key: cord-1006728-8yleernc
authors: Janusziewicz, Ashlee N; Glueck, Shannon N; Park, Sophia Y; Nguyen, Dien N; Rimmel, Susan C; Cascio, Laurelle A; Doh, Gina Y; Martin-Yeboah, Garrette F
title: A pharmacist-driven Food and Drug Administration incident surveillance and response program for compounded drugs
date: 2021-04-23
journal: Am J Health Syst Pharm
DOI: 10.1093/ajhp/zxab176
sha: 6a8b001acb01430b7d447c90af9ac8b39e9f957d
doc_id: 1006728
cord_uid: 8yleernc

DISCLAIMER: In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: To provide an overview of compounding under sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act, and to describe the pharmacist’s role within the US Food and Drug Administration’s (FDA’s) Compounding Incidents Program, whose efforts are aimed at protecting the public against poor-quality compounded drugs through surveillance, review and response to adverse events and complaints. SUMMARY: Compounded drugs may serve an important medical need for patients who cannot be treated with medications approved by FDA; however, compounded drugs are not approved by FDA and are not subject to premarket review for safety, efficacy, or manufacturing quality; thus, they may pose safety risks to patients. Prompt reporting of adverse events or complaints related to compounding is important in identifying these risks and implementing safeguards to protect the public. FDA’s Compounding Incidents Program consists of a team of pharmacists dedicated to the surveillance and review of adverse events and complaints and follow-up actions related to safety risks associated with compounded drugs. Pharmacists are a vital component of FDA’s Compounding Incidents Program, utilizing their clinical skill set and regulatory knowledge to review and act on safety issues that affect public health. CONCLUSION: As FDA continues to expand the Compounding Incidents Program and its efforts to protect the public against poor-quality compounded drugs, we encourage the continued submission of adverse event reports by healthcare professionals and consumers to FDA’s MedWatch reporting system in addition to adverse event reporting compliance by outsourcing facilities.

allergy to an inactive ingredient in a commercial product, or if a particular dose, dosage form, or drug combination is not commercially available, a compounded drug would be necessary to meet that particular patient's needs. However, compounded drugs are not approved by FDA and therefore have not undergone premarket review by the agency for safety, efficacy, or manufacturing quality. As such, compounded drugs can pose health risks.

For example, compounded drugs made using poor-quality compounding practices may be sub-or superpotent, contaminated, or otherwise adulterated. FDA has historically received many reports of cases of serious patient injury linked to poor-quality compounded drugs.

The risks associated with compounded drugs were brought to the forefront in 2012 when contaminated intrathecal and intra-articular drugs compounded at the New England Compounding Center in Massachusetts led to more than 750 cases of fungal meningitis and more than 60 patient deaths in 20 states. 2 In 2013, in response to the fungal meningitis outbreak, Congress passed the Drug Quality and Security Act (DQSA), which (as described further below) amended the Federal Food, Drug, and Cosmetic Act (FD&C Act). As a result of the DQSA, 2 provisions in the FD&C Act apply to human drug compounding, sections 503A and 503B. 3, 4 Section 503A, which had initially been added to the FD&C Act by the Food and Drug Administration Modernization Act of 1997, describes the conditions that must be met for A c c e p t e d M a n u s c r i p t drug products compounded by a licensed pharmacist in a state-licensed pharmacy or federal facility, or by a licensed physician, to qualify for exemptions from 3 key provisions of the FD&C Act. These provisions pertain to approval of drugs under new drug applications (NDAs) or abbreviated new drug applications (ANDAs) (section 505 of the FD&C Act 5 ), labeling of drugs with adequate directions for use (section 502(f)(1) of the FD&C Act 6 ), and current good manufacturing practice (CGMP) requirements (section 501(a)(2)(B) of the FD&C Act 7 ).

In 2013, the DQSA eliminated the provisions of section 503A concerning advertising of compounded drugs that had been found to be unconstitutional, thereby removing uncertainty about the validity of section 503A, and added section 503B to the FD&C Act in response to the 2012 fungal meningitis outbreak.

Section 503B describes the conditions that must be met for drug products compounded in an outsourcing facility under the supervision of a pharmacist to qualify for exemptions from sections 505, 502(f)(1), and the drug supply chain security requirements (section 582) of the FD&C Act. 5, 6, 8 Outsourcing facilities remain subject to CGMP requirements and must meet certain other conditions, such as reporting adverse events and providing FDA with certain information about the products they compound. A compounder engaged in sterile compounding operations may elect to register as an outsourcing facility, and FDA inspects these facilities according to a risk-based schedule. Approximately 73 entities are registered with FDA as outsourcing facilities. 9 Information regarding outsourcing facilities, including past product reports, is available on FDA's website. 10 The website also includes information about inspections, recalls, and other actions regarding compounding. 11 Since enactment of the DQSA, FDA has devoted resources to implement many programs aimed at enforcing the provisions of the FD&C Act in an effort to protect the public from unsafe and poor-quality compounded drugs. FDA works with stakeholders, such A c c e p t e d M a n u s c r i p t as state regulatory authorities, to ensure transparency and collaboration on important safety issues. Some examples of state regulatory authorities that FDA has communicated and collaborated with include state boards of pharmacy, departments of health, and nursing boards and chiropractic boards, to name a few. 12 Due to the safety issues and risks posed by poor-quality compounded drugs, the Compounding Incidents Program was conceived to track, review, take action, and address adverse events and complaints.

The Compounding Incidents Program includes dedicated pharmacists whose mission is to protect the public against unsafe compounded drugs. This is accomplished through surveillance, research and follow-up, and action to address incidents as well as through communications to raise stakeholder and public awareness of safety issues related to

compounding. An incident is either a report of an adverse event or a complaint associated with a compounded drug, including product quality issues. FDA defines an adverse event as any untoward medical occurrence associated with the use of a drug in humans, whether drug related or not. 13 A complaint is a report not related to an adverse event regarding topics such as potential copies of FDA-approved drugs and potential adulteration issues, such as insanitary conditions.

Surveillance. The role of the pharmacist in the Compounding Incidents Program is vital to the process of surveilling incidents related to compounded drugs. A report generated from FDA's Adverse Event Reporting System (FAERS) that identifies cases related to compounded drugs or compounding firms is reviewed daily. This report includes voluntary MedWatch reports from consumers, patients, and healthcare professionals, as well as mandatory reports from outsourcing facilities. Review of the reports can be complex A c c e p t e d M a n u s c r i p t and time-consuming due to the large proportion of reports (>90%) that appear to be related to compounding but are "false positives" because the word "compounded" appears on the report in a different context or a reporter mistakenly selects "compounded" as the product type on a MedWatch form concerning an FDA-approved, commercially manufactured product. A pharmacist's clinical expertise is important to correctly identify reports of safety and product quality issues associated with compounded drugs.

In addition to MedWatch reports, the pharmacist also reviews reports from other sources, such as FDA's Division of Drug Information and state regulatory authorities. Once a case has been reviewed and determined to be compounding related, the case is then entered into a database. The database provides the ability to search for trends that may alert the Compounding Incidents Program to potential safety issues associated with compounded drugs.

Program lack the information necessary to thoroughly assess the incident. Part of the investigative process involves the pharmacist contacting the reporter to gather additional information. The pharmacist also conducts research on the compounding pharmacy or 503B outsourcing facility that made the product, including FDA history regarding past incidents, FDA also identified the presence of an impurity known as diethylene glycol (DEG), a central nervous system depressant and potent kidney and liver toxin commonly used in antifreeze and brake fluids, in an amount of 0.21% weight per weight. As a result of these investigations into the 2 incidents, an inspection of ImprimisRx was initiated and the curcumin emulsion products were recalled. In addition, FDA's first-ever CRA was issued to share its findings about these 2 cases involving compounded curcumin. 14 in fiscal year 2020 we saw a significant increase in the number of reports received. Figure 2 shows an 81% year-over-year increase in the volume of reports in quarter 1 and a 123% increase in quarter 2. Outreach efforts targeting outsourcing facilities and the public and our collaborative work with the state boards of pharmacy have helped to increase the awareness and importance of reporting adverse events associated with compounded drugs.

In response to many of these incident reports and other program inspectional initiatives, from 2013 to 2020 the Compounding Program worked with FDA's Office of Regulatory Affairs to conduct over 780 inspections, issue over 245 warning letters advising compounders of significant violations of federal law, issue more than 160 letters referring A c c e p t e d M a n u s c r i p t inspectional findings to state regulatory agencies, and oversee over 250 recalls involving compounded drugs; and worked with the Department of Justice on more than a dozen injunctions, amongst other civil and criminal enforcement actions. As FDA continues to be alerted to potential safety issues with compounded drugs, the Compounding Incidents Program expands on its processes and services to discover potential risks associated with compounded drugs and to implement safeguards to protect the public. 

Compounded drugs are not FDA approved and are not subject to the extensive rigors of the regulatory approval process to ensure safety, efficacy, and quality before they reach patients. FDA has identified many cases of serious patient injury linked to poor-quality compounded drugs.

Outsourcing facilities are required to submit all reports of serious and unexpected adverse events associated with the use of their compounded prescription drug products to FDA. These reports must be submitted electronically through the Safety Reporting Portal or Electronic Submissions Gateway, in accordance with section 503B of the FD&C Act and FDA's guidance document titled "Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act." 4, 18 Traditional pharmacies, such as state-licensed pharmacies and hospital pharmacies, operate in accordance with section 503A of the FD&C Act; however, generally, they do not submit reports of adverse events A c c e p t e d M a n u s c r i p t associated with their compounded drugs to FDA. Therefore, FDA may not be aware of certain adverse events or quality issues, which is why voluntary reporting of adverse events by healthcare professionals and consumers through MedWatch is critical. Such reports enable FDA to identify safety signals and potential quality issues associated with compounded drugs that are not captured through the required reporting by outsourcing facilities.

Information related to compounded drugs received through voluntary MedWatch report submissions is individually reviewed by the pharmacist in the Compounding Incidents Program to determine if FDA action is warranted. Often, the investigation of adverse event reports reveals substandard processes or conditions at an outsourcing facility or a traditional pharmacy that may call into question the quality of the compounded drugs produced in the facility. In order to ensure the Compounding Incidents Program receives the reports for review and investigation, products must be appropriately designated as compounded in the "product type" section of the report. Figure 3 provides helpful tips on how to report an adverse event associated with a compounded drug on the MedWatch form. FDA is grateful to healthcare professionals and consumers who have submitted adverse event reports for compounded drugs and encourages their continued submission via the MedWatch portal. 19 We understand there are limitations that may make reporting difficult (eg, limited information about the event, time constraints on medical staff who are busy caring for patients). In order to submit a MedWatch report, reporters should provide a description of the adverse event or problem, the name of the suspect product, and their name, at minimum. If an adverse event or safety issue associated with a compounded product is suspected, it can be reported to FDA by telephone at 1-800-FDA-1088 or submitted online at https://www.accessdata.fda.gov/scripts/medwatch/.

A c c e p t e d M a n u s c r i p t MedWatch reports that FDA receives are housed in the FAERS database, which is designed to support the agency's safety surveillance program. The FAERS Public Dashboard is an interactive, Web-based tool specifically designed for public viewing and querying of FAERS data. 20 It is intended to expand access to the public and increase the transparency of the adverse event reports submitted to FDA.

Compounded drugs can meet important medical needs for patients who cannot be treated with FDA-approved drugs. However, compounded drugs may pose unique risks to patients because they do not undergo premarket review by FDA for safety, efficacy, or quality. Prompt, detailed, and accurate reporting of adverse events or complaints related to compounded drugs is imperative to enable FDA to protect the public against unsafe A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 

US Food and Drug Administration

Multistate outbreak of fungal meningitis and other infections

Federal Food, Drug, and Cosmetic Act

Federal Food, Drug, and Cosmetic Act

Federal Food, Drug, and Cosmetic Act, 21 USC §355

Federal Food, Drug, and Cosmetic Act, 21 USC §352(f)(1)

Federal Food, Drug, and Cosmetic Act

Federal Food, Drug, and Cosmetic Act

Registered outsourcing facilities

Information for outsourcing facilities

Compounding: inspections, recalls, and other actions

Compounding information for states

FDA investigates two serious adverse events associated with ImprimisRx's compounded curcumin emulsion product for injection

Guidance for industry: safety considerations for container labels and carton labeling design to minimize medication errors

United States Pharmacopeia

Differences in strength expression on product labels of compounders and conventional manufacturers may lead to dosing errors

Guidance for industry: adverse event reporting for outsourcing facilities under section 503B of the Federal Food, Drug, and Cosmetic Act

MedWatch online voluntary reporting form

FDA Adverse Event Reporting System (FAERS) Public Dashboard

The authors thank Frances Gail Bormel, of the [department/division]; Kathleen Anderson, of the [department/division]; Maria Edisa Gozun, of the Division of Compounded Drugs; and Joanne Berger, of the FDA Library, for manuscript editing assistance.

The authors have declared no potential conflicts of interest.

A c c e p t e d M a n u s c r i p t