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We disagree with plenty of courts on plenty of things, but most of the time it’s at least arguably just a conflict with one of our pro-defense views.  But occasionally, very occasionally, we run into a decision that’s just plain wrong on some factual or legal aspect.  Blackburn v. Shire U.S., Inc., 2022 WL 16729466 (11th Cir. Nov. 7, 2022) (thankfully unpublished), is such a decision.

We last mentioned the Blackburn litigation, here, where we were not very happy about the Alabama Supreme Court’s loosening of the warning causation standard applicable that state’s learned intermediary rule.  Before that, we discussed the Eleventh Circuit’s certification of those learned intermediary questions to Alabama’s highest court.

We’re not rehashing those decisions.  They are what they are.  But one thing they weren’t was completely dispositive of the Blackburn appeal, which we will hereafter designate “Blackburn III” to avoid confusion.  As one would expect, the Alabama Supreme Court decided only questions of Alabama state law in Blackburn II, leaving federal preemption issues for the Eleventh Circuit to decide on remand.  That occurred in the latest, Blackburn III decision – and that decision simply got a significant aspect of the FDCA regulatory scheme dead wrong.

In Blackburn III’s haste to render a pro-plaintiff ruling on preemption under Merck Sharp & Dohme Corp. v. Albrecht, 139 S. Ct. 1668 (U.S. 2019), it simply misconstrued the FDA’s rather (that’s an understatement) complicated supplemental application/changes being effected regulation, 21 C.F.R. §314.70, as it pertained to the “highlights” section of prescription drug labeling – something we know a little about, since in 2019 we wrote a rather lengthy blogpost about highlights and prescription drug preemption here.

The defendant in Blackburn III made a preemption argument similar to what we had hypothesized might work in our 2019 post, contending “that it was precluded from changing the warning because it was contained in the “Highlights” section of the [drug’s] label.”  2022 WL 16729466, at *3.  The defendant relied upon 21 C.F.R. §314.70(b)(2)(v), which lists three types of label changes that absolutely, positively must be made by prior approval supplement – and since those changes require FDA preapproval, the Mensing independence principle preempts tort claims demanding such changes.  See PLIVA, Inc. v. Mensing, 564 U.S. 604, 620 (2011) (“The question for ‘impossibility’ is whether the private party could independently do under federal law what state law requires of it.”).  That part of the CBE regulation reads:

(b) Changes requiring supplement submission and approval prior to distribution of the product made using the change (major changes).

*          *          *          *

(2) These changes include, but are not limited to:

*          *          *          *

(v) The following label changes:

(C) Any change to the information required by §201.57(a) of this chapter . . . .

21 C.F.R. §314.70(b)(2)(v)(C) (emphasis added).  Sub-sub-sub-subsection (C) references the “highlights” part of the FDA’s general drug labeling regulation, 21 C.F.R. §201.57(a) (“Highlights of prescribing information.”).  Thus, any change to drug “highlights” demanded in a tort case simply cannot be made through a CBE supplement – requiring preemption.

Blackburn III, however, said “no”

But [defendant] overlooks subsection (b)(2)(v)(A), which exempts “[c]hanges in labeling … described in paragraph[] (c)(6)(iii).” Id. §314.70(b)(2)(v)(A).  Subsection (c)(6)(iii), of course, is the very subsection at issue here….

2022 WL 16729466, at *3.  That’s just wrong.  Sub-Subsection (v) doesn’t list exceptions to what the FDA considers “major changes” (requiring FDA preapproval) – but rather, lists examples of such “major changes.”

To establish that error, we’ll quote, with appropriate emphasis, that entire hideously long subsection, which makes clear what’s going on.  We don’t like such long quotations, but the complete language demonstrates that each one of eight types of changes “include[d]” in 21 C.F.R. §314.70(b)(2) is a type of change that could alter a drug’s safety and effectiveness profile – which is the core definition of a “major change” requiring pre-approval:

(b) Changes requiring supplement submission and approval prior to distribution of the product made using the change (major changes).

(1) A supplement must be submitted for any change in the drug substance, drug product, production process, quality controls, equipment, or facilities that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product.

This is the core “major change” definition.

(2) These changes include, but are not limited to:

(i) Except those described in paragraphs (c) and (d) of this section, changes in the qualitative or quantitative formulation of the drug product, including inactive ingredients, or in the specifications provided in the approved NDA;

Major changes “include” these items, the first being changes in drug formula, which obviously can affect its safety and effectiveness.

(ii) Changes requiring completion of studies in accordance with part 320 of this chapter to demonstrate the equivalence of the drug product to the drug product as manufactured without the change or to the reference listed drug;

Alteration of the basis for concluding that two drugs are “equivalent” can affect the safety and effectiveness of the drug claimed to be equivalent.

(iii) Changes that may affect drug substance or drug product sterility assurance, such as changes in drug substance, drug product, or component sterilization method(s) or an addition, deletion, or substitution of steps in an aseptic processing operation;

Sterility is another no-brainer for affecting a drug’s safety and effectiveness.

(iv) Changes in the synthesis or manufacture of the drug substance that may affect the impurity profile and/or the physical, chemical, or biological properties of the drug substance;

Duh. The presence of impurities affects a drug’s safety and effectiveness.

(v) The following labeling changes:

(A) Changes in labeling, except those described in paragraphs (c)(6)(iii), (d)(2)(ix), or (d)(2)(x) of this section;

Label changes obviously can affect drug safety and effectiveness. That’s why we have labels. The regulation also provides certain exceptions, such as “(C)(d)(iii),” which is the CBE exception that Wyeth v. Levine, 555 U.S. 555 (2009), relied upon to limit impossibility preemption.

(B) If applicable, any change to a Medication Guide required under part 208 of this chapter, except for changes in the information specified in §208.20(b)(8)(iii) and (b)(8)(iv) of this chapter; and

Since FDA requires medication guides only for safety reasons, most changes to them can affect safety and effectiveness.

(C) Any change to the information required by §201.57(a) of this chapter, with the following exceptions that may be reported in an annual report under paragraph (d)(2)(x) of this section:

This is the corresponding reference to the “Highlights” section we quoted above.  The FDA considers everything in it to affect safety and effectiveness – with two listed “exceptions.”

(1) Removal of a listed section(s) specified in §201.57(a)(5) of this chapter; and

(2) Changes to the most recent revision date of the labeling as specified in §201.57(a)(15) of this chapter.

These two items – sub-sub-sub-sub-subsections (1-2) − are the only specified “exceptions” to all “Highlights” label changes being considered major changes that affect safety and effectiveness; not “(c)(6)(iii),” which is an exception solely to a separate set of otherwise “major” label changes.

(vi) Changes in a drug product container closure system that controls the drug product delivered to a patient or changes in the type (e.g., glass to high density polyethylene (HDPE), HDPE to polyvinyl chloride, vial to syringe) or composition (e.g., one HDPE resin to another HDPE resin) of a packaging component that may affect the impurity profile of the drug product.

Changes to container childproofing, or that could result in impurities, affects drug safety and effectiveness.

(vii) Changes solely affecting a natural product, a recombinant DNA-derived protein/polypeptide, or a complex or conjugate of a drug substance with a monoclonal antibody for the following:

(A) Changes in the virus or adventitious agent removal or inactivation method(s);

(B) Changes in the source material or cell line; and

(C) Establishment of a new master cell bank or seed.

All of these changes to genetically engineered products could affect their safety and effectiveness.

(viii) Changes to a drug product under an NDA that is subject to a validity assessment because of significant questions regarding the integrity of the data supporting that NDA.

The possibility that the data supporting a drug’s approval may be invalid also obviously affects its safety and effectiveness.

The structure of this subsection − §314.70(b) – thus demonstrates that entire, general CBE exception is not an exception to “highlights” changes being major changes as Blackburn III erroneously held.  Highlights are dealt with separately in sub-sub-sub-subsection §314.70(b)(2)(v)(C), and have only two specified “exceptions.”  Rather, CBEs generally are an exception to §314.70(b)(2)(v)(A), which addresses warnings generally.  The general CBE exception is to the general rule what warning changes are major changes.

If further confirmation is needed that Blackburn III simply made a mistake – reading an exception to one sub-sub-sub-section of §314.70 as being an exception to another example on the same level to which it facially does not apply – that confirmation is found in the CBE part of the regulation.  21 C.F.R. §314.70(c)(6)(iii) contains a parallel exception that expressly specifies that the CBE process for label changes is inapplicable to “highlights”:

(iii) Changes in the labeling to reflect newly acquired information, except for changes to the information required in §201.57(a) of this chapter (which must be made under paragraph (b)(2)(v)(C) of this section), to accomplish any of the following:

(A) To add or strengthen a contraindication, warning, precaution, or adverse reaction for which the evidence of a causal association satisfies the standard for inclusion in the labeling under § 201.57(c) of this chapter. . . .  

Emphasis emphatically added.  The reading that Blackburn III gives to §314.70(b)(2)(v) is further erroneous because effectively nullifies the above emphasized exception to the CBE regulation altogether, contrary to established principles of statutory/regulatory interpretation.

Even further confirmation is found in the FDA’s regulatory history for §314.70(b), which states that:  (1) “CBE supplement procedures are narrow exceptions” to the Agency’s prior approval requirements for label changes; and (2) “Highlights cannot be amended by a CBE supplement.”  73 Fed. Reg. 2848, 2849-50 & 2850 n.4 (FDA Jan. 16, 2008).  Subsequently, while discussing its ill-fated attempt to eliminate generic preemption, FDA repeated that “highlights” are not generally amenable to CBE supplementation.  “Current §§314.70(c)(6) . . . exclude most changes to the information required in the Highlights, which are classified as a “major change” that must be made by a prior approval supplement” unless “specifically request[ed]” or “waived” by the FDA.  78 Fed. Reg. 67985, 67993 (FDA Nov. 13, 2013).

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There’s a lot else we don’t like about the preemption holdings in Blackburn III, and maybe we’ll discuss them further sometime.  However, the point we’re trying to make in this post is that, in trying to sort through an extremely complex FDA regulation, Blackburn III simply erred.  It misconstrued an “exception” to one subpart of the major change portion of §314.70 as applicable to a different subpart that had its own separate exceptions – and not that one.  As a result, its preemption analysis is fatally flawed.  We acknowledge at the outset of this post that a lot of our criticism of judicial opinions on the Blog is a matter of viewpoint.  This one is not.  It’s simply a mistake.  In baseball terminology it would be “E-11.”