US Pharm. 2010;35(8):60-63.
Can the manufacturer of an FDA-approved generic drug be held liable for damages if the plaintiff—allegedly harmed by taking the generic drug—can show the manufacturer knew of a problem with the drug’s formulation and failed to warn the health care community about the known danger? This question may sound vaguely familiar. In the May 2009 edition of this column, a similar question was addressed: Can the manufacturer of an FDA-approved drug be held liable under state product liability laws for injuries allegedly incurred from use of the drug? Or does the Food, Drug, and Cosmetic Act (FDCA) preempt state liability laws?1
In that case, Wyeth v. Levine,2 the U.S. Supreme Court held that the FDA’s authority to regulate the marketing of drugs in the United States does not preempt state product liability laws. Plaintiffs are permitted to bring claims for damages if they can show that the manufacturer knew of dangers associated with the use of the drug, learned after premarketing approval and not included in the original FDA-approved labeling. As such, it may be determined that the manufacturer has not taken adequate steps to warn of the problem by seeking to amend the labeling as permitted by regulation.
In the current case under consideration, In Re: Budeprion XL Marketing and Sales Litigation,3 a federal court in Pennsylvania extended the Levine decision to the makers of generic drugs that have been judged by the FDA to be bioequivalent to the innovator product. It should be noted that the memorandum opinion only rejected the defendant’s motion to dismiss the case; no liability determination has been made yet.
Facts of the Case
This nationwide class action lawsuit was brought under California law claiming that the manufacturers of generic bupropion failed to warn of differences in the manufacturing process from the innovator product, Wellbutrin (GlaxoSmithKline). Originally marketed in the late 1980s for treatment of depression, by 2007 bupropion was the fourth most prescribed antidepressant in the U.S., with over 20 million prescriptions issued annually.4
In 1996, the manufacturer introduced Wellbutrin SR, a sustained-release (SR) formulation that utilized a matrix release mechanism allowing the drug to be metabolized in the upper gastrointestinal (GI) tract. With the SR formulation, peak blood concentrations were reached 3 hours after oral ingestion. However, it was disclosed in the labeling that the drug was subject to the “dose dumping” phenomenon of being absorbed faster when it was taken with food. This was not considered to be a clinically significant event. The normal dose of the SR formulation was two 150-mg doses daily.
In 2003, the manufacturer released Wellbutrin XL, an extended-release (XL) formulation that only needed to be taken once daily. This formulation utilized a membrane-release technology, meaning that the drug was not released through dissolution of the pill but was seeped at a controlled rate through a membrane that passed through the entire GI tract. This eliminated the dose-dumping issue, and the labeling was changed to disclose the new dissolution characteristics. Peak blood concentrations were reached 5 hours after taking an oral dose. The membrane-release technology was patented, which prevented generic manufacturers of bupropion from marketing XL formulations using it.
In 2006, the defendants began marketing generic versions, including Budeprion XL (Teva Pharmaceuticals), a 300-mg XL formulation that uses the older matrix technology. These generic versions tend to reach peak plasma concentrations in 2 hours compared to the 5-hour rate of the innovator product. In addition, the amount and rate of active chemical released from the generic versions are influenced by factors such as food, alcohol consumption, and GI changes. Despite these differences, the FDA found the generic versions to be bioequivalent to the innovator product and the differences in absorption and metabolism to be clinically insignificant.
After the generic versions were put on the market, “complaints poured in from patients who claimed that the generic drugs they were taking were not as effective as Wellbutrin XL and they were experiencing adverse side effects.”5 Allegedly, patients who switched back to Wellbutrin XL improved. During this postmarketing surveillance period, the defendant manufacturers failed to notify the FDA, prescribers, or patients of the known differences between the drugs. The plaintiffs claimed that in spite of this knowledge, the defendants continued to misrepresent that the release profiles of the generic products were the same as the brand-name drugs. Somewhat inconsistently, however, during patent litigation the generic companies made distinct claims showing the differences between the dose-delivery methods employed by the generics as compared to the branded drug. Undoubtedly, this difference was touted by the defendants as a distinguishing feature to avoid claims of patent infringement.
In addition, postmarketing studies showed that Budeprion XL released 34% of its bupropion within the first hour, compared to only 8% for Wellbutrin XL (300 mg). Within 2 hours of ingestion, Budeprion XL released 25% to 50% of the drug, compared with <20% for Wellbutrin XL.6
In April 2008, under pressure from consumers, nonprofit watchdogs, and the medical community, the FDA issued a report explaining some of the differences between Wellbutrin XL and the defendants’ generic products; however, the FDA made no determination as to whether the defendants’ warnings were adequate.7,8 Following this announcement, the market share of Budeprion XL decreased while the sales of Wellbutrin XL increased, along with the price of the drug. Physicians began demanding that pharmacists dispense the more expensive brand-name drug to avoid the bioequivalence problems that had now become widely known.
An innovator manufacturer will register patents on that product in order to obtain exclusivity rights to market the drug without competition from other potential manufacturers.9 In most circumstances, the patent term runs 20 years from the date of filing. In reality, however, the patent term for marketing the drug is a much shorter period of time because the manufacturer must prove to the satisfaction of the FDA that the drug is safe and effective. The FDA prohibits marketing of new drugs before a new drug application (NDA) has been approved. It often takes 10 to 12 years from the time a patent is registered and the NDA is approved, thereby limiting the effective exclusivity rights to a much shorter period of time. Getting an NDA is, of course, a very expensive proposition costing hundreds of millions of dollars or more. The application must include: 1) full reports of investigations that have been made to show whether or not the drug is safe and effective, and 2) specimens of the proposed drug labeling.
A generic drug maker may file an abbreviated new drug application (ANDA) for the approval of a generic drug.10 The ANDA must include information to show that:
1) the conditions of use prescribed, recommended, or suggested in the proposed labeling for the drug have been previously approved for a listed drug; 2) the active ingredient(s) of the new drug is the same as that of the listed drug; 3) the route of administration, the dosage form, and the strength of the new drug are the same as those of the listed drug; 4) the new drug is bioequivalent to the listed drug; and 5) the labeling proposed for the new drug is the same as the labeling approved for the listed drug.11 A failure to demonstrate bioequivalence or show that the proposed label for the generic drug is the same as the label approved for the listed drug is grounds to deny the ANDA.12 Absent certain exceptions, federal regulations require that the labeling for a proposed generic drug be the same as the listed drug before an ANDA will be approved.13
A drug is considered to be bioequivalent to a listed drug if “the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug” or if the rate of absorption does show a significant difference, such difference “is intentional, is reflected in its proposed labeling…and is considered medically insignificant for the drug.”14 This abbreviated process allows a generic drug maker to skip the premarket trials conducted by the brand-name drug manufacturer.15
After a drug is approved, the manufacturer may submit additional information to the FDA to change the label to add or strengthen a contraindication, warning, precaution, or adverse reaction.16 This provision, known as the “changes being effected” or CBE provision, allows a drug maker to immediately implement any proposed change in the label while awaiting a ruling from the FDA on the proposed changes.17
Oftentimes, innovator manufacturers will introduce a new dosage form and obtain a process patent. This might be thought of as a sort of “back door” method of extending the patent protection. After the original patent expires, other generic companies will be allowed to market the now “off patent” drug, but without using the new protected technology.
The plaintiffs complained that they would not have purchased the generic product had they known the truth about it, and that they have suffered physical and emotional damages, including increased bouts of depression and anxiety, as well as actual damages incurred in paying for the generic drug. They also alleged that the generic companies had a duty to change the labeling and notify the FDA of the postmarketing surveillance problems under the CBE process.18
In addressing this issue, the court noted: “A plain reading of the federal regulations demonstrates that generic drug makers may avail themselves of the CBE process.”19 Furthermore, federal regulations require both brand-name and generic drug makers to revise their labeling to “include a warning about a clinically significant hazard as soon as there is reasonable evidence of a causal association with a drug; a causal relationship need not have been definitely established.”20
After surveying the relevant jurisprudence addressing similar issues, the court rejected the defendants’ arguments that they cannot be held liable for any differences between the brand-name and generic versions of drugs because the FDA made a determination that the drugs are bioequivalent. The court stated: “A generic drug manufacturer is not absolved of liability because the FDA has approved its generic product. The Hatch-Waxman Act [amending the FDCA to allow for the ANDA process] allows generic drug makers to expeditiously get their products to market—it does not allow generic drug makers to wash their hands of any responsibility for monitoring the safety and efficacy of their drugs once sold.21…Manufacturers of generic drugs, like all other manufacturers, are responsible for the representations they make regarding their products.22 Furthermore, plaintiffs would be left without a remedy if their state law claims were preempted…In every case involving a prescription drug, whether a name-brand drug or a generic is involved, the FDA will at some point have approved the drug as safe and effective and the label as adequate. Defendants would turn that approval into a lock that would forever shut the courthouse door and would remove any incentive for generic drug makers to monitor the safety of their medications and update their labels accordingly…[The] ultimate responsibility for the labeling of drugs remains with the maker of the drug, not the FDA. Federal laws and regulations do not leave generic drug makers impotent upon learning that their labels are inadequate or that their medication causes adverse side effects that must be reported. Generic drug makers may add or strengthen warning labels, even without prior FDA approval.”
There are several take-away points pharmacists should appreciate from the findings in this case. The first is that generic drug manufacturers, just like brand-name drug companies, are not exempt from state drug-product liability laws merely because the FDA has approved the drugs. While not particularly favorable to drug makers, this is a good result for pharmacy because an injured plaintiff is far more likely to go after the “deep pockets” of the pharmaceutical companies even if a pharmacy or pharmacist is also sued for failing to warn patients about known problems with the use of a drug. The pharmacist can always point the finger at the drug maker, claiming it was their fault for not giving adequate warnings to pass along to the patient.
The second and perhaps more onerous implication is that pharmacists cannot make a blanket assumption that the labeling of a brand-name drug will be identical to the labeling of its generic. Because of the CBE provision, manufacturers of brand-name drugs and generic producers have the ability to make unilateral labeling changes that could impact the safety and efficacy of drugs under certain circumstances.23 Thus, it is no longer safe to assume the labeled indications, uses, dosages, and administration or pharmacokinetic profiles of brand-name and generic equivalents will be exactly the same. This will require a higher level of scrutiny by pharmacists when engaging in either permissible or mandatory generic selection activities. Clinical judgment regarding generic interchange for a prescribed brand-name drug will become more important than ever before.
There are also other potential ramifications. Mandatory generic substitution contracts with third-party payers and prescription benefit managers will have to be reexamined in light of the new standards envisioned by this case. Mere availability of a generic version cannot automatically replace professional discretion. This will be most important with certain classes of drugs such as narrow therapeutic index products. Remember that the pharmacist’s first responsibility is to protect the welfare of the patient irrespective of other factors that might jeopardize good clinical outcomes.
1. Vivian JC. Federal preemption of states’ drug product liability laws DOA: FDA labeling regulations are floors, not ceilings. US Pharm. 2009;34(5):50-52. www.uspharmacist.com/content/
2. Slip Op No 06-1249, 2009 US Lexis 1774, 555 U.S. (2009).
3. In Re: Budeprion XL Marketing and Sales Litigation. 09-md-2107, MDL No 2107, D Penn, 2010 US Dist Lexis 51980. May 26, 2010. www.fdalawblog.net/files/
4. See Note 3, supra, p. 2-3.
5. See Note 3, supra, p. 4.
6. See Note 3, supra, p. 4.
7. Silverman E. FDA probe clears Teva’s generic Wellbutrin XL. Pharmalot. April 16, 2008. www.pharmalot.com/2008/04/fda-
8. FDA issues “Review of Therapeutic Equivalence Generic Bupropion XL 300 Mg and Wellbutrin XL 300 Mg.” April 16, 2008. www.drugs.com/news/fda-issues-
9. 21 USC § 355(b)(1).
10. 21 USC§ 355(j)(1). See also Note 3, supra, p. 8.
11. 21 USC § 355(j)(2)(A)(i)-(v).
12. 21 USC § 355(j)(4)(F)-(G).
13. 21 CFR § 314.94(a)(8)(iv).
14. 21 USC § 355(j)(8)(B)(i-ii).
15. See Fulgenzi v. Wyeth, Inc., 2010 WL 649349, at 3 (ND Ohio February 19, 2010); see also Stacel v. Teva Pharms. USA, 620 F Supp 2d 899, 905 (ND Ill. 2009) (“The underlying presumption is that so long as the [generic] drug is shown to be pharmaceutically equivalent to an existing reference-listed drug…FDA approval can be assumed without requiring duplication of previously-performed studies.”)
16. 21 CFR § 314.70(c)(6)(iii)(A) & (C).
17. See Fulgenzi v. Wyeth, Inc., 2010 WL 649349, at 3 (ND Ohio February 19, 2010).
18. See Note 12, supra.
19. See Dorsett v. Sandoz, Inc., 2010 WL 1174204, at 17-18 (CD Cal March 26, 2010); Stacel v. Teva Pharms. USA, 620 F Supp 2d 899, 905 (ND Ill 2009) at 905 (“In other words, the regulations affecting generic drug applications state explicitly that the CBE provisions apply to generic drug manufacturers just as they do to name-brand manufacturers.”); Bartlett v. Mutual Pharm. Co., 659 F Supp 2d 279, 296 (DNH 2009) (“Just as nothing in the text of the Hatch-Waxman Amendments forbids a generic manufacturer from changing its label from the listed version’s post-approval, nothing in the text of the CBE regulation forbids a generic manufacturer from using the CBE process to do so.”)
20. 21 CFR § 201.57(c)(6).
21. See Note 3, supra, pg 22.
22. Citing Foster v. Am. Home Prods. Corp., 29 F3d 165, 170 (4th Cir. 1994).
23. See Note 12, supra.
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