Mary Ellen McCann is a HERO

Myron Yaster MD and Mark Schreiner MD

One of the great things about the Society for Pediatric Anesthesia is the camaraderie and life-long friendships that one can develop by frequent attendance at the annual meetings and by joining its various committees (which are open to all members).   I first Mary Ellen McCann about 20 years ago and my life has been greatly enriched by her friendship.  Simply, she is one of the “stars” in our profession.  She has published extensively including this sample of papers (1-6) and ran the Boston Children’s Hospital’s annual pediatric review for many years. Of her many contributions perhaps the most important was her leadership in the GAS neurodevelopment trials.  She is also member of the US Food and Drug Administration’s Center for Drug Evaluation and Research (CDER) Anesthetic and Analgesic Drug Products Advisory Committee.  In the February 2021 issue of the journal Anesthesiology she wrote an editorial commenting on two papers about liposomal bupivacaine (Exparel) in that issue by Hussain et al.(7) and Ilfeld et al.(8). The two concluded that liposomal bupivacaine was no better than regular bupivacaine but a lot more expensive. The manufacturer of Exparel (Pacira Biosciences) sued Mary Ellen, the editors of Anesthesiology, the authors of the 2 papers, and the ASA (owners of the journal) for defamation and libel.  This week, U.S. District Judge Madeline Cox Arleo dismissed the case and “this decision from the federal court makes clear that pharmaceutical companies are not free to intimidate the scientific process by filing lawsuits. This is a landmark win for science.” (ASA website: https://www.newswise.com/articles/pacira-s-lawsuit-against-anesthesiology-dismissed )  I’ve asked Mark Schreiner, who like Ron Litman of blessed memory, is an expert in FDA labeling and new drug approval by the agency to join me in today’s PAAD.  We will review the editorial and the implications of the lawsuit. 

Mary Ellen went thru hell during this process.  She is simply a hero and when I and you see her at a SPA meeting give her a hug and “one of these”:  Myron Yaster MD

Editorial

Mary Ellen McCann. Liposomal Bupivacaine. Anesthesiology. 2021 Feb 1;134(2):139-142. PMID: 33433621

“One of the missions of the Food and Drug Administration (Silver Spring, Maryland) is to protect the public health by assuring the safety, efficacy, and security of human drugs. According to FDA guidance, new drugs can be approved as long as they show efficacy compared to placebo, even if there are already drugs approved and available that have been deemed effective.”(1)  In other words, superiority is not required for drug approval.  It’s really about the drug’s safety and does the drug work for its proposed indication. For the most part, comparison between a new drug and existing drugs is left to academic investigators. This means that clinicians usually lack data on which to base their choice between similar drugs. A superior drug would of course be preferred provided it was as safe and the margin of superiority justified its higher cost.

The idea of a slow release, long acting (72+ hour) local anesthetic has been the holy grail of regional anesthesia and postoperative pain management for decades.   Liposomal bupivacaine entered the marketplace precisely to fill this need.  As the editorial in today’s PAAD and the 2 papers on which the editorial is based point out “the preponderance of current evidence fails to support the routine use of liposomal bupivacaine over standard local anesthetics when treating postoperative pain.”  In other words, it is a safe and effective local anesthetic (which was the basis for FDA for approval) but is no better than the much cheaper, generic, local anesthetic alternatives (bupivacaine and ropivacaine).  The difference in price isn’t trivial. “The cost of a single dose of 266 mg of Exparel brand liposomal bupivacaine is about $334.  Non-liposomal bupivacaine costs about $3 per dose”.  Mary Ellen concluded her editorial: “In this era of medical austerity, when the benefits and costs of expensive drugs are being considered, one would hope that newly approved expensive drugs would at least be an improvement over existing, inexpensive drugs.” And the improvement must also be sufficient to make a difference to patients.  

Ioannidis (Epidemiology 2008;19: 640–648) has shown that most true associations are inflated. He demonstrated that most initial estimates of efficacy are overstated and that as more studies are done and the sample size increases, the subsequent estimate of the magnitude of the effect size usually diminishes. It is therefore not surprising that when more studies are performed, that minor improvements of one drug compared to another fail to hold up over time.

How could a company sue Dr. McCann, the authors of the two papers, the editors of the journal, and the ASA be for doing what they are supposed to be doing – evaluating the emerging data?  Just because a company isn’t happy with the results of studies and editorials, does not give that company the right to sue for slander and defamation. 

The court, in its opinion, laid out the basis on which a company could win this type of case.  “The element of falsity [in a trade libel case] requires a threshold showing that the allegedly defamatory statement is a statement of fact "capable of objective proof of truth or falsity," as opposed to an opinion protected by the First Amendment… By their nature, scientific conclusions published in an academic journal are "tentative," and made "available to other scientists who may respond by attempting to replicate the described experiments, conducting their own experiments, or analyzing or refuting the soundness of the experimental design or the validity of the inferences drawn from the results." The peer-review process—not a courtroom—thus provides the best mechanism for resolving scientific uncertainties.”  “Consequently, courts have determined that scientific conclusions are protected speech to the extent they are "draw[n] … from non-fraudulent data, based on accurate descriptions of the data and methodology underlying those conclusions, on subjects about which there is legitimate ongoing scientific disagreement." … "Scientific controversies must be settled by the methods of science rather than by the methods of litigation." …. This is especially true where, as here, a challenged statement occurred in a peer-reviewed journal "directed at the scientific community," as opposed to an advertisement directed at consumers.

“Absent an allegation that the author of a scientific article falsified the data from which she drew her conclusions, a plaintiff cannot sustain a claim for trade libel by alleging that some methodological flaw led to a scientifically "incorrect" answer. Stated differently, a scientific conclusion based on nonfraudulent data in an academic publication is not a "fact" that can be proven false through litigation.” The path to address differences of opinion expressed by protected speech is more protected speech not litigation. The plaintiff is free to do its own meta-analysis (which it alluded to in its complaint) and submit the results for peer review and publication

Fortunately, Mary Ellen and the other defendants in this suit and all scientific investigators can take a deep breath, exhale, and be thankful for the decision.  It doesn’t mitigate the grief and anxiety she and the others went through.  So, once again, when you see her, give her a hug and “one of these”. Had the company prevailed, the effect on scientific research would have been chilling. 

Myron Yaster and Mark Schreiner

References

1.           McCann ME. Liposomal Bupivacaine. Anesthesiology 2021;134:139-42.

2.           McCann ME, de Graaff JC, Dorris L, Disma N, Withington D, Bell G, Grobler A, Stargatt R, Hunt RW, Sheppard SJ, Marmor J, Giribaldi G, Bellinger DC, Hartmann PL, Hardy P, Frawley G, Izzo F, von Ungern Sternberg BS, Lynn A, Wilton N, Mueller M, Polaner DM, Absalom AR, Szmuk P, Morton N, Berde C, Soriano S, Davidson AJ. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet 2019;393:664-77.

3.           Davidson AJ, Disma N, de Graaff JC, Withington DE, Dorris L, Bell G, Stargatt R, Bellinger DC, Schuster T, Arnup SJ, Hardy P, Hunt RW, Takagi MJ, Giribaldi G, Hartmann PL, Salvo I, Morton NS, von Ungern Sternberg BS, Locatelli BG, Wilton N, Lynn A, Thomas JJ, Polaner D, Bagshaw O, Szmuk P, Absalom AR, Frawley G, Berde C, Ormond GD, Marmor J, McCann ME. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet 2016;387:239-50.

4.           Davidson AJ, Morton NS, Arnup SJ, de Graaff JC, Disma N, Withington DE, Frawley G, Hunt RW, Hardy P, Khotcholava M, von Ungern Sternberg BS, Wilton N, Tuo P, Salvo I, Ormond G, Stargatt R, Locatelli BG, McCann ME. Apnea after Awake Regional and General Anesthesia in Infants: The General Anesthesia Compared to Spinal Anesthesia Study--Comparing Apnea and Neurodevelopmental Outcomes, a Randomized Controlled Trial. Anesthesiology 2015;123:38-54.

5.           Loepke AW, McCann JC, Kurth CD, McAuliffe JJ. The physiologic effects of isoflurane anesthesia in neonatal mice. AnesthAnalg 2006;102:75-80.

6.           McCann ME, Kain ZN. The management of preoperative anxiety in children: an update. AnesthAnalg 2001;93:98-105.

7.           Hussain N, Brull R, Sheehy B, Essandoh MK, Stahl DL, Weaver TE, Abdallah FW. Perineural Liposomal Bupivacaine Is Not Superior to Nonliposomal Bupivacaine for Peripheral Nerve Block Analgesia. Anesthesiology 2021;134:147-64.

8.           Ilfeld BM, Eisenach JC, Gabriel RA. Clinical Effectiveness of Liposomal Bupivacaine Administered by Infiltration or Peripheral Nerve Block to Treat Postoperative Pain. Anesthesiology 2021;134:283-344.