Trial Magazine

After a series of U.S. Supreme Court decisions governing the liability of manufacturers of brand-name versus generic drugs, many consumers who use generic drugs have been left without recourse when they are injured. However, these consumers may have viable claims when a generic drug is contaminated because the drug has failed to meet the many conditions under which it was approved.

A contaminant is an unintended product or ingredient that ends up in the drug. Contaminated drug cases may involve generics because the generic manufacturer altered the manufacturing process, which produced the contaminant.¹ Using the recent Valsartan multidistrict litigation (MDL) as an example, here is an overview of how to litigate contaminated generic drug cases and avoid losing the preemption battle.

Mensing

In PLIVA, Inc. v. Mensing, the U.S. Supreme Court held that generic drug manufacturers are not liable for failure-to-warn claims because they are required to maintain the same warning labels as the brand-name drugs.² In other words, because generic manufacturers cannot add or strengthen warnings as brand-name manufacturers do, federal law preempts state law tort claims.

However, in highlighting this duty of sameness, Mensing left open the possibility of claims against a generic manufacturer that fails to make a drug that is the same as its brand-name counterpart. In Mensing, the generic drug manufacturers prevailed in large part by arguing that they did not have the ability to update their warning label due to FDA regulations requiring the label on a generic drug to mirror that of the brand-name drug.

When a generic manufacturer stops making a drug that meets all terms of its approval, meaning the drug is not the same as its corresponding brand-name drug, then the manufacturer has created an entirely new (and unapproved) drug. This new and unapproved drug cannot be required to have the same label as the brand-name drug, as the two products are no longer the same. Under these circumstances, the manufacturer has forfeited the shield of federal preemption—and a plaintiff’s state law claims stemming from injuries related to the contamination do not conflict with the federal regulatory scheme.

Implied Preemption

Mensing is not the only hurdle to consider: Manufacturers in contaminated drug cases may also raise implied preemption defenses based on Buckman Co. v. Plaintiffs’ Legal Committee, which held that the Federal Food, Drug and Cosmetic Act (FDCA) impliedly preempts “fraud on [the] FDA” claims and prohibits private causes of action for this fraud.³ For this reason, consider including language in your complaint expressly indicating that your client’s state law claims exist entirely independently from the federal regulatory scheme and that the plaintiff is not asserting a claim premised on fraud on the FDA.

For example, you might include: “Plaintiffs reference federal law herein not in any attempt to enforce it but only to demonstrate that their state law tort claims do not impose any additional obligations on the Defendants, beyond what is already required of them under federal law.” In other words, these violations of federal law are evidence of negligence and demonstrate that the contaminated product is different from the approved product. All of this would remain the case even if all citations to federal law were removed.

Valsartan: A Case Study

To show how these preemption arguments play out, consider a recent and pending MDL concerning valsartan, the generic version of the hypertension drug Diovan. Several companies manufacture valsartan, which has been on the market since 2012. In July 2018, the FDA began recalling certain lots and batches of it, citing the presence of N-Nitrosodimethlyamine (NDMA) and N-Nitrosodiethylamine (NDEA).⁴

The EPA classifies both NDMA and NDEA as known animal carcinogens and probable human carcinogens, and they have been linked to various types of digestive cancers, including stomach, intestinal, esophageal, colorectal, and liver cancers.⁵ The contamination was later traced back to a change in a solvent used during the manufacture of the drug’s active ingredient.

In October 2018, the FDA posted the results of gas chromatography-mass spectrometry (GC/MS) testing conducted on samples of recalled valsartan tablets, which showed the pills contained somewhere between 3.1 and 177 times the level of NDMA deemed safe for human consumption.⁶

Because NDMA and NDEA continued to be detected in so many brands of valsartan and other angiotensin II receptor blockers (ARBs), in February 2019 the FDA imposed interim limits for NDMA and NDEA in ARBs to prevent drug shortages. The interim limit for NDMA is 96 nanograms per day, and the limit for NDEA is 26.5 nanograms per day.⁷ In doing so, the FDA reminded “manufacturers that they are responsible for developing and using suitable methods to detect impurities, including when they make changes to their manufacturing processes. If a manufacturer detects a new impurity or a high level of impurities, it should fully evaluate the impurities and take action to ensure the product is safe for patients.”⁸ As of the time of this writing, these interim limits are still in place.

The FDA’s recall notice stated that the NDMA in valsartan-containing drugs was “thought to be related to changes in the way the active substance was manufactured”—specifically, a change in a solvent used during the manufacture of the drug’s active ingredient.⁹ Critically, this is a manufacturing defect, which will be discussed in more detail later.

The Drug Approval Process

Understanding some basics about the generic drug approval and regulatory process is an important component in these cases and will help you focus on areas where the defendant manufacturer departed from the regulatory standards.

Don’t accept the drug’s name. From the moment you file a complaint in a contaminated drug case, don’t refer to the drug by the name under which it was marketed and sold. In the Valsartan MDL, we refer to the contaminated drug as a “valsartan-containing drug” or “VCD.” By referring to the drug as a “valsartan-containing drug,” rather than valsartan, you avoid making any concession about the drug’s sameness to its brand-name counterpart. This is important for preemption reasons and for helping to overcome FDA defenses that exist under certain states’ laws, such as Michigan’s.¹⁰ Similarly, Michigan’s law protects manufacturers of FDA-approved drugs. But failing to concede that the drug as it was sold (in its contaminated form) was FDA-approved provides a way for clients injured by the contaminated drug to recover under Michigan law.

Show the drug is not identical to the approved brand-name drug. According to the FDA, “a generic drug is a medication created to be the same as an already marketed brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use. These similarities help demonstrate bioequivalence, which means that a generic medicine works in the same way and provides the same clinical benefit as its brand-name version. In other words, a consumer should be able to take a generic medicine as an equal substitute for its brand-name counterpart.”¹¹

While brand-name medications undergo a more rigorous safety and effectiveness review before being approved, generic manufacturers are permitted to submit an abbreviated new drug application (ANDA), which requires only that they demonstrate the generic medicine is the same as the brand-name version in certain ways. Most notably, the active ingredient must be the same and the medication must be manufactured under the same strict standards as the brand-name equivalent.¹²

ANDA applications do not require manufacturers to repeat animal studies or clinical research on ingredients or dosage forms already approved for safety and effectiveness.¹³ Because generic drugs are supposed to be nearly identical to their brand-name counterparts, they also are supposed to have the same risks and benefits.¹⁴ But in contaminated drug cases, this is not true for the consumers who are injured after ingesting these medications.

Contaminants often qualify as active ingredients. The FDCA defines the term “drug,” in part, by reference to its intended use “in the diagnosis, cure, mitigation, treatment, or prevention of disease” and how it “affect[s] the structure or any function of the body of man or other animals.”¹⁵ So the FDA will regulate as a drug almost any ingested, topical, or injectable product that, through its label or labeling (including websites, promotional pamphlets, and other marketing material), claims to be beneficial for such uses. The definition also includes components of drugs, such as active pharmaceutical ingredients.¹⁶

The FDA defines an “active ingredient” in a drug as any component “intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect.”¹⁷ In the Valsartan MDL, the contaminants NDMA and NDEA both have the ability to cause cancer by triggering genetic mutations in humans. This mutation affects the structure of the human body, so NDMA and NDEA arguably are, by definition, active ingredients in a drug.

If a new, active ingredient was added to a drug, argue that the drug became an entirely new one, necessitating the submission of a new drug application. The manufacturer’s failure to submit this application and obtain FDA approval essentially renders the drug a completely unapproved product being sold in violation of both federal and state law.

Under these circumstances, you can argue that the manufacturer is not entitled to any protection under federal law that might be afforded to the manufacturer of an FDA-approved product.¹⁸ Establishing this claim may be very helpful in overcoming preemption under Mensing. This is because, arguably, the failure to adhere to the terms of an ANDA approval, or alternatively, the failure to obtain FDA approval for a new drug deprives the manufacturer of the shield of federal preemption.

Liability Theories

Once you’ve gotten a handle on the drug’s regulatory approval, here are some possible claims to bring and how to counter defense arguments that they are preempted.

Demonstrate that the drug is adulterated and misbranded. A drug is adulterated if it is contaminated, if the product is not manufactured in accordance with proper methods, if the manufacturer holds it out to be a product that it isn’t, or if the quality or strength is reduced.¹⁹ Similarly, a drug is misbranded if its labeling is false or misleading, if the label does not contain a proper list of active ingredients, or if the label purports to be a drug that is approved when it is not.²⁰

The manufacture of any adulterated or misbranded drug is prohibited under federal law.²¹ Moreover, the introduction into commerce of any adulterated or misbranded drug is similarly prohibited.²² And the receipt in interstate commerce of any adulterated or misbranded drug is also unlawful.²³

If any of these violations apply, then you can argue that the manufacturer forfeited any protections it might have otherwise had when it received FDA approval for its drug. Keep in mind that these are not causes of action but rather violations of federal law that constitute evidence of negligence and that can also strip manufacturers of protections they would otherwise be entitled to as manufacturers of FDA-approved products.

At the very least, if the generic drug that injured your client had a different, dangerous ingredient not in its brand-name counterpart, it is considered adulterated under federal law, and therefore its sale or introduction into commerce is illegal.²⁴ A plaintiff bringing a state law tort claim (rooted in strict products liability) based on such a violation is not asking the manufacturer to do anything different from what federal law already requires.

If a manufacturer labels a drug but omits the ingredients (the contaminant), it has misbranded the drug and violated the duty of sameness required under Mensing.²⁵ If the contaminant in the drug was not disclosed by the defendant as an ingredient, then the drug was misbranded. Again, it is unlawful to introduce a misbranded drug into interstate commerce,²⁶ and therefore, the sale and distribution of those drugs is illegal. For example, in the Valsartan MDL, NDMA was not disclosed as an active ingredient in the labels of the contaminated drugs. The complaint therefore argues that

(1) the presence of this new active ingredient renders the product an entirely new drug or at least makes the drug adulterated valsartan

(2) the failure to disclose the NDMA as an active ingredient in the label renders the drug misbranded, whether the drug is viewed as valsartan or as an entirely different drug.

Manufacturing defect. At its core, a contamination case is often a manufacturing defect claim. In addition to alleging that the drug became contaminated, it can be helpful to identify manufacturing rules that have been broken. One great source for these are Current Good Manufacturing Practices (cGMPs).²⁷ These regulatory requirements are intended to ensure that drugs will be safe and effective and in compliance with the FDCA. These regulations establish the basic requirements applicable to manufacturers of pharmaceutical drugs and require that drug ingredients be accurately disclosed²⁸; that advertisements properly disclose active ingredients²⁹; and that manufacturers maintain strict policies and procedures relating to manufacturing, quality control, testing, and complaint handling—among many other things.³⁰

In addition to pleading all of these violations, begin discovery by asking for the approved formula for the drug, as well as all quality and purity testing performed that might have been designed to pick up the presence of the contaminant at issue in the case. These testing results can immediately help to demonstrate that the end product deviated from the intended one. By alleging that the manufacturer failed to adhere to cGMPs, a plaintiff can further argue that the contaminated, generic drug is not the same drug as the brand-name drug and that the drug was adulterated and misbranded.

Failure to warn. A manufacturer is required to give adequate directions for the use of a pharmaceutical drug such that a “layman can use a drug safely and for the purposes for which it is intended”³¹ and to conform to requirements governing the appearance of the label.³² Under FDA regulations, “labeling” encompasses all written, printed, or graphic material accompanying the drug or device,³³ and therefore broadly covers nearly every form of promotional activity, including not only “package inserts” but also advertising.³⁴

Labeling extends far beyond what appears on a drug’s bottle or box. It can be helpful to think about how the drug was marketed. While generic drugs are not marketed as heavily to physicians directly, manufacturers often develop marketing materials for other entities in the distribution chain, such as pharmacy benefit managers, wholesalers, and distributors. Company websites also often contain boastful language regarding the company’s supposed high safety and purity standards.

Design defect. Generic drug manufacturers have an ongoing federal duty of sameness in their products.³⁵ To receive approval through the ANDA process, a generic manufacturer must demonstrate that the active ingredients are the same as those in the brand-name drug and that the generic drug is a bioequivalent in that it can be expected to have the same therapeutic effect.³⁶

A generic manufacturer (like a brand-name manufacturer) must also make “a full statement of the composition of such drug” to the FDA.³⁷ In other words, the design of a generic drug is supposed to mirror that of the brand name, but the defendant selling a contaminated drug actually made and sold something else.

For example, in the Valsartan MDL, the complaint alleges that the valsartan sold by defendants was supposed to be bioequivalent to its brand-name counterpart, Diovan. However, Diovan was not contaminated with NDMA, and therefore, the contaminated valsartan was not a true bioequivalent. Instead, the contaminated drug was a “valsartan-containing drug” that had never received FDA approval.

Finally, in states that require the plaintiff to establish the presence of a reasonable alternative design, the reasonable alternative design is the brand-name drug or the approved generic formula. In these cases, the reasonable alternative was entirely feasible to make and indeed was what the FDA contemplated when it approved the drug.

While preemption defenses present challenges, you can successfully plead manufacturing defect, failure-to-warn, and design defect claims by emphasizing the generic defendant’s failure to adhere to its duty of sameness. Any departure from the warning or design of the FDA-approved product leaves an opening for claims against generic drug manufacturers to proceed.

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Marlene Goldenberg is a partner at Goldenberg Law in Minneapolis. She can be reached at mjgoldenberg@goldenberglaw.com.

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Notes

1. That is not to say that contaminants can’t occur in brand-name drugs, but that didn’t happen in the Valsartan cases.
2. PLIVA, Inc. v. Mensing, 564 U.S. 604 (2011).
3. Buckman Co. v. Plaintiffs’ Legal Comm., 531 U.S. 341 (2001).
4. U.S. Food & Drug Admin., FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan), https://tinyurl.com/y57kyulh.
5. U.S. EPA, Technical Fact Sheet—N-Nitroso-dimethylamine (NDMA) (Jan. 2014), https://www.epa.gov/sites/production/files/2014-03/documents/ffrrofactsheet_contaminant_ndma_january2014_final.pdf; U.S. EPA, N-Nitrosodimethylamine (Jan. 2000), https://www.epa.gov/sites/production/files/2016-09/documents/n-nitrosodimethylamine.pdf. See, e.g., J. Cui et al., Relationship Between N-nitrosodimethylamine and Risk of Digestive Tract Cancers: A Meta Analysis Based on Cohort Studies, Chinese Med. Ass’n Publishing House Ltd. (May 2016). 
6. U.S. Food & Drug Admin., Laboratory Analysis of Valsartan Products (May 2, 2019), https://www.fda.gov/drugs/drug-safety-and-availability/laboratory-analysis-valsartan-products; U.S. Food & Drug Admin., GC/MS Headspace Method for Detection of NDMA in Valsartan Drug Substance and Drug Products (Jan. 25, 2019), https://www.fda.gov/media/115965/download.
7. FDA Updates and Press Announcements on Angiotensin II Receptor Blocker Recalls, supra note 4.
8. Id. at 10/30/2018: Update. 
9. Eric Palmer, FDA Cites Solvent Recovery Firm as a Player in the Valsartan Mess, FiercePharma (Aug. 15, 2019), https://www.fiercepharma.com/manufacturing/fda-cites-solvent-recovery-firm-as-player-valsartan-mess; Tien Nguyen, A Side Reaction May Have Led to Impurities Found in Valsartan Heart Drugs, Chem. & Eng. News (Feb. 19, 2019), https://cen.acs.org/pharmaceuticals/process-chemistry/side-reaction-led-impurities-found/97/web/2019/02. 
10. See, e.g., Mich. Comp. Laws §600.2946(5) (1995) (granting nearly full immunity to manufacturers of FDA-approved medications).
11. U.S. Food & Drug Admin., Generic Drugs: Questions & Answers (June 1, 2018), https://www.fda.gov/Drugs/ResourcesForYou/Consumers/QuestionsAnswers/ucm100100.htm (emphasis in original). 
12. U.S. Food & Drug Admin., Generic Drug Facts (June 1, 2018), https://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/GenericDrugs/ucm167991.htm. 
13. Generic Drugs: Questions & Answers, supra note 11. 
14. Id. 
15. 21 U.S.C. §321(g)(1) (2016) (Note that food is excluded from this definition of “drug.”).
16. U.S. Food & Drug Admin., Human Drugs: What is a Drug? (Sept. 14, 2018), https://www.fda.gov/ForIndustry/ImportProgram/ImportBasics/RegulatedProducts/ucm511482.htm#drug. 
17. 21 C.F.R. §210.3(b)(7) (2009). 
18. See 21 C.F.R. §310.3(h) (1985). 
19. 21 U.S.C. §351(a)(2)(A), (a)(2)(B), (b), and (c) (2017).
20. 21 U.S.C. §352 (2018).
21. 21 U.S.C. §331(g) (2018).
22. 21 U.S.C. §331(a).
23. 21 U.S.C. §331(c).
24. See generally U.S. Dep’t of Justice, Generic Drug Manufacturer Ranbaxy Pleads Guilty and Agrees to Pay $500 Million to Resolve False Claims Allegations, cGMP Violations and False Statements to the FDA (May 13, 2013), https://www.justice.gov/opa/pr/generic-drug-manufacturer-ranbaxy-pleads-guilty-and-agrees-pay-500-million-resolve-false. 
25. 21 C.F.R. §201.6 (1976); §201.10 (2002).
26. 21 U.S.C. §331(a). 
27. 21 C.F.R. §210 (2009); 21 C.F.R. §211 (2016); U.S. Food & Drug Admin., Current Good Manufacturing Practice (CGMP) Regulations (Mar. 30, 2018), https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations.
28. 21 C.F.R. §201.6.
29. 21 C.F.R. §202.1 (2007).
30. 21 C.F.R. §211 (2016).
31. 21 C.F.R. §201.5 (1976).
32. 21 C.F.R. §201.128 (1976); 21 C.F.R. §202.1.
33. Id.; Decision in Washington Legal Foundation v. Henney, 65 Fed. Reg. 14286, 14286 (Mar. 16, 2000).
34. U.S. v. Research Labs., 126 F.2d 42, 45 (9th Cir. 1942) (“Most, if not all, labeling is advertising. . . . Congress did not . . . exclude from the definition printed matter which constitutes advertising.”); 21 U.S.C. §321(m) (2016).
35. Mensing, 564 U.S. at 613.
36. 21 U.S.C. §355(j) (2018).
37. 21 U.S.C. §355(b)(1)(C).