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Category: Clinical Safety and Pharmacovigilance

Is it Drug Induced Liver Injury (DILI), or something else?

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Ever faced a hepatic signal in a trial that looked like classic drug-induced liver injury (DILI), but turned out to be something entirely different?

Here’s a hypothetical scenario that might resonate, where hepatic physiology,
herbal pharmacology, and cultural practices intersected to produce a pseudosignal that mimicked hepatotoxicity.

A Complex Signal in an Early Phase Trial

During an early Phase trial of a novel drug, one site reported liver enzyme elevations in three participants from the high-dose cohort:

  • ALT 2–3 × ULN
  • Bilirubin: mildly elevated (1.2 × ULN) in one case
  • No clinical symptoms, no jaundice, fatigue, or right upper quadrant pain.

It looked like hepatocellular injury, potentially qualifying as a Hy’s Law signal. But something didn’t add up.

The Hidden Variable: Herbal Co-Exposure

Upon deeper review of case narratives and follow-up interviews, the medical monitor discovered that the participants had been consuming traditional herbal decoctions:

  • Andrographis paniculata
  • Phyllanthus amarus

These were considered “health tonics” in the local culture and were not disclosed during standard medication history. Their omission was unintentional, these herbs were simply part of daily life.

Why Would These Matter?

Both herbs are pharmacologically active:

  • Andrographolide, the key compound in Andrographis paniculata, is a known CYP3A4 inhibitor
  • Phyllanthin and hypophyllanthin, from Phyllanthus amarus, inhibit CYP3A4, CYP2C9, and potentially conjugation enzymes like UGT

The mechanism likely involved:

  • CYP enzyme inhibition
  • Impaired clearance of the parent drug
  • Accumulation of reactive intermediates
  • Oxidative and mitochondrial stress in hepatocytes
  • ALT/AST leakage

This wasn’t classic immune-mediated DILI, it was a pharmacokinetically driven pseudo-DILI, shaped by metabolic interference from herbal products.

Pharmacological Evidence (CYP Modulation) Andrographis paniculata

  • Primary active compound: Andrographolide

Pharmacological Evidence (CYP Modulation) Andrographis paniculata

  • Mechanism: Inhibits CYP3A4 activity (in vitro studies)

Reference:
Elza Sundhani, Endang Lukitaningsih, Arief Nurrochmad, Agung Endro Nugroho. Potential pharmacokinetic and pharmacodynamic herb-drug interactions of Andrographis paniculata (Burm. f.) and andrographolide:
A systematic review.

Phyllanthus amarus

  • Active compounds: Phyllanthin, hypophyllanthin
  • Mechanism: Inhibits CYP3A4 and CYP2C9

Reference:
Taesotikul T, Dumrongsakulchai W, Wattanachai N, Navinpipat V, Somanabandhu A, Tassaneeyakul W, Tassaneeyakul W. Inhibitory effects of Phyllanthus amarus and its major lignans on human microsomal cytochrome P450 activities: evidence for CYP3A4 mechanism-based inhibition. Drug Metab Pharmacokinet. 2011;26(2):154-61. doi: 10.2133/dmpk.dmpk-10-rg-107. Epub 2010 Dec 17. PMID: 21178301.

Medical Monitoring Strategy

Once the pattern became clear, the safety team responded rapidly and decisively:
Pharmacokinetic (PK) Substudy
Goal: Determine if herbal co-use altered systemic exposure and metabolite profiles

  • Used stored plasma samples
  • Compared AUC, Cmax, and metabolite-to-parent ratios between herbalexposed vs. unexposed participants
  • Analysis conducted using non-compartmental modeling

Key Results:

  • Significant increase in AUC of parent compound in herbal users
  • Strikingly higher metabolite-to-parent ratio
  • Modestly extended half-life

Conclusion: Exposure was exaggerated due to impaired metabolism, likely contributing to hepatic stress, but not direct hepatotoxicity.

In Vitro Microsome Assay
Goal: Test direct inhibition of hepatic CYP enzymes by the herbal extracts

  • Human liver microsomes used (pooled donor panels)
  • Co-incubated with midazolam and diclofenac to probe CYP3A4 and 2C9 activity
  • Enzyme kinetics analyzed via LC-MS/MS

Key Results:

  • Andrographis extract inhibited CYP3A4 activity
  • Phyllanthus extract inhibited both CYP3A4 and CYP2C9
  • No CYP induction observed in PXR-based reporter assays

Outcome and Protocol Response

Following the findings:

  • Dose escalation was paused temporarily
  • CRF and ICF were updated to include herbal/traditional supplement disclosure
  • A 14-day washout period was implemented for known hepatic modulators
  • ALT/AST/bilirubin monitoring was intensified on Days 4, 7, 10, and 14

After herbal intake was discontinued, enzyme levels normalized within 10 days. No further cases were reported. The trial resumed with stronger hepatic safety controls in place.

Still Reflecting….

Even now, this scenario raises important questions:

  • Are we doing enough to proactively uncover culturally “invisible” exposures in global trials?
  • Are PK/PD insights being used early enough to differentiate real signals from pseudo-DILI?
  • Are we integrating hepatic physiology, enzyme modulation, and cultural pharmacology into our signal detection framework?

This wasn’t just a pharmacovigilance issue. It was a clinical, cultural, and mechanistic puzzle; one that we solved by looking beyond lab values.

Let’s Keep the Conversation Going!

  • Have you managed hepatic safety signals that turned out to be driven by cultural or dietary confounders?
  • How do you screen for herb-drug interactions in early-phase settings?
  • Let’s share ideas — because the more perspectives we hear, the better we can safeguard participants and protect the integrity of our science.

Medication Errors & Patient Safety – Part I

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Why Medication Errors Matter More Than We Think

Medication errors are a significant public health concern, often occurring during various stages of care, whether preventive, diagnostic, therapeutic, or rehabilitative. These errors not only affect patient outcomes but also highlight critical gaps in the safe use of medicinal products. There is a growing need to strengthen risk mitigation strategies and enhance prevention efforts through existing regulatory mechanisms. Beyond the clinical impact, medication-related harm also places a substantial financial burden on healthcare systems globally, with associated costs estimated at around US $42 billion each year. Medication errors are unintended mistakes that can happen at any stage ofthe medication process, whether it’s during prescribing, storing, dispensing, preparation, or administration. When such errors occur repeatedly, follow a recognizable pattern, or lead to serious patient harm, it becomes critical to investigate the root causes and contributing factors. Understanding the clinical impact of these incidents, along with identifying practical solutions and preventive strategies, is key to ensuring they do notrecur.

Stages of Medication Use Process

  1. Storage
  2. Prescribing Stage
  3. Transcribing Stage
  4. Preparation Stage
  5. Dispensing Stage
  6. Administation Stage
  7. Monitoring Stage

What is a Medication Error?

A medication error is an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient.

Adverse Event:
GVP Annex I (Rev 3) defines an adverse event as any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Medication related adverse events should be distinguished from other adverse events (e.g. fall, surgery on wrong body site etc.).

Adverse Reaction:

An adverse reaction (ADR) is a response to a medicinal product which is noxious and unintended (Directive 2001/83/EC, Article 1 (11)). This includes adverse reactions which arise from:

  • the use of a medicinal product within the terms of the marketing authorization.
  • the use outside the terms of the marketing authorization, including overdose, off label use, misuse, abuse and medication errors;
  • occupational exposure.

Patient Safety Incident

WHO’s Conceptual Framework for International Classification for Patient Safety (WHO ICPS) defines a patient safety incident as an event or circumstance that could have resulted, or did result, in unnecessary harm to a patient. The scope of patient safety incidents covers the entire health care process whereas the scope of (suspected) adverse reactions in pharmacovigilance is limited to the use of medicines by a consumer or healthcare professional. Patient safety incidents may occur in hospitals or other health care communities and may or may not involve a medicinal product.

Correlation Among Medication Errors, Preventable and Non-Preventable Adverse Reactions, and Intercepted Errors

The diagram is provided for illustrative purposes only to support understanding of medication errors in the context of patient safety, and is not intended to inform or replace pharmacovigilance reporting obligations.

Ref: European Medicines Agency Good practice guide on recording, coding, reporting and assessment of medication errors. EMA/762563/2014

 

Ref: Contemporary View of Medication–Related Harm. A New Paradigm. NCC MERP and Medication Errors. www.nccmerp.org

Classification of Medication Errors Reports

To support effective recording, coding, reporting, and assessment, medication errors should be classified based on factual information specific to each case.
Itis important to clearly distinguish between:

  • Medication errors associated with adverse reaction(s)
  • Medication errors without harm
  • Intercepted medication errors
  • Potential medication errors

The classification depends on where the break occurs in the sequence of events leading to the error and the resulting consequences forthe patient, as illustrated below:

Ref: European Medicines Agency Good practice guide on recording, coding, reporting and assessment of medication errors. EMA/762563/2014

 

Intercepted Medication errors (Near Miss)
An intercepted error indicates that an intervention caused a break in the chain of events in the treatment process before reaching the patient which would have resulted in a ‘potential’ ADR. The intervention has prevented actual harm being caused to the patient. A near miss from a patient safety perspective is a random break in the chain of events leading up to a potential adverse event which has prevented injury, damage, illness or harm, but the potential for harm was nonetheless very near.
Example: A wrongly prepared medicine is intercepted by a nurse before being administered.

 

Potential medication errors
The recognition of circumstances that could lead to a medication error, and may or may not involve a patient. Refers to all possible mistakes in the prescribing, storing, dispensing, preparation for administration or administration of a medicinal product by all persons who are involved in the medication process and may lead to: a) medication error with harm, but without knowing the actual cause, b) medication error without harm and without knowing the actual cause, or c) medication error without harm, but with the awareness ofthe actual cause.
Example: Pharmacist noticed that the names of two medicines are similar and could clearly lead to product name confusion in practice, but no patient was actually involved or has taken the medicine.(Scenario c)

 

Medication Errors with Harm (Adverse Reactions)Medication errors that result in harm to the patient, specifically those associated with one or more adverse reactions. These cases also involve preventability.
Example: A patient receives an incorrect dose leading to hypotension and hospitalization.

 

Medication Errors without harm

NCC MERP Index for Categorizing Medication Errors

Ref:©2025 National Coordinating Council for Medication Error Reporting and Prevention. All Rights Reserved. *Permission is here by granted to reproduce information contained here in provided that such reproduction shall not modify the text and shall include the copyright notice appearing on the pages from which it was copied.
This copyright statement will change to the new year after the 1st of every year

Postmarketing Adverse Drug Experience (PADE) Inspections – Part IV

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Legal Framework of PADE Inspections

Good Corrective Action Plan – Four Reasons to Submit a Complete and Timely

Written Response

  1. May be considered in an FDA compliance decision.
  2. Demonstrates your acknowledgment and understanding of the observations to the FDA
  3. Demonstrates your commitment to correct the observations to the FDA
  4. Establishes credibility with the FDA

Points to Consider for Written Responses to the FDA

(SUBMIT THE REPORT WITHIN 15 WORKING DAYS)

Inspection Reporting: FORM FDA 483, Inspectional Observations

Inspection Classifications

No Actions Indicated

(NAI)

 Voluntary Action Indicated (VAI) Official Action Indicated (OAI)
No Objectionable conditions

or practices were found

during an inspection (or the

objectionable conditions

found do not justify further

regulatory action).

 

 Objectionable conditions or practices were found, but do not rise to the level warranting OAI classification. Objectionable conditions or practices were found, whose scope, severity, or pattern warrants the recommendation for a regulatory action.

a) Warning Letters

The issuance of a Warning Letter (WL) may be warranted when the inspection uncovers significant objectionable conditions related to noncompliance with PADE requirements. The CDER PVC Team and OSI management will evaluate all inspections classified as OAI by OBIMO on a case-by-case basis.

b) Untitled Letters

An Untitled Letter (UL) may be warranted when the deficiencies found at the firm are severe enough to justify a formal letter to the firm, but do not meet the threshold of regulatory significance for a WL.

Factors that influence the issuance of a WL or UL include the nature and extent of the violations (for example, if they are repeated or deliberate), the compliance history of the inspected firm, and the corrective actions implemented by the firm.

c) Enforcement Actions

  1. Injunction: Injunction should be considered when follow-up inspection(s) show that the firm has a continuing pattern of significant and substantial deviations, despite previous attempts by FDA to obtain compliance. 1.
  2. Seizure: Seizure for failure to comply with post marketing adverse drug experience reporting regulations would be possible only if the approval of the application for the product has first been withdrawn (FD&C Act, section 304(a)(1)). Seizure would then be based on distribution of an unapproved drug product. 2.
  3. Prosecution: Evidence that a firm is submitting false information, not submitting required reports for serious post marketing adverse events, or withholding important information, the submission of which may have resulted in the Agency requiring labelling changes or withdrawing an application, should be referred to the Office of Criminal Investigations (OCI) for consideration of prosecution.

 

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.

Postmarketing Adverse Drug Experience (PADE) Inspections – Part II

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Legal Framework of PADE Inspections

  1. LAW: Federal Food, Drug and Cosmetic Act (FDCA)
  2. Title 21 of the Code of Federal Regulations (CFR)
  3. FDA’s Current Thinking

Inspectional Observations: USFDA 2023

1 21 CFR 314.80(b) Failure to develop written procedures Written procedures have not been developed for the [surveillance] [receipt] [evaluation] [reporting to FDA] of post marketing adverse drug experiences.
2 21 CFR 314.81(b)(1)(ii) Failure to meet specifications An NDA-Field Alert Report was not submitted within three working days of receipt of information concerning a failure of one or more distributed batches of a drug to meet the specifications established for it in the application.
3 21 CFR 314.80(c)(1)(i) Late submission of 15-day report. 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.
4 21 CFR 314.80(c)(1)(ii) Failure to investigate serious, unexpected events Adverse drug experiences that were the subject of post marketing 15-day reports were not [promptly] investigated.
5 21 CFR 314.80(c)(2) Late submission of annual safety reports Not all annual periodic adverse drug experience reports have been submitted within 60 days of the anniversary date of the approval of the application.
6 21 CFR 314.80(c)(2)(ii)(A) Incomplete periodic safety report Failed to submit a periodic report containing

  • [a narrative summary and analysis of the ADE information for the reporting interval in the report.]
  • [an analysis of the post marketing 15-day Alert reports submitted during the reporting interval.]
  • [a history of actions taken since the last report because of adverse drug experiences.]
  • [an index with a line listing of your patient identification code and adverse reaction term(s) for all ICSRs you submitted for the reporting interval.]
7 21 CFR 314.80(d) Failure to submit scientific article A postmarketing 15-day Alert report based upon scientific literature was not accompanied by a copy of the published article.
8 21 CFR 314.80(j) Failure to maintain records Failed to maintain for a period of 10 years records of all adverse drug experiences known to you, including raw data and any correspondence.
9 21 CFR 314.81(b)(2) Timely submission An annual report was not submitted [each year] [within 60 days of the anniversary date of U.S. approval of the application] to the FDA division responsible for reviewing the application.

Ref: Number of 483 issued from the System*

Inspections ending between 10/1/2022 and 9/30/2023
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/inspection-observations

Written Procedures Must Address

  1. Surveillance
    • Account for all sources
    • Spontaneous
    • Solicited
    • Internet sources (firm sponsored)
    • Literature …and more!
  2. Receipt
    • ADE info
    • Initial
    • Follow-up
    • Receipt from any source
  3. Evaluation
    • Seriousness
    • Expectedness
    • Relatedness
    • ADEs from any source
    • Follow-up procedures
  4. Reporting
    • 15-day Alert Reports
    • Non-expedited individual case safety reports (ICSRs)
    • Aggregate Reports
    • All info must be submitted electronically

Ref: Postmarketing Drug Safety and Inspection Readiness June 19, 2018. Center for Drug Evaluation and Research (CDER) Small Business and Industry Assistance (SBIA) Webinar. USFDA

Written Procedures

  1. Develop written procedures for the surveillance, receipt, evaluation, and
    reporting of postmarketing safety information, including procedures for
    managing safety information with contractors and business partners, as
    applicable.
  2. Written procedures should be maintained and followed.
  3. Determine if written procedures provide for complete, accurate, and timely reporting of safety data to FDA.
  4. Regulations pertaining to the requirements for written procedures: 21 CFR 4 310.305(a), 21 CFR 314.80(b), and 21 CFR 600.80(b).

Surveillance

  • Determine if the firm is monitoring potential sources of adverse event information
  • Determine if the firm is surveilling both foreign and domestic sources.
  • Determine if the firm is promptly reviewing all postmarketing safety information received from any source


Many other sources such as firm-sponsored websites, firmsponsored social media, legal cases, product complaint files etc.

  • The timeline for submission of adverse experiences to FDA begins the day that the applicant, nonapplicant, or its contractors or business partners, obtain the minimum data set for a valid adverse event report.
  • The minimum dataset required to consider information reportable is
    • an identifiable patient
    • an identifiable reporter
    • a suspect product and
    • an event.
  • The date of receipt must be accurately determined and documented for the receipt of initial and follow-up information received by any method (for example, by phone, electronic mail, postal mail, fax, literature, websites, or employees).

Evaluation

Determine how:

  • Safety information from any source is evaluated to determine if an adverse experience is present.
  • Adverse experience reports are evaluated to establish if each report is spontaneous or solicited.
  • All adverse experiences, both spontaneous and solicited, are evaluated for seriousness and expectedness.
  • For adverse experiences originating from solicited sources, determine how the causal relationship between the product and the adverse experience is assessed.
  • If adverse experiences that are both serious and unexpected are promptly investigated and if all attempts to obtain additional information are documented.

Reporting

  1. Spontaneous adverse experiences, foreign or domestic, that have been evaluated as both serious and unexpected are submitted to FDA no later than 15 calendar days from the initial receipt of the information.
  2. For solicited adverse experiences, foreign or domestic, determine if all adverse experiences that have been evaluated as serious, unexpected, and possibly related to the suspect product are submitted to FDA no later than 15 calendar days from initial receipt of the information.
  3. Review 15-day Alert reports submitted late to the Agency.
  4. For each late report, the firm should provide justification for why the reports were late and appropriate corrective actions, if applicable.
  5. Domestic spontaneously reported non-expedited ICSRs are being submitted to FDA with or before the Periodic Report.
  6. The firm is in possession of any adverse event data that were not reported to the Agency as required.

Stay tuned for Part III, where we will explore the safety reports.

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.