In re Avandia Mktg., Sales Practices & Prods. Liab. Litig.

• Decision Date: 07 September 2011
• Docket Number: MDL No. 1871.No. 07–md–01871.
• Citation: 817 F.Supp.2d 535
• Parties: In re AVANDIA MARKETING, SALES PRACTICES AND PRODUCTS LIABILITY LITIGATION.This Document Applies To: All Actions.
• Court: U.S. District Court — Eastern District of Pennsylvania

817 F.Supp.2d 535

In re AVANDIA MARKETING, SALES PRACTICES AND PRODUCTS LIABILITY LITIGATION.This Document Applies To: All Actions.

MDL No. 1871.No. 07–md–01871.

United States District Court, E.D. Pennsylvania.

Sept. 7, 2011.

MEMORANDUM OPINION & ORDER

RUFE, District Judge.

This MDL action arises from injuries allegedly suffered by patients who were prescribed Avandia—an FDA-approved diabetes medication. In 2007, the United States Judicial Panel on Multidistrict Litigation transferred thousands of individual cases to this Court for consolidated pre-trial proceedings. The cases allege that Avandia (and its sister drugs Avandamet and Avandaryl) cause an increased risk of heart attack, heart failure, and other physical injury, and that manufacturer GlaxoSmithKline (“GSK”) failed to adequately warn of those risks.¹ Before the Court is GSK's Omnibus Motion for Summary Judgment on the adequacy of Avandia's label warnings regarding congestive heart failure (“CHF”).² It seeks dismissal of claims brought by plaintiffs from New York, Florida, Texas and Pennsylvania who suffered CHF-related injuries and who ingested Avandia after February 8, 2001 ³—the date on which GSK amended the Avandia package insert to include CHF-related risk information. In the alternative, GSK seeks summary judgment on the adequacy of Avandia's label as revised on August 14, 2007 as to all plaintiffs from New York, Florida, Pennsylvania, and Texas who ingested Avandia after that date.⁴ The Plaintiffs' Steering Committee (“PSC”) opposes the motion on its merits, and also urges denial, pursuant to Rule 56(d) of the Federal Rules of Civil Procedure, because insufficient discovery on CHF-related issues to date prevents it from presenting disputed facts essential to support its opposition.

The Avandia label adopted on February 8, 2001 generally warned that Avandia, like other drugs of its class, when used alone or with other antidiabetic agents, causes fluid retention, which can exacerbate or lead to CHF; that patients should be observed for signs and symptoms of heart failure; that Avandia should be discontinued upon deterioration of cardiac status; that Avandia should be used cautiously in patients with edema or at risk for heart failure; and that, in postmarketing experience, incidents of CHF had been reported. The 2007 label included the same or similar warnings with additional detail from clinical trials regarding risks for specific patient subpopulations, but also included a prominent boxed warning that Avandia directly causes CHF in some patients. GSK's motion presents a single question: Did the format and content of the 2001 and 2007 labels, as a matter of law, adequately warn of CHF risks? Because the PSC has presented sufficient evidence of labeling omissions regarding CHF risks, including those concerning certain patient subpopulations and sufficient evidence that GSK knew or should have known about those risks well before the labels disclosed them, as well as evidence of inconsistencies and ambiguities within the 2001 label, the Court finds that a reasonable jury could conclude that the labels were incomplete, inaccurate, or misleading as to CHF risks. Thus, the issue cannot be resolved as a matter of law and summary judgment on the adequacy of the labels is inappropriate.

I. FDA Labeling Requirements & Avandia Label RevisionsA. FDA Labeling Requirements

When the FDA approves a new drug application, it also approves the drug's labeling, which must be used verbatim.⁵ The “label,” as used by the Court here, is also known as the “package insert” or “professional labeling,” and is intended for use by health care practitioners, not patients. The label includes a range of information necessary for safe and effective use.

The FDA requires specific content and a particular format for prescription drug labels.⁶ The agency may also require the label to include, at a location specified by the agency, a prominently displayed “boxed warning” that highlights risks that may lead to death or serious injury that are more fully described elsewhere in the label.⁷ Also known as a “black box warning,” it is the strongest warning available.⁸

Additionally, for drugs approved before June 30, 2001, including Avandia, sections of the label relevant to risk information must be presented under the following headings and in the following order: Contraindications, Warnings, Precautions, and Adverse Reactions.⁹ The risk information sections must appear after sections on drug description, clinical pharmacology, and indications and usage.¹⁰

These risk information sections reflect, in descending order, the seriousness of the risks identified in each category.¹¹ For example, the “Warnings” and “Contraindications” sections must identify any potentially fatal adverse reactions.¹² “Contraindications” caution use where the risks outweigh the benefits, such as use in patients hypersensitive to the drug or with particular vulnerabilities that pose a substantial risk of harm from the drug.¹³ The “Warnings” section must describe any serious adverse reactions and potential safety hazards, treatment limitations that might be required by those risks, and advice as to steps that should be taken if the adverse event occurs. The “Warnings” section should also be updated with new warnings when there is evidence of an association, rather than causation, with a serious hazard.¹⁴ The “Precautions” section requires information about special care practitioners should use when treating patients with the drug, and should include information regarding study results that may be helpful to practitioners in monitoring patients and identifying adverse reactions.¹⁵ Finally, the “Adverse Reactions” section requires disclosure of “undesirable effect[s], reasonably associated” with the drug. ¹⁶ But this section should include “only those adverse events for which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event.” ¹⁷ The “Adverse Reactions” section should reflect information from the entire safety data base, including clinical studies as well as postmarketing experience, which includes information compiled from spontaneous adverse event reports (“AERs”). ¹⁸ Manufacturers may make claims “comparing the drug ... with other drugs in terms of frequency, severity, or character of adverse reactions” in this section only if the findings are “based on adequate and well-controlled studies.” ¹⁹

Finally, FDA regulations permit “a manufacturer ... to add or strengthen a contraindication, warning, precaution, or adverse reaction” without receiving prior FDA approval, by filing a “changes being effected” supplement with the FDA.²⁰

B. Avandia Label Revisions

Avandia, the brand name for rosiglitazone maleate, was approved by the Food and Drug Administration in 1999. It is a member of a class of drugs known as thiazolidinediones (“TZDs”), used to manage non-insulin-dependent diabetes, or Type 2 diabetes.²¹ Avandia competes with Actos, the brand name for pioglitazone, the only other competitor TZD currently on the market.

The Food and Drug Administration (“FDA”) first approved Avandia for use only as monotherapy or in combination with metformin, another diabetes medication.²² The “Precautions” section of the first Avandia labels, in 1999, warned that the drug should be used cautiously in patients with edema—a condition in which large amounts of fluid accumulate in subcutaneous tissue; ²³ that TZDs can cause fluid retention, which can exacerbate CHF; that preclinical studies showed TZDs caused plasma volume expansion and cardiac hypertrophy; ²⁴ and that Avandia was not indicated for patients with moderate or severe symptoms of heart failure (i.e., New York Heart Association (“NYHA”) Class 3 or 4 status) because such patients had not been studied.²⁵ The label was subsequently revised several times—in 2001, 2005, 2006, 2007, and 2011—to include increasingly detailed, and, ultimately, heightened warnings about CHF and other risks.

The dispute here centers on the adequacy of CHF warnings in the 2001 and 2007 Avandia label revisions. Because the FDA's labeling format and content requirements and GSK's various label revisions provide important context, the Court details them below.²⁶

1. The February 8, 2001 Avandia Label

On February 8, 2001, GSK revised the label to include another indication: use in combination therapy with sulfonylureas, another type of diabetes medication, in addition to the prior indication for monotherapy and Avandia+metformin therapy.²⁷ The 2001 label also included, in the Warnings section, a class-wide warning that Avandia, like all TZDs, can cause fluid retention, which in turn can lead to or exacerbate CHF. This new class-wide warning thus expanded the prior warning about fluid retention in the “Precautions” section by including it in the more prominent “Warnings” section of the label and by indicating fluid retention can both exacerbate as well as lead to CHF. It also warned that Avandia was not recommended for patients with NYHA Class 3 and 4 cardiac status. The 2001 revision additionally included, in the “Adverse Events” section, clinical trial results that showed an increased incidence of edema in Avandia monotherapy as well as increased CHF risks from Avandia+insulin therapy, and warned that Avandia+insulin therapy was not indicated. The label did not include clinical trial results for combination therapy with metformin or sulfonylurea. The 2001 revision included the following statements: ²⁸

WARNINGS

Cardiac Failure and Other Cardiac Effects: Avandia, like other [TZDs], alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. Avandia should be discontinued if any deterioration in cardiac status occurs.

Patients with [NYHA] class 3 or 4 cardiac status were not...