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Day: October 1, 2024

Risk Evaluation and Mitigation Strategy (REMS) Compliance & Inspection

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REMS are Enforceable under Section 505-1

  • REMS must be fully operational before drug introduced into interstate commerce.
  • Drug is deemed to be misbranded (Section 502(y)) – If the applicant holder fails to comply with approved REMS.
  • FDA can impose civil monetary penalties for violations of the FD&C Act – 303(f) (4).

 

Objectives of Rems Compliance Programme

  1. Assess compliance with the requirements of Section 505-1.
  2. Assess compliance with the requirements mentioned in REMS approval letter.
  3. Document the company’s or contractor’s implementation of the REMS.
  4. Verify the accuracy of the REMS assessment information submitted to the FDA.

 

 Penalties

  • FDA may impose civil monetary penalties of up to $250,000 per violation of REMS requirements, not to exceed $1 million in a single proceeding (Section 303(f)(4)(A)).
  • Civil monetary penalties may increase if the violation continues more than 30 days after FDA notifies the applicant holder of the violation.
  • The penalties double for the second 30-day period and continue to double for subsequent 30-day periods, up to $1 million per period and $10 million per proceeding.
  • The Centre for Drug Evaluation and Research (CDER) Office of Scientific Investigations (OSI) takes the lead on enforcement when firms do not comply with REMS requirements.

 

REMS Inspections

  • REMS inspections are conducted to determine compliance with Section 505-1 of the Act, and the REMS approval letter for the specific product.
  • Inspections under this program are domestic and are generally preannounced.

 

FDA may consider a risk-based approach to select REMS programs each year for inspection. The following factors may generally be considered in the risk-based approach:

  1. REMS with elements to assure safe use (ETASU);
  2. REMS with identified issues or violations from a previous REMS inspection.
  3. REMS with approved modifications since the last inspection.
  4. REMS that have been identified by the Office of New Drugs (OND) or Office of Surveillance and Epidemiology (OSE) with recognized issues.
  5. REMS with issues identified during review of the REMS Assessment Report.
  6. REMS that have never been inspected; and
  7. REMS not inspected in the last 2-3 years.

 

Each Risk Evaluation & Mitigation Strategy (REMS) is unique and hence may have different elements and tools for risk mitigation. The inspection may focus on the requirements of FDA approved REMS.

 

Medication Guide

   Do you know what FDA may look for during REMS Inspection?

  • The REMS requires that the company develops a Medication Guide (per 21 CFR 208) that defines requirements for patient labelling for human prescription drugs.
  • Under 21 CFR 208 and in accordance with Section 505-1 of the Act, the company must make sure that the Medication Guide is available for distribution to patients at the time of dispensing the drug.
  • Medication Guide should be in non-technical language, in a standardized format (font size, headers, etc.), and provided in addition to General Information Sheets.

 

  1. Is the Medication Guide being distributed to each patient when the drug is dispensed?
  2. FDA may collect a copy of the Medication Guide in the version or format (hardcopy) that is provided to each patient & verify that is identical to the copy at REMS@FDA
  3. Documentation of the Company’s activities related to the assessment of healthcare provider’s and patient’s understanding of the messages communicated in the Medication Guide.
  4. Any documentation the Company has regarding procedures to identify, report and correct failures to adhere to distribution and dispensing requirements.

 

Communication Plan

  1. The REMS may require that the company develops a communication plan targeted to healthcare providers.
  2. A communication plan informs, educates, and raises awareness of risk.
  3. A communication plan includes tools for distributing information about the risks included in the REMS, including risk messages and messages related to operations and requirements to assure safe use (505-1(e)(3)).
  4. Some examples of REMS tools mentioned in a communication plan are:
    1. Dear Healthcare Provider (DHCP) letters, REMS letters, or letters addressed to HCPs through professional organizations.
    2. REMS website; REMS Factsheets.
    3. Patient counselling tools for HCPs; or Journal information piece.

 

Certain aspects that might be evaluated during an inspection

  1. Were the distribution dates of the Communication Plan consistent with the dates provided in the REMS document?
  2. Method of distribution of the Communication Plan tools?
  3. FDA may collect a copy of all Communication Plan tools and may verify they are identical to the documents appended to the REMS.
  4. Source and accuracy of the mailing lists used to distribute letters to the target audience? Corrective actions taken to ensure return mailings were reissued.
  5. The number of REMS tools (e.g., REMS Factsheets, Patient counseling kits) distributed by company’s personnel during follow-up visits with HCPs during the specified time-period after REMS approval?
  6. Were the professional journal communications in the journal as per the dates provided in the REMS document?
  7. Is the REMS Website fully operational and Is the communication plan available on the REMS website, if applicable?
  8. Documentation related to the assessment of targeted REMS stakeholder’s (e.g., HCP, patient, pharmacist) understanding of the information communicated by the REMS program (e.g., knowledge surveys for analysing HCP’s understanding of REMS program requirements).
  9. Documentation of the company’s activities for surveillance of the risks addressed by the REMS program (e.g., Drug utilization information, Post marketing case reports)?

Navigating Risk Evaluation and Mitigation Strategy (REMS) Audits Inspections

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What is REMS?

Per the USFDA, REMS is defined as:
– A required risk management plan that uses risk minimization strategies beyond professional labelling to ensure that the benefits of the drug outweigh the risks.

 

How Rems Requirement Came into Force?

Historical Background

  1. On September 27, 2007, the FDA Amendments Act (FDAAA) was enacted as a Public Law 110-85.
  2. Title IX, Subtitle A, Section 901 of the statute created a new Section 505-1 of the FDC Act (the Act).
  3. This act authorizes FDA to require persons submitting or holding certain applications to submit a proposed REMS as part of such application, if the FDA determines that a REMS is necessary to ensure that the benefits of a drug outweigh the risks (Section 505-1(a)).
  4. The REMS program is a statutory program of the Act and does not have a code of federal regulations (CFR) designation.

 

Factors the USFDA may Consider if a Drug Requires REMS

Per Section 505-1(a)(1) of the FDC Act, the following factors are considered to determine if a drug requires REMS:

  • Approximate population size expected to use the drug.
  • Seriousness of the disease/condition intended to be treated with the drug.
  • Expected benefit of the drug with respect to the disease/condition being treated.
  • Expected or actual treatment duration.
  • Seriousness of any potential or known adverse events that may be related to the drug and the background incidence of such events in the population.
  • Whether the drug is a new molecular product.

 

Tools FDA requires to ensure Risk Mitigation & attain goals of REMS (Section 505-1(e)) – FDA requires the following tools to mitigate the risks of the drug & and attaining the goals of REMS

 

  • Information to Patients

–  Medication Guides (21CFR 208)

–  Patient Package Inserts (Section 505- 1(e)(2))

  • Information to Healthcare Providers

– Communication Plan (Section 505-1(e)(3))

 

(Section 505-1(f)(3)) If the tools mentioned above under section 505-1(e) are not considered adequate for risk mitigation, FDA may require more restrictive measures, termed Elements to Assure Safe Use (ETASU).

ETASU A Healthcare Providers
ETASU B Pharmacies
ETASU C Certain Healthcare Settings
ETASU D Documentation of Safe Use
ETASU E Monitoring
ETASU F Registry

 

How to assure safe use of the drug under ETASU B, C & D.

The REMS that include ETASUS under the following Elements, an Implementation System is required under Section 505-1(f)(4):

  • ETASU Element B (Pharmacies)
  • ETASU Element C (Certain Healthcare Settings)
  • ETASU Element D (Documentation of Safe Use)

Implementation System

Should be in place, through which the company is able to take reasonable steps to monitor and evaluate REMS implementation by healthcare providers, pharmacists, and others responsible for implementing those elements, & work upon to improve them.

 

REMS Supporting Document

Additional details about Implementation system are included in REMS Supporting Document which is a document prepared by the company that includes a comprehensive description of the rationale and supporting information for REMS content; however, it is not part of the approved REMS.

 

REMS Assessments

  1. NDAs and BLA applicant holders are required to perform and submit REMS assessments as per the intervals described in the approved REMS.
  2. FDAAA specifies the minimal timeframe (18 months, 3 years, and 7 years) for the submission of assessments from the date of the initial approval of the REMS (section 505-1(d)).
  3. The provision for scheduled REMS assessments does not apply to ANDAs
  4. In the Approval Letter, FDA provides the applicant holder with a comprehensive assessment plan, addressing the specific content areas in the REMS to include, at a minimum, in their assessment report. FDA provides the applicant holder with the schedule and the timeframe for performing REMS Assessments.

 

Assessments are also required:

  • When the applicant holder submits a supplemental application for a new indication for use, OR
  • When FDA determines, an assessment is needed to evaluate whether the approved strategy should be modified to ensure the benefits of the drug outweigh the risks of the drug, OR
  • To minimize the burden on the health care delivery system that is complying with the strategy (section 505-1(g)(2)).
  • Additionally, applicant holders may voluntarily submit an assessment of the REMS at any time (section 505-1(g)(1)).

Signal Detection in Early Phase Clinical Drug Trials

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Why Should You Perform Signal Detection in Early Phase Clinical Drug Trials?

The term ‘pharmacovigilance’ has conventionally been related with post-marketing activities; however, it is also equally applicable to the pre-marketing process for collecting, managing & assessing safety information during clinical development of the molecule. Similarly, the concepts of signal detection and assessment, risk assessment and risk minimization are as applicable to the pre-marketing scenario as they are to the post-marketing scenario.

The importance of this is evident from the following examples:

 

  1. Drugs not approved in USA

–  Examples of drugs not approved in USA as premarketing experience provided evidence of the potential for severe DILI e.g., Dilevalol, Tasosartan, Ximelagatran.

 

  1. Drugs withdrawn from market worldwide after initial regulatory approval

–  E.g., Rimonabant, Rofecoxib, celecoxib etc.

The safety information generated at the end of clinical development program should be extensive enough to permit comprehensive regulatory review and determination of benefit-risk profile for supporting marketing approval. The information should be comprehensive so that product label can be adequate to provide prescribers & patients adequate information for safe use of the drug.

 

What Do the Regulators Say?

USFDA 21CFR312.32 USFDA Draft Guidance on Sponsor Responsibilities
June 2021

Sponsors must adopt a systematic approach to safety surveillance to meet IND safety reporting requirements and enhance quality of safety reporting.
Such an approach involves promptly reviewing, evaluating, and managing safety information from all sources, including animal studies, clinical investigations, scientific literature, professional meetings, foreign regulatory authorities, and commercial marketing experience.

USFDA 21CFR312.56 USFDA Draft Guidance on Sponsor Responsibilities June 2021

– The sponsor’s review should involve assessing data from all sources and monitoring the progress of investigations:

  • To identify previously undetected potential serious risks (§312.56(a)).
  • To update investigator’s brochure, protocol, and consent forms with new information.
  • As necessary, to take measures for protecting subjects (e.g. monitoring, modifying dosing, or participant selection) (§312.56(d)).

 

CIOMS Working Group VI

– The purpose of ongoing safety evaluation during drug development is to ensure that important safety signals are detected early and to have a better understanding of benefit-risk profile of study drug.
Sponsors should develop a system to analyse, evaluate and take actions on the safety information on a continuous basis. This is to ensure the earliest possible detection of safety concerns and allow suitable risk minimization.

 

Systemic Approach for Signal Detection

Essential Elements for Effective Signal Detection in a Clinical Development Program

  • Early Initiation is Crucial
  • Written Process Required for Review
  • Multidisciplinary Safety Management Team (SMT)
  • Data from Licensing Partners to be Considered
  • Project Management Function
  • Background Incidence
  • Ready Data Accessibility
  • Initiative Proactive Strategy
  • Establish Timeframes and Milestones
  • Decision Making
  • Advisory Bodies

 

Signal Detection: Effective Data Review

Below are some of the key points that support effective data review during signal detection process in a clinical development program:

 

Parameters Overview
Analyse all AEs – Serious and Non-serious The safety analysis is complete when all adverse events (serious and non-serious) are reviewed, with a greater emphasis on those leading to treatment discontinuation
Review of Individual Cases Individual case analysis is essential for safety analysis. SARs and AESIs are important for detecting safety signals. Consider patient population, drug indication, and disease history during analysis.
Aggregate Review of Safety Data Aggregate review helps analyse evolving safety information, comparing interval and cumulative data. Data should be analysed per dose, cohort, gender, age, etc.
Review of Clinical Lab Data Laboratory tests are useful for screening subjects, early detection of organ toxicity & detection of potential toxic effects. Special focus should be on lab values correlating with organ toxicity e.g., endocrine abnormalities, hepatotoxicity etc.
Adverse Events of Special Interest (AESI) The protocol should define AESIs, emphasizing identification, monitoring, and reporting. Includes events like rhabdomyolysis or hair loss.

 

Structure of Safety Management Team

Development Risk Management Plan (DRMP)

A Development Risk Management Plan (DRMP) is a natural extension of high-quality pharmacovigilance. In DRMP, a compound-specific approach should be adopted, possibly as part of the broader Clinical Development Plan. It should contain early documentation of identified, expected, or potential risks, along with strategies for addressing them throughout development. As appropriate, the DRMP may develop into a post-marketing risk management plan.
The DRMP is a guide for safety surveillance during development and is not a legal or regulatory document; however, the following two actions must be considered during development of the process:
Recognize the potential for legal discovery of DRMP and ensure appropriate
language clarifying its status as a working document.

  1. Recognize the potential for legal discovery of DRMP and ensure appropriate language clarifying its status as a working document.
  2.  Establish robust processes, including project management to ensure the diligent execution of the action plans.

The DRMP should include the following sections: anticipated product profile, epidemiology, non-clinical safety experience, clinical safety experience, identification and assessment of known or anticipated risks, identification and assessment of potential new risk, and actions and/or plans for evaluating and mitigating risk.

 

Conclusion

The concepts of signal assessment, risk assessment and risk minimization are as
applicable to pre-marketing scenario as they are to the post-marketing scenario. The purpose of ongoing safety evaluation is to ensure that safety signals are detected early and to obtain an understanding of benefit-risk profile of the drug. Signal detection during clinical trials is usually performed based on clinical judgement, since there is limited data available during premarketing clinical trials. The three basic attributes for signal detection includes quick medical assessment, periodic aggregate assessment, and safety evaluation of completed unblinded trials. To ensure effective signal management, it is important to establish an effective system, beginning early, having proactive approach, analysing all serious and non-serious events, periodic reviews by scientific committees, and prompt decision making.