by David J. Elpern, M.D.
The Skin Clinic
12 Meadow Street
Williamstown, Massachusetts
djelpern@gmail.com

Something is rotten in the State of Phrma

Abstract: Pharmaceutical companies, clinical researchers, key opinion leaders and respected medical journals often work in concert to promote and sell new medications. The biologics are the most profitable and competitive pharmaceutical market today. Herein, I analyze the background of a publication on the biologic, adalimumab in a prominent medical periodical. This cautionary tale may guide readers when they encounter similar ghost-driven PhRMA-sponsored research.

Keywords: adalimumab, key opinion leaders, hidradinitis supprativa, medical publications, ghost writing, risankizumab, disclosures, conflict of interest

For some years, I had been struggling to treat a young man with disabling and painful Stage III Hidradenitis suppurativa.  It was with hope that I read an article in a respected journal on two Phase 3 studies of the biologic adalimumab in the treatment of HS.¹ My academic colleagues who were also treating him and I recommended the biologic with encouragement to our hapless patient and he began using it at the recommended dosage. After a year and a half and an expense ~$180,000 (retail value on GoodRx)), it was unclear whether this had helped and clinically the patient was, if anything, more disabled than at the onset of biologic therapy. At this point, I went back, carefully reread the article and made some worrisome observations.

2 phase 3 Trials Adalimumab was prominently published in an academic periodicalwhose high impact factor makes it arguably one of the most influential medical journals in the world.¹ The article is a free and open access making it available in full text to all interested readers. Shortly after publication in 2016, the company’s drug reps started arriving at my office to sing the praises of their company’s newly FDA-approved treatment for HS.  Indeed more than one AbbVie pharmaceutical reps come to my clinic on an almost weekly basis. I do not see drug reps, but these men-in-suits seemed happy to schmooze with my front office staff and have offered food and small gifts that we have declined.

The article in question has 23 authors. Eight were full-time employees of AbbVie, eight are US dermatologists (mostly respected academics); two are Canadian dermatologic researchers, five are European academic dermatologists. One (MMO) was listed as an AbbeVie employee and also a U.S. dermatologist who has taken money from other drug companies as well. The disclosures for the 15 authors who are not AbbVie employees, run 91 small font lines and payments and the number of companies they received payments from are in the Table I and II.

In the article’s  Methods Section under “Study Oversight” we learn that “[A]ll the authors had full access to the data and signed confidentially agreements with the sponsor before the data were provided for their review.”¹ Also, “The first draft of the manuscript was written by a medical writer employed by the sponsor.”¹

In the United States the Physician Payment Sunshine Act makes financial relationships between healthcare providers and pharmaceutical manufacturers transparent.²  The Phrma income received by the eight U.S. authors of this article as found on the OpenPayments website from 2014 – 2018 was over $15,000,000 (Table I). We can only guess at the payments received by the authors from Canada and Europe, but can assume they similar. The Tables also shows the number of drug companies from which each U.S. and foreign authors has received funding.  The U.S. authors averaged 14 companies and the foreign authors averaged 13 companies.

This article¹ is clearly Pharma research: conceived, performed, analyzed, written and published; and its conclusions were driven by what the sponsor wanted to emphasize. A careful parsing of the paper showed that of the number of original 633 patients registered only 46% finished the study. Therefore, the results reported are probably of a smaller and selected subset of subjects.

In the discussion section one reads, “[I]n conclusion, these two randomized trials involving patients with moderate-to-severe hidradenitis suppurativa showed that adalimumab substantially increased the likelihood of a clinically significant response at week 12…”.¹ In reality, when combining Pioneer I and II adalimumab studies, this “substantial reduction” was found in only 286 of the 633 patients who entered the study. Thus, a prestigious medical journal has published a drug company-sponsored promotional article and brazenly placed it in a prominent location.  The article was ghost-written and signed-off on by prominent academic key opinion leaders (KOLs) who were paid handsomely for their participation. Busy clinicians all over the world have paid attention to the sound bites; but few will have read it critically. Every time adalimumab is prescribed,10,000s of dollars go to the pharmaceutical company. AbbVie aggressively markets this drug, whose trade name is Humira, and it is now the best selling pharmaceutical in the world with an estimated sales of almost $20 billion dollars in 2018.³

Analysis of this article at the granular level, explains why my unlucky patient with Stage 3 HS had, at best, a 46% chance of benefitting from adalimumab and it took a year and a half of his life to find that out. At the same time, academic researchers, who are respected key opinion leaders, made out like bandits. Ghost-written articles like this have shaped the narrative for adalimumab and have helped to make it the world’s best selling drug.  Key Opinion Leaders receive monies for research, speaking gigs, travel expenses, advisory board payments. What Barbara Ehrenreich in 1970 called “The Medical-Industrial Complex”⁴ seems more accurately to be The Medical-Industrial-Academic Complex; since academic physicians were key actors in the drug-company directed research, marketing and promotion of adalimumab.

Sadly, a respected medical journal appears to be complicit like so many of our academic super-star KOLs.  Everyone seems happy, but where does that leave our patients?

Coda: Recently, a new AbbVie drug rep has been coming to my office. He is aggressively promoting risankizumab, a newly FDA-approved biologic drug for psoriasis that was featured in yet another free full-text article in the same respected journal⁵ that is remarkably similar in design to the one on adalimumab.¹ In 2016, AbbVie paid $595M to the drug’s developer Boehringer Ingelheim for sole marketing rights.⁶ The patent on Humira expired in 2018 and there are a host of competitors in the wings. AbbVie is positioning itself for what it hopes will be the next mega-blockbuster biologic. It has expertise in all aspects of promotion so this should be interesting to watch. Many KOLs will feed at this gravy train.

References

1. Two Phase 3 Trials of Adalimumab for Hidradenitis Suppurativa. Kimball AB et. al. Two Phase 3 Trials of Adalimumab for Hidradenitis Suppurativa. N Engl J Med. 2016 Aug 4;375(5):422-34
2. Physician Payment Sunshine Act.  Wikipedia https://en.wikipedia.org/wiki/Physician_Payments_Sunshine_Act
3. World Sales of Humira  https://www.creative-biolabs.com/blog/index.php/prediction-top10-best-selling-drugs/
4. Ehrenreich B. The Medical-Industrial Complex. The New York Review of Books, December 17, 1970. URL.
5.  Papp KA1, et. al 16. Risankizumab versus Ustekinumab for Moderate-to-Severe Plaque Psoriasis. N Engl J Med. 2017 Apr 20;376(16):1551-1560. Free Full Texr
6.  Carroll J. AbbVie hands over $595M upfront to partner with Boehringer on PhIII psoriasis drug. FierceBiotec. March 7, 2016 URL: tiny.cc/aomecz (accessed 9.8.19)

Table I 8 U.S. Authors
** Open Payments: https://openpaymentsdata.cms.gov/ Includes research grants from Industry.

Table II 7 Foreign Authors
AbbVie Employees (8)
MMO: Orkin
DAW: Williams
EA: Alwawi
NMM: Mostafa
BP: Pinsky
MS: Sundaram
YG: GU
DMC: Carlson