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Home » REMS Audits and Inspections: What You Need to Know

REMS Audits and Inspections: What You Need to Know

Risk Evaluation and Mitigation Strategies Audits Inspections

Risk Evaluation and Mitigation Strategies (REMS) are special safety programs required by the U.S. Food and Drug Administration (FDA) for certain drugs and biologics with serious safety concerns. These programs are designed to ensure that a product’s benefits outweigh its risks. REMS may include strategies such as restricted distribution, prescriber certification, patient education, training, and ongoing monitoring and reporting. These requirements are customized for each product and can range from simple Medication Guides to complex systems involving multiple stakeholders. This article provides an overview of REMS inspections and audits, outlines key focus areas for FDA reviewers and inspectors, and offers practical strategies for compliance.

 

Although REMS are relatively rare—fewer than 100 approved REMS programs are active today—the burden of compliance for affected companies is significant. Manufacturers and application holders are required to implement these programs as approved, track their effectiveness, and submit periodic assessments to the FDA. Inadequate REMS implementation can lead to regulatory consequences, including warning letters, product seizures, and even market withdrawal. Consequently, the FDA has increased its oversight of REMS programs, including routine and for-cause audits and inspections. 

Regulatory Implications of REMS Noncompliance

REMS are legally enforceable under the Federal Food, Drug, and Cosmetic Act (FDCA). Failure to comply with REMS requirements can result in a product being deemed misbranded, subjecting the manufacturer to regulatory action. The FDA has the authority to issue warning letters, seek injunctions, impose civil monetary penalties, and withdraw product approval if REMS obligations are not met. 

 

In 2021, the FDA withdrew approval for five generic versions of opioid analgesics after the sponsors failed to comply with the shared REMS program. The agency stated that the manufacturers did not demonstrate that their products would be dispensed with appropriate restrictions in place. Similarly, in 2017, Novo Nordisk agreed to pay $58.6 million to resolve allegations that it downplayed REMS-related risks for its diabetes drug Victoza, including failing to provide accurate risk information to prescribers. 

FDA’s Oversight of REMS Programs

The FDA monitors REMS compliance through several mechanisms: 

 

  1. Periodic REMS Assessments: Application holders must submit periodic REMS assessment reports (typically at 18 months, 3 years, and 7 years) outlining program effectiveness, compliance metrics, and corrective actions. 
  2. Surveillance Activities: The FDA’s Office of Compliance reviews complaints, surveillance data, and adverse event reports to identify potential REMS violations. 
  3. REMS Inspections: The FDA conducts both pre-approval and post-approval inspections of facilities, third-party vendors, and REMS participants (e.g., specialty pharmacies, distributors) to assess compliance. 

The FDA’s Compliance Program Manual (CPM 7341.002) provides detailed guidance on conducting REMS inspections. These inspections are typically conducted by the Office of Regulatory Affairs (ORA) in coordination with the Center for Drug Evaluation and Research (CDER). Inspectors evaluate the adequacy of REMS implementation, recordkeeping, training, communication plans, and third-party oversight. 

 

The REMS Compliance Team (RCT), a dedicated group within CDER, oversees REMS-related inspections and works closely with ORA. The RCT may initiate an inspection based on concerns raised during REMS assessment review, surveillance findings, or complaints from stakeholders. 

Elements of REMS Subject to Audit and Inspection

FDA inspectors typically focus on the following elements during REMS audits: 

 

  • Implementation of REMS Elements: Inspectors assess whether the company is properly implementing each REMS element, such as Medication Guides, Communication Plans, and Elements to Assure Safe Use (ETASU). For example, if a REMS requires that only certified prescribers may prescribe a drug, the inspector will verify the certification process and records. 
  • Training and Certification: Inspectors review the training materials, certification forms, and documentation showing that prescribers, pharmacists, and other stakeholders have been appropriately trained. 
  • Restricted Distribution Systems: For drugs with restricted distribution, inspectors examine how the product is ordered, shipped, and dispensed. They review pharmacy and wholesaler agreements, dispensing logs, and procedures to prevent unauthorized access. 
  • Monitoring and Auditing: Companies must demonstrate that they are monitoring REMS implementation and conducting internal audits. Inspectors may request audit reports, corrective action plans, and documentation of follow-up activities. 
  • Recordkeeping and Reporting: Inspectors assess the quality and completeness of records maintained to demonstrate compliance. This includes training logs, call center records, prescriber and pharmacy enrollment forms, patient consent forms, and REMS assessment reports submitted to the FDA. 
  • Third-Party Oversight: If the company outsources REMS functions to a contract research organization (CRO), specialty pharmacy, or data aggregator, the inspector will evaluate the oversight mechanisms in place. Contracts, quality agreements, and audit reports are typically reviewed. 

What Happens During a REMS Inspection

REMS inspections generally follow a standard FDA inspection protocol: 

 

  1. Pre-Inspection Notification (if applicable): Although many inspections are unannounced, the FDA may provide advance notice in some cases. 
  2. Opening Meeting: The inspection begins with an opening meeting where inspectors outline the purpose and scope. 
  3. Facility Tour and Document Review: Inspectors tour the facility and review relevant records related to REMS implementation. 
  4. Interviews: FDA staff may interview personnel responsible for REMS compliance, including QA, regulatory affairs, and commercial teams. 
  5. Exit Meeting and Form FDA 483: At the end of the inspection, findings are discussed. If any deficiencies are observed, the inspector issues a Form FDA 483 (Inspectional Observations). 
  6. Establishment Inspection Report (EIR): The FDA later issues an EIR summarizing the inspection findings. Based on the outcome, the agency may take further action. 

Best Practices for REMS Audit Readiness

Manufacturers should take a proactive approach to REMS readiness. Key best practices include: 

  1. Clear and up-to-date Standard Operating Procedures (SOPs) for each REMS component are essential. 
  2. Routine internal audits help identify gaps and ensure continuous improvement. 
  3. All personnel involved in REMS activities must be adequately trained and able to demonstrate understanding of their responsibilities. 
  4. A centralized repository for REMS-related documents facilitates rapid access during an inspection. 
  5. Perform due diligence and ongoing monitoring of outsourced REMS activities to ensure compliance. 
  6. Regularly analyze data related to prescriber certification, distribution patterns, and adverse events to detect potential issues early. 

Recent Trends and Challenges in REMS Compliance

The landscape of REMS enforcement is evolving. Key trends include: 

 

  • Integration of REMS and DEA Training Requirements: Under the Medication Access and Training Expansion (MATE) Act, DEA-registered providers must complete training that overlaps with REMS requirements for opioids. Sponsors must ensure alignment between REMS training and DEA compliance. 
  • COVID-19 Flexibilities and Resumption of Enforcement: During the COVID-19 public health emergency, the FDA allowed temporary flexibilities for certain REMS requirements (e.g., waiving in-person lab tests). With the expiration of the emergency declaration, full compliance with REMS obligations is once again expected. 
  • Digital REMS Platforms: Some sponsors have implemented electronic systems to manage REMS elements, such as e-portals for prescriber certification. These systems must be validated and compliant with FDA regulations (e.g., 21 CFR Part 11). 

Conclusion

REMS compliance is a critical component of post-marketing safety obligations for certain high-risk drugs and biologics. As the FDA increases its scrutiny of REMS programs, companies must be prepared for audits and inspections that assess not only documentation but also the effectiveness of REMS implementation. 

 

A proactive compliance strategy including thorough training, meticulous recordkeeping, robust SOPs, and regular internal audits can help mitigate the risk of enforcement actions and ensure that REMS obligations are met. Companies that treat REMS as a core compliance function, rather than a peripheral requirement, will be better positioned to navigate the complexities of regulatory oversight. 

About DDReg

DDReg supports pharma and biotech companies in building and maintaining FDA-compliant REMS programs. From ETASU implementation to inspection readiness, our experts help design SOPs, conduct internal audits, and ensure complete documentation. We provide end-to-end REMS solutions to keep your programs compliant, effective, and inspection ready. 

 

For further information, connect with our experts. Read more about REMS regulations from the experts here: Risk Evaluation and Mitigation Strategies (REMS) for US Drug Development