Jay D. Amsterdam and Leemon B. McHenry : The Paroxetine 352 Bipolar Study Revisited : Desconstruction of Corporate and Academic  Misconduct 

Karen Starko’s comment on Daniel Kanofsky’s comment

       I thank Dr. Kanofsky for the invitation to comment. Emyr Gravell (2018) wrote a story about WC Fields in the British Journal of General Practice in which he said, “Apparently, a friend called to see him when he was dying and was surprised to see the hard-drinking, misanthropic comedian intently absorbed in the Bible. The friend asked him if he was seeing the error of his ways, but Fields put him straight ‘I'm just looking for the loopholes’.”

       Like WC Fields, individuals and corporations look for loopholes in existing processes such as standard procedures and laws to advance a purpose. Over the years, food and drug laws have closed loopholes regarding, for example, secrecy of ingredients in the early 20^th century and the lack of safety testing and free-wheeling advertisements of the 1950s that led to the promotion of children’s aspirin as safe and gentle until it was linked to the mysterious and deadly Reye’s syndrome (Starko, Ray, Dominguez et al. 1980; Monto 1999).  A loophole in the process of assuring the integrity of scientific writing can result  when reports written by a combination of academics and paid ghostwriters gradually, by omission, error or intent, develop potentially important misinterpretations of data. The saga of the paroxetine study discussed herein shows how multiple revisions and authors can create a slippery slope towards challenges in scientific integrity.

       With regard to comments about marketing of aspirin during the 1918 pandemic, “Aspirin” was launched worldwide in 1899 and promoted first to physicians then to the public. In anticipation of the looming loss of the patent in 2017 Bayer decided to emphasize its trademark, the easy to recognize quasi-religious Bayer cross. An international agreement in 1883 protected trademarks indefinitely. According to business historians Charles C. Mann and Mark L. Plummer (1991), “Bayer would try to make consumers so thoroughly identify relief with ‘Bayer Aspirin’ that its rivals would have no chance... [Beginning in 1914] Each tablet was stamped with the Bayer Cross, and the tablets were put in Bayer packages, which for the first time let customers see the name of the company that cured their headaches.”  

       Meanwhile, the United Drug Company (U.D.C), which had been repackaging Aspirin for Bayer, began buying acetylsalicylic acid from a company in Missouri called Monsanto, labeling tablets as it always had — 5 grains Aspirin U.D.C. (Jeffries 2005). In addition, Herbert Dow, founder of Dow Chemical of Midland, Michigan, set his intentions on making acetylsalicylic acid (Mann and Plummer 1991). Facing these challenges, Bayer abandoned its previously conservative marketing approach and decided to advertise to the public. “In the fall of 1916, Aspirin ads appeared in newspapers across the United States.  ‘BAYER’ read a headline above a picture of an Aspirin box, ‘Tablets of Aspirin’” (Mann and Plummer 1991).  By the time the patent expired, Bayer had created two valuable assets: a trademarked name and the widely, recognized symbol — the Bayer cross. 

       On April 6, 1917, the United States declared war on Germany and in December 2018, one month after Germany surrendered, the U.S. Alien Property Custodian sold Bayer assets to Sterling Drugs. In early 1917, Bayer sued the United Drug Company of Boston for trademark infringement (Mann and Plummer 1991).  U.S. federal Judge Learned Hand heard this case and approved generic use of the word "aspirin" in 1920 (Jeffries 2005). “Aspirin” simply became aspirin, an iconic medicine for relief of common ailments and many companies jumped on the lucrative bandwagon. Sterling, however, one of the most successful companies, needed Bayer’s manufacturing expertise and, in 1923, the companies reached two agreements that would distribute between them worldwide marketing rights, profits, and manufacturing (Mann and Plummer 1991).

       While salicylate (aspirin) use was promoted during the 1918 influenza pandemic, physicians of the day determined the dose schedule. Doses were commonly chosen by trial and error for patients with rheumatic diseases. When influenza hit, the vigorous regimens similar to those used for serious rheumatic diseases under a doctor's supervision were widely recommended for influenza with few warnings regarding signs of toxicity as discussed in my 2009 paper (Starko 2009). I agree with Dr. Kanofsky that uncovering case specific information on aspirin use during the 1918 influenza in various geographic areas would further inform the role of aspirin in the pandemic mortality.

       Finally, although the initial cases of the enigmatic encephalitis lethargica (EL) were noted in 1916, the year that Bayer began promoting aspirin to the public, the clinical presentation of EL differs from that of Reye’s syndrome. Aspirin-associated Reye’s syndrome is an acute condition primarily of children with either rapid deterioration or resolution.  Although RDK Reye’s paper was published in the Lancet in 1963, most researchers have traced the illness back to the 1920s (Anderson 1923; Brain, Hunter and Turnbull 1929). Cerebral edema and brain stem compression contribute to fatalities. Fatty degeneration of the liver, a marker of the illness, may be significant but it is quickly reversible. Reye’s syndrome is now rare due to warnings about use of aspirin in children (Monto 1999). EL presents with an acute phase of “excessive sleepiness, disorder of ocular motility, and movement disorders” and a chronic phase perhaps months or years later “most commonly characterized is by parkinsonian-like signs” (a finding not reported in Reye’s syndrome to my knowledge),  although other presentations have been described (Hoffman and Vilensky 2017). That a drug or chemical exposure might be a factor in the pathogenesis of EL remains an interesting possibility although investigations to date have not identified any one exposure (Hoffman and Vilensky 2017).

References:  

Anderson AF. Report of five cases of acute encephalitis. Boston M & S J, 1923;189:177-9.

Brain WR, Hunter D, Turnbull HM. Acute meningoencephalitis of childhood. Lancet, 1929;1:221-7.

Gravell E. Loopholes. British Journal of General Practice, 2008;58(551): 450. 

Hoffman LA, Vilensky JA. Encephalitis lethargica: 100 years after the epidemic. Brain, 2017;140(8):2246-51. 

Jeffries D. The Remarkable Story of a Wonder Drug Aspirin. New York: Bloomsbury, 2005, p. 151-2. 

Mann CC, Plummer ML. The Aspirin Wars. Boston: Harvard Business School Press, 1991, p. 37, 66, 69-70. 

Monto AS. The disappearance of Reye’s syndrome—A public health triumph. N Engl J Med,  1999;340:1423-4. 

Starko KM, Ray CG, Dominguez LB, Stromberg WL, Woodall DF. Reye's syndrome and salicylate use. Pediatrics, 1980;66(6):859-64.

Starko KM. Salicylates and Pandemic Influenza Mortality, 1918–1919 Pharmacology, Pathology, and Historic Evidence. Clin Infect Dis, 2009;49(9):1405-10.

March 4, 2021