The MedWatch system was introduced in 1993 by David A. Kessler, MD, then commissioner of the U.S. Food and Drug Administration, for “voluntarily reporting a serious adverse event, product quality problem, product use error, or therapeutic inequivalence/failure that may be associated with the use of an FDA-regulated drug, biologic, medical device, dietary supplement or cosmetic.”1 While pre-marketing clinical trials can last several years and involve hundreds of patients, they can’t ensure the complete safety of a new drug, nor can they evaluate all adverse events. It’s not until a product is introduced to the market that a more realistic vision of its safety can be assembled over the ensuing months and even years.
Data drawn from the MedWatch system combined with required reports from manufacturers make up the Adverse Event Reporting System. Although the AERS system has registered more than 4 million reports since its inception,2 it’s clear that reporting rates in the United States are extremely low compared to other countries, and when patient populations are considered.3 This leaves an unknown number of serious adverse event reports without documentation.
Ophthalmologists have the breadth of knowledge needed to report adverse events and can assist the FDA with post-marketing drug safety surveillance. In this month’s column, we’ll refresh your knowledge of the MedWatch program and its benefits.
MedWatch was established with the intention of educating patients and health-care providers on the importance of identifying and reporting adverse events, facilitating the submission of those reports, and dispersing relevant safety information.4 However, adverse events aren’t always reported. Dr. Kessler proposed three reasons for under-reporting of serious adverse events.4 First, with an unexpected outcome of treatment, physicians may believe the event to be related to the course of the disease itself, not necessarily a product of the drug or device. This is especially relevant to physicians who observe patients with unique or rare diseases. Second, it’s not an ingrained practice for physicians to notify the FDA about adverse events or product problems. This is likely due to the historically bureaucratic nature of reporting procedures. It can be difficult to determine whether or not an adverse event has occurred or whether it should be reported. In some instances, an adverse event may not be considered until it has surfaced a second or third time, or until another physician has encountered it as well.
Ultimately, the goal of MedWatch is to make it easier for providers to report serious events, to specify what types of reports the FDA wants to receive, to inform the public about actions that have resulted from adverse event reporting and to increase physician awareness of drug- and device-related issues.4 This system is an asset—but we get out of it what we put in.
How to Report
There are several ways to report to MedWatch. Voluntary reports can be submitted using FDA Form 3500 by mail using the postage-paid form, by fax at 1 (800) 332-0178, or by submitting a report via telephone to 1 (800) 332-1088. In addition, the MedWatch website, fda.gov/medwatch, offers online reporting to facilitate the submission process. The necessary elements of the report include the reporter’s name, the suspect drug or device, a description of the adverse event and general patient information.5 Reports can also be sent to manufacturers, which are required by law to forward reports to the FDA. While patients and consumers are encouraged to fill out a report, it’s also suggested that the form be taken to their doctor for a more extensive outline. Alhough patients can give an account of the adverse event, it is the ophthalmologist who can make a detailed report.
One drawback prior to the inception of MedWatch was too many forms. Separate forms have been consolidated into one form, which makes it simpler to report and investigate adverse events.4 It’s estimated that the MedWatch form may take five to 10 minutes to complete. While this may seem like a short time, finding time to fill out the form is a challenge to accurate reporting, as spare time is rare.
What to Report
The FDA’s goal is to increase the reporting of serious events, rather than all adverse events.4 The FDA doesn’t want and most likely couldn’t handle information regarding every adverse event. The FDA defines an adverse event as any undesirable experience associated with the use of a medical product in a patient. When the patient outcome is any of the following the event should be reported:6
- a life-threatening condition;
- initial or prolonged hospitalization;
- disability; • congenital anomaly; or
- intervention is required to prevent permanent damage.
One might wonder how to determine whether an adverse event is serious enough to be reported. We’ve established some steps to aid in reporting.
First, anything unexpected or not already listed in the insert is likely to be a reportable adverse event. Second, any event that alters visual function and is sight-threatening or could lead to permanent impairment should be reported. Third, an increase in frequency of previously known adverse events is also cause for concern. Finally, these should all be instances of reasonable expectation of an adverse event associated with a drug or device.
These are cases in which an FDA-regulated product may be associated with a serious outcome. If the physician believes that a serious adverse event may be connected to the drug, then it should be noted in the patient’s file and a report submitted. By the same token, over-reporting is just as harmful as under-reporting, as it clutters a system designed to pinpoint critical information. Other events that warrant reporting include suspected counterfeit products, product contamination, and defective components or packaging.7
The term “adverse event” isn’t always helpful to physicians due to its somewhat vague nature, but it does provide context for the more clinically useful term “adverse drug reaction.”8
One paper defines an adverse drug reaction as “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts a hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.”9 In simple terms, adverse drug reactions are adverse events with a causal link to a drug;8 the physician need only suspect that the reaction is linked to the drug. As such, the FDA is interested in receiving reports on serious, unexpected adverse drug reactions from marketed drugs and devices.8 Equally important to report are adverse events from drugs or devices that have only been on the market for a short time (less than three years) because that’s often when the most critical problems are discovered.4 After a drug is marketed, voluntary reporting may be the best source of information the FDA has.
Issues with Reporting
The AERS was searched in September 2010 for adverse events of a topically administered ophthalmic product.5 Out of the 24,183 reports identified in this search, in 1993 there were 769 reports, vs. 1,960 for 2010 to date. While the search shows that the annual number of reports has increased since the start of MedWatch, it’s generally acknowledged that a small number of adverse events are actually reported. The “spontaneous” nature of reports submitted using the MedWatch/AERS system has strengths and limitations.
Unlike clinical trials, which are strictly controlled and documented, spontaneous reporting is subject to the influence of reporting biases.10 Some of these biases include whether or not reporting is a common practice for physicians, ambiguity of causality, time restraints, liability concerns of reporting, and publishing aspirations. Many of us are familiar with the Seven Deadly Sins; with those in mind, one study examined William H. W. Inman’s unique spin on the seven deadly sins that inhibit reporting:11
- Ignorance: “I am unsure how to report an ADR”;
- Diffidence: “I may appear foolish if I report a suspected ADR”;
- Fear: “I may expose myself to legal liability by reporting an ADR”;
- Lethargy: “I am too busy to report ADRs”;
- Guilt: “I am reluctant to admit that I caused harm”;
- Ambition: “I would rather collect cases and publish them”;
- Complacency: “Only safe drugs are marketed.”
Sometimes the FDA has to require reports. For example, in 2002 the FDA was prompted to caution consumers against using decorative contact lenses that hadn’t been prescribed and fitted by a qualified eye-care professional. These products are believed to cause corneal ulcers, leading to internal ocular infection if left untreated. The FDA requested adverse event reports resulting from the use of these lenses without professional consent.12
Why We Should Report
Historically, ophthalmologists have played a significant role in preventing adverse events by reporting potential hazards. Toxic anterior segment syndrome, a postop inflammatory reaction caused by a noninfectious substance,13 saw an increase in reported rates in 2006. In response, a TASS task force was formed and ophthalmologists were encouraged to report adverse events related to TASS. The causes of the outbreaks varied, though the FDA did recall a specific brand of BSS due to levels of endotoxin.14 Another example of MedWatch’s success lies in reports logged of corneal melts associated with generic NSAIDs. Members of the American Society of Cataract and Refractive Surgery reported several cases of complications, including corneal melts, mostly associated with generic diclofenac.15,16 Although there are no regulations regarding health-care professionals reporting, the benefits to patients are extensive.
Also the FDA has ways to keep effective drugs and devices on the market once a report is made. The most common strategy is label changes, which can range from boxed warnings, to added information in contraindications and dosage modifications. Recently, the precautions and adverse reactions were changed on both the Natacyn (natamycin ophthalmic suspension) 5% and Trusopt (dorzolamide hydrochloride ophthalmic solution) labels.17,18 While label changes don’t impact the safety of the drug, they do offer better safety education.
Even if a drug has been marketed for years, spontaneous reports still have value. After an event has been entered into the post-marketing database, it’s reviewed by an evaluator. If the hazard is deemed potentially significant, the database is examined for similar reports. Once action has been taken, the MedWatch program offers updated safety information. One great resource is the MedWatch website.
Spontaneous reporting of adverse events continues to play a role in ensuring the effectiveness of MedWatch; the more information generated about specific drugs and devices, the safer they can be. Ophthalmologists can enhance the effectiveness of MedWatch by using it as a reliable resource for contributing to drug and device safety.
Dr. Abelson, an associate clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at Schepens Eye Research Institute, consults in ophthalmic pharmaceuticals. Ms. Lafond is a medical writer at Ora in Andover.
1. Reporting Serious Problems to the FDA. http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm. Accessed September 2, 2010.
2. Adverse Event Reporting System (AERS) Statistics. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm070093.htm. Accessed September 2, 2010.
3. Edlavitch SA. Adverse drug event reporting. Improving the low US reporting rates. Arch Intern Med 1988;148:7:1499-1503.
4. Kessler DA. Introducing MEDWatch. A new approach to reporting medication and device adverse effects and product problems. JAMA 1993;269:21:2765-2768.
5. Direct Communication with FDA-Normal S. Marks MD, MedWatch, 29 September 2010.
6. What is a Serious Adverse Event? http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm. Accessed September 2, 2010.
7. Product Problems. http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053091.htm. Accessed September 27, 2010.
8. Nebeker JR, Barach P, Samore MH. Clarifying adverse drug events: A clinician’s guide to terminology, documentation and reporting. Ann Intern Med 2004;140:10:795-801.
9. Edwards IR, Aronson JK. Adverse drug reactions: Definitions, diagnosis, and management. Lancet 2000;356:9237:1255-1259.
10. Landow L. Monitoring adverse drug events: The FDA MedWatch reporting system. Reg Anesth Pain Med 1998;23:6 Suppl 2:190-193.
11. Belton KJ, Lewis SC, Payne S, et al. Attitudinal survey of adverse drug reaction reporting by medical practitioners in the UK. Br J Clin Pharmacol. 1995;39:3:223-226.
12. FDA Public Health Web Notification: Non-Corrective Decorative Contact Lenses Dispensed Without a Prescription. http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/PublicHealthNotifications/UCM062171. Accessed September 15, 2010.
13. Mamalis N, Edelhauser HF, Dawson DG, et al. TASS. J Cataract Refract Surg 2006;32:2:324.
14. Cytosol Laboratories, Inc. BSS. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150520.htm. Accessed December 10, 2010.
15. Lin JC, Rapuano CJ, Laibson PR, Eagle RC Jr., Cohen EJ. Corneal melting associated with use of topical nonsteroidal anti-inflammatory drugs after ocular surgery. Arch Ophthalmol 2000;118:8:1129.
16. Flach AJ. Corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs. Trans Am Ophthalmol Soc 2001;99:205-210;discussion 210.
17. Natacyn (natamycin ophthalmic suspension) 5% July 2008. http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety-RelatedDrugLabelingChanges/ucm121947.htm. Accessed September 2, 2010.
18. Trusopt (dorzolamide hydrochloride ophthalmic solution). http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm218885.htm. Accessed September 2, 2010.