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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.

 

Medication Errors Why is it Important to Record, Assess, and Prevent Them

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Medication errors are an important concern in healthcare systems around the world. They can occur at any stage of the medication process, from prescribing to administration, and can have serious consequences in patients. Some examples of medication errors could include giving a medication to the wrong patient, giving the wrong dose of a medication, not prescribing a medication that was indicated, entering an order for the wrong patient, or forgetting to give a medication that was due. In this article, we will explore the definition of medication errors, the various stages where they can occur, the role of healthcare professionals in reporting and preventing these errors, and strategies for reducing their occurrence.

Defining Medication Errors

A medication error is a commonly used term and is defined as an unintended failure in the treatment process that leads to, or has the potential to lead to, harm to the patient (Ferner & Aronson, 2006; EMA Guidance 2015). These errors can take place at multiple stages of the medication-use system, such as during prescribing, entering data into computer system, preparing or dispensing the drug, or administering the drug to the patient.

Why are Medication Errors Important – Prevalence and Impact of Medication Errors

The FDA receives more than 100,000 US reports each year associated with a suspected medication error. Individual studies have reported hospital inpatient medication error rates of 4.8% to 5.3% and in another study, prescribing errors for inpatients occurred 12.3 times per 1,000 patient admissions. One study on the frequency of medication errors revealed that fewer than 1% of medication errors resulted in an adverse event.

These medication error reports come from various sources, including drug manufacturers, healthcare professionals, and consumers. These reports are reviewed by the FDA and are classified to determine the cause and type of the error. Medication errors can also result in serious consequences. In addition to the harmful impact on patients, medication errors can also impose significant costs on healthcare systems. Estimates suggest that these errors, in addition to decreasing the patients’ confidence in medical services, can cost between $6 billion and $29 billion per year in the United States alone.

Relationship between Medication Errors and Adverse Effects

The Figure below reflects the interplay between medication errors and harm (i.e. associated with adverse reaction and preventability).

Adverse reactions that result from medication errors are considered preventable, in contrast to generally non-preventable adverse reactions which are mentioned in the Product Label (e.g. in Prescribing Information, SmPC etc.) for which the chances of adverse event occurrence is usually known and accepted and will likely occur depending on the frequency of the adverse reaction and on other circumstances such as concomitant medication use, underlying disease condition etc.

There are medication errors which do not essentially result in adverse reaction, but which are important from their unwanted effects e.g. from an economic or environmental standpoint.

Figure 1: Figure: Correlation between medication errors, preventable and generally non-preventable adverse reactions and intercepted errors (modified according to Morimoto et al., Qual Saf Health Care 2004; 13:306-314). Ref: EMA Good Practice Guide on recording, reporting & assessment of medication errors; 23 Oct 2015.

Stages of Medication Errors

Medication errors can occur at various stages of the drug delivery process. These stages include:

  1. Prescribing

Errors during this phase can occur due to incorrect drug selection, dosage, or frequency, or by failing to consider the patient’s medical history or potential drug interaction.

  1. Transcribing

Errors can occur when entering prescription information into a computer system, such as incorrect drug selection, dosage, or frequency.

  1. Dispensing

Errors can happen during the preparation and distribution of the drug, such as dispensing the wrong medication, incorrect dosage, or improper labelling.

  1. Administration

Errors can occur when administering the drug to the patient, such as administering the wrong drug, dose, or route, or at the wrong time

  1. Monitoring

Errors can happen when healthcare professionals fail to monitor the patient’s response to the medication, leading to potential adverse reactions or failure to achieve therapeutic goals.

Recording and Reporting Medication Errors

Medication errors associated with drug use may be spontaneously reported as unsolicited reports by a consumer, healthcare professional or marketing authorization holder, or may be reported as solicited reports of suspected adverse reactions from data collection systems e.g. non-interventional studies or registries.

Suspected (serious and non-serious) adverse reactions associated with medication errors should be recorded, reported and assessed. The reports of medication errors not associated with adverse reaction should also be recorded; however, these cases are not reportable as valid ICSR.

The marketing authorization holders should summarize relevant information on medication errors, even when not associated with adverse outcomes, in the periodic safety update reports and the risk management plans. The figure below provides a summary of recording of medication errors from the perspective of pharmacovigilance and patient safety.

Category Medication Error with AR Medication Error without AR Intercepted Error Situations Capable of Causing Medication Error
Medication Error Yes Yes Yes No
Adverse Reaction (AR) Yes No Not Applicable Not Applicable
Recording of Medication Error Medication Error with AR Medication Error without AR Intercepted Medication Error Situations capable of causing Medication Error
Report Type / Relevance Record ICSR Report, if applicable PSUR, RMP PSUR, RMP PSUR, RMP PSUR, RMP

Strategies for Reducing Medication Errors

Various mechanisms can be employed to reduce the occurrence of medication errors.

The FDA is actively involved in efforts to prevent medication errors. Before approving drugs for marketing, FDA reviews the drug name, labelling, packaging, and product design to identify and revise information that may contribute to errors. FDA reviews the following to reduce the incidence of medication errors:

  • Proposed brand names to minimize confusion among drug names. Look-alike and sound-alike names are to be avoided.
  • Container labels to ensure healthcare providers and patients can select the correct drug and easily differentiate between different strengths of the same drug.
  • Prescribing and patient information to ensure clear and easy-to-read instructions for use.

After the drugs are approved for marketing, FDA continues to monitor and evaluate medication error reports.

  • FDA may require manufacturers to revise labels, packaging, product design, or proprietary names to prevent errors.
  • FDA may also issue communications to alert the public about medication error safety issues.
  • FDA collaborates with regulators, external stakeholders, standard-setting organizations, patient safety organizations, and researchers to understand the causes of medication errors and develop interventions to prevent them.

Implementing Barcodes on Drug Labels

The FDA has introduced rules requiring barcodes on certain drug and biological product labels. These barcodes allow healthcare professionals to use barcode scanning equipment to verify that the correct drug, dose, and route of administration are being given to the right patient at the right time, to reduce medication errors in hospitals and other healthcare settings.

Providing Guidance to Manufacturers

The FDA has published guidance documents to help manufacturers design drug labels, packaging, and select drug names in a way that reduces or eliminates hazards contributing to medication errors. These guidance documents offer recommendations on various aspects of drug design, such as imprint codes on tablets, appropriate dosing devices, and package design to protect consumers against incorrect use.

Importance of Consumers in Reducing Medication Errors

Consumers play a crucial role in reducing medication errors. Some tips for the consumers to minimize the risk of medication errors include the following:

  1. Be aware of the various causes and risks of medication errors.
  2. Know the name and purpose of the medications that is prescribed.
  3. Know how to take the medication and follow the directions properly including directions for storage.
  4. Check the container’s label every time the medication is taken.
  5. Keep medications stored in their original containers.
  6. Maintain an updated list of all medications, including over-the-counter drugs, supplements, and other substances and share this list with your healthcare provider.
  7. Be aware of the risk of drug-drug and drug-food interactions.
  8. Ask the pharmacist or healthcare provider in case of any questions about the medication.
  9. Report suspected medication errors.

Specific Consideration of Medication Errors in High-Risk Groups

Consumers play a crucial role in reducing medication errors. Some tips for the consumers to minimize the risk of medication errors include the following:

  1. Paediatric patients

Paediatric patients may be at especially high risk of medication errors, with dosing errors being the most common type of error. This may be due to the variation in age, size and weight, and body surface area in children. Overdose was the most commonly reported medication error (accounting for 21% of all reports) in a study of paediatric patients while underdosing was the most commonly reported medication error in certain paediatric specialties in another study. These conflicting findings suggests a more general risk of dosing errors (leading to either over- or underdosing) in paediatric patients.

Paediatric prescribing is often decided by the patient’s weight, yet weight is not measured before each prescription and can change over time. Further, mathematical miscalculations may also occur. Accidental ingestion or other unintended use of medicinal products by children should be prevented. A standard statement that drugs should be kept out of the sight and reach of all children is included on the labelling for all products and use of child-resistant packaging may also be considered.

  1. Elderly patients

Elderly patients are at a high risk of medication errors. These patients may have physical and cognitive impairment and therefore may have difficulties in taking medicines, e.g. swallowing tablets, opening packaging or reading user instruction. Moreover, elderly patients frequently use multiple drugs (polypharmacy) which in itself may cause compliance problems which may be partly overcome by the design of the drugs (e.g. a wider range of colours, sizes and tablet shapes is known to assist the recognition of medicines).

Elderly patients are more likely to experience impaired swallowing. This may result in accidental underdosing, which can be appropriately managed by the use of formulations which are easier to swallow. It is important that appropriate materials for elderly patients are developed, including use of large print text and Braille for patients with impaired eyesight. Older people may also more frequently require the assistance of caregivers. The caregiver, nurse and family can play an important role for the correct use of the medicines and should be proactively involved by the doctor or pharmacist.

Conclusion

Medication errors are a significant concern in healthcare systems worldwide and is an important cause of patient morbidity and mortality. Medication errors can occur due to varied factors such as medication factors (e.g. similar sounding names, low therapeutic index), patient factors (e.g. poor renal or hepatic function, impaired cognition, polypharmacy), and health care professional factors (e.g. use of abbreviations, cognitive biases) which can precipitate medication errors. With the combined efforts of the FDA, healthcare professionals, manufacturers, and consumers, it can be ensured that the medication-use process is safer and more effective for all involved.

Why you Should Incorporate Signal Detection Process in Early Phase Clinical Development Programs

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What is a Safety Signal in Pharmacovigilance?

Information arising from one or multiple sources, including observations and experiments, which suggests a new potentially causal association, or a new aspect of a known association between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action. New aspects of a known association may include changes in the frequency, distribution (e.g. gender, age and country), duration, severity or outcome of the adverse reaction. A signal often relates to all medicinal products containing the same active substance, including combination products. Certain signals may only be relevant for a particular medicinal product or in a specific indication, strength, pharmaceutical form or route of administration whereas some signals may apply to a whole class of medicinal products.

Signal Management – What it is:

A set of activities performed to determine whether, based on an examination of individual case safety reports (ICSRs), aggregated data from active surveillance systems or studies, scientific literature information or other data sources, there are new risks associated with an active substance or a medicinal product or whether known risks have changed, as well as any related recommendations, decisions, communications and tracking.

What do the regulators say:

  1. 21CFR312.32

Review of safety information:

The sponsor must promptly review all information relevant to the safety of the drug obtained or otherwise received by the sponsor from foreign or domestic sources, including

information derived from any clinical or epidemiological investigations, animal or in vitro studies, reports in the scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities and reports of foreign commercial marketing experience for drugs that are not marketed in the United States.

  1. USFDA draft guidance on sponsor responsibilities – safety reporting requirements and safety assessment for IND and Biovailability / Bioequivalence studies

Systematic Approach for Review of Safety Information (§ 312.32(b)):

Sponsors should have a systematic approach to safety surveillance to comply with the IND safety reporting requirements and to improve the overall quality of safety reporting. Such an approach should include a process for promptly reviewing, evaluating, and managing accumulating data on SAEs from the entire drug development program that are sent from domestic or foreign sources. During the course of drug development, investigators who conduct clinical trials generally report to the sponsor adverse event information; however, a sponsor may become aware of new safety information from a variety of sources, both domestic and foreign. Compliance with post marketing safety laws and regulations for human drugs and therapeutic biologics.

The sponsor must review and evaluate safety information from any source regardless of whether the data came from studies conducted under the IND (§ 312.32(c)(1)(ii) and (iii)) to determine if there is a newly identified significant risk to trial participants. Sources include but are not limited to:

  • Animal or in Vitro Studies
  • Clinical or epidemiological investigations
  • Reports in the scientific literature, including unpublished reports of which the sponsor becomes aware
  • Information presented at professional or scientific meetings (e.g. abstracts)
  • Reports from foreign regulatory authorities
  • Reports from commercial marketing experience, including outside the United States
  1. European Medicine Agency (EMA)

Safety surveillance: The sponsor along with the investigators is responsible for the ongoing safety

surveillance and risk minimization of the study subjects during the clinical study duration, taking, if required, appropriate urgent safety measures for protection of study subjects. The Member State Concerned will monitor the risks of investigational medicinal products considering the available information according to the procedures laid down in the implementing Regulation on rules and procedures for the cooperation of the Member States in safety assessment of clinical trials. Safety reporting with regard to authorised Auxiliary Medicinal Products shall be made in accordance with the normal safety reporting requirements

for authorised medicinal products.

The notifications required from sponsor or investigator in relation to safety of the clinical study subjects include:

  1. Reporting of adverse events and serious adverse events
  2. Reporting of suspected unexpected serious adverse reactions (SUSARs)
  3. Other unexpected events relevant for the subject’s safety
  4. Annual safety report
  5. Reporting of serious breaches
  6. Urgent safety measures
  7. Temporary halt of the study due to safety reasons

 

  1. CIOMS Working Group VI

Identification and Evaluation of Risk from Clinical Trial Data – Ongoing Safety Evaluation: The purpose of ongoing safety evaluation during drug development is to ensure that important safety signals are detected early and to gain a better understanding of the benefit-risk profile of the study drug.

 

  • Clinical trial sponsors should develop a system to analyse, evaluate and take actions on the safety information received during drug development on a continuous basis. This is to ensure the earliest possible detection of safety concerns and allow suitable risk minimization, such as of ongoing study protocol revisions, to ensure that clinical trial participants are not exposed to undue risk.

 

  • Safety monitoring, evaluation and analysis should be performed in such a way so that the integrity of the individual studies or the overall development program is not compromised. Study sponsor should be totally aware of the potential risks of the investigational product and the morbidities characteristic of the study population at every stage of drug development.

How Soterius can help you in Setting Up Signal Detection Process:

  1. Team of Experienced Physicians and Product Specific Trained Resources

–  The signal management team adheres to a process involving a thorough review and medical evaluation of safety data.

  1. Safety Surveillance Plan

– The components of the safety surveillance plan include the following:

Data Collection from

Various Sources

 Preparation of Detailed

Signal Evaluation Reports

 Signal Report Discussion

in Safety Review Meeting
·         Safety database line listings, Clinical database line listings including laboratory investigations

·         Published literature

·         Aggregate reports/Risk management plans

·         Regulatory Websites depending on authorization of client’s products in various countries/regions e.g.

·         FDA website*

*(Potential Signals of Serious Risks/New Safety Information Identified from FAERS)

 ·         Sources of signal detection Identified drug-event pairs

·         Signal validation Other relevant safety issues

 ·         Discussion with key stakeholders prior to finalization on periodic basis

·         Further actions (Routine monitoring, Potential Signals Y/N, Additional data search)

Signal Management Process:

Signal detection, Signal validation, Signal analysis and prioritization, Signal assessment, and Recommendations for action.

In conclusion, signal management is a process that requires a high-level standard operating procedure (SOP) describing:

  • How signal prioritization and evaluation are approached (e.g. what does the signal prioritization imply?
  • How are the sources of safety data queried? Who performs the signal evaluation?).
  • How is the risk determination performed (e.g. what criteria have been considered and what data are available to qualify the risks?).
  • How is the best course of action determined?
  • How, when and to whom the potential or identified risks are communicated.

Once a signal is identified, the following steps are necessary:

  • Assess public health impact.
  • Validate and assess the strength of the signal.
  • Define data sources and limitations.
  • Compile safety data.
  • Compare data from different sources.
  • Evaluate characteristics and likelihood of the risk associated with the signal.
  • Determine appropriate actions for evaluation, communication, and risk reduction.

Remember…. if the information available suggests that there could be a risk that requires prevention or minimization in a timely manner

  • Always use clinical judgement and flexibility throughout the process.
  • Be prepared to take action at any stage before the formal signal assessment is completed.
  • Points for consideration: severity, seriousness, outcome, reversibility, exposure in vulnerable populations, expected extent of regulatory intervention, consequences of treatment discontinuation & availability of other therapeutic options etc.

This was a small start with a quick reference to importance of Signal detection in Early Phase Clinical Development Programs. I would be discussing various aspects of signal management process in the upcoming articles.

Overview of Regulatory Requirement for Post-Marketing Medical Device Reporting in the USA and the EU

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Overview of Regulatory Requirement for Post-Marketing Medical Device Reporting in the USA and the EU

Meteriovigilance is the term used in the context of surveillance of medical devices and its purpose is to improve the protection of health and safety of patients, healthcare professionals, and other users by reducing the likelihood of reoccurrence of incidents related to the use of a medical device.

Presented below in brief is the post-marketing regulatory landscape as exist for USFDA and EMA in terms of Medical Device Reporting.

  1. Regulations that Govern Medical Device Reporting

  • USFDA
  • 21 CFR PART 803
  • 21 CFR PART 806
  • EMA
  • Regulation (EU) 2017/745

  1. Type of Report and Reporting Timelines

  • USFDA
  • 5-day report: No later than 5 workdays after becoming aware of a reportable event that requires
  • Remedial action to prevent an unreasonable risk substantial harm to the public health.
  • A reportable event for which FDA made a written request.
  • 30-Day report: No later than 30 calendar days after becoming aware of a reportable death, serious injury, or malfunction
  • EMA
  • Serious public health threat: Immediately, but not later than

days after the manufacturer becomes aware of that threat.

  • Death or an unanticipated serious deterioration in a person’s state of health: Immediately, but not later than 10 days after the date on which the manufacturer becomes aware of the serious incident.
  • Other serious incident: Immediately, but no later than 15 days after manufacturer become aware of the incident.

  1. Method to submit Reportable Medical Device Reports

  • USFDA
    • Electronic Submissions Gateway (Web Trader)
    • Gateway to Gateway
  • EMA
    • Submission of Manufacturer’s Incident Report (MIR) form via email to the approving Competent Authority.
    • Under development: EUDAMED

  1. Requirement for submission of Periodic Report

  • USFDA
    • Not mentioned*
    • Guidance for Combination product has specific requirements; will be detailed in subsequent posting.
  • EMA
    • Class IIb and class III devices: Annual PSUR Submission
    • Class IIa devices: PSUR to be submitted at least every two years

  1. Requirement for Trend reporting

  • USFDA
  • Not mentioned
  • EMA
  • Manufacturers shall electronically report any statistically significant increase in the frequency or severity of incidents that are not serious incidents or that are expected undesirable side effects that could have a significant impact on the benefit-risk analysis, and which have led or may lead to risks to the health or safety of patients, users or other persons that are unacceptable when weighed against the intended benefits

Navigating the Unique Challenges of AI and Automation in Pharmacovigilance: The Vital Role of Computer System Validation (CSV)

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Artificial Intelligence, Machine Learning, Automation, Cost Reduction: all the buzzwords in pharmacovigilance! Everyone seems to be implementing Automation and AI in pharmacovigilance to reduce manual work and reduce costs of safety monitoring. However, compared to all other fields where Automation and AI is being implemented, pharma as an industry is facing a unique set of challenges in implementing these systems.

 

Regulators such the USFDA and EMA require that computerized systems should be fit for intended use and meet current regulatory requirements. ‘Fit for intended use’ is a broad term that encompasses detailed testing, documentation, qualification and validation activities to demonstrate that the ‘use’ and ‘fitness for such use’ of a system is demonstrated effectively and is available for review during audits and inspections.

 

The method for achieving this is Computer System Validation, which is rooted in the principles of Good Automated Manufacturing Practice (GAMP), Title 21 CFR Part 11, and EU Annex 11. In the pharma space, the requirements become all the more critical, since it is no longer just about compliance; it’s about safeguarding lives.

 

The Indispensable role of CSV in Pharmacovigilance

End Point Regulation Requirement How CSV Helps to Achieve the Requirement
Patient Safety EU Annex 11 Patient Safety Aids in the timely detection, management, and mitigation of risks associated with pharmaceutical products
Data Precision GAMP Precise Reporting Ensures data accuracy, reducing the risk of errors that could significantly impact patient safety.
Regulatory Compliance Title 21 CFR Part 11, EU Annex 11 Robust compliance standards for

electronic records and signatures in

FDA-regulated industries, guidelines

For computerized systems in the

European Union

 Adherence to these regulations, ensuring that you consistently meet the stringent requirements of regulatory authorities
Operational Efficiency GAMP, Title 21 CFR, and EU Annex 11 Importance of efficient systems Streamlined processes not only improve productivity but also lead to faster responses, an invaluable asset in pharmacovigilance where time can mean the difference between life and death

 

In the next few parts of this series, I will be discussing some approaches that we have followed in implementing CSV procedures for software systems developed for the pharmacovigilance space, what we have learned in the process, how CSV can be applied by harmonizing international regulatory requirements and how it can

be applied to the agile development. Stay tuned for more updates and reach out to me if you would like to see any other topics covered as part of the series.