Pharmacovigilance in practice: erythropoiesis-stimulating agents

Abstract

Pharmacovigilance (PV) is the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or other problems related to medical products after they have been licensed for marketing. The purpose of PV is to advance the safe use of marketed medical products. Regulatory agencies and license holders collaborate to collect data reported by health care providers, patients, and the public as well as data from systematic reviews, meta-analyses, and individual clinical and nonclinical studies. They validate and analyze the data to determine whether safety signals exist, and if warranted, develop an action plan to mitigate the identified risk. Erythropoiesis-stimulating agents (ESAs) provide an example of how PV is applied in reality. Among other approved indications, ESAs may be used to treat anemia in patients with chemotherapy-induced anemia. ESAs increase hemoglobin levels and reduce the need for transfusions; they are also associated with a known increased risk of thromboembolic events. Starting in 2003, emerging data suggested that ESAs might reduce survival. As a result of PV activities by regulatory agencies and license holders, labeling for ESAs addresses these risks. Meta-analyses and individual clinical studies have confirmed that ESAs increase the risk of thromboembolic events, but when used as indicated, ESAs have not been shown to have a significant effect on survival or disease progression. Ongoing safety studies will provide additional data in the coming years to further clarify the risks and benefits of ESAs.

Keywords: Adverse event; chemotherapy induced anemia; erythropoiesis-stimulating agent; pharmacovigilance; safety signal.

Figure 1

Pharmacovigilance overview. After a drug is approved for use in clinical practice, assessment of its risk and benefits is a continuous process based on new data obtained through various pharmacovigilance activities. License holders work closely with regulatory agencies to analyze these data and respond with appropriate action, which might include label changes, risk mitigation activities, and required additional (safety) studies to further characterize the drug.

Figure 2

Regulatory history of ESAs in the United States. After approval for CIA, three FDA oncologic drug advisory meetings (ODACs) were conducted to review safety data from studies of ESAs used in patients with cancer. ESAs in cancer are currently indicated only for patients receiving concomitant chemotherapy; the U.S. label also specifies that ESAs should not be used when the anticipated treatment outcome is cure. CIA, chemotherapy-induced anemia; CT, chemotherapy; ESA, erythropoiesis-stimulating agent; FDA, Food and Drug Administration; HNSCC, head and neck squamous cell carcinoma; NSCLC, non–small-cell lung cancer; ODAC, oncology drug advisory committee; RCT, randomized controlled trial; RT, radiotherapy; SA, supplemental approval for chemotherapy-induced anemia; SCLC, small-cell lung cancer.

Figure 3

Ongoing safety studies in metastatic breast cancer and non–small-cell lung cancer ,. NSCLC, non–small-cell lung cancer; SC, subcutaneous.