nature publishing group THE RED SECTION 501 How the FDA Manages Drug Safety With Black Box Warnings, Use Restrictions, and Drug Removal, With Attention to Gastrointestinal Medications Eli D. Ehrenpreis, MD1, Arthur A. Ciociola, PhD2, Prasad M. Kulkarni, MD, FACG3 and the FDA-Related Matters Committee of the American College of Gastroenterology Am J Gastroenterol 2012;107:501–504; doi:10.1038/ajg.2011.449 Introduction the FDA developed additional activities to ies to define and clarify adverse events. A Physicians play a key role in helping the enhance medical product safety (4). common strategy involves requiring man- Food and Drug Administration (FDA) The FDA evaluates all medical products ufacturers to change drug labeling, also monitor the safety of medical products. before and after approval. During product known as “prescribing information” or the Physicians follow the principle of Hip- development, the manufacturer performs “package insert.” A black box warning on pocrates, primum non nocere (“first, do in vitro, animal, and human studies. Pre- a drug—the most serious type of label- no harm”). Some adverse drug reac- market testing takes place in a sequential ing change—is designed to call attention tions (ADRs) are expected due to known fashion. Typically, testing begins with nor- to serious or life-threatening risk. While mechanisms of action. Others may be mal volunteers and then proceeds to stud- the FDA is considering labeling changes idiosyncratic or not previously identified ies to define the lowest effective dose, then for a drug, it may release an Early Com- and therefore may not be preventable. The to define patient populations with the opti- munication About an Ongoing Safety FDA’s post-approval safety surveillance mal risk–benefit profile. However, because Review. After the review is completed, the activities are an attempt to control these the total number of subjects evaluated is FDA may issue a Public Health Advisory unexpected ADRs. relatively small (<10,000), rare ADRs may providing updated drug safety informa- not be detected before approval. The num- tion. The FDA may also require the drug Background ber of patients with comorbid conditions manufacturer to send a “Dear Healthcare The FDA is responsible for assuring the for whom safety data are collected is usu- Professional” letter outlining safety issues safety, efficacy, and security of human ally insufficient to allow for a robust risk with advice for corrective action. A medi- and veterinary drugs, biological prod- evaluation. As a result, safety information cation guide, an instruction sheet provided ucts, medical devices, foods, cosmetics, collected in the postmarketing period is of to the patient by the pharmacist, may be and radiation-emitting products (1–5). In considerable importance (13). The FDA used. If these educational strategies are 1938, Congress passed the Federal Food, launched the MedWatch Safety Informa- inadequate, additional management tools Drug, and Cosmetic Act after elixir of tion and Adverse Event Reporting System are required. These Risk Evaluation and sulfanilamide (containing ethylene gly- (AERS) in 1993 to stimulate voluntary Minimization Strategies are designed to col) caused 107 deaths (5–8). The act reporting of ADRs by health-care profes- ensure that the benefits of the product out- required companies to prove a product’s sionals and patients. weigh patient risk (4). They may also limit safety (2,9,10). Phocomelia and other birth who prescribes or dispenses drugs and defects were observed following maternal How the FDA manages the safety of a require physician training, laboratory test- use of thalidomide, prompting passage of drug ing, or registration and tracking of patients the Kefauver–Harris Amendment in 1962. If the FDA identifies a previously unrec- receiving the drug. This required pharmaceutical manufac- ognized safety issue, a variety of tools are At times, further restriction or removal turers to report all ADRs directly to the available to keep effective drugs and devices of a product from the market will be man- FDA (11,12). In 2007, following a series on the market while reducing risk of harm. dated. However, if it is determined that a of highly publicized drug withdrawals, The FDA may request further clinical stud- drug is longer safe to remain on the mar- 1Gastroenterology and Endoscopy, Highland Park Hospital, NorthShore University Health System, Chicago, Illinois, USA; 2Pharmaceutical Regulatory Strategy, Process, and Policy, Bausch+Lomb, Madison, New Jersey, USA; 3University of South Florida Physician’s Group, Tampa, Florida, USA. Correspondence: Eli D. Ehrenpreis, MD, Highland Park Hospital, NorthShore University HealthSystem, 777 Park Avenue, West Highland Park, Illinois 60035, USA. E-mail: ehrenpreis@ gipharm.net © 2012 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 502 THE RED SECTION ket, the FDA will request that the product is tions for gastrointestinal conditions that Tegaserod withdrawn. The FDA has the legal author- have undergone safety alerts. Tegaserod is a 5-HT4 receptor partial ago- ity to immediately withdraw authorization nist manufactured by Novartis under the to market a drug in the United States. In Metoclopramide name Zelnorm. Activated 5-HT4 recep- extreme situations, products may be seized Metoclopramide is a dopamine D2 recep- tors in the gastrointestinal tract stimulate to prohibit further sales. Withdrawal of a tor antagonist in the chemoreceptor intestinal peristalsis and secretion and drug is communicated to the public by the trigger zone as well as a mixed 5-HT3 inhibit visceral sensitivity. Tegaserod was manufacturer using normal media chan- receptor antagonist/5-HT4 receptor ago- approved for the management of abdomi- nels. The Recalls, Market Withdrawals, nist and cholinomimetic. Metoclopramide nal discomfort, bloating and constipa- and Safety Alerts website (http://www.fda. increases antral contractions and small- tion associated with IBS (July 2002), and gov/Safety/Recalls/default.htm) also gives bowel peristalsis and is a treatment for chronic idiopathic constipation (August information about withdrawn drug prod- nausea and vomiting. It has also been used 2004). In March 2007, the FDA suspended ucts. The FDA also provides MedWatch as a prokinetic agent. Although a variety marketing and sales of tegaserod because Safety Alerts and Drug Safety Podcasts and of ADRs are associated with metoclo- a safety analysis found increased myocar- publishes a Drug Safety Newsletter. Pre- pramide, the development of tardive dys- dial infarction, stroke (cerebrovascular scribing information is available on Dai- kinesia (TD) prompted an FDA black box accident), and unstable angina in patients lyMed of the National Library of Medicine warning in February 2009 (14). Chronic treated with tegaserod compared with pla- (http://dailymed.nlm.nih.gov/dailymed/ treatment with metoclopramide can cause cebo. Subsequent observational studies about.cfm). TD, characterized by involuntary move- did not concur (18). In July 2007, the FDA These regulatory actions are based on the ments of the extremities, lips, tongue, and permitted the restricted use of tegaserod evaluation of postmarketing ADRs. Data face and eyes. TD is associated with cen- under a treatment–investigational new are obtained from a number of sources, trally acting dopamine blockers, includ- drug (T-IND) protocol for IBS with con- including the mandatory safety reporting ing phenothiazines (e.g., thorazine and stipation and chronic idiopathic constipa- from the manufacturer, the AERS, pub- prochlorperazine). Development of TD is tion in women younger than 55. Novartis lished literature, and clinical and non- related to the duration of metoclopramide subsequently abandoned this T-IND. Zel- clinical studies. Unfortunately, fewer than use and its cumulative dose. TD has no norm may be available in emergency situa- 10% of all adverse safety events with medi- known treatment and is often irreversible. tions that are immediately life-threatening cal products are reported to the FDA (13). The elderly, especially women, are at high- or that qualify for hospitalization. Physi- The AERS system has also been publicly est risk. The black box warning states that cians with patients who may qualify for criticized for taking years to understand prolonged treatment with metoclopramide emergency treatment with Zelnorm may the risk profile of a drug and delaying (longer than 12 weeks) should be avoided contact the FDA’s Division of Drug Infor- removal of products from the market. In in all but rare cases in which the therapeu- mation at [email protected]. an effort to improve the postmarketing tic benefit outweighs the risks of develop- surveillance, the FDA has mandated that ing TD. Cisapride drug advertisements encourage patients Cisapride, a serotonin-4 (5-HT4) receptor to report ADRs. In addition, the FDA has Alosetron agonist (and partial 5-HT3 antagonist), now made the reporting form simpler and Alosetron is an antagonist of serotonergic promotes gastric motility by enhancing more accessible to patients and health-care 5-HT3 receptors of the enteric nervous release of acetylcholine at the myenteric providers. The FDA also initiated devel- system. Alosetron diminishes gastro- plexus. Cisapride (marketed as Propulsid) opment of the Sentinel System in 2008, a intestinal motility, decreases noxious was used between 1993 and 1999 for the nationwide electronic system for postmar- sensations, slows colonic