Saturday, July 28, 2018

Linear gadolinum imaging agents and clear and convincing evidence

In this post, we look at how different medical bodies, specifically those in Europe (the European Medicines Agency (EMA) ) and in the United States (the FDA) look at evidence that might be considered "clear and convincing." Specifically, in the context of linear gadolinium imaging agents, they have reached different conclusions. But first, a quick trip to the law of "clear and convincing" evidence.

In Halo v. Zimmer, 136 S. Ct. 1923; 195 L. Ed. 2d 278; 2016 U.S. LEXIS 3776; 84 U.S.L.W. 4386; 118 U.S.P.Q.2D (BNA) 1761 , the U.S. Supreme Court delved into the evidentiary standard of clear and convincing evidence:

The Seagate test is also inconsistent with §284 because it requires clear and convincing evidence to prove recklessness. On this point Octane Fitnessis again instructive. There too the Federal Circuit had adopted a clear and convincing standard of [***20] proof, for awards of attorney's fees under §285 of the Patent Act. Because that provision supplied no basis for imposing such a heightened standard of proof, we rejected it. See Octane Fitness, 572 U.S., at ___, 134 S. Ct. 1749, 188 L. Ed. 2d 816. We do so here as well. Like §285, §284 "imposes no specific evidentiary burden, much less such a high one." Ibid. And the fact that Congress expressly erected a higher standard of proof elsewhere in the Patent Act, see 35 U.S.C. §273(b), but not in §284, is telling. Furthermore, nothing in historical practice supports a heightened standard. As we explained in Octane Fitness, "patent-infringement litigation has always been governed by a preponderance of the evidence standard." 572 U.S., at ___, 134 S. Ct. 1749, 188 L. Ed. 2d 816. Enhanced damages are no exception.

The Supreme Court did not get into definitions. Earlier, in 1983, the CAFC in SSIH, 718 F.2d 365 , gave some explanatory text:

A particular quantum or burden of proof at the trial level (standard of proof) is generally a judge-made requirement shaped in accordance with considerations of due process and/or the importance of certain facts. Herman & MacLean v. Huddleston, 459 U.S. 375, 103 S. Ct. 683, 691, 74 L. Ed. 2d 548 (1983). As explicated in Addington v. Texas, 441 U.S. 418, 423-25, 60 L. Ed. 2d 323, 99 S. Ct. 1804 (1979), three levels of proof are generally recognized: preponderance (or weight) of the evidence, clear and convincing proof, and beyond a reasonable doubt.


We probably can assume no more than that the difference between a preponderance of the evidence and proof beyond a reasonable doubt probably is better understood than either of them in relation to the intermediate standard of clear and convincing evidence. Nonetheless, even if the particular standard-of-proof catchwords do not always make a great difference in a particular case, adopting a "standard of proof is more than an empty semantic exercise. " Tippett v. Mar-yland, 436 F.2d 1153, 1166 (CA4 1971) (Sobeloff, J., concurring in part and dissenting in part), cert. dismissed sub nom. Murel v. Baltimore City Criminal Court, 407 U.S. 355, 32 L. Ed. 2d 791, 92 S. Ct. 2091 (1972). [Footnote omit-ted.]

Within Pfizer v. Apotex, 480 F.3d 1348; 2007 U.S. App. LEXIS 6623; 82 U.S.P.Q.2D (BNA) 1321 , one has the text:

Although an exact definition is elusive, "clear and convincing evidence" has been described as evidence that "place[s] in the ultimate factfinder an abiding conviction that the truth of its factual contentions are highly probable." Colorado v. New Mexico, 467 U.S. 310, 316, 104 S. Ct. 2433, 81 L. Ed. 2d 247 (1984) (internal quotations omitted).

In New Jersey, the Supreme Court of New Jersey has supplied a useful definition of clear and convincing evidence as that which

produce[s] in the mind of the trier of fact a firm belief or conviction as to the truth of the allegations sought to be established, evidence so clear, direct and weighty and convincing as to enable [the factfinder] to come to a clear conviction, without hesitancy, of the truth of the precise facts in issue.

In re Jobes, 108 N.J. 394, 529 A.2d 434, 441 (N.J. 1987)

With these definitions in mind, one has some questions about the safety of linear gadolinium contrast agents.

From ITNonline:

August 29, 2017 — The European Medicines Agency (EMA) issued a final opinion that recommended restricting the use of some linear gadolinium-based contrast agents (GBCAs) and suspending the marketing authorizations of others, while supporting the continued use of macrocyclic GBCAs.

Importantly, the EMA confirmed that “there is currently no evidence that gadolinium deposition in the brain has caused any harm to patients; however EMA has recommended restrictions for some intravenous linear agents in order to prevent any risk that could potentially be associated with gadolinium brain deposition.”

From Eur Radiol. 2018 Apr;28(4):1579-1584. doi: 10.1007/s00330-017-5065-8. Epub 2017 Oct 23:

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) earlier this year recommended to suspend some marketing authorisations for Gadolinium Containing Contrast Agents (GCCAs) based on linear chelators due to the potential risk of gadolinium retention in the human body. These recommendations have recently been re-evaluated by EMA's Committee for Medicinal Products for Human Use (CHMP), and confirmed the final opinion of the European Medicines Agency. This editorial provides an overview of the available GCCAs and summarises the recent evidence of gadolinium retention. Moreover, a critical appraisal of the strengths and limitations of the scientific evidence currently available on gadolinium retention is given.

• EMA recommended suspension of some EU marketing authorisations of four linear GCCAs. • Brain MRI findings indicating gadolinium retention have been confirmed by mass spectrometry. • Current scientific evidence for gadolinium retention has several methodological limitations. • No clear clinical evidence exists indicating that gadolinium retention causes neurotoxicity. • Long-term safety of GCCAs, however, remains unclear.

See also Gadolinium should go: Risk experts want MRI contrast agent pulled off market,

The first committee, the PRAC, found convincing evidence of accumulation of gadolinium in brain tissue many months after the last contrast MRI was performed. (...) It noted deposits had been found in other organs and tissues and non-clinical studies had shown it to be harmful in tissues.

See also Neeley et al., Br J Radiol. July 2016; 89(1063): 20160027. Acute side effects of three commonly used gadolinium contrast agents in the paediatric population

***As to the impact of gadolinium being retained in the brain on LATER brain MRIs, note

Recent papers have demonstrated that gadolinium accumulation with concomitant T1 shortening
can be seen in the brains of patients who have received multiple doses of gadolinium contrast.
The effect is most noticeable in the globus pallidi, thalami, pons, and dentate nuclei.
The magnitude of the effect is proportional to the cumulative lifetime dose administered
and occurs without renal or hepatic dysfunction.


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