Shaping Up: A Fitness Check for Pharmacovigilance Practices


The beginning of a new year is normally the time when people (author included) make resolutions and decide to work out and get in shape. Some people set measurable goals and work to achieve them. Others (author included) eventually find themselves back in the same ole rut with little improvement. No judgment here. Finding a level of comfort with one’s body is a personal journey, and only you can determine which fitness practices work best for you. Evaluating the fitness of a pharmaceutical company, however, is a different story and a judge or jury may decide whether certain exercises and practices are rigorous enough. This article provides information to permit a self-check on how well your company’s Pharmacovigilance department is functioning. Read further to brush up on requirements and case law to make sure that your company’s Pharmacovigilance department is in shape.


The World Health Organization defines Pharmacovigilance (“PV”) as the science and activities related to the detection, assessment, understanding and prevention of adverse effects or other drug-related problems. Regardless of the moniker, most – if not all – pharmaceutical companies have a PV or Drug Safety department. And, most pharmaceutical companies are all too familiar with the regulations that govern PV practices. Here are some examples:

21 CFR § 314.80 governs postmarketing reporting of adverse drug experiences and, in part, provides:

New Drug Applicant (“NDA”) Holders shall promptly review all adverse drug experience information obtained or otherwise received by the applicant from any source, foreign or domestic, including information derived from commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological/surveillance studies, reports in the scientific literature and unpublished scientific papers…. Applicants shall also develop written procedures for the surveillance, receipt, evaluation and reporting of postmarketing adverse drug experiences to FDA.

21 CFR § 314.98 requires Abbreviated New Drug Applicant (“ANDA”) Holders to comply with 21 CFR § 314.80. And, 21 CFR § 600.80 requires biologics license holders to report adverse experiences as well.

21 CFR § 310.305 governs records and reports concerning adverse drug experiences on marketed prescription drugs and, in part, provides:

FDA is requiring manufacturers, packers and distributors of marketed prescription drug products that are not the subject of an approved new drug or abbreviated new drug application to establish and maintain records and make reports to FDA of all serious, unexpected adverse drug experiences associated with the use of their drug products and they shall also develop written procedures for the surveillance, receipt, evaluation and reporting of postmarketing adverse drug experiences to FDA.

21 CFR § 201.80(e) governs the warnings on prescription product labels and, in part, provides:

The labeling shall describe serious adverse reactions and potential safety hazards, limitations in use imposed by them, and steps that should be taken if they occur. The labeling shall be revised to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug; a causal relationship need not have been proved.


A review of case law reveals the importance of PV and its role in pharmaceutical litigation.


Although the regulations require pharmaceutical companies to report PV information to the FDA, “Congress did not intend FDA oversight to be the exclusive means of ensuring drug safety and effectiveness.” The Supreme Court, in Wyeth v. Levine, clarified that pharmaceutical companies are responsible for monitoring their drugs:

It has remained a central premise of federal drug regulation that the manufacturer bears responsibility for the content of its label at all times. It is charged both with crafting an adequate label and with ensuring that its warnings remain adequate as long as the drug is on the market.


In Decker v. GE Healthcare, Inc. (In re Gadolinium-Based Contrast Agents Products Liability Litigation), the plaintiff filed suit against the manufacturer of an injectable dye used to enhance the quality of magnetic-resonance-imaging. Plaintiff alleged that the defendant’s injectable dye caused him to develop a debilitating disease, Nephrogenic Systemic Fibrosis (“NSF”), and the defendant failed to warn that its product could cause such injuries to renal-impaired persons. To support the failure-to-warn claim, plaintiff presented evidence that defendant was aware of four (4) related adverse-event reports (“AERs”) prior to plaintiff’s use of the injectable dye. Plaintiff also presented scientific evidence to include chemistry, toxicology and human studies to show the defendant was aware that its product was toxic to renal-impaired patients. After 12 days of testimony, the jury determined that defendant knew or should have known about the risks of its product in renal-impaired patients and failed to warn about them. The jury returned a verdict for plaintiff and awarded $4.5 million in compensatory damages, $1 million for economic loss, $3.5 million for noneconomic loss and $500,000 to plaintiff’s spouse for loss of consortium.

The defendant filed a motion for a new trial or remittitur on several grounds, two of which had a basis in PV. As to PV, the defendant first argued that the court should have given a limiting instruction on the use of AERs. While an AER tells the company that a patient experienced a harmful event after using its product, the defendant argued that AERs are not proof of causation. The court disagreed, however, and noted that “courts have held that AERs may be used to prove causation.” Further, the court noted that plaintiff did not present the AERs as evidence of causation; instead, plaintiff presented the AERs to show notice. The court held “it is entirely proper to use AERs to show that a drug manufacturer had notice of adverse events of the type suffered by plaintiffs in failure-to-warn claims.”

As to the second PV-related argument for a new trial, the defendant argued unfair prejudice based on the admission of a foreign AER. Plaintiff presented evidence that the defendant’s PV department received letters from a governmental agency in Denmark, and those letters concluded the product at issue caused NSF in a patient in 2003 (two years prior to plaintiff’s use of the product). The defendant acknowledged that the foreign AER was admissible to prove notice; however, the defendant argued it was unfairly prejudiced because plaintiff used the foreign AER to show causation. The court disagreed and found that plaintiff presented the foreign AER only to show notice. The court ultimately denied the defendant’s motion for a new trial.


In Fraser v. Wyeth, Inc., the plaintiff filed suit against the manufacturer of a hormone therapy medication and alleged failure to warn, failure to test and a host of other claims. Plaintiff alleged the defendant’s product caused her breast cancer, and plaintiff presented evidence that the defendant’s label failed to warn about the serious risks of breast cancer. Plaintiff presented testimony from her expert as to the industry standard for PV and how the defendant violated the standard by failing to include the severity of the risk of breast cancer and death on the product label. Specifically, plaintiff presented evidence that the defendant failed to study/test whether its product caused breast cancer in the face of mounting evidence (or “red flags”) that suggested it did. Such evidence included: internal documents that expressed concern as to whether defendant’s product caused an increase in the incidence of breast cancer, minutes from a 1990 meeting with an FDA advisory committee that concluded there was insufficient data to determine if the product posed an increased risk of breast cancer, testimony that the defendant failed to perform the necessary studies to answer the question in twenty-five (25) years, testimony that the defendant “ignored multiple red flags” about the risks of breast cancer from its product, and testimony that the defendant actively failed to perform studies and tests that would have required stronger warnings on its product.

Following three-and-a-half weeks of trial, the jury returned a verdict for plaintiff and awarded $3.75 million in compensatory damages, $250,000 to plaintiff’s spouse for loss of consortium and $1.7 million in punitive damages. The defendant filed a motion for a new trial and remittitur on several grounds, but the court denied the motion.


The purpose of PV is to ensure that all drugs are “used as safely as possible and that, where necessary, steps [are] taken to improve [their] safety and ensure that users are informed promptly.” The goal is straightforward, but much is required for the practice. To help provide a roadmap for “good PV practices,” the FDA issued a Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. While certainly not intended to substitute a much-needed, careful review of the FDA’s PV Guidance for Industry, the pointers below permit an initial self-check of your company’s PV practices.


According to the FDA, “good pharmacovigilance practice is generally based on acquiring complete data from spontaneous adverse-event reports.” Because the quality and completeness of an adverse event permits further investigation, the FDA “recommends that sponsors make a reasonable attempt to obtain complete information for case assessment during initial contacts and subsequent follow-up, especially for serious events.” Pharmaceutical companies understand the importance of collecting and reporting adverse events. After all, the regulations clearly require the collection and reporting of AERs to the FDA; see above. It is the suggestion that the manufacturers collect complete information that likely poses the problem for most PV departments.

Adverse events are collected from multiple sources to include consumers, healthcare professionals, medical literature and clinical studies. It can be difficult to collect complete information prior to submitting timely the AER to the FDA due to cooperation (or lack thereof) from the reporter, issues with receiving medical authorizations for the collection of medical records and other factors. To assist with the endeavor of collecting complete information, PV departments should have Standard Operating Procedures (“SOPs”) in place with directives regarding the information needed and the process for follow-up, documentation and storage of all information related to each adverse event. Equally important, PV departments need to ensure that staff members are actually following the SOPs. It is one thing to have an exercise plan, and another thing to activate and follow the plan. Get active.


According to the FDA, the goal of PV is to understand the nature, frequency and potential risk factors of adverse events associated with a product’s use to identify and evaluate safety signals. A safety signal is a concern about an excess number of adverse events compared to what a manufacturer expects to be associated with a product. Safety signals indicate the need for further investigation that may lead to the conclusion that a product causes a certain adverse event. While the FDA defines a safety signal as a concern about an excess number of adverse events, the FDA also notes that even a single case report can be viewed as a signal.

Identifying and evaluating safety signals require a manufacturer to go a step beyond collecting and reporting AERs to the FDA, and this additional step heavily relies on the collection of complete information. Once a PV department identifies a safety signal, the PV department should further evaluate it to determine if it presents a potential safety risk that requires additional action. An SOP regarding the identification and evaluation of safety signals may be useful to guide PV departments as to the frequency of review of collected AERs in the aggregate, the criteria to determine whether an event constitutes a safety signal, the process for potential next steps after identifying a safety signal to include determining whether the drug caused the event and requirements to document and store all related information. It bears repeating: it is one thing to have a plan, and another thing to activate and follow the plan. Get active.


There are multiple scenarios or occasions when a safety signal requires further investigation to include: the detection of new unlabeled adverse events, an increase in the severity of a labeled event, and the identification of a previously unrecognized at-risk population. Companies can further investigate those and other safety signals through randomized trials or nonrandomized observational studies. The FDA encourages companies “to consider all methods to evaluate a particular safety signal” and “choose the method best suited to the particular signal and research question of interest.” If further evaluation suggests that a safety signal is actually a potential safety risk, a company should submit the available safety information and analysis to the FDA and, if appropriate, propose to investigate the issue further and/or propose risk minimization actions such as product label changes.


Similar to other pharmaceutical issues, there are no clear-cut answers as to how much PV is enough. Even the FDA’s PV Guidance for Industry only “contains nonbinding recommendations.” But keep in mind that PV practices need to be active and consistent just like an effective workout plan. (Think: reps, reps, reps.) A pharmaceutical company should not, however, permit its PV practices to become so routine to the point that it misses a signal or red flag. In other words, a PV department cannot simply just “go through the motions.”

A PV department must be active. It is not easy, but getting in shape is never easy; however, the end-result is rewarding. Personally, you can wear your skinny jeans again. Professionally, you can help your company avoid becoming the “Biggest Loser” in court.