Adverse Event Reporting for Pharmaceutical Products

Use of AE Reports at Trial

For example, based in part on AE reports, in May 2012, the U.S. Court of Appeals for the First Circuit affirmed a district court's holding that a non-steroidal anti-inflammatory drug (NSAID) was in a “defective condition” by showing that it was unreasonably dangerous due to the incidence of adverse events. Bartlett v. Mut. Pharm. Co., 678 F.3d 30 (1st Cir. May 2012). The district court permitted the plaintiff's pharmacologist/toxicologist and medical experts to discuss the drug's overall risks and benefits, prescribing doctors' AEs reports, and disease-related reporting rates, based partly on the number of AEs. Id. at 38-39. Rejecting the drug manufacturer's defense that these opinions were unreliable, the court held that the experts' opinions were admissible, because ” ' proof that a significant number of adverse reports exists is part of the calculus and surely relevant input for a witness who is prepared to opine on the risk-benefit ratio .' ” Id. at 39. The court noted that both the FDA and the manufacturer, in separate occasions, relied on AE reporting rates of NSAIDs ' the FDA in its recommendation to withdraw another NSAID, and the manufacturer in its expert's analysis of the injury risk associated with NSAIDs described in a peer-reviewed publication. Id.

Admitting Testimony

Even if courts do not use AE reports directly against manufacturers, many courts still admit testimony based on them into evidence against manufacturers, thereby demonstrating the significant role an AE report can play at trial. For example, a U.S. district court in Kentucky permitted into evidence testimony relating to AE reports that linked osteonecrosis of the jaw (death of the jaw bone) and two cancer drugs. Mahaney v. Novartis Pharms. Corp., 835 F. Supp. 2d 299, 302-03 (W.D. Ky. 2011). The court ruled against the drug manufacturer's motion to exclude these reports. While the court noted the “tenuous role AE reports play when showing a causal link between a drug and a side effect,” it held that experts may rely on, and refer to, aggregate number of AE reports related to the drugs at issue to prove “causation in correlation” when “appearing alongside other evidence.” Id. at 312.

In a case involving the same drugs and drug manufacturer, another court also permitted experts to reference certain AE reports' aggregate numbers “to prove medical causation, insofar as they relied on it to form their opinions.” Brown v. Novartis Pharms Corp., 2012 U.S. Dist. LEXIS 104985 (E.D.N.C. July 26, 2012). Another district court in New York withdrew a prior requirement that, for testimony to be admitted based on AE reports, the expert testifying needed to have reviewed the AE reports. Deutsch v. Novartis Pharms. Corp., 768 F. Supp. 2d 420, 451 (E.D.N.Y. 2011). The district court admitted an expert's causation testimony, which cited AE reports that the expert had not reviewed. These reports were admitted, because the expert did not cite the unreviewed AE reports for the truth but, rather, for the accepted theory that “a vast number of reports contributes to the plausibility of causation.” Id.

Courts have provided different rationales for admitting expert testimony based on AE reports. For instance, the district court for the Northern District of Ohio specifically recognized the significance and potential admissibility of AEs concerning the injuries caused by a weight-loss drug. In re Meridia Prods. Liab. Litig., 328 F. Supp. 2d 791 (N.D. Ohio 2004). The court noted that the AE submissions of the defendant-drug company were not legally shielded under the Federal Rules of Evidence, because the court has discretion to determine if an AE is considered an admission (citing 21 C.F.R ' 314.80). Id. at 809, n 15. Referring to the fact that many complaints had been submitted about the drug, the court said that the regulation's “permissive language places the task of determining whether a particular statement is an admission with the courts,” and “It would hardly make sense for a drug company to file a report stating, 'Our drug caused patient X's death' with the FDA, yet later escape liability by denying that the report constitutes an admission.'” Id.

FDA Warning Letters

Not only must manufacturers recognize that AE reports may be admitted into evidence and used against them, but they also must realize that a court may admit into evidence an FDA Warning Letter, a publicly issued enforcement letter for non-compliance, particularly if it mentions that a company has failed to submit AE reports. The United States Supreme Court was asked to review a drug case, where it was alleged that a drug manufacturer failed to disclose AE reports associated with its cold remedy intranasal product. Matrixx Initiatives, Inc. v. Siracusano, 131 S. Ct. 1309, 1311, 1313 (U.S. 2011). In 2009, the FDA had issued a Warning Letter to the drug manufacturer, concluding that its drug presented a serious risk to consumers. Warning Letter issued by FDA to Matrixx
(June 2009) available at' www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm166909.htm. Referencing the many AE reports associating the drug's use with a loss of sense of smell, the FDA noted that it had received few reports of these AEs with other intranasal cold remedies. Id. The agency then requested that the manufacturer correct this violation, notify the FDA of the manufacturer's plan to do so, and submit the additional AE reports related to loss of sense of smell, which, according to the FDA, were in the manufacturer's possession. Less than two years later, the Supreme Court cited the Warning Letter, which referred to the many AE reports, to explain that the FDA sometimes acts “on the basis of evidence that suggests, but does not prove causation,” even if not statistically significant. Matrixx Initiatives, Inc., 131 S. Ct. at 1320.

Conclusion

Companies must walk a fine line of ensuring regulatory compliance with the FDA's AE requirements, while not disclosing unnecessary information, which can only be used against them. To navigate this dangerous territory, one might follow this paraphrased lesson from the rock band Depeche Mode: “Words are very unnecessary, they can only do harm.” The FDA requirements describe with specificity what must be provided to the agency, and the disclaimer does help to minimize liability exposure. Although providing more information than is necessary might engender good will with the agency, it is important to remember that for every action, there is a reaction. Companies must be aware that any information provided to the FDA is subject to disclosure under the Freedom of Information Act, thereby offering competitors, plaintiffs' lawyers, and other government agencies access to information relating to potential negatives about products. Compliance is the law, but excess in description or information can increase the risk of liability. To achieve that appropriate balance may require a second pair of eyes, one with an objective perspective and sensitivity to the nuances of FDA rules.

Alan G. Minsk, a member of this newsletter's Board of Editors, is a partner and practice leader of the Food and Drug Practice at the Atlanta firm of Arnall, Golden Gregory LLP. He serves as general counsel of PDMA Alliance Inc., a pharmaceutical trade organization focused on compliance with the Prescription Drug Marketing Act and sample accountability and focuses his practice on advising pharmaceutical, biologic, medical device, cosmetic and food companies, on all legal and regulatory matters relating to the U.S. Food and Drug Administration (FDA) and the Drug Enforcement Administration (DEA).

The Food and Drug Administration (FDA) provides some protection to drug companies regarding adverse event reports by allowing a disclaimer statement about liability. However, this is not a blanket defense against other potential liability exposure.

According to the FDA's regulations, drug companies with approved marketing applications must report certain types of adverse drug experiences or adverse events (AEs), depending on the nature of the facts and within specific periods of times. 21 C.F.R. ' 314.80. The FDA defines “adverse drug experience” as “any adverse event associated with the use of a drug in humans, whether or not considered drug related ' .” 21 C.F.R. ' 314.80(a). However, the FDA recognized that companies would be reluctant to disclose such AE information for fear of government prosecution or potential liability concerns. Therefore, the agency provides:

A report or information submitted by an applicant under this section (and any release by FDA of that report or information) does not necessarily reflect a conclusion by the applicant or FDA that the report or information constitutes an admission that the drug caused or contributed to an adverse event. An applicant need not admit and may deny, that the report or information submitted under this section constitutes an admission that the drug caused or contributed to an adverse effect ' .

21 C.F.R. ' 314.80(k).

In the preamble to the final regulation, the agency said that the disclaimer is consistent with the Medical Device Reporting regulations. 50 Fed. Reg. 7452, 7476 (Feb. 22, 1983). However, the disclaimer is only an FDA protection; it does not protect companies from potential product lawsuits. In fact, the agency said that, although the FDA does not intend for such a report to be viewed as an admission of liability, whether a court will treat a submission to the FDA as an admission will depend on factors outside of the agency's control, such as the contents of the report itself. 50 Fed. Reg. at 7476; see also FDA, Center for Drug Evaluation and Research, Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (Mar. 2005). available at www.fda.gov/downloads/regulatoryinformation/guidances/ucm126834.pdf. Consequently, achieving the correct scope and substance in the AE report is a formidable task.

Use of AE Reports at Trial

For example, based in part on AE reports, in May 2012, the U.S. Court of Appeals for the First Circuit affirmed a district court's holding that a non-steroidal anti-inflammatory drug (NSAID) was in a “defective condition” by showing that it was unreasonably dangerous due to the incidence of adverse events. Bartlett v. Mut. Pharm. Co. , 678 F.3d 30 (1st Cir. May 2012). The district court permitted the plaintiff's pharmacologist/toxicologist and medical experts to discuss the drug's overall risks and benefits, prescribing doctors' AEs reports, and disease-related reporting rates, based partly on the number of AEs. Id. at 38-39. Rejecting the drug manufacturer's defense that these opinions were unreliable, the court held that the experts' opinions were admissible, because ” ' proof that a significant number of adverse reports exists is part of the calculus and surely relevant input for a witness who is prepared to opine on the risk-benefit ratio .' ” Id. at 39. The court noted that both the FDA and the manufacturer, in separate occasions, relied on AE reporting rates of NSAIDs ' the FDA in its recommendation to withdraw another NSAID, and the manufacturer in its expert's analysis of the injury risk associated with NSAIDs described in a peer-reviewed publication. Id.

Admitting Testimony

Even if courts do not use AE reports directly against manufacturers, many courts still admit testimony based on them into evidence against manufacturers, thereby demonstrating the significant role an AE report can play at trial. For example, a U.S. district court in Kentucky permitted into evidence testimony relating to AE reports that linked osteonecrosis of the jaw (death of the jaw bone) and two cancer drugs. Mahaney v. Novartis Pharms. Corp. , 835 F. Supp. 2d 299, 302-03 (W.D. Ky. 2011). The court ruled against the drug manufacturer's motion to exclude these reports. While the court noted the “tenuous role AE reports play when showing a causal link between a drug and a side effect,” it held that experts may rely on, and refer to, aggregate number of AE reports related to the drugs at issue to prove “causation in correlation” when “appearing alongside other evidence.” Id. at 312.

In a case involving the same drugs and drug manufacturer, another court also permitted experts to reference certain AE reports' aggregate numbers “to prove medical causation, insofar as they relied on it to form their opinions.” Brown v. Novartis Pharms Corp., 2012 U.S. Dist. LEXIS 104985 (E.D.N.C. July 26, 2012). Another district court in New York withdrew a prior requirement that, for testimony to be admitted based on AE reports, the expert testifying needed to have reviewed the AE reports. Deutsch v. Novartis Pharms. Corp. , 768 F. Supp. 2d 420, 451 (E.D.N.Y. 2011). The district court admitted an expert's causation testimony, which cited AE reports that the expert had not reviewed. These reports were admitted, because the expert did not cite the unreviewed AE reports for the truth but, rather, for the accepted theory that “a vast number of reports contributes to the plausibility of causation.” Id.

Courts have provided different rationales for admitting expert testimony based on AE reports. For instance, the district court for the Northern District of Ohio specifically recognized the significance and potential admissibility of AEs concerning the injuries caused by a weight-loss drug. In re Meridia Prods. Liab. Litig., 328 F. Supp. 2d 791 (N.D. Ohio 2004). The court noted that the AE submissions of the defendant-drug company were not legally shielded under the Federal Rules of Evidence, because the court has discretion to determine if an AE is considered an admission (citing 21 C.F.R ' 314.80). Id. at 809, n 15. Referring to the fact that many complaints had been submitted about the drug, the court said that the regulation's “permissive language places the task of determining whether a particular statement is an admission with the courts,” and “It would hardly make sense for a drug company to file a report stating, 'Our drug caused patient X's death' with the FDA, yet later escape liability by denying that the report constitutes an admission.'” Id.

FDA Warning Letters

Not only must manufacturers recognize that AE reports may be admitted into evidence and used against them, but they also must realize that a court may admit into evidence an FDA Warning Letter, a publicly issued enforcement letter for non-compliance, particularly if it mentions that a company has failed to submit AE reports. The United States Supreme Court was asked to review a drug case, where it was alleged that a drug manufacturer failed to disclose AE reports associated with its cold remedy intranasal product. Matrixx Initiatives, Inc. v. Siracusano , 131 S. Ct. 1309, 1311, 1313 (U.S. 2011). In 2009, the FDA had issued a Warning Letter to the drug manufacturer, concluding that its drug presented a serious risk to consumers. Warning Letter issued by FDA to Matrixx
(June 2009) available at' www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm166909.htm. Referencing the many AE reports associating the drug's use with a loss of sense of smell, the FDA noted that it had received few reports of these AEs with other intranasal cold remedies. Id. The agency then requested that the manufacturer correct this violation, notify the FDA of the manufacturer's plan to do so, and submit the additional AE reports related to loss of sense of smell, which, according to the FDA, were in the manufacturer's possession. Less than two years later, the Supreme Court cited the Warning Letter, which referred to the many AE reports, to explain that the FDA sometimes acts “on the basis of evidence that suggests, but does not prove causation,” even if not statistically significant. Matrixx Initiatives, Inc., 131 S. Ct. at 1320.

Conclusion

Companies must walk a fine line of ensuring regulatory compliance with the FDA's AE requirements, while not disclosing unnecessary information, which can only be used against them. To navigate this dangerous territory, one might follow this paraphrased lesson from the rock band Depeche Mode: “Words are very unnecessary, they can only do harm.” The FDA requirements describe with specificity what must be provided to the agency, and the disclaimer does help to minimize liability exposure. Although providing more information than is necessary might engender good will with the agency, it is important to remember that for every action, there is a reaction. Companies must be aware that any information provided to the FDA is subject to disclosure under the Freedom of Information Act, thereby offering competitors, plaintiffs' lawyers, and other government agencies access to information relating to potential negatives about products. Compliance is the law, but excess in description or information can increase the risk of liability. To achieve that appropriate balance may require a second pair of eyes, one with an objective perspective and sensitivity to the nuances of FDA rules.

Alan G. Minsk, a member of this newsletter's Board of Editors, is a partner and practice leader of the Food and Drug Practice at the Atlanta firm of Arnall, Golden Gregory LLP. He serves as general counsel of PDMA Alliance Inc., a pharmaceutical trade organization focused on compliance with the Prescription Drug Marketing Act and sample accountability and focuses his practice on advising pharmaceutical, biologic, medical device, cosmetic and food companies, on all legal and regulatory matters relating to the U.S. Food and Drug Administration (FDA) and the Drug Enforcement Administration (DEA).