Category: Ethics

The Hand that Feeds the Hand that Feeds the Hand that ….

Pharmaceutical development is all about the blockbuster drug. Many of our brightest minds are research scientists and bioinformaticians working at translating in vitro discoveries to improving the lives of human kind.

Many of our brightest minds are also working to ensure, even if their drug candidates are – say – a little flawed, there’s a clinical trial design, trial implementation, and post-approval marketing plan to maximize return to shareholders.

A critical portion of in this chain of survival is publication – the higher the impact a journal, the better. One of the gatekeepers to publication remains peer review, a critical step in ensuring the integrity, transparency, and reproducibility of science. Naturally, this step would be independent and untainted by bias, a vigilant final guardian protecting the public.

It would … wouldn’t it?

This brief report from JAMA finds it would absurd even to imagine such a fanciful state of affairs. Evaluating lists of peer reviewers from The BMJ, JAMA, The Lancet, and The New England Journal of Medicine from 2022, the authors analyzed 1,962 U.S.-based physician reviewers. Of these reviewers, the Open Payments database indicated 58.9% of these reviewers had received payments from industry, totalling USD$1.06 billion between 2020 and 2022. The vast majority – $1.01 billion – were payments supporting research activities, with a mere $60M going towards such things as consulting fees, speaker fees, honoraria, etc. Male reviewers and those in medical and surgical specialties, rather than primary care or hospital-based specialties, were the dominant recipients of said payments.

While these data are not meant to illuminate some sort of dark money ecosystem, it is clear the “peers” doing the reviews are playing at the same game. There is going to be an obvious bias towards allowing publication of content and spin consistent with the output the reviewers themselves would anticipate using in their own work. A receptive audience, if you would.

Just another happy reminder how so much of our medical practice is swept along in a current powered by many moneyed forces at work.

“Payments by Drug and Medical Device Manufacturers to US Peer Reviewers
of Major Medical Journals”
https://jamanetwork.com/journals/jama/article-abstract/2824834

Cancer Clinical Trials Don’t Benefit Patients

Hearkening back to my former life as the chair of an Institutional Review Board: you do not promise or imply a potential for benefit to clinical trial participants.

Why? Because clinical trials aren’t designed to benefit participants. Participants may be randomized to the “standard of care” arm. The trial drug may not have any improvement in efficacy over the “standard of care”. Worse, the trial drug may, in fact, have greater toxicity than the current options. Finally, there are the frequent – and frequently invasive – trial procedures: blood draws, repeat imaging, and repeat tumor sampling.

The perception remains clinical trials produce better outcomes for some trial participants – but the whole of the literature does not support this conclusion. This systematic review and meta-analysis from JAMA clearly shows the data are insufficient to support a net benefit from cancer clinical trial participation. Small signals of benefit are most likely the result of trial effects and publication bias.

The unquestioned benefit? To pharma – and, distantly, potentially to future patients.

While this study does not exclude such benefits for cancer clinical trial participation, it remains unsubstantiated.

https://pubmed.ncbi.nlm.nih.gov/38767595

Let’s Sell Andexxa

Have you heard the Good News (from Portola) about andexanet?

It’s an ever-changing landscape of anticoagulants and reversal agents in the Emergency Department – though, it’s not so much as a whirlwind as it is a creeping ooze. The latest developments have all been covered ad nauseum over the past few years – dabigatran, idarucizumab, factor Xa inhibitors, and coagulation factor Xa (recombinant) inactivated-zhzo (andexanet alfa). This final product, trade name Andexxa, has generally been held in a dim view over the past year by many, including yours truly, Rebel EM, the Skeptic’s Guide to Emergency Medicine, EmCrit, first10EM, the American Society of Hematology, and both the European Medicines Agency and the Food and Drug Administration’s own clinical reviewers.

There is, however, a competing viewpoint in which Andexxa is Tier 1 therapy for treatment of major bleeding in the context of of direct Xa inhibitor use – such as this recent “Recommendations of a Multidisciplinary Expert Panel” piece in Annals of Emergency Medicine. What aspect of their review differs so greatly in their affinity for Andexxa?

The expert panel meeting was convened with funds from unrestricted educational grants from Portola Pharmaceuticals and Boehringer Ingelheim to the American College of Emergency Physicians.

And, to no great surprise, the convened panel reflects the funding source:

Dr. Baugh has worked as a consultant for Janssen Pharmaceuticals and previously received research funding from Janssen Pharmaceuticals and Boehringer Ingelheim as a coinvestigator. Dr. Cornutt has received speaker’s fees from Boehringer Ingelheim. Dr. Wilson has worked as a consultant for Janssen Pharmaceuticals, Boehringer Ingelheim, BMS/Pfizer Pharmaceuticals, and Portola Pharmaceuticals, and has also received research funding from them. Dr. Mahan has served on the speaker’s bureau and as a consultant for Boehringer Ingelheim, Janssen Pharma, Portola Pharma, and BMS/Pfizer and as a consultant to Daiichi-Sankyo, WebMD/Medscape, and Pharmacy Times/American Journal of Managed Care. Dr. Pollack is a scientific consultant to Boehringer Ingelheim, Janssen Pharma, Portola Pharma, and BMS/Pfizer; he also received research support from Boehringer Ingelheim, Janssen Pharma, Portola Pharma, Daiichi-Sankyo, CSL Behring, and AstraZeneca. Dr. Milling’s salary is supported by a grant from the National Heart, Lung, and Blood Institute. He serves on the executive committee for the ANNEXA-4 and ANNEXA-I trials, the steering committee for the LEX-209 trial, and the publications committee for the Kcentra trials. He has received consulting fees or research funding from CSL Behring, Portola, Boehringer Ingelheim, Genentech, and Octapharma. He received speaker’s fees from Janssen. Dr. Peacock has received research grants from Abbott, Boehringer Ingelheim, Braincheck, CSL Behring, Daiichi-Sankyo, Immunarray, Janssen, Ortho Clinical Diagnostics, Portola, Relypsa, and Roche. He has served as a consultant to Abbott, AstraZeneca, Bayer, Beckman, Boehringer-Ingelheim, Ischemia Care, Dx, Immunarray, Instrument Labs, Janssen, Nabriva, Ortho Clinical Diagnostics, Relypsa, Roche, Quidel, and Siemens. He has provided expert testimony on behalf of Johnson & Johnson and has stock and ownership interests in AseptiScope Inc, Brainbox Inc, Comprehensive Research Associates LLC, Emergencies in Medicine LLC, and Ischemia DX LLC. Dr. Rosovsky has served as an advisor or consultant to Janssen, BMS, and Portola and has received institutional research support from Janssen and BMS. Dr. Sarode has served as a consultant for CSL Behring and Octapharma and advisor to Portola Pharmaceuticals. Dr. Spyropoulos is a scientific consultant to Janssen, Bayer, Boehringer Ingelheim, Portola, and the ATLAS Group; he also has received research support from Janssen and Boehringer Ingelheim. Dr. Woods is a scientific consultant to Boehringer Ingelheim. Dr. Williams serves as a consultant to Janssen Pharmaceuticals, Boehringer Ingelheim, and Portola Pharmaceuticals.

This work is effectively an advertorial, masquerading as serious academic literature, and part of a well-executed marketing and promotional campaign by the manufacturers of these drugs – particularly Portola, which is having difficulty getting Andexxa on formulary due its cost and controversial clinical data. This publication in Annals is just one of many sponsored products:

The further afield these pseudo-guidelines permeate, the more likely the product – the $25k or $50k a dose Andexxa – is incorporated into hospital formularies and local practice. These also have implications for risk-management assessments, in which the costs – passed along to the patient or payor – are far outweighed by the potential liability of a decision to make the drug unavailable for treatment.

It should be clear from all the non-conflicted opinion the role of Andexxa is yet to be clearly established, with true RCT evidence unfortunately years away. To state otherwise – and to make Tier 1 recommendations – is simply misleading.

“Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel”
https://www.annemergmed.com/article/S0196-0644(19)31181-3/fulltext

Dialysis Purgatory

This little article is not terribly generalizable and the results are eminently predictable – but this barbaric practice was my daily routine a couple years ago while working in Houston.

To received routinely scheduled dialysis, someone must, of course, pay for it. For those U.S. citizens without the means to pay, various federal mechanisms provide coverage. For non-U.S. citizens in this country without the means to pay, there is no external payor source – unless “necessary for the treatment of an emergency medical condition.” Therefore, many facilities simply restrict dialysis to non-citizen patients in extremis.

As you might expect, this is bad and bad for you. This retrospective cohort study follows 5-year survival and resource utilization, comparing those at hospitals where non-U.S. citizens could be eligible for scheduled dialysis with those at facilities where only emergency dialysis was available. The sample sizes are small – 169 in the “emergency-only” cohort and 42 in “standard” – but at 5 year follow-up, over half the “emergency-only” cohort had died, as compared with about 10% of the standard hemodialysis. Various statistical analyses and propensity matching further quantify the exact excess hazard of emergency dialysis.

Patients receiving emergency dialysis received, obviously, fewer sessions per month – 6.2 instead of 10.3. However, these savings are potentially offset by a ten-fold increase in acute care days, probably associated with those episodes of emergency dialysis. In the most morbid sense, unfortunately, total cost-savings probably favor the emergency dialysis cohort owing to the greatly increased mortality.

There are uncertainties and holes in these sorts of retrospective studies, particularly in a cohort whose deaths are potentially not documented in our national registries. The face validity for the overall findings is strong, however, even if the specific numbers are not reliable.

Regardless, just as a manner of respecting basic human decency, it is simple cruelty to layer this additional suffering onto the already miserable state of being dialysis-dependent. All feasible efforts should be made to provide access to regular dialysis, considering the burden on the health system infrastructure is likely similar.

“Association of Emergency-Only vs Standard Hemodialysis With Mortality and Health Care Use Among Undocumented Immigrants With End-stage Renal Disease”
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2665387

Emergency Physicians are Mostly Just Hungry

Starving – but not for money – is probably the best way to sum up these descriptive statistics from CMS Open Payments.

This is simply a summary and breakdown of the 2014 calendar years’ worth of physician payments from industry, as reported to Open Payments.  This includes a range of details, from as mundane items as free snacks to large institutional grants for research.  All told, there were 46,405 payments to 12,883 emergency physicians, or approximately 1/3rd of all practicing EM physicians.  39,774 of these payments were related to “Food and Beverage”, and typically between $10 and $50.

So, most EM physicians are just hungry.

However, such food-related expenses were just 12.2% of the total pharmaceutical spend on EM physicians.  The two highest-grossing categories were 1,257 physicians with lecture fees and 833 with consulting fees, averaging over $1000 each.  The products associated with the greatest number and/or largest payments were antibiotics and anti-thrombotics, mostly: rivaroxaban, apixaban, dabigatran, ticagrelor, alteplase, ceftaroline, and linezolid.  Rather unexpectedly to me, at least, a few of the other top spots were taken up by agents for glycemic control: insulin detemir, canagliflozin, and liraglutide.

Finally, EM physicians were actually fairly low on the payout list, compared with other specialties, ranking 25th of 28th evaluated by this study.  The “winners”, if it weren’t already obvious from your hospital parking garage: orthopedic surgery, cardiology, endocrinology, allergy & immunology, gastroenterology, and urology.

“Financial Ties Between Emergency Physicians and Industry: Insights From Open Payments Data”

ClinicalTrials.gov Registration & Cleaning Up Primary Outcomes

It is an oft-repeated pseudoaxiom that half of your medical knowledge is wrong – we just don’t yet know which half.  This hyperbole is founded, in part, in the work of Ioannidis and examinations of refutations of clinical trials.  This study represents another log to toss onto our conflagaration of uncertainty.

These authors noted a recent analysis of large clinical trials funded by the National Heart, Lung, and Blood Institute showed these trials had mostly neutral results.  Neutral trials, of course, are still valuable – they frequently help inform efforts to prevent unnecessary or low-value care.  However, the prior analysis only evaluated studies published after year 2000, the year trials began being registered in ClinicalTrials.gov.  This new analysis extended the review window back to 1975, to see if this trend of predominantly null outcomes was a historical trend, or whether the requirement to publicly pre-specify a primary outcome might have had some effect.

Not terribly surprisingly, there is a relatively clear difference in the frequency of null outcomes in the post-ClinicalTrials.gov period compared with prior:

The authors’ quite reasonable conclusion: prior trials, not having the requirement to pre-specify a primary outcome, were probably more likely to retroactively promote a positive outcome as the primary outcome of a study.

Should all these primary outcomes prior to 2000 be re-tested?  Considering all these prehistoric trials noted ties to industry, it’s probably a fair suggestion – and, certainly, it fuels our further skeptical re-examination of established medical practices.

“Likelihood of Null Effects of Large NHLBI Clinical Trials Has Increased over Time”
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132382

Which Review of Tamiflu Data Do You Believe?

Ever since its introduction, there have been skeptics regarding the utility of oseltamivir and other neuraminidase inhibitors for the treatment of influenza.  Roche has profited tremendously off strategic stockpiling by many governments as a response to pandemic influenza – yet, nearly all the data comes from Roche-conducted trials, and the data has been persistently cloaked from independent review.  This past year, after much strife and public shaming, the Cochrane Collaboration received some access to clinical trial reports to conduct an independent review.  This review found, on average, adults receiving early treatment with oseltamivir benefited by reduction in symptom duration from 7 days to 6.3 days.  No benefit was found for reduction in respiratory infectious complications or hospitalization, the truly critical need during influenza outbreaks.

However, a second group also conducted an independent review – the “Multiparty Group for Advice on Science”.  Their results, based on an individual-patient meta-analysis, are published in the Lancet and offer similar – yet wildly different – conclusions.  They find, as did the Cochrane group, approximately a 17-hour reduction in symptoms in the intention-to-treat population across the eight Roche trials evaluated.

Similar to the Cochrane review, they perform secondary analyses for “lower respiratory tract infection”(e.g., bronchitis or pneumonia) and hospitalization, stratified by ITT and ITT-infected populations.  Most prominently emphasized are the results for the ITT-infected population, in which the antibiotics for LRTI were provided to 4.2% in the oseltamivir cohort, compared with 8.7% in placebo.  Likewise, 0.9% of patients were hospitalized for any cause compared with 1.7% of placebo.  The authors therefore conclude oseltamivir use decreased infectious complications of influenza.

These numbers, however, are entirely different from the Cochrane review.  The Cochrane review found a 1.4% hospital admission rate in the oseltamivir cohort and 1.8% in the placebo cohort.  Broken down by trial, the admit rates for the oseltamivir cohort in the MUGAS analysis compared with the Cochrane review:

  • M76001: 7/965 vs. 9/965
  • WV15670: 1/241 vs. 1/484
  • WV15671: 1/210 vs. 6/411
  • WV15707: 2/17 vs. 2/17
  • WV15812+: 6/199 vs. 9/199
  • WV15819+: 6/360 vs. 9/362
  • WV16277: 2/226 vs. 2/225

The differences in WV15670 and WV15671 appear to stem, at least in part, due to the MUGAS analysis being restricted to only trial patients taking 75mg twice daily, and not 150mg twice daily.  However, it is otherwise entirely unclear how the Cochrane group found extra hospitalizations in the other trials the MUGAS group did not – particularly considering the hospitalization numbers in the placebo cohorts were essentially identical.  Might it be partly a result of the MUGAS group receiving their data directly from a Roche web portal, while the Cochrane group reviewed the individual clinical study reports?

Rather, might it be revealing to pry into the genesis of the “Multiparty Group for Advice on Science”?  Is it an unbiased, independent clearinghouse for re-analysis of trial data?  Do they have a long track record of respected publications in multiple disciplines?  Unfortunately, neither of these conjectures are true – making it increasingly likely they are a puppet foundation fraught with conflict-of-interest.  MUGAS and the present work were funded by an unrestricted grant from Roche.  Furthermore, MUGAS, along with the European Scientific Working group on Influenza (ESWI), are projects of Semiotics, a scientific branding and communication company specializing in influenza.  The stated goal of Semiotics is promoting corporate science and ensuring its place on top of the policy agenda – and MUGAS is one of their “brands”.  This ought to very clearly demonstrate MUGAS is not a scientific enterprise, and rather an organization tasked with the sort of advocacy as best represents the needs of its sponsors.

Any bias might also be clear just in the style used to present results.  These authors present the tiny absolute differences in hospitalization and infectious complications in forest plot figures using only relative risk, rather than absolute risk.  This serves to inflate the apparent effect size.  Conversely, they present the increased incidence of adverse effects in a table culminating in adjusted absolute risk, with the opposite effect.  This manner of presentation persists in their Discussion, highlighting a “significant 63% reduction in risk of hospitalization”, compared with “absolute increases of 3.7% for nausea and 4.7% for vomiting.”

So – the results of an analysis performed by a “brand”, highlighting results discordant with a prior unbiased analysis.  Where is the peer review vetting such discrepancies?  With so many professional reputations and so much revenue at stake – which report do you believe?

“Oseltamivir treatment for influenza in adults: a meta-analysis of randomised controlled trials”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62449-1/abstract

Additional editorial content:
“The BMJ Today: The FDA and CDC’s disagreement over Tamiflu, and the spy who isn’t”
http://blogs.bmj.com/bmj/2015/02/05/the-bmj-today-the-fda-and-cdcs-disagreement-over-tamiflu-and-the-spy-who-isnt/

The Remarkable Power of Placebo

Have you ever felt pressured to provide a patient with something at the time of discharge?  Something, anything to ease their suffering for an illness of unalterable benign progression?  Never?  You cold-hearted bastard.

This tiny trial, despite its small size, provides yet another beautiful look at the magical healing power of placebo.  Or, more accurately, rather than healing power, at least the satisfying power.  After all – most families in the ED at two in the morning are not there because their child is awake from coughing, but because the parents are.

This trial, in the same vein of several honey trials before it, compared no treatment, a placebo treatment (grape-flavored water), and agave nectar for the treatment of pediatric cough-related illness.  Agave nectar was chosen for its similarity to honey, while not carrying the hypothetical botulism risk.  With ~40 patients in each group, all patients improved during the duration of the study.  However, despite the small sample, both agave nectar and placebo provided durable advantage over no treatment across all surveyed measures of patient and parent comfort.  There was, however, no difference between placebo and agave nectar – or, if there was, it was too small to be detected in this study.

What is most remarkable about this study is the authors discussion – that placebo treatments could be considered ethical, even when no benefit to such treatment is found in controlled studies.  Providing patients – or parents – with, at least, an inexpensive, harmless treatment option takes advantage of the power of belief, to the extent that real patient/parent-oriented benefits may be observed.

Unfortunately, the lead author of this study was a paid consultant to Zarbee’s Inc (a maker of “natural” over-the-counter remedies) at the time the study was initiated, and Zarbee’s provided funding for the study.  But, thanks to their contribution to science, we now know they only work as well as you expect ….

“Placebo Effect in the Treatment of Acute Cough in Infants and Toddlers”
http://www.ncbi.nlm.nih.gov/pubmed/25347696

by Darren Cullen
Copyright Darren Cullen – Spellingmistakescostlives
Homeopathic Accident & Emergency

Scientific Writing is a Tragicomedy! Destroy!

Modern scientific writing – both in the exercises of writing and reading – is obtuse and uninviting.  Rather than clearly communicate an unbiased reflection of the conduct and findings of a particular study, the medical literature most commonly succeeds in doing the opposite.  After all, how else would I find enough to complain about on this blog?

This editorial elucidates so many joyfully preposterous notions it cannot help yet be loved.  It is best described as a no holds-barred cagematch versus all the inane pageantry of scientific writing.  Just a few of the gems, paraphrased:

  • Don’t let the authors write the abstract; they’ll just misrepresent the study!
  • Delete the introduction; uninsightful filler.
  • No one cares the brand and manufacturer of the statistical package used.
  • Unequal composite end-points and subgroup analyses should be banished.
  • The discussion section only serves authors’ purposes of dubious claims through selective reporting and biased interpretation of their results.

Some elements of this brief report are, indeed, novel.  Others are simply accepted best practices long since forgotten.  Regardless, it is a refreshing reminder of how brutally poorly the current medical literature serves effective knowledge translation.

“Ill communication: What’s wrong with the medical literature and how to fix it.”
http://www.ncbi.nlm.nih.gov/pubmed/25145940

Who Loves Tamiflu?

Those who are paid to love it, by a wide margin.

This brief evaluation, published in Annals of Internal Medicine, asks the question: is there a relationship between financial conflicts-of-interest, and the outcomes of systematic reviews regarding the use of neuraminidase inhibitors for influenza?  To answer such a question, these authors reviewed 37 assessments in 26 systematic reviews, published between 2005 and 2014, and evaluated the concluding language of each as “favorable” or “unfavorable”.  They then checked each author of each systematic review for relevant conflicts of interest with GlaxoSmithKline and Roche Pharmaceuticals.

Among those systematic reviews associated with author COI, 7 of 8 assessments were rated as “favorable”.  Among the remaining 29 assessments made without author COI, only 5 were favorable.  Of the reviews published with COI, only 1 made mention of limitations due to publication bias or incomplete outcomes reporting, versus most of those published without COI.

Shocking findings to all frequent readers, I’m sure.

“Financial Conflicts of Interest and Conclusions About Neuraminidase Inhibitors for Influenza”
http://www.ncbi.nlm.nih.gov/pubmed/25285542

Original link in error … although, it’s a good article, too!
http://www.ncbi.nlm.nih.gov/pubmed/24218071