When last we tuned into the In re Incretin-Based Therapies (“Incretin”) multi-district litigation, the Ninth Circuit had just undone a preemption-based dismissal – but only on procedural grounds. As we discussed, here, the Ninth Circuit avoided the merits, but ruled that the MDL court had erred in “rel[ying] on Buckman [Co. v. Plaintiffs Legal Committee, 531 U.S. 341 (2001)] to circumscribe discovery.” In re Incretin-Based Therapies Products Liability Litigation, 721 F. Appx. 580, 582 (9th Cir. 2017). The Ninth Circuit thus allowed the Incretin plaintiffs to rummage through the defendant’s submissions to the FDA in search of “newly acquired information” that might have justified an unpreempted warning based claim, notwithstanding FDA approval of all the labels of the relevant products, including the omission of warning about a purported pancreatic cancer risk. Id. at 583. As we discussed, the Ninth Circuit relied on Wyeth v. Levine, 555 U.S. 555 (2009), for the “clear evidence test” that defined what was relevant, holding that:
Uncertainty about whether the FDA considered the “new safety information” and whether it would have altered the FDA’s conclusion establishes that a disputed issue of material fact should have prevented entry of summary judgment on the defendants’ preemption claim.
721 F. Appx. at 584. The decision also relied on Stengel v. Medtronic Inc., 704 F.3d 1224, 1233 (9th Cir. 2013) (en banc), to limit the scope of preemption under Buckman. 721 F. Appx. at 583.
So Incretin was reversed and remanded for additional discovery on FDA’s repeated determinations that these drugs (Byetta, Januvia, Janumet, and Victoza) – which are mainstays in treatment of diabetes – had not been shown to cause pancreatic cancer. In the interim, the United States Supreme Court reformulated Levine in Merck Sharp & Dohme Corp. v. Albrecht, 139 S. Ct. 1668 (2019), and the Arizona Supreme Court spanked the Ninth Circuit for improperly expanding that state’s law in Stengel. See Conklin v. Medtronic, Inc., 431 P.3d 571, 578 (Ariz. 2018) (“We disagree with Stengel”).
If at first, you don’t succeed….
After three years, and who knows how many more millions of dollars and thousands of hours expended, the Incretin defendants tried again to get the action dismissed – and once again succeeded. The lengthy opinion, In re Incretin-Based Therapies Products Liability Litigation, ___ F. Supp.3d ___, 2021 WL 880316 (S.D. Cal. March 9, 2021), unloaded the same one-two punch on the plaintiffs that we blogged about the last couple of weeks: preemption and Daubert. We’re splitting this one up, too, and covering the Incretin preemption rulings today.
As for preemption, Incretin is one more reason why we think that, on the whole, Albrecht is a big win for the defense side. As you read this post, think about how easy it would have simply to dismiss a lot of these issues as “fact questions” prior to Albrecht. As regular readers of this Blog know, and as the Incretin court pointed out, “in [Albrecht], the Supreme Court clarified that courts should treat the question of whether clear evidence is met ‘not as a matter of fact for a jury, but as a matter of law for the judge to decide.’” 2021 WL 880316, at *3 (quoting Albrecht, 139 S. Ct. at 1679).
Albrecht held that when conducting a preemption analysis, a judge may have to resolve contested brute facts, such as whether a manufacturer submitted all material information to the FDA because such factual questions are part and parcel of the broader legal question and do not warrant submission to a jury. Thus, the Court will determine whether the FDA’s regulatory scheme and state law failure-to-warn requirements “irreconcilably conflict” and resolve issues regarding materiality along the way.
2021 WL 880316, at *4 (citation omitted).
The fundamental reason that the Incretin defendants won is why we have preemption in the first place. The FDA has been all over the purported link between these diabetes drugs and pancreatic cancer since day one. Time and time again, the Agency as evaluated the relevant science, and every time it has concluded that this asserted “risk” is fictitious. In finding FDA’s actions preemptive, Incretin weighed in on many of the major post-Albrecht controversies. Plaintiffs got blasted with both barrels – their claims were preempted both for lack of any “newly acquired information” that would allow a “changes being effected” (“CBE”) label change in the first instance, and because there was “clear evidence” that the FDA would have rejected such a label change if it had been permissible.
We start with the FDA’s prerequisites to the availability of CBE label changes.
[W]hile a manufacturer bears responsibility for maintaining the adequacy of its labels for as long as the drug is on the market, it “cannot propose a change that is not based on reasonable evidence.” There must be sufficient evidence of a causal association between the drug and the information sought to be added.
Incretin, 2021 WL 880316, at *3 (Albrecht citations omitted).
Opposing preemption, the Incretin Plaintiffs opened with their by-now-familiar assertion that “Albrecht limited preemption to cases where the manufacturer has proposed a label change.” Id. at *4. Not so in the least. While a manufacturer-generated label supplement certainly makes preemption easier, the fact remains that “this general principle cannot be applied in every case” because “manufacturers cannot propose a change that is not based on reasonable evidence.” Id. Moreover, Albrecht specifically declined to decide any “question of disapproval method.” Id. (Albrecht citations, in both instances omitted). Because the Incretin defendants, unlike the defendant in Albrecht, “maintain that the CBE regulations did not permit them to change their labeling,” the issues Albrecht resolved were “distinguishable.” Id. Thus, “the Court decline[d] to find that Albrecht forecloses preemption merely because there was no CBE or other label change request in this case.” Id. (citations omitted). Down goes one frequent plaintiff-side argument.
Thus, Incretin “agree[d] with Defendants that whether federal and state laws irreconcilably conflict entails the threshold inquiry of whether there is ‘newly acquired information’ to support a CBE submission.” 2021 WL 880316, at *5 (citing Albrecht). Only “if the answer is yes” to that question, does it become necessary to consider the “clear evidence” issues addressed by Albrecht. Id. “As such, the preemption framework provides two potential avenues by which Defendants may establish that federal and state laws irreconcilably conflict.” Id.
With respect to each of the four drugs at issue, Incretin concluded, first, that the requisite “newly acquired information” did not exist. Much of this discussion is intensely product specific, so we will simply hit the legal highlights. Plaintiffs’ basic problem throughout was that the FDA has been “investigating reports of possible increased risk” of various pancreatic conditions, including pancreatic cancer, since 2009. 2021 WL 880316, at *5-6. Here’s what the FDA concluded:
- 2009: “[L]ittle inference for risk is appreciated from review of spontaneous reports of pancreatic cancer” and “a causal association between exposure to one of these agents and pancreatic cancer is indeterminate.” Id. at *5.
- 2013: “FDA also stated that it had not concluded that incretin mimetics cause or contribute to the development of pancreatic cancer, and advised health care professionals to continue following the prescribing recommendations in the drug labeling.” Id.
- 2013: “FDA official reaffirmed that adverse event data was “less suitable for detecting relatively more common events with long latency periods” such as pancreatic cancer,” and “incretin-based drugs were not associated with “[o]vert pancreatic toxicity or pancreatic neoplasms.” Id. at *6.
- 2014: Four FDA officials published an article in the New England Journal of Medicine (“NEJM”) on the results of “a comprehensive evaluation” of “more than 250 toxicology studies, as well as a review of clinical safety databases and the results of cardiovascular outcome trials.” They “concluded that ‘assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer . . . are inconsistent with the current data.’” Id. (citing NEJM article).
- 2014: FDA denied a citizen petition raising the same pancreatic cancer risk claims. “[I]ts review [of] 49 cases recovered from FAERS [a voluntary adverse event reporting database] . . ., found no new evidence regarding the risk of pancreatic carcinoma . . . that would support any changes to the current approved labeling.” Id.
- 2014: FDA concluded that as to “[r]isk for pancreatic cancer,” “animal, observational, and clinical trial data reviewed by FDA to date have not supported a causal association.” Id. at *7. A new drug was therefore approved “without requiring a pancreatic cancer warning.” Id. at *6.
- 2017: FDA determined that “data generated” in a new study “do not appear to substantively alter the original FDA conclusions regarding the lack of sufficient information to conclusively determine whether long term exposure to [the drugs at issue] increase the risk of pancreatic cancer.” Id.
- 2019 & 2020: In connection with still more drug approvals, “for the last several years, the FDA has approved new incretin-based medications without requiring a reference to pancreatic cancer in their labels.” Id. at *7.
- Through 2020: “Despite their close monitoring and comprehensive evaluation of the pancreatic safety of incretin-based therapies, the FDA has never required Defendants to include a pancreatic cancer warning in their drug labeling.” Id.
As for the plaintiffs’ purported “newly acquired information,” applying the FDA’s definition (see 21 C.F.R. §314.3), Incretin concluded that some of it was not “new,” other items didn’t qualify as “information,” and none of it qualified as both. Plaintiffs, for their part, nitpicked practically everything that was ever submitted to the FDA. Plaintiffs relied on foreign regulatory activity. Id. at *8-9. However, this material was “preliminary,” “did not rely on information different” than what the FDA had, and ultimately reached the same conclusion as the FDA – being “that there is not enough evidence at this time to confirm a link between incretin-based therapies and pancreatic cancer.” Id. at *9. Thus, this material failed on the facts. It also failed on the law: “Foreign drug labeling is the product of different and distinct regulatory standards and decisions” so that “warnings approved for a foreign label are not in and of themselves newly acquired evidence.” Id. (quoting Ridings v. Maurice, 444 F. Supp.3d 973, 994 (W.D. Mo. 2020)).
Plaintiffs also criticized studies submitted, or not submitted, to the FDA. The minutiae in their nitpicking was dramatic, and frankly was exactly the kind of second-guessing of FDA submissions that the Supreme Court intended to stop in Buckman Co. v. Plaintiffs Legal Committee, 531 U.S. 341 (2001). But because of the Ninth Circuit’s prior opinion, the once-bitten Incretin court stayed away from Buckman entirely, not citing that case at all, except to describe the prior Ninth Circuit opinion. 2021 WL 880316, at *4.
How’s this for nitpicking? Plaintiffs raised: (1) supposed exclusion of studies where the reason for the exclusion was shared with the FDA, id. at *9; (2) excluding adverse events that were, in fact, reported, id.; (3) supposed omission of studies about entirely different drugs, id.; (4) omission of “nonclinical studies” in mice and baboons, id., at *9-10; (5) claimed omissions with “no explanation as to the data’s source, context, or meaning,” id. at *10; (6) their own expert’s “re-analysis” of certain “images” that was “generated in preparation for litigation” and was “unsupported by any published research,” id.; (7) supposedly “misleading” summaries of studies submitted to the FDA that in fact had the “same” number of relevant events while analyzing “different data sets,” id. at *11; (8) purported “cherry-picking” in a published study when, in fact “all” of the information was “available for FDA scrutiny,” id.; (9) alleged deficiencies in “study protocols [that] were submitted to and approved by the FDA,” id.; (10) omission of a “tumor” event that was, in fact, “benign,” id.; (11) more summaries, despite their “context . . . [being] plainly stated in the document,” id.; (12) animal studies without any expert explanation of why they were significant, and that made “similar observations” to other studies that had been “found insufficient for a causal link by the FDA,” id. at *12; (13) a “post-hoc secondary . . . analysis” in which the “data would not be sufficient to reach any meaningful conclusions,” id.; (14) adverse events in animal studies that studied different organs and thus “assessed data different from [the drug’s] pancreatic safety,” id.; (15) supposed “burying” of data from a study that was not only “disclosed” to the FDA by “publicly posted” on its website, id. at *13; and (16) criticism of a cancer “background rate” from a study involving a different drug, id.
In sum, the Incretin plaintiffs plumbed the depths of the defendants’ FDA submissions (in direct violation of Buckman’s warning that “[a]pplicants would then have an incentive to submit a deluge of information that the [FDA] neither wants nor needs, resulting in additional burdens on the FDA’s evaluation of an application,” 531 U.S. at 351) and raised an olio of irrelevant, immaterial, and often simply false criticisms of those submissions. Pre-Albrecht, the sheer volume of minutiae might have led a court to throw up its hands and exclaim “fact question” – but no longer. The debunking of such pseudoscientific flotsam and jetsam is precisely the sort of factual analysis that Albrecht requires courts to undertake themselves with respect to preemption motions. Incretin concluded, as to newly acquired information:
[T]he FDA’s CBE regulations are designed to ensure that only scientifically justified information is provided in the labeling for an approved product. The regulations reflect the FDA’s cautious approach to drug labeling, recognizing that exaggeration of risk, or inclusion of speculative or hypothetical risks, could discourage appropriate use of a beneficial drug or decrease the usefulness and accessibility of important information by diluting or obscuring it. . . . [T]he FDA, through its own evaluation and armed with information from Defendants and other sources, considered the specific issue raised by Plaintiffs in this case: the pancreatic safety of incretin mimetics. At no point in its years-long monitoring of these drugs did the FDA require Defendants or any other manufacturer of incretin-based therapies to add a pancreatic cancer warning to its labels.
Id. (Albrecht citations and quotation marks omitted). Instead, the FDA did quite the opposite. Its “finding of an indeterminate causal link between pancreatic cancer and incretin mimetics is not reasonable evidence of a causal association.” Id. at *14. “[I]nconclusive” data cannot be considered “newly acquired information” that would allow a unilateral label change. Id. “[N]one of the purported new safety information reflects well-grounded scientific evidence of causal association that would have made the risk of pancreatic cancer apparent to Defendants.” Id. Therefore, all plaintiffs’ claims were preempted.
But Incretin didn’t stop there. It opted for a belt-and-suspenders approach, also concluding that the record established “clear evidence” that, in any event, the FDA wouldn’t have permitted the label change plaintiffs demanded. 2021 WL 880316, at *14-17. Once again, Incretin is significant in rejecting the other side’s arguments that sought to use Albrecht to roll back preemption.
And here’s an important preemption practice point: The absence of any ”newly acquired information” (step one) also had effect of establishing the obverse proposition in step two (clear evidence) – that under Albrecht, “[d]efendants fully informed the FDA of the justifications for a pancreatic cancer warning.” Id. at *14. If nothing “new” of any significance was withheld, then necessarily the FDA was “fully” informed.
Plaintiffs also argued that the Incretin defendants couldn’t point to “any agency action carrying force of law.” 2021 WL 880316, at *14. They lost again. Everything that the FDA did was “within the scope of the authority Congress has lawfully delegated.” Id. In particular, the Agency’s “[a]ssessment and formal rejection of the citizen petition . . . communicated the FDA’s official position that assertions concerning a causal association between pancreatic cancer and incretin-based drugs were inconsistent with the current data.” Id. So was the NEJM article: “Four FDA officials authored the Assessment,” it was “identified as coming from [CDER],” it was published in “the top medical journal in the world,” and it “lack[ed] the disclaimer required when publications of FDA employees do not necessarily reflect the opinions of the agency.” Id.
Albrecht did not purport to limit the means that FDA could legitimately use to communicate rejection of a litigation-inspired warning change. Id. at *15. While, according to FDA regulations, statements by FDA employees “do not necessarily represent the formal position of FDA,” id., (quoting 21 C.F.R. § 10.85(k)), “by its own text, th[at] regulation contemplates that other “employee-written statements” can be “representative of the FDA’s formal position.” Id. Given the number of FDA authors, the prestige of the publication, and the lack of a disclaimer, the NEJM article was sufficient to qualify as a “formal” agency position. Id. (“the Court finds that the 2014 [NEJM article] amounts to ‘other agency action carrying the force of law.’” (quoting Albrecht)).
Nor could plaintiffs claim that the FDA’s rejection of a scientific basis for a pancreatic cancer risk wasn’t sufficiently “communicated” to the defendants. The NEJM article “specifically communicated that the FDA believed that current knowledge is adequately reflected in the product information or labeling.” Id. at *16 (citation and quotation marks omitted). Even plaintiffs’ own expert testified that “[i]t would be a little absurd for the FDA to allow the addition of a pancreatic cancer warning after its robust and comprehensive evaluation of that specific risk did not yield evidence of causal association.” Id. (citation and quotation marks omitted).
Further, standard language that the FDA would “continue to monitor” the issue did not deprive its conclusion of sufficient finality. The FDA always “monitors” evolving science. This was another plaintiff-side argument that proved too much, and would essentially eliminate preemption.
[A]s a matter of routine practice, FDA continuously monitors every medication for new or evolving information as long as a drug is on the market.” The Supreme Court acknowledged the same in [Levine] when it noted that the CBE regulation accounts for the fact that risk information accumulates over time and that the same data may take on a different meaning in light of subsequent developments. . . . As such, the Court rejects Plaintiffs’ contention that “the FDA’s rejection of the petition did not inform the manufacturers of incretin mimetics that any proposed pancreatic cancer warning would be rejected.
2021 WL 880316, at *17 (citations and quotation marks omitted).
Incretin also invoked 21 U.S.C. §355(o)(4)(a), conferring on the FDA “authority to mandate a label change if it learns of new safety information that should be included in the labeling of a drug.” Id. For that reason “[t]he Court also disagree[d]s with Plaintiffs’ claim that FDA inaction can never support a preemption finding.” Id. Given the FDA’s obligation to order label changes on its own volition when “new safety information” warrants, “the FDA’s silence on this issue is highly relevant to its preemption analysis.” The record showed sustained FDA interest in the purported risk at suit – as well as the Agency’s continued approval of labeling that did not contain the sort of cancer warnings the these plaintiffs demanded.
Put another way, the Court cannot simply ignore the FDA’s demonstrated commitment to actively and continuously monitoring the pancreatic safety of incretin mimetics. . . . Given the specific attention the agency has given to the very matter at issue in this litigation, the Court finds the FDA’s approval of new incretin-based drugs, as well as its continued approval of other label changes to the medications at issue − without requiring a pancreatic cancer reference in the label − only further supports the Court’s preemption findings.
Id. at *17 (citing Ridings).
Incretin thus stands as a comprehensive rejection of the other side’s attempts to use Albrecht as a means of rolling back implied preemption in the prescription drug arena. It confirms that two routes to preemption exist – lack of newly acquired information and “clear evidence.” The opinion enforces FDA standards for such information, rejecting information no different than what the FDA has, “inconclusive” information, and a wide variety of minutiae that plaintiffs’ Buckman-ignoring, second-guessing of the defendants’ FDA submissions dredged up. On clear evidence, Incretin strongly rejects the argument that preemption only exists where the defendant itself submitted an unsuccessful label change, recognizes that FDA rejection of citizen petitions is a formal FDA action with preemptive effect under Albrecht, and holds that FDA “inaction” in situations where the FDA is actively monitoring the relevant science, is in and of itself preemptive. On both, Incretin recognizes that the absence of “newly acquired information” supporting a CBE label change also establishes that the FDA was “fully informed” under Albrecht‘s reformulated “clear evidence” test.
We’ll address the Daubert rulings in Incretin – excluding all seven of the P-side experts that the defendants challenged – in a future blogpost.