FDA being stripped of its regulatory, consumer-protective role.
  • Also, there was an interesting report by STAT on drug company direct-marketing to the consumer (see http://statnews.com/2016/03/09/drug-industry-advertising/ ). It turns out that:
    • ​Drug companies are spending $5.2 billion in 2015 (70% on TV ads) on direct-to-consumer advertising, growing dramatically each year (was $4.3 billion last in 2014). These numbers do not include hundreds of millions spent on digital and social media ads.
    • ​1/4 of advertising was for 5 drugs: humira (adalimumab, used in several inflammatory diseases), lyrica (pregabalin, for neuropathy etc.), eliquis (apixaban, a “novel” anticoagulant, see below for link to blogs critiquing them), cialis (tadalafil, used for erectile dysfunction), and xeljanz (tofacitinib, used for rheumatoid arthritis); all really really expensive and need to be taken for a very long time for continued efficacy.
    • 9 drugs this year are on  schedule to break $100 million/drug  in TV ads (e.g. Harvoni, for hepatitis C)
    • Of note, only the US and New Zealand are the only countries allowing direct-to-consumer advertising
    • The AMA has called for a ban on this direct-to-consumer advertising
    • And, shockingly to me (but perhaps I should not be surprised), drug companies get tax breaks for these ads; Senator Al Franken and others have introduced bills to eliminate these tax breaks, mostly based on the fact that these really expensive drugs add to the exorbitant costs of health care, and probably should not be subsidized by the populace….

See http://blogs.bmj.com/ebm/category/pharmacy/ for several blogs on drug company malfeasance, including several on the novel anticoagulants, poor drug company compliance in reporting mandated data to the FDA, and even an earlier one (9/10/15) looking at Vascepa and with a review of FDA history

Primary Care Corner with Geoffrey Modest MD: Profits From Cancer Drugs – Further Drug Company Shenanigans

11 Mar, 16 | by EBM

By Dr. Geoffrey Modest

BMJ just had another of their many articles on drug company malfeasance, this one on mega-profits from their packaging of cancer drugs​​ (see BMJ2016;352:i788). The authors are from Memorial Sloan Kettering in New York and the University of Chicago.

Details:

  • Background:
    • The issue is that cancer drugs dosed by body size are often in single-dose vials and are typically packaged in quantities larger than needed.
    • The leftover drug, which could have been used for another patient, needs to be used within 6 hours and only in specialized pharmacies.
    • Hospitals and doctors also profit by buying these meds through the “buy and bill” system (they buy the drugs, then bill the insurers but with a mark-up which can vary widely — the current Medicare mark-up is 4% but can be as high as 58% if the hospital has a 340B pharmacy (see below), for commercial insurers it is 22% for doctors and 142% for hospitals and even higher through a 340B pharmacy). And they benefit more from buying more drug than they use.
  • Extent of the problem:
    • The researchers looked at the top 20 cancer drugs that are dosed by body size and packaged as single-dose vials (which they say accounts for 93% of all sales of such drugs)
    • Their methodology: estimate how often vial-sharing occurred (using Medicare claims, from which they can ascertain the amount of drug used that did not total the full vial contents); then calculate what they thought would be the most efficient packaging method based on the general US population height/weight measurements from the National Health and Nutrition Examination Survey, which they adjusted “to mirror a cancer patient population”
    • Their estimate: 10% of the drugs are discarded. But this seemingly small % translates to $1.8 billion from the $18 billion in sales. the amount discarded varies by drug (from 1-33%), for example:
      • Rituximab: 7% of $3.9 billion was discarded, for a loss of $254 million (and drug company profit of the same)
      • Carfilzomib: 33% of $697 million was discarded, for a pretty similar loss of $231 million
    • Sensitivity analyses did not provide much variation:
      • If the drugs were prescribed at the highest dose suggested by the FDA, the overall loss would be $1.4 billion
      • If every cancer patient weighed 10% lower than the survey population, the loss would be $2 billion
    • Why are there such variations in waste?
      • It really varies by drug packaging, e.g.:
        • Bendamustine (used for leukemia) is packaged in varying sized vials (25, 45, 100, and 180mg), so there can be pretty precise dosing/minimal waste
        • Bortezomib (used to treat multiple myeloma) only comes in one size (3.5 mg vial), which is much larger than the average dose of 2.5 mg, with $309 million in waste (in the UK the drug is sold in 1mg vials)
        • ​Pembrolizumab was initially marketed as 50-mg vials, then was changed so that 100-mg vials were the only ones made in the US (vs continuing the 50-mg vials in Europe). The average 70 kg patient needs 140mg of drug (ie three 50-mg vials, with minimal waste, or two 100-mg vials with lots of waste). So, the net effect of the repackaging is an extra $1.2 billion for the company over the next 5 years.
      • Hospital and doctor billing, and the effects on patients
        • As above, there are considerable markups by hospitals and doctors, which is projected to translate to > $1 billion in 2016
        • In terms of patient costs, about 1/2 of cancer patients have Medicare B, which has 20% copay and no upper limit, and 14% of them have no additional coverage for their coinsurance.
      • Other diseases:
        • Infliximab (one of largest selling drugs in the US at $4.3 billion in 2015, used for a variety of inflammatory conditions) is only available as 100mg single dose vials, which by above type of calculations leads to $500 million in extra revenues for the drug company.
        • ​Omalizumab (for asthma), used in 75 mg dosing increments, is available only as 150 mg vials
      • Conflicting regulations
        • One issue is conflicting regulations: e.g.
          • FDA: encourage drug companies to package drugs responsibly to minimize waste
          • Medicare: okay to share open vials with other patients, if precautions taken
          • But, CDC: only use single dose vials for one patient.

So, a few points:

  • Yet again we are confronted with drug companies making huge profits by manipulating the system. The Feds deserve some credit/blame for not having a consistent directive on using leftovers of these extremely expensive drugs, as I do all the time with leftover lidocaine or immunizations from multi-use bottles (there may be issues of shelf-life that vary with different drugs, of course). But the bigger regulatory let-down is that, unlike almost all other countries, we have no regulatory restraints on the drug industry. They can charge whatever they want. As we see again and again. For example, when the new drug for hepatitis C infection Harvoni came out, there was not even the pretense that the price reflected drug company reported costs (however inflated they might be), but instead were considered “reasonable” given the cost of treating the complications of otherwise untreated hep C.
  • The 340B program began in 1992 to “stretch scarce federal resources as far as possible, reaching more eligible patients and providing more comprehensive services.” The goal of the 340B pharmacy act was to make meds more available at a lower price in areas of need, not to allow larger profits for hospitals and doctors.
  • The magnitude of these profits is shocking/mind-numbing (and, remember, the $2 billion/yr is only for the top 20 cancer drugs). Just think how many more uninsured/underinsured people in the US could receive accessible, affordable care if the $$ were channeled there instead of drug company coffers…..

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