1. Purpose and Scope of 21 CFR Part 600.80

This regulation applies to:

• Biologic manufacturers and license holders (BLA holders).
• It ensures that any adverse experiences related to a biologic product are reported to the FDA in a timely and organized manner.

The purpose is to protect public health by monitoring adverse experiences that occur after the product is on the market, detecting any new safety concerns, and taking action if needed.

2. Key Definitions

Several critical terms are defined in 21 CFR Part 600.80:

• Adverse Experience: Any adverse event associated with the use of a biologic in humans, regardless of whether it is considered to be related to the product.
  • Serious Adverse Experience: An adverse experience that results in any of the following:
    • Death
    • Life-threatening event
    • Inpatient hospitalization or prolongation of existing hospitalization
    • Persistent or significant disability/incapacity
    • Congenital anomaly/birth defect
    • Any event that requires medical or surgical intervention to prevent one of the outcomes above.
  • Unexpected Adverse Experience: An event not listed in the product’s labeling or differs in nature, severity, or specificity from the information in the labeling.

3. Reporting Responsibilities Under 21 CFR Part 600.80

BLA holders have the responsibility to monitor, collect, and submit reports on adverse experiences related to their biologic products. Reporting is divided into expedited and non-expedited processes.

A. Expedited Reporting (15-Day Alert Reports)

For serious and unexpected adverse experiences, the BLA holder must submit a 15-day alert report to the FDA.

• What is required?:
  • The company must submit the report to the FDA within 15 calendar days of becoming aware of a serious and unexpected adverse event.
  • This report must provide as much detailed information as possible, including the patient’s demographics, the nature of the adverse event, and the biologic product used.
• Follow-Up Reports:
  • After the initial 15-day alert report, the company must submit follow-up reports if additional or updated information becomes available about the event, within 15 days of receiving new information.
  • Follow-up reports help the FDA get a complete picture of the adverse experience, as initial reports may not have all details available.

B. Periodic Reporting (Non-Expedited)

For adverse events that are non-serious or expected, the BLA holder must include these in periodic safety reports.

• Quarterly and Annual Reporting:
  • For the first three years after approval of the biologic, the company must submit quarterly safety reports. These reports include a summary of all adverse experiences, both serious and non-serious.
  • After three years, the company can switch to annual reports that summarize the previous year’s adverse experience data.

C. International Reporting

• BLA holders must also report adverse events from sources outside the United States if they are serious and unexpected. This includes adverse experiences reported in foreign clinical trials or marketing environments.

4. Content of Adverse Experience Reports

The adverse experience report submitted under 21 CFR Part 600.80 must include specific information, including:

• Patient Information: Non-identifying details such as age, gender, and relevant medical history.
• Product Information: Details about the biologic product, including the lot number, dosage, route of administration, and duration of therapy.
• Description of the Adverse Event: A detailed clinical description of the adverse experience, including symptoms, outcomes, and treatment provided.
• Outcome: The outcome of the adverse experience (e.g., recovery, hospitalization, or death).
• Reporter Information: Contact information for the healthcare professional or other individual who reported the event.

5. Electronic Reporting Requirements

Biologic manufacturers are required to submit adverse event reports to the FDA electronically, similar to other products regulated by the FDA.

• FDA Adverse Event Reporting System (FAERS): This is the electronic system used to submit adverse event reports related to biologics, similar to the process used for drugs.
• Electronic Submissions: Reports must follow the ICH E2B format, an international standard for electronic safety reporting that is used globally for pharmacovigilance.

6. Recordkeeping Requirements

BLA holders must maintain records of all adverse experience reports for a minimum of 10 years. These records should include:

• All data related to adverse experiences, including raw data, source documents, and follow-up information.
• Internal documents related to the evaluation and investigation of adverse events.
• Correspondence with the FDA regarding adverse experiences.

The records should be readily available for FDA inspection if required.

7. FDA’s Role and Risk Assessment

The FDA monitors all adverse event reports submitted under 21 CFR Part 600.80. The FDA uses these reports to assess the ongoing safety of biologics in the post-marketing environment. This process is part of post-marketing surveillance and may lead to regulatory actions if a safety signal is detected.

The FDA may take the following actions based on adverse experience reports:

• Labeling changes: If new risks are identified, the FDA may require updates to the product's labeling to include new safety information.
• Safety communications: The FDA may issue warnings or other safety communications to healthcare professionals and the public.
• Risk Evaluation and Mitigation Strategies (REMS): The FDA may require a REMS for certain biologics that have been associated with new or previously unrecognized risks.
• Product recalls or withdrawals: In extreme cases, the FDA can mandate a product recall or withdraw a product’s approval if the risks outweigh the benefits.

8. Compliance and Enforcement

Non-compliance with 21 CFR Part 600.80 can result in various enforcement actions by the FDA. These actions include:

• Warning Letters: Issued to companies that fail to comply with reporting obligations or timelines.
• Seizure of products: The FDA may seize biologic products that are deemed unsafe due to unreported adverse experiences.
• License Revocation: In severe cases, failure to comply with adverse event reporting requirements could lead to the revocation of a company’s Biologics License (BLA), effectively prohibiting the sale of the biologic product.

9. Relation to Other Pharmacovigilance Requirements

• 21 CFR Part 600.80 works in conjunction with other pharmacovigilance regulations, including those related to Risk Evaluation and Mitigation Strategies (REMS) and Post-Marketing Requirements (PMRs).
• Biologic manufacturers are also expected to follow international reporting standards, such as those outlined by the International Council for Harmonisation (ICH), particularly the E2E Pharmacovigilance Guidelines for periodic safety reports.

10. Industry Best Practices for Compliance

To comply with 21 CFR Part 600.80, biologic companies typically implement several best practices, including:

• Automated Pharmacovigilance Systems: These systems allow for efficient capture, evaluation, and reporting of adverse experiences.
• Signal Detection and Risk Management: Biologic companies often employ advanced signal detection methods to identify emerging safety issues as early as possible.
• Internal SOPs (Standard Operating Procedures): Companies establish clear procedures to ensure staff are aware of reporting requirements, timelines, and the type of information required for each report.
• Training Programs: Regular pharmacovigilance training ensures that employees recognize adverse events and understand how to report them correctly and promptly.

Conclusion:

21 CFR Part 600.80 is a critical FDA regulation that governs the post-marketing safety reporting for biologic products. The rule ensures that biologics manufacturers continuously monitor the safety of their products, report serious and unexpected adverse events promptly, and keep the FDA informed of any new risks associated with their products. Compliance with this regulation is essential for maintaining a Biologics License and ensuring the ongoing safety of biologic therapies on the market.