Chapter 16: Product Quality Complaints versus Adverse Event Reports

The United States Food and Drug Administration (FDA) places a significant amount of emphasis on the need for pharmaceutical companies to develop an effective approach to complaint management, including the establishment of well-written procedures. In fact, the Agency believes that complaint management is such a salient element for drug manufacturers that 21 CFR 211 has a dedicated section for the management and retention of complaint files, 21 CFR 211.198. Additionally, 21 CFR 314 expands on the post-market surveillance process under 21 CFR 314.80. Equally important is the reporting of adverse events through the use of the FDA Adverse Event Reporting System (FAERS). Although the management of complaint files and subsequent investigative process is distinctly different from the voluntary and in some cases mandatory reporting of adverse events through the use of FAERS, the two processes are linked.

Although FDA citation for failure to comply with 211.198 in a warning letter is a rare event, the Agency does occasionally cite such violations. More common is the citing of a failure to complete and/or document investigations pursued as a result of a complaint.

Importance of 21 cFr 314.80 and 21 CFR 314.81

As part of the drug application process, FDA wants to reinforce the need for review and reporting of adverse drug experiences (that is, adverse drug event), post-marketing studies, periodic reporting requirements, annual reporting requirements, and the importance of record keeping. Similarly to medical devices, drug manufacturers are required to report adverse drug experiences through the use of form FDA 3500A. Once a drug manufacturer becomes aware of an adverse drug experience, the company is required to perform a thorough investigation followed by the completion and submission of form 3500A; however, an exemption is noted for post-marketing studies. A 15-calendar-day window must be adhered to when reporting an adverse drug experience. Within 15 calendar days of initial receipt of information, the drug applicant is required to report every serious adverse drug experience and every unexpected adverse drug experience. The best practice is to notify FDA has soon as possible when such adverse drug experiences occur. Additionally, drug manufacturers are required to script procedures that delineate their processes for managing surveillance, receipt, evaluation, and reporting of post-marketing adverse drug experiences to FDA, including record keeping (10 years).

Additional reporting requirements delineated within 21 CFR 314 include periodic adverse drug experience reports and annual reports. Periodic adverse drug experience reports are required to be filed quarterly with FDA for a period of three years from the date the initial drug application was approved. These quarterly reports are due within 30 days after close of the quarter. At the discretion of the Agency, the quarterly reporting requirement can be extended. Annual reports are due to the Agency within 60 days of the anniversary date of the application approval.

Building an Effective Complaint Management System

The building of an effective complaint management system compliant with 21 CFR 211.198 commences with the establishment of written procedures. From a compliance perspective, FDA requires specific steps to be included in written procedures needed to support an effective complaint management system. When scripting procedures, a single well-written procedure delineating an organization’s approach to complaint management should be the goal. That being said, as a minimum, the following components of complaint management should be included in the procedure:

• An applicability statement for oral and written complaints.

• A mandatory review of all complaints by the quality function.

• A discussion on the complaint investigation process; all decisions made in regard to not performing an investigation need to be documented and supported by written rationale.

• A provision for reporting a complaint as an adverse event when deemed necessary (recommend creating a decision tree to support the reporting process).

• The need to create and retain a complaint file for each complaint.

• Complaint files (record) retention time periods (one year after the expiration of the drug product or one year after the complaint was received, whichever is longer).

Additionally, the complaint record must include the name and strength of the drug product, the lot number in question, the name of the individual and/or organization filing the complaint, the nature of the complaint, and the pharmaceutical company’s response to the complainant. Furthermore, if an investigation is performed, it is imperative that the result of the investigation be included in the complaint file. As previously stated, if the organization determines that a complaint investigation is not warranted, the decision not to investigate, including supporting rationale and the responsible person making the decision will need to be documented and retained in the complaint file. Finally, ensure that personnel tasked with complaint management duties are trained on the procedure and the training is documented.

Adverse Event Reporting—FAERS

FAERS is simply a database that captures adverse events and medication error reports submitted to the Agency. The primary purpose of FAERS is as a tool to support the Agency’s post-marketing safety and surveillance program. FDA uses the data to assess product safety concerns, and can use the data to drive regulatory actions necessary to protect the public health.

It should be noted that the reporting of adverse events and medication errors is considered voluntary for drug consumers and healthcare professionals; however, if a manufacturer of a drug product receives an adverse event report, the manufacturer is required by law to send the adverse event report to the agency.

Salient Differences between Complaints and Adverse Events

The first salient difference between complaints and adverse events is that not all complaints will result in the reporting of adverse events. Complaint files, however, must be opened and retained by drug manufacturers regardless of a report of an adverse event. A complaint that is identified as the cause of a serious and unexpected adverse drug experience is required to be reported to the Agency in accordance with 21 CFR 310.305.

The second salient difference between complaints and adverse events is that complaint files are managed by the drug manufacturer, and adverse events are entered into FAERS and tracked by FDA. The expectation is that the pharmaceutical companies perform a thorough review of all received complaints. The FDA is continuously monitoring FAERS for trends in adverse events as part of its post-market safety surveillance program. If the Agency determines that there are issues associated with a drug, it will take appropriate regulatory action. It is an immensely important task to keep accurate, current, and complete complaint file records.

The third salient difference between complaints and adverse events is that the reporting of adverse events is voluntary for healthcare providers and consumers; however, when complaints are reported to a drug manufacturer (verbal or written), entering the complaint into the complaint management system is not optional. It is strongly recommended that pharmaceutical manufacturers visit FAERS frequently to ensure that a negative trend pertaining to drug performance is not occurring.

Keys to Compliance

Drug manufacturers can pursue several steps to ensure that compliance issues never occur. To start, compliance is always rooted in a well-scripted procedure that complies with all 21 CFR 211.198 requirements. It is strongly recommended that complete and thorough complaint investigations occur for all reported complaints. If a decision is made not to investigate a complaint, the decision always needs to be documented and supported by a written rationale. Build an adverse event reporting decision tree into the procedure. It is always prudent to side with caution when it comes to reporting an adverse event. The data can be updated when the complaint investigation has been completed. Always take the position that FDA will review complaint files as part of any Agency inspection. Records must be complete, accurate, exhibit good documentation practices (GDP), and be available for review. Do not overlook the training piece. All individuals handling complaint calls, performing complaint investigations, or managing the complaint files must be adequately trained on the established procedure(s).