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Postmarketing Adverse Drug Experience (PADE) Inspections – Part I

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Legal Framework of PADE Inspections

 

PADE Statutory Provisions / Regulations: Prescription Drug Products for Human Use

S.no FD&C Act, subchapter V, part A, section 505 (21 U.S.C. 355) Comments
1 21 CFR 310.305 New Drugs: Records and reports concerning adverse drug experiences (ADEs) for marketed prescription drugs for human use without an approved new drug application
2 21 CFR 314.80 New drug applications: Post marketing reporting of ADEs
3 21 CFR 314.81(b)(2) New drug applications: Annual reports
4 21 CFR 314.90 New drug applications: Waivers
5 21 CFR 314.98 Abbreviated applications: Post marketing reports
6 21 CFR 314.540 Accelerated approval of new drugs for serious or life-threatening illnesses: Post marketing safety reporting
7 21 CFR 314.630 Approval of new drugs when human efficacy studies are not ethical or feasible: Post marketing safety reporting
8 21 CFR part 4, subpart B Post marketing safety reporting for combination products

 

Approval vs. Marketing

Once a drug is approved, applicant holders MUST receive, evaluate, and report adverse drug experiences (ADEs) to FDA, even if the drug is not marketed.

PADE Inspection – Scope

  1. Written procedures
  2. Product list (approval date, status, etc.)
  3. Late or Missing Periodic Reports or Annual Reports
  4. Late, missing, incomplete, or inaccurate 15-day reports
  5. ADEs from all sources
  6. Root cause analyses and corrective actions for deviations
  7. Confirmations for electronic submissions
  8. Training Documents
  9. Safety Contracts, Agreements, and Business Partners
  10. Organization, roles, and responsibilities
  11. Waivers

Who can be inspected for PADE Compliance?

  1. Application holders: 

    Applicants with approved drugs and therapeutic biologics (prescription and non-prescription)

    • New Drug Application (NDA)
    • Abbreviated New Drug Application (ANDA)
    • Biologics License Application (BLA)

  2. Non- Applicants: 

    Manufacturers, packers, distributors, retailers, and certain others named on product labels (responsibilities vary based on product type)

    • Approved prescription and non- prescription drugs and therapeutic biologics (NDA, ANDA, BLA)
    • Unapproved prescription drugs
    • Unapproved non-prescription drugs

  3. Third parties: 

    Contractors, vendors, and other third parties

    • Pharmacovigilance activities conducted on behalf of application holders or non-applicants

Risk Based Selection for PADE Inspection

  1. Inspection History:

    • Compliance and inspection history

      • Never inspected for PADE compliance
      • Inspection findings from other program areas
    • Firm’s written responses to previous PADE inspections

  2. Firm Information:

    • Corporate changes
    • Portfolio (type and number of products)
    • Complaints
    • Internal FDA information
    • Information from other health authorities

  3. Product Portfolio:

    • New molecular entities
    • High-risk
    • Patient exposure
    • Recalls Submissions to FDA
      • Individual Case Safety Reports (ICSRs)
      • Annual reports
      • Periodic report

Audits in Pharmacovigilance: A commitment to Safety

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In the realm of healthcare, ensuring patient safety is the most important aspect. That’s where pharmacovigilance plays a role in safeguarding lives by monitoring the safety of medicinal products. But how do license holders ensure that these systems are working perfectly well? The answer lies in audits. Audits are the safety checkpoints in the lifecycle of a drug. Audit’s serve as a critical process to assess, verify, and enhance the compliance and effectiveness of the pharmacovigilance processes, and that’s why they matter:

 

What are the common 483 Observations in recent USFDA inspections:

A fundamental issue in pharmacovigilance is that many cases concern suspected adverse drug reactions. In real-life situations, a very limited number of adverse reactions qualify as ‘certain’ or ‘unlikely’; most are usually in between, i.e., either ‘possible’ or ‘probable’. To address this issue, many methods have been developed to harmonize causality assessment. However, causality assessment has become a common routine activity in pharmacovigilance.

The advantages of causality assessment include the following:

  • Written procedures have not been developed for the surveillance, receipt, evaluation and reporting to FDA
  • of post marketing adverse drug experiences.
  • A post marketing 15-day Alert report based upon scientific literature was not accompanied by a copy of the published article.
  • Not all adverse drug experiences that are both serious and unexpected have been reported to FDA within
  • 15 calendar days of initial receipt of the information.
  • Periodic reports of non-alert adverse drug experiences have not been submitted.
  • An NDA-Field Alert Report was not submitted within three working days of receipt of information.

 

What to expect from a PADE Inspection:

  • Compliance with post marketing safety laws and regulations for human drugs and therapeutic biologics.
  • Ensure that accurate, reliable, and timely safety data are submitted correctly to FDA.

Who are the responsible firms and what are the applicable regulations:

  • Holders of approved new drug applications (NDAs) and abbreviated new drug applications (ANDAs) (21 CFR 314.80, 314.81(b)(2), 314.98, 314.540, and 314.630).
  • Nonapplicant manufacturers, packers, or distributors named on the label of approved drug products (21 CFR 314.80, 314.98, 314.540, and 314.630).
  • Any person holding a biologics license (21 CFR 600.80, 601.44, 601.93, 601.28, and 601.70).

 

What NDA/ANDA/BLA Holders shall do to be compliant:

Surveillance Receipt Evaluation Reporting
  • Account for all sources
    • Spontaneous
    • Solicited
    • Internet sources (firm-sponsored)
    • Literature
  • ADE Info
    • Initial
    • Follow-up
    • Receipt from any source
  • Expectedness
  • Relatedness
  • ADEs from any source
  • Follow-up Procedures
  • 15-day Alert Reports
  • Non-expedited individual case safety reports (ICSRs)
  • Aggregate

 

  1. Written Procedures

Develop written procedures for post marketing safety information,   including procedures for managing safety information with contractors and business partners, as applicable. Written Procedures Must Address the following

  1. Individual Case Safety Reports (ICSRs)

  • Applicable Regulations: 21 CFR 314.80 (f), 21 CFR 314.600(f).
  • Cases from all Sources (including business partners, social media etc.
  • Timely submission of complete ICSR data.
  • Follow-up procedure for missing information.

  1. Scientific Literature Reports

  • Applicable Regulations: 21 CFR 314.80(b), (c)(2), (d), and (f); 21 CFR 600.80(b), (c)(2), (d), and (f).
  • Reviews scientific literature at a determined frequency.
  • Submit a copy of the published article as an ICSR attachment for each expedited ICSR.

  1. Aggregate Safety Reports

  • Applicable Regulations: 21 CFR 314.80(c)(2) or 21 CFR 600.80(c)(2), 21 CFR 314.81.
  • Contains all the required content and
  • PADER, annual reports submitted quarterly/annually in electronic format as per the regulations.

  1. Contractor Oversight

  • Written procedures for obtaining and processing safety information from the contractors.
  • Contractors develop written procedures for the outsourced services and activities.
  • Day 0, as soon as the minimum information for a valid ICSR is received by the contractor or its representatives.

 

How does FDA classify its Inspection:

  • No Action Indicated (NAI) – No objectionable conditions or practices were found during an inspection (or the objectionable conditions found do not justify further regulatory action).
  • Voluntary Action Indicated (VAI) – Objectionable conditions or practices were found, but do not rise to the level warranting OAI classification.
  • Official Action Indicated (OAI) – Objectionable conditions or practices were found, whose scope, severity, or pattern warrants the recommendation for a regulatory action.

Causality Assessment in Pharmacovigilance

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The causality assessment of adverse events, to determine the relationship or connection between the drug and adverse events, is an essential and complex approach in pharmacovigilance. The recognition of a potential safety issue for a drug requires adverse drug reactions to be readily differentiated from adverse events.

 

An adverse drug reaction is distinguished from an adverse event by the fact that in an adverse drug reaction, a causal relationship is suspected between a drug and an adverse event. Hence, all cases assessed by either the reporting healthcare professional or the sponsor as having a reasonable suspected causal relationship to the drug qualify as adverse drug reactions.

For the purposes of regulatory reporting, if an adverse event is reported spontaneously, even if the relationship is unknown, it meets the criteria of an adverse drug reaction. Hence, all spontaneous reports reported by healthcare professionals or consumers are considered suspected adverse drug reactions since they denote the suspicion of the primary sources, unless the reporters specifically mentions that that a causal relationship can be excluded, or they consider the events to be unrelated.

 

Need for Causality Assessment

A fundamental issue in pharmacovigilance is that many cases concern suspected adverse drug reactions. In real-life situations, a very limited number of adverse reactions qualify as ‘certain’ or ‘unlikely’; most are usually in between, i.e., either ‘possible’ or ‘probable’. To address this issue, many methods have been developed to harmonize causality assessment. However, causality assessment has become a common routine activity in pharmacovigilance.

 

The advantages of causality assessment include the following:

  • Provides uniformity and reduce disagreement between reviewers
  • Provides likelihood of relationship
  • Mark individual cases
  • Improves case evaluation and benefit-risk assessment

 

Methods of Causality Assessment

There are numerous methods published for causality assessment of adverse events. These fall into the following 3 broad categories: Expert judgement/Global introspection, Algorithms and Probabilistic methods (Bayesian approaches):

 

Categories of Causality Assessment Methods
Expert Judgement / Global Introspection Algorithms Probabilistic Methods
Examples WHO UMC causality assessment Naranjo Scale Bayesian Approaches
Feature Individual assessments are performed based on clinical experience and previous knowledge using no standardized tool to arrive at causality conclusion. Sets of specific questions with associated scores for calculating the likelihood of a causal relationship. Specific findings in a case are used to transform the prior estimate of probability into a posterior estimate of probability of drug causation. The prior probability is determined from epidemiological information, and the posterior probability combines this background information with the individual case evidence to deduce the estimate of causation.

 

The 2 commonly accepted and used methods for causality assessment across the globe are the following:

WHO UMC causality assessment

A method developed by World Health Organization (WHO) and Upsala Monitoring centre (UMC) at Sweden as a practical instrument for the assessment of causal relationship. This is a combined assessment considering the clinical-pharmacological aspects of the case and the quality of documentation of the observation.

The main criteria for causality assessment in this method includes temporal relationships between the drug and the adverse event; absence of other confounding factors (e.g., drugs, underlying disease etc.); response to drug withdrawal (DE challenge); and response to drug re-administration (rechallenge).

The various causality categories include the following:

Here is the information arranged by topic with the points listed underneath:

Naranjo causality assessment (Naranjo Scale)

The Naranjo algorithm (Adverse Drug Reaction (ADR) Probability Scale) was developed by Naranjo and coworkers in 1991 to determine the possibility of whether an ADR is due to the drug rather than due to other contributory factors. The probability is assigned using a simple questionnaire to assign scores. There are 10 questions in the questionnaire scale that are answered as either “Yes”, “No”, or “Do not know”. Different point values (-1, 0, +1 or +2) are assigned to each answer.

The total scores in the actual ADR Probability Scale range from -4 to +13; the reaction is considered definite when the score is 9 or higher, probable between 5 to 8, possible between 1 to 4, and doubtful if 0 or less.

 

Conclusion

Causality assessment to assess the relationship or connection between the drug and adverse events is a key component for benefit-risk assessment and identification / assessment of safety signals. Despite various methods developed and standardized, no specific method is accepted universally, although the expert judgement/global introspective method is most commonly used, as algorithm-based and probabilistic methods have been shown to be tough to reliably implement in real situations.

Pharmacovigilance for Decentralized Clinical Trials

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Pharmacovigilance for Decentralized Clinical Trials: Challenges and Way Forward

Decentralised clinical trials make clinical trials easier for patients by reducing the need to travel to clinical sites. They are also known as “Direct-to-participant trials” or “virtual” studies.

DCTs are highly technology driven that often require the use of the following:

Depending upon the clinical trial design and practicality, DCTs may be:

 

Challenges posed by multiple data systems and processing teams

  • Challenges in consolidation of data at the time of document preparation.
  • Reconciliation of data can potentially take longer.
  • Submission delays.
  • Inspections & Audits become more complex.
  • Vendor management is complex and more expensive.
  • Partner Notifications/Exchange of Information, additional tracked activities.

 

Requirements of the Centralized Safety System

A Centralized Safety System requires the following key elements to cater to the challenging requirements of ensuring prompt monitoring of safety:

  • Technical Agreement
  • Safety Management Plans
  • Central SOPs with Work Instructions
  • Site Communication Protocol
  • Safety Database + Processes
  • Compliance and Governance
  • Validated Safety Database System
  • EDC <> Safety Data Exchange
  • Secure Notifications to Sites
  • Follow Ups and Site Queries Tracking Tools
  • Literature Management Tools
  • Signal and Trending Tools, Volume Dependent
  • AI Based Tools to process large volumes of data
  • Data Migration Tools to support product transfers, etc

Medical Literature Monitoring

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The medical literature is a vital source of information for monitoring the safety and benefit-risk profile of medicinal products. It is a significant source of information of suspected adverse reaction case reports (also known as Individual Case Safety Reports (ICSRs).

The Medical Literature Monitoring (MLM) is a service provided by the European Medicines Agency (EMA) for a number of medicinal products with multiple marketing authorisations and many marketing authorisation holders (MAHs), to identify suspected adverse reactions (ICSRs). The EMA is also responsible for entering the relevant information (identified from the MLM service) into the EudraVigilance database. The MAHs are not required to report to EudraVigilance, the suspected adverse reactions recorded in the listed medical literature for products being monitored by EMA. It is important to note that MAHs shall however, monitor all other medical literature not covered by MLM service, and report any suspected adverse reactions.

 

The purpose of the MLM service is to:

Medical Literature Monitoring by the European Medicines Agency

Active Substances Monitored by EMA

The EMA monitors a variety of active substances in the medicinal products for which a large number of authorisations were granted to various MAHs. The list of active substances monitored is published by the EMA on a specific webpage of the EMA website titled ‘MLM Substance and Herbal Substance Groups’.

Medical Literature Databases/Journals used by EMA

The EMA employs daily updated, extensive, comprehensive, and indexed reference literature databases for performing literature search activities. These literature reference databases along with their journal coverage is mentioned below:

 

Medical and Scientific Literature Search by the EMA

Frequency of Literature Search by the EMA

  • Daily search – The indexed biomedical reference database is searched daily; daily refers to the calendar days except the weekends (Saturday and Sunday).
  • Monthly search– Two references databases focusing on pharmaceutical information and drug therapy as well as alternative treatments and complimentary medicine are searched monthly.

 

Search Strategies

EMA customize the search strategies for each substance group based on specific strings and publish the strategy on a specific webpage of the EMA website titled ‘MLM Search Strategies’. In order to enhance precision of the search, the search strategy is updated, as required. The updates are also evident in the ‘MLM Search Strategies’.

Search Results

The next calendar day after the search is conducted, the search results are published at a specific area of the EudraVigilance website. The key elements of the search results include name of substance group, the reference database used, time and date of conducting the search, title of the publication, name of the author(s), name of the journal etc.

 

Screening and Assessment of Medical Literature and Recording of Activities

Within one calendar day of the execution of literature search, EMA performs a review and preliminary assessment of each record.

The aim of screening and assessment procedure is to recognize valid Individual Case Safety Reports (ICSRs) relating to:

  • Suspected adverse reactions (spontaneous reports or solicited reports).
  • Special situations such as use of a medicinal product during pregnancy or breastfeeding, paediatric or elderly population.
  • Reports of off-label use, misuse, overdose, medication errors, lack of therapeutic effect, lack of efficacy etc.

 

The ICSRs refer to suspected serious adverse reactions occurring both within and outside the EU and suspected non-severe adverse reactions occurring within the EU.

 

To simplify the screening process and make it efficient, inclusion/exclusion criteria are used by the EMA. These criteria are periodically reviewed and modified, as appropriate, and are made available on a specific webpage of the EMA website.

 

The publication records that do not meet the requirements for ICSR reporting are moved to an exclusion group, with the exclusion criteria noted. The records that might be eligible for ICSR reporting are moved to an inclusion group, where a duplicate check is performed. The records are then grouped into those that may refer to either as confirmed ICSRs or as potential ICSRs based on the criteria for valid ICSRs. For records of potential ICSRs, the full text publication (and if required, an English translation) is obtained and reviewed with the inclusion/exclusion criteria. Publications which do not qualify for a valid ICSR are moved to the exclusion group after recording the exclusion criteria. The results of these records after screening are published by the EMA on a specific webpage titled ‘MLM Search Results’.

 

The concerned MAH can access the ICSRs identified by the EMA (by the MLM service) from the EudraVigilance database.

 

They can also be downloaded in an Extensible Markup Language (XML) format.

There are documented quality controls to ascertain promptness, accuracy, and thoroughness of the literature screening, review, and the assessment process.

 

In order to assure the safety and effectiveness of medicines, global literature monitoring is a crucial part of pharmacovigilance. Pharmacovigilance teams can discover and assess potential adverse drug reactions and other safety issues early by keeping an eye on a variety of literature sources for potential safety concerns, which is essential for preserving patient health and ensuring the success of drug development programmes.

Responsible Person for EudraVigilance

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Introduction

EudraVigilance is a centralised European database of suspected adverse reactions to medicines that are authorised or being studied in clinical trials in the European Economic Area (EEA).

EudraVigilance is the system for managing and analysing information on suspected adverse reactions to medicines which have been authorised or being studied in clinical trials in the European Economic Area (EEA). The European Medicines Agency (EMA) operates the system on behalf of the European Union (EU) medicines regulatory network.

EudraVigilance supports safe and effective use of medicines by facilitating:

  • Electronic exchange of ICSRs (Individual Case Safety Reports) between EMA, NCAs, MAHs and CT Sponsors in the EEA
  • Early detection and evaluation of possible safety signals
  • Better product information for medicines authorised in the EEA.

 

This electronic reporting is mandatory for marketing authorisation holders and sponsors of clinical trials. Marketing authorisation holders and sponsors of clinical trials must report and evaluate suspected adverse drug reactions during the development and following the marketing authorisation of medicinal products in the European Economic Area (EEA). Marketing authorisation holders must also electronically submit information on medicinal products authorised in the European Union (EU).

 

Why do we need a Responsible Person for EudraVigilance (RPEV)?

The Qualified Person for Pharmacovigilance (QPPV, for MAHs), or the Responsible Person (RP, for Sponsors/ Non-Commercial Sponsors) is responsible for managing an organization and its users in the EudraVigilance Production system.

For an individual to provide RP services to a sponsor/non-commercial sponsor, any one user in the individual’s organization should successfully complete the EudraVigilance ICSR knowledge evaluation and XEVMPD knowledge evaluation. To ensure the quality of data submitted to the EMA, the EMA offers training courses on ICSR and Product submissions using EVWeb, after which users may undergo knowledge evaluations.

 

Registration of Responsible Person in EudraVigilance

Registration of a Responsible Person could entail one of the following two scenarios:

Scenario 1: Change of RP (when there is still an RP in the organization), or

Scenario 2: New RP registration (when the first user of a new organization is registering as RP)

A set of documents must be submitted to the EMA to register the Responsible Person in either of the above scenarios.

 

Documents Required Scenario 1

(Change of RP)

 Scenario 2

(New RP)
Cover letter from the headquarters lever of the organization on a headed paper. The Cover letter should be signed by the new RP of by a person in a position above that at the headquarters leverl= (i.e., director of the organization or similar), or by the legal representative or Commercial and Non-Commercial Sponsors. The cover letter should state the name and position of the previous RP and the name, position and contact details of the new RP. The cover letter should state the name, position and contact details of the new RP.
Email Confirmation from the OMS Data Stewards acknowledging the successful creation of the new organization. Not required, as the organization is already registered with OMS by the

older RP.

 Required
Copy of the ID card or driver’s license or passport, with the full name and signature visible. Any other information contained on the ID document may be blacked out. Required Required

 

Documents Required Scenario 1

(Change of RP)

 Scenario 2

(New RP)
User declaration form for RP, including the type and same of the organization, user’s details, and dated and signed by the user Required Required
EudraVigilance ICSR and XEVMPD submission training. A declaration from the QPPV/RP that the organization has a suitably trained person or submission of ICSRs and XEVPRMs. This declaration can be included in the cover letter or in the body of the email submitted via the EV Registration Service Desk. Submitting copies of ICSR and XEVMPD Certificates is not necessary when changing the QPPV/RP. A copy of the notification of successful completion of the EudraVigilance ICSR

and XEVMPD knowledge evaluation for at least one user to access the production environment, as applicable
Form A- for Sponsor based

in the EEA. Signed by the Sponsor’s legal representative person appointing the new responsible person for clinical trials, including the

name and the contact

details of this person.

The legal representative

person and responsible

person address should be

for the respective

organizations the work for.

 Required Required
Form B- for Sponsor’s based outside the EEA only. Signed by someone from the Sponsor appointing the Sponsor’s legal

representative person in the EEA, including the name and the contact details of this person.

 Required Required

The legal representative person address should be for the organization the legal representative works for.
A EudraCT number for a study the sponsor is conducting. Required Required

 

Conclusion

We hope that this blog was helpful in understanding the role of a Responsible Person and the process of registration of a RP with the EMA. Please reach out to us if you require RP services in the EEA or wish to understand more about the registration process for the RP.

Serious Adverse Event Reconciliation in Clinical Studies

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What is Serious Adverse Event (SAE) Reconciliation and why is it required?

The aim of Good Clinical Practice (GCP) and Good Pharmacovigilance Process (GVP) is to keep patients at the centre of drug development efforts and ensure their safety and wellbeing, while at the same time researching more effective, safer cures for diseases. At the juncture of GCP and GVP is the process of SAE Reconciliation, which ensures that the clinical database and pharmacovigilance database are in sync with each other. Completeness and accuracy of data in these two databases is a significant driver in determining outcomes in a clinical trial, affecting clinical reports and safety reports, data management reports, etc. This blog post emphasizes the importance of this critical process in order to achieve better outcomes for clinical trial sponsors and patients alike.

Key Stakeholders in the SAE Reconciliation process

SAE Reconciliation is a group effort by teams that manage the clinical database (i.e., sites, data management), and the safety database (i.e., pharmacovigilance). Support is often required from Clinical Operations in co-ordinating with sites & site personnel in resolving issues that arise, Regulatory in co-ordinating submissions where required, and contract research organizations that may have been contracted by Sponsors in the study.

Manual vs. Automated SAE Reconciliation

SAE Reconciliation may be a manual or automated process, depending on the size of the study population and the volume of adverse event data in a study. Sponsor personnel, along with their Data Management and Pharmacovigilance teams, agree to a list of fields that would be reconciled during the course of a study, and the frequency at which such reconciliation is to be done. Detailed documents, e.g., Data Management Plans may be prepared to document the process, responsibilities & timelines. Regular meetings may be required for parties to clarify any discrepancies that may arise during the SAE reconciliation process.

Frequent challenges faced during SAE reconciliation and their remedial measures

Some frequent challenges include MedDRA version differences, irresolvable discrepancies, disagreement between involved parties, lack of responses from sites, etc. With effective management of the process, and automation tools, where the volumes justify their use, the process efficiency can be maximized, thus bringing about higher accuracy of data across both the databases.

 

SERIOUS ADVERSE EVENT RECONCILIATION IN CLINICAL STUDIES

Aim: To ensure the completeness and accuracy of the clinical trial data which is the key driver in determining outcomes in a clinical trial, affecting clinical reports and safety reports, data management report.

Here is the updated and organized table as per your request:

GVP SAE Reconciliation and GCP Manual Reconciliation

Reconciliation Type Details
Manual Reconciliation – Lower AE volume

– Smaller Studies
Automated Reconciliation – High volume of data to be reconciled

– Larger Studies

Frequent Challenges

  • MedDRA Version Differences
  • Irresolvable Discrepancies
  • Disagreement Between Involved Parties
  • Lack of Response from Sites

Stakeholders Involved in the Process

  1. Regulatory
  2. Data Management
  3. Clinical Operation
  4. Pharmacovigilance

Post marketing Adverse Drug Experience (PADE) Inspections – Part III

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Legal Framework of PADE Inspections

Scientific Literature Reports

Determine:

  • If the firm reviews scientific literature and the frequency of the review.
  • If the applicant or non-applicant is submitting expedited ICSRs for adverse experiences obtained from the published scientific and medical literature that are both serious and unexpected.
  • If the applicant or non-applicant is submitting a copy of the published article as an ICSR attachment for each expedited ICSR of an adverse experience obtained from the published scientific and medical literature. Foreign language articles should be accompanied by an English translation of the abstract.

 

Foreign Postmarketing Adverse Experience Reporting

Determine:

  • If written procedures address the surveillance, receipt, evaluation, and reporting of adverse experiences from affiliates, subsidiaries, contractors, and business partners outside the United States.
  • If serious and unlabelled (i.e., unexpected) adverse experiences from foreign sources have been submitted to FDA within 15 calendar day.

 

Solicited Safety Data

Determine:

  • How the firm identifies and monitors all sources of solicited safety information including, but not limited to, post marketing studies, nonapplicant-sponsored clinical data obtained by the firm, and patient engagement programs, to ensure that the firm’s pharmacovigilance personnel receive all potential adverse experiences. The identification and monitoring of solicited safety data should be addressed in the firm’s written procedures.
  • If the firm is monitoring its firm-sponsored internet and social media sites, and the frequency of the monitoring.
  • If solicited safety data has been assessed for seriousness, unexpectedness, and causality.
  • If solicited safety data that has been assessed as serious, unexpected, and possibly related to the suspect product has been submitted to FDA within 15 days of receipt of the information.
  • During inspection, auditor may select several Annual Reports and confirm that the status of the firm’s post marketing studies is included in the reports.

 

Aggregate Safety Reports:

The reporting interval is quarterly for the first three years following the approval of the application or license, and annually thereafter, unless FDA instructs the Firm otherwise.

Determine:

  • If the PADER or PAER contains all the required content as described in 21 CFR 314.80(c)(2) or 21 CFR 600.80(c)(2), respectively.
  • If the PADER or PAER has been submitted within the required regulatory timelines.
  • Several Annual Reports may be selected to confirm that the status of the firm’s post marketing studies is included in the reports, as required by 21 CFR 314.81.
  • All reports must be submitted in electronic format, as described in 21 CFR 314.80(g) and 21 CFR 600.80(h).

 

Contractor Oversight

  • Oversight of outsourced services may include a broad range of activities to ensure that all outsourced services and activities associated with post marketing safety are performed according to applicable FDA regulations.
  • Identify the name, business location, and contact information for any contractor involved in the surveillance, receipt, evaluation, or reporting of adverse experiences to FDA, including all domestic and foreign locations where safety information is processed.
  • If the applicant or non-applicant has written procedures for obtaining and processing safety information from its contractors.
  • Assess how the applicant or non-applicant ensures that its contractors develop written procedures.
  • Determine the contractor’s specific responsibilities. Determine how the applicant or non-applicant ensures that its contractors fulfil their responsibilities. Applicants or non-applicants may outsource some or all of their post marketing safety obligations, but remain responsible for complete, accurate, and timely reporting to FDA.
  • Determine how the contractor documents its receipt date for obtaining the minimum dataset for a valid ICSR and how it communicates this information to the applicant or non-applicant. The clock for expedited reporting starts as soon as the minimum information for a valid ICSR has been received by the contractor or its representatives.

 

Electronic Submissions

  • Determine if safety report submissions are in an electronic format that FDA can process, review, and archive, as required.
  • Review system-generated delivery confirmation notices from either the Electronic Submission Gateway (ESG) or the Safety Reporting Portal (SRP) and determine if the firm has a procedure for correcting and resubmitting any submission for which the message delivery notice (MDN) indicated that the submission was not accepted.
  • Determine if the firm has a corrective action for each late submission to the Agency, according to the MDN
  • Determine if MDNs are being retained.

 

Waivers & Record Keeping

  • A copy of the waiver for any regulatory requirement pertaining to post marketing safety, may be requested to determine compliance with the terms of the waiver.
  • For approved drugs or biologics, if all records containing information relating post marketing safety reports (whether or not submitted to FDA) have been maintained for a period of 10 years, or for combination products, the longest retention period applicable.
  • Anyone marketing a prescription drug for human use without an approved new drug application or abbreviated new drug application must comply with the recordkeeping and reporting requirements of 21 CFR 310.305.

Liver Injury With Cancer Chemotherapy

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Liver Injury with Cancer Chemotherapy -Importance of the Product Label in Risk Satisfaction

Cytotoxic chemotherapy is frequently associated with serum Aminotransferase elevations that are self-limited and that may subside with continued therapy. However, rare occurrences of jaundice and liver failure have been reported in association with many of these drugs. Hepatotoxicity identified during clinical development (instead of post-marketing data) is often the basis for the liver toxicity information in the labels for oncology drugs.

Generally, the evidence of potential liver injury is consistent with hepatotoxicity information in the EU Summary of Product Characteristics (SmPC) and U.S. Product Information (PI). However, there is a lack of harmonization regarding location, format, and details of information on hepatotoxicity. Although guidance on liver monitoring is generally mentioned; time to onset of Drug-induced liver injury (DILI), dose modification tables, biochemical profile, or re-challenge information are not always provided.

It is recommended to standardize the information obtained during drug development relating to liver toxicity (time of onset, pattern of injury) and to harmonize the location (sections within the label), format, and level of detail (e.g., monitoring schedule, dose modification table) in the product label.

For combination drugs, the information on liver toxicity of individual drugs (i.e., mechanism, time of onset, pattern of injury) should be used for assessing overlapping liver toxicities.

In oncology clinical trials, the NCI-CTCAE grading system is generally used for grading the severity of liver test abnormalities for suspected DILI cases, and risk management actions are recommended in the product labels based on these severity grades. Standard serum liver testing should be performed in all oncology patients prior to, during and after chemotherapy, immunotherapy or new treatments that cause liver injury.

Pre-treatment analysis for hepatic metastases with CT or MRI imaging is recommended in all oncology patients who are at increased risk for hepatic spread of tumour, prior to administration of potentially hepatotoxic chemotherapy or immunotherapy. It is important to understand the pattern of hepatotoxicity with standard chemotherapeutic drugs and the newer class of immunotherapies.

I) Standard Chemotherapeutic Drugs

Some level of hepatotoxicity as well as toxicity to other organs is generally associated with almost all anticancer drugs. With standard chemotherapeutic drugs, the hepatotoxicity is generally direct and dose-dependent; however, with many drugs, serious liver injury may also be due to idiosyncratic mechanisms. Further, hepatotoxicity may manifest in a variety of abnormal histological forms and clinicopathological phenotypes (few examples are mentioned in the Figure below).

Type Mechanism(s) of Hepatotoxicity (Known or Suspected) Examples of Associated Drugs Liver Injury Phenotype
Direct Alkylation of DNA leads to damage to small blood vessels in liver

Inhibition of methionine synthesis leading to endoplasmic reticulum (ER) stress & activation of stellate cells by excess of homocysteine

 Busulfan (when given for prolonged periods), Methotrexate Nodular regenerative hyperplasia (NRH), Steatohepatitis, Fibrosis, Cirrhosis
Indirect Estrogenic effects on fat metabolism in the liver

Secondary to effects on gastrointestinal motility, gut microbiome, and bile acid levels

 Tamoxifen, Octreotide Fatty liver, Steatohepatitis, Acute liver injury
Idiosyncratic Unclear Temozolomide, Cyclophosphamide, Melphalan, Chlorambucil, Azathioprine, Tamoxifen Acute liver injury (mostly cholestatic)

 

II) Immunotherapy

Immunotherapy includes drugs that are intended to activate or increase immunological activity against the patient’s neoplasm.

  • Immune checkpoint inhibitors (ICIs)

The patient survival in several metastatic solid organ tumours has significantly improved by immunotherapy, but these generally results in immune-related adverse events (IRAEs) including hepatotoxicity in both clinical trials and post-marketing set-up.

The use of hepatotoxic immunotherapy drugs and/or biological agents with certain other cancer drugs may result in more severe hepatotoxicity than treatment with each single drug.

The hepatic abnormalities with ICIs may range from asymptomatic increases in aminotransferases to acute hepatitis resulting in fulminant hepatic failure. These usually occur 6 to 14 weeks after initiation of treatment, although liver injury can occur after longer treatment duration and even after drug discontinuation.

  • Protein kinase inhibitors

The protein kinases whose activities are altered in cancer cells are specifically targeted by these anticancer drugs. The clinically evident liver injury with many protein kinase inhibitors is usually self-limited but may be fatal with some drugs and may be hepatocellular or cholestatic.

Features of autoimmunity have been observed in some cases of protein kinase-induced DILI, suggesting that the liver injury may be caused by an immunological autoreactive reaction. Imatinib and nilotinib have been linked to the reactivation of hepatitis B that may be due to the potentiation of hepatitis B virus replication or due to the drug’s immunosuppressive effects.

Many of the protein kinase inhibitors have been on the market only for just a few years and there is currently limited understanding as to why protein kinase inhibitors are hepatotoxic. Although there are various mechanisms that may explain the hepatotoxicity with many of these drugs, there is not enough scientific evidence in this area to make solid conclusions.

  • An overview of some of the newer cancer drugs and their currently known hepatotoxic potential is provided in the figure below:

Drug Class Mechanism of Action Examples Currently Observed Liver Injury Potential
Immune Checkpoint Inhibitors (ICIs) Blocks cell surface activities of CTLA-4, PD-1, or PD-L1 to stimulate anti-tumor immune responses CTLA-4 inhibitor: Ipilimumab, PD-1 inhibitors: Pembrolizumab, Nivolumab, PD-L1 inhibitors: Atezolizumab, Durvalumab Immune-mediated liver injury including hepatitis (a) with some distinct histological patterns (b)
Antibody Drug Conjugates (ADCs) Cytotoxic drugs covalently linked to monoclonal antibodies directed to antigens differentially overexpressed in tumour cells Gemtuzumab ozogamicin, Trastuzumab deruxtecan, Trastuzumab emtansine Most but not all ADCs are associated with liver toxicity, including fatal liver failure. The pattern of liver injury may differ depending on the toxophore.
Alpha-Specific VEGF Inhibitor and PD1/PDL-1 Combination VEGF inhibitors may potentiate the effect of PD1/PDL-1 Pembrolizumab plus axitinib, Avelumab plus axitinib These combination treatments with axitinib increase the rates of higher CTCAE grades of hepatotoxicity.

 

It can be difficult to characterize the risk of DILI because of low occurrence of event, limited information available, and uncertainties in pathogenesis.

In a real-world scenario, post-marketing risk management is vital to manage the risk of DILI. This is accomplished by periodic reviews and updates to the safety profile of a drug along with risk minimization measures. The product label is the basic information for healthcare professionals to refer for product safety and efficacy and which contains both preclinical and clinical information in a structured format. The product label discusses product risks in the patient population who may potentially be treated with the drug.

Risk stratification is a method for determining and predicting the possibility of a specific outcome among patients who may be exposed to certain anticancer drugs. The product label forms the basis of risk stratification by which the risks of the drug are communicated with the patients who may be treated with the drug. A risk management plan may be effective to manage the risk of DILI if the risk factors are characterized, if there are well defined patterns of liver injury, and/or there are reliable measures on which risk management and monitoring can be based upon.

Are ALT & AST Elevations Really Liver Function Tests

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Liver biochemical tests are very commonly performed in clinical studies/clinical practice. These tests include:

  • Alanine/aspartate aminotransferases (ALT/AST), Alkaline phosphatase (ALP), Gamma-glutamyl transferase (GGT)
  • Bilirubin, Albumin
  • Prothrombin time (PT), International normalized ratio (INR)

These tests are commonly used for the diagnosis and evaluation of acute and chronic liver disease, irrespective of the ethology.

  • Liver Injury Vs. Liver Function

There are two separate concepts for drug-induced liver injury: severity of liver injury and the grade of liver function impairment

  1. Liver Injury Indicators:

    • Tests: ALT (Alanine Aminotransferase) and AST (Aspartate Aminotransferase): Elevated levels of ALT and AST indicate liver cell damage, suggesting liver injury.

  2. Liver Function Impairment Indicators:

    • Tests: Albumin, PT (Prothrombin Time), INR (International Normalized Ratio), and Bilirubin: Decreased albumin or increased PT, INR, or bilirubin levels indicate impaired liver function.

Therefore, the term Liver function tests (LFTs) being used for elevations of ALT and AST is somewhat of a misnomer because these enzymes do not represent liver function but rather indicate the damage of liver cells. On the other hand,

albumin, bilirubin, and vitamin K-dependent clotting factors represent synthetic function of the liver. The decreased synthesis of clotting factors by the liver may lead to prothrombin time (PT) prolongation and an increase in the

international normalized ratio (INR).

Some of the commonly used scores to predict mortality in patients with cirrhosis such as the Child-Pugh score and Model for End Stage Liver Disease (MELD) score do not use AST, ALT, or ALP but instead use INR, bilirubin and albumin in

Child-Pugh score and INR and bilirubin in MELD score.

 

The following table reflects a summary of the commonly used serum liver tests in clinical studies/clinical practice:

Liver Injury Tests

Category Test Conditions Associated with Abnormal Liver Injury Tests Site of Localization
Hepatocellular Injury ALT Hepatocellular injury, muscle injury, rhabdomyolysis Liver, cardiac muscle, skeletal muscle
AST Hepatocellular injury, muscle injury, rhabdomyolysis, haemolysis Liver, cardiac muscle, skeletal muscle, brain, kidney, RBC
Cholestasis ALP Cholestasis, biliary injury, bone disorders, late pregnancy Liver, kidney, bone, intestine, placenta
GGT Cholestasis, biliary injury, alcohol intake, obesity, smoking Liver, pancreas, kidney, intestine, spleen, prostate
Total Bilirubin (Direct + Indirect) Direct > Indirect: Hepatocellular injury, cholestasis; Indirect > Direct: Haemolysis, Gilbert’s syndrome Circulates in blood in unconjugated (indirect) form and undergoes conjugation (direct) in the liver

 

Liver Function Tests

Test Site & Function Conditions Associated with Abnormal Liver Function Tests
Albumin Main protein produced by the liver, circulates in serum, and maintains serum oncotic pressure. Acute Liver Disease: Albumin synthesis usually preserved. Chronic Liver Disease: Low serum albumin indicates cirrhosis.
PT/INR Indicates the function of vitamin K-dependent clotting factors mainly synthesized in the liver. Test measures the extrinsic coagulation pathway. Aids in the diagnosis of both acute and chronic hepatic disorders.

 

The below table indicates a pattern of alterations of liver injury tests and liver function tests in hepatocellular injury & cholestasis:

TEST HEPATOCELLULAR INJURY CHOLESTASIS
Liver Injury Tests
ALT/AST ++/+++ 0/+
ALP 0/+ ++/+++
Total Bilirubin 0/+++ 0/+++
Liver Function Tests
PT/INR Prolonged Prolonged
Albumin -/—- 0

 

Stopping Rules for the Drugs in Premarketing Clinical Studies for Hepatotoxicity:

In clinical trials, it is often difficult to determine when the study drug should be stopped. This is because transient increase of ALT or AST are quite common and progression to severe DILI or acute liver failure is usually uncommon, stopping the study drug on an increase in ALT or AST greater than 3xULN may be unnecessary. For most individuals, the liver appears capable of adapting to injury by chemical substances, which may render a person tolerant to the drug despite continued exposure. Stopping a drug at the first indication of mild injury does not allow knowledge if adaptation will occur, as it does for drugs such as tacrine, which cause liver injury but do not cause severe DILI. On the other hand, if there is marked increase in serum aminotransferases or there is evidence of functional liver impairment (as indicated by rising INR or bilirubin) which represent substantial liver injury, continuing with the study drug appears unacceptably dangerous.

Hence, the USFDA guidance mentions that in the premarketing clinical studies, discontinuation of the study drug should be considered if any of the following occurs:

  • ALT or AST >8 x Upper Limit of Normal (ULN)
  • ALT or AST >5 x ULN for more than 2 weeks
  • ALT or AST >3 x ULN and (Total bilirubin >2 x ULN or INR >1.5)
  • ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

It is important to note that these stopping rules are guidelines and may further evolve based on advances in medical research and knowledge. The safety of study participants should always be the top priority, and the final decision to stop a study due to hepatotoxicity will be made by the study sponsor in consultation with multiple key stakeholders including regulatory agencies, investigators, and independent safety monitoring committees.