United States District Court, N.D. Oklahoma
IN RE GENENTECH, INC., HERCEPTIN (TRASTUZUMAB) MARKETING AND SALES PRACTICES LITIGATION
OPINION AND ORDER
TERENCE C. KERN UNITED STATES DISTRICT JUDGE.
the Court is the Amended Motion for Summary Judgment Based on
Federal Preemption (Doc. 201) filed by defendant Genentech,
Inc. (“Genentech”). Plaintiffs oppose the motion.
manufactures, markets and distributes Herceptin®
(hereafter, “Herceptin”), a biologic drug used to
treat breast cancer. Plaintiffs are cancer treatment
providers who have purchased Herceptin for treatment of their
patients. Plaintiffs do not challenge the efficacy or safety
of the drug, but contend that Herceptin's labeling is
misleading because, although the Herceptin label states that
each vial contains 440 mg of Herceptin at a concentration of
21 mg/mL, not every vial contains that amount or more. They
assert California state law claims for breach of express and
implied warranties and unjust enrichment, and they seek
actual damages, costs and attorneys' fees. Doc. 45 at
13-20. Genentech, in its Motion for Summary Judgment,
contends that Plaintiffs' claims are preempted by federal
law gives the Food and Drug Administration
(“FDA”) the authority and responsibility to
regulate prescription drugs. See 21 U.S.C. § 301 et seq.
The FDA regulates virtually every aspect of the
manufacturing, distribution, evaluation and labeling of drugs
marketed and sold in the United States. See Bruesewitz v.
Wyeth LLC, 562 U.S. 223, 237 (2011) (noting pervasive
regulation of vaccine licensing). The FDA drug approval
process is “onerous and lengthy.” Mutual
Pharm. Co., Inc. v. Bartlett, 570 U.S. 472, 476 (2013).
Biologics such as Herceptin are
similarly regulated. See 21 U.S. § 321(g)(1). Before a
biologic product can be distributed, the FDA must approve the
sponsor's biologic license application
(“BLA”). 21 U.S.C. § 355(b), 42 U.S.C.
§262(a). The BLA contains “specifications”
for the product, which establish criteria for determining
whether each lot of the biologic satisfactorily conforms to
the drug product, as approved by the FDA. 21 C.F.R. §
211.165(a). It also includes data from studies showing that
the product meets prescribed requirements for safety, purity
and potency; a full description of manufacturing methods;
data establishing product stability; samples of the product,
labeling, and containers; and summaries of product test
results. Id., §§ 601.2(a), 600.3(kk).
Manufacturers of biologic products are required to test each
lot of the product for, inter alia, potency, safety, purity
and sterility. Id., §§ 610.10, 610.12-14.
If a lot does not meet the specifications, it cannot be
distributed to the public and must be rejected. Id.,
will approve a BLA only if it determines that the
manufacturer's biological product and facilities comply
with federal regulations. Id., § 601.4.
Essentially, a biologics license reflects the FDA's
determination that the product is safe, pure and effective,
and that the manufacturer's facilities and processes are
adequate to meet these high standards. Id., §
biologic product's accompanying labeling must also
conform to federal law. 21 U.S.C. §§ 331(a), 352;
21 C.F.R. § 601.2(a). The FDA will approve a BLA only if
it finds that the drug is “safe for use” under
the conditions “prescribed, recommended, or suggested
in the proposed labeling, ” and it will approve the
labeling only if it is not “false or misleading in any
particular.” 21 U.S.C. § 355(d)(1) & (7).
applicants must notify the FDA about “each change in
the product, production process, quality controls, equipment,
facilities, responsible personnel, or labeling established in
the approved license application(s).” 21 C.F.R. §
601.12(a). Prior FDA approval is usually required for
labeling changes, particularly if the proposed change would
affect the information that must appear in the Highlights of
Prescribing Information section of the physician package
insert. Id., § 601.12(f)(1) (citing §
Statement of Undisputed Material Facts
to thirty percent of breast cancers are known to have
amplification of a growth factor receptor gene known as HER2,
and women whose breast cancers have a high level of
expression of this gene have a shortened survival rate. Doc.
201-2, Def. Ex. 2 at 7. Herceptin- known generically as
trastuzumab-is a prescription drug that helps stop the
cancer's growth by targeting HER2 protein. Doc. 201-1,
Def. Ex. 1 at 2. Trastuzumad's effect in fighting this
aggressive form of cancer has been described as
“dramatic, ” and trials have shown that addition
of the drug to chemotherapy “resulted in a remarkable
50% reduction in disease recurrence compared with patients
receiving chemotherapy alone.” Doc. 201-3, Def. Ex. 3
at 3, Korkaya, H., et al., HER2 and Breast Cancer Stem
Cells: More than Meets the Eye, 73 Cancer Research
3489-93 (June 15, 2013)).
is a biologic product produced from living organisms-namely,
Chinese hamster ovary cells that have been genetically
modified to produce trastuzumab, the active ingredient. Doc.
201-5, Def. Ex. 5, Dec. of Dr. David T. Lin, ¶30; Doc.
201-6, Def. Ex. 6, Dec. of Dana L. Swisher, ¶¶ 5-7.
Its production begins in large bioreactor tanks with modified
cells replicating in a culture medium and producing
trastuzumab. Id., Swisher Dec., ¶ 7.
Eventually, the protein trastuzumab is harvested from the
cells, a process involving several purification steps to
remove cell debris and other unwanted elements. Id.
The resulting protein solution is referred to as the
“drug substance.” Id. The drug substance
is tested to ensure the protein concentration is within the
FDA-approved range of 25 milligrams per milliliter (mg/mL),
plus or minus 1 mg/mL. Id., ¶ 8. If the drug
substance concentration is outside the approved range, the
batch is rejected. Id. If it is within the approved
range, it is frozen for storage and shipping. Id.
of frozen Herceptin drug substance are shipped to
manufacturing facilities, where they are thawed and tested
again to ensure the concentration is still within the
FDA-approved range of 25 mg/mL ± 1mg/mL. Id.,
¶9. From there, one or more tanks of Herceptin substance
may be pooled. Id. Generally, the next step prior to
filling is sterile filtration. Id., ¶10. During
this step, the drug substance passes through a
sterilization-grade filter and on to the fill line.
Id. The drug substance is then filtered, sterilized
and dispensed into glass vials by filling machines.
Id., ¶ 11. The target fill weight for each vial
is 17.92 grams, but the FDA-approved acceptable outer range
is 17.56 to 18.28 grams, i.e. 17.92 g ± 2%.
Id. A range around the target fill weight of 17.92
grams is necessary because the filling equipment is incapable
of filling every vial with precisely 17.92 grams.
vials of drug substance are lyophilized or freeze-dried,
removing most of the water and leaving what is known as the
Herceptin “cake, ” comprised of the dry solid
protein and some inactive ingredients. Id.,
¶12. The FDA-approved specification for protein content
of the drug product is 440 mg± 35mg/mL per vial.
Id., ¶12. After the vials are filled and
sealed, sample vials are submitted to Quality Control, where
they undergo final testing prior to release for distribution.
Id., ¶13. The sample vials are identified in
the Certificate of Analysis (“COA”). Id.
The protein content of the vials is tested in accordance with
protocol Q12398. Id. ¶¶13, 16.
the precise concentration of the drug substance and the
precise fill weight varies from batch to batch, the weight of
the Herceptin cake in each vial will also vary in a range
around 440 mg. Id., ¶ 14. When shipped, each
vial of Herceptin is accompanied by a vial of sterile water
that providers use to dissolve the powder cake-a process
known as reconstitution. Id., Doc. 201-1, Ex. 1,
Highlights of Prescribing Information.
approved the BLA for Herceptin on September 25, 1998. Doc.
201-4, Def Ex. 4. The BLA provides for Herceptin drug
substance concentrations within a range of 25 mg/mL ±
1mg/mL and drug product levels within a range of 440 mg
± 35 mg. Id. The FDA also approved Herceptin
labeling that claimed 440 mg per vial, recognizing in
subsequent correspondence with Genentech that the
“expected recovery from each vial is approximately 19
mL or 400 mg.” Doc. 377-1, Def. Ex. 13. Additionally,
in 1999, the FDA drafted a letter to providers explicitly
referring to the fact that the vials were designed to deliver
400 mg. Doc. 201-5, Def. Ex. 5, Lin Dec, ¶¶47-49
(citing Def. Ex. 13, supra). U.S. Pharmacopeia
(“USP”) General Chapter ˂905˃,
Uniformity of Dosage Units, provides for an
allowable variation of 15 percent from the stated weight.
Id., Lin Dec, ¶ 29 and Ex. D thereto, p. 494,
own data show that:
• Herceptin drug substance concentrations have always
complied with the FDA-approved range of 25 mg/mL ± 1
• Herceptin drug product levels always complied with the
FDA-approved range of 440 mg± 35 mg.
368, Pls.' SOF 5, 10, 26.
term “nominal” in prescription drug labeling
refers to a “theoretical” amount, signaling that
the actual amount in each vial will vary. Doc. 201-5, Def.
Ex. 5, Lin Dec., ¶ 36; Doc 377-2, Def. Ex. 14 at
Prescribing Information states that Herceptin is shipped in
multi-dose vials “nominally containing 440 mg Herceptin
as a lyophilized, sterile powder.” Doc. 201-1, Def. Ex.
1, Highlights of Prescribing Information at 1. Similarly, the
carton for each vial states that “the nominal content
of each HERCEPTIN vial is 440 mg Trastuzumab.”
Id., Doc. 201-7, Def. Ex. 7. This description in
labeling is consistent with the FDA-approved specification of
440 mg ± 35 mg and the variability permitted under FDA
Herceptin carton and vial labels state that reconstitution
will “yield a multiple-dose solution containing
approximately 21 mg/mL Trastuzumab.” 201-7, Def. Ex. 7;
Doc. 201-8, Def. Ex. 8. The concentration is
“approximately” 21 mg/ml because the actual
concentration depends on the amount of Herceptin in each
vial, which varies, and the amount of sterile water a
provider injects during reconstitution, which also varies.
Doc. 201-5, Def. Ex. 5, Lin Dec., ¶¶ 38-40, 43.
Additionally, each vial of Herceptin contains a residual and
variable amount of moisture-up to three percent-that may be
lost over time due to absorption by the stopper on the vial.
Id., ¶ 33.
each year from 2000 through 2008, a majority of the Herceptin
batches released in the United States contained at least 440
mg of trastuzumab. Doc. 368 at 16, Pls. SOF 10. In 2000,
2001, and 2006, more than 82 percent of Herceptin batches
contained at least 440 mg of trastuzumab, and in 1998 and
2005, 100 percent of batches met or exceeded the label claim.
Id. Pls.' SOF 11. However, the proportion of
batches containing at least 440 mg of trastuzumab dropped
below 50 percent by 2009 and has not exceeded 50 percent
since then. Id., Pls. SOF 10. Only one of the 125
batches tested in the three-year period of 2012-2014
contained at least 440 mg of trastuzumab per vial, and in
2012 and 2014, none of the 89 Herceptin batches tested
contained 440 mg or more. Id., Pls. SOF 10-11, 14.
Nevertheless, at no time from 1998 to 2017 did any
batch contain less than the lower limit of 405 mg of
trastuzumab approved by the FDA. Doc. 201-6, Def. Ex. 6,
Swisher Dec., ¶14.
the FDA's initial approval of Herceptin on September 25,
1998, and February 3, 2017, the FDA approved more than 10
supplemental applications from Genentech proposing revisions
to the Herceptin Prescribing Information without ever
directing Genentech to change the description of net weight
or concentration. Doc. 201-5, Def. Ex. 5, Lin Dec., ¶
50. For example, on October 12, 2012, Genentech submitted a
prior approval supplement to the FDA requesting approval for
the Hillsboro Technical Operations manufacturing facility to
manufacture 440 mg vials. Doc. 377-13, Def. Ex. 25. The
supplement included data on three qualification batches of
Herceptin drug product, and the protein content for all three
batches was below 440 mg. Doc. 377-14, Def. Ex. 26. The FDA
approved the supplement on February 14, 2013. Doc. 377-15,
Def. Ex. 27. On June 6, 2014, the FDA approved a supplement
for a manufacturing facility, that also included data on
three qualification batches for which the protein content was
below 440 mg. Doc. 377-16, Def. Ex. 28.
March 2014, the FDA published a Draft Guidance for Industry
Allowable Excess Volume and Labeled Vial Fill Size in
Injectable Drug and Biological Products. Doc. 370-31, Pls.
Ex. 31. The Draft Guidance stated that “with respect to
allowable excess volume, the sponsor/applicant of drugs in
ampules or vials, intended for injection must follow the
requirements in 21 CFR 201.51(g).” The Draft
Guidance was finalized in June 2015. Doc. 370-34, Pls. Ex.
October 30, 2014, after the FDA received complaints from an
unidentified oncology pharmacy specialist and other oncology
institutions about the inability of end users to withdraw a
full 21 mL volume from a vial of Herceptin, FDA and Genentech
representatives conducted a teleconference. Doc. 201-9, Def.
Ex. 9 at 2. During the teleconference, the FDA asked
Genentech to provide a formal written response addressing the
FDA's concerns regarding labeling of the Herceptin 440 mg
multi-dose vial. Id. at 4. The FDA also proposed that
in order to provide further clarity, the Herceptin 440 mg
label should be revised to reflect the maximum amount that
can be withdrawn from the vial, in accordance with the
agency's interpretation of 21 C.F.R. § 201.51(g), as
reflected in the 2014 Draft Guidance for Industry: Allowable
Excess Volume and Labeled Vial Fill Size in Injectable Drug
and Biological Products, March 2014. Doc. 201-9, Def. Ex. 9,
Resp. to FDA's Comments Regarding Herceptin 440 mg
Multi-Dose Vial Fill at October 3, 2014 Teleconference, at
a month later, in its December 5, 2014, response, Genentech
proposed the addition of language stating that recovery of
Herceptin may be lower when the 440 mg vial is used as a
multi-use vial. Id. at 4-5. The FDA did not reply to
Genentech's response until February 3, 2017-more than two
years after Genentech submitted proposed labeling changes.
Doc. 201-10, Def. Ex. 10. During that time, in April 2015 and
March 2016, it approved two unrelated labeling supplements
that did not change the way net contents were described. Doc.
201-5, Def. Ex. 5, Lin Decl., ¶¶ 58, 71 n. 68.
February 3, 2017, Advice Letter, the FDA disagreed with
Genentech's proposed labeling changes and directed the
company to submit a plan to address revision of the labeling
from 440 mg per vial to 420 mg per vial on all labeling and
to prepare a communication plan to educate healthcare
practitioners on the labeling change. Doc. 201-10, Def. Ex.
submitted a response to the letter on February 10, 2017.
Id., Doc. 201-11, Def. Ex. 11. In its response,
Genentech agreed to “update the Herceptin USPI of the
previously referred to as the ‘440 mg' strength to
the 420 mg strength that reflects the minimally recoverable
volume for the Herceptin vial presentation;” to
“commit to providing updated carton/container labeling
as a Post-Marketing Commitment, ” and to “provide
an updated communication plan at the time the revised
carton/container are submitted.” Id. The FDA
approved the supplemental BLA the same day. Id.,
Doc. 201-12, Def. Ex. 12.
Genentech were required to ensure that every vial contained
exactly (or at least) 440 mg of Herceptin, it would have to
either change its manufacturing processes-including filling
and lyophilization, and possibly the amount of diluent for
reconstitution-and seek FDA approval for a protein content
specification that deviates from the currently approved range
of 440 mg ± 35 mg., or-as Plaintiffs suggest-stop
selling vials that fail to meet the approved range. Doc. 201,
Def. Ex. 6, Swisher Dec., ¶ 15; Doc 368 at 68-69.
manufacture of Herceptin is an aseptic (sterile) processing
operation, and substituting steps in an aseptic processing
operation is a “major change” requiring FDA
approval. Doc. 377, Ex. 17, U.S. BLA Herceptin,
GENE-FL0000000527-529, 55521; C.F.R.§ 601.12(b)(2)(vi).
Moreover, changing the target fill rate, which is an
in-process specification identified in the BLA, also requires
prior FDA approval. Doc. 377, Def. Ex. 14, Lin Dep. at
151:1-25; 21 C.F.R. § 601.12(b)(2)(i) (referencing
changes in qualitative or quantitative formulation or in the
specifications provided in the approved application). See
also 21 C.F.R. §211.110(a)(), (b) (referencing
“in-process specifications” applicable to drug
product “weight variation”); Ex. 22, FDA Guidance
for Industry, Changes to an ...