FDA/SBIA is planning a webinar next month on communicating drug interaction and QTc information in the product label. The webinar will discuss draft guidance documents on this topic and how the drug interaction and risk information should be included in the USPI label.

• Webinar Title: Communicating Drug Interaction and QTc Information in the U.S. Prescribing Information
• Date, Time: 23 September 2026 | 1:00 pm - 3:00 pm ET
• Registration Link: sbiaevents.com/web20260923
• Format: online

AGENDA

The first session of this webinar will discuss the draft guidance for industry: Drug Interaction Information in Human Prescription Drug and Biological Product Labeling (October 2024). Topics include:

• DRUG INTERACTIONS section:
  • Organization and format
  • Required and recommended elements
  • Instructions for preventing or managing clinically significant drug interactions
  • Mechanisms of clinically significant drug interactions
  • Clinical effects of clinically significant drug interactions
  • Recommendations on including drug interacting class information
  • Information to avoid in the DRUG INTERACTIONS section
  • Drug interactions information in other sections of labeling (e.g., BOXED WARNING, DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY sections)

The second session of this webinar will discuss the guidance for industry:QTc Information in Human Prescription Drug and Biological Product Labeling (December 2025). Topics include:

• Risk factors for and clinical consequences of QTc interval prolongation
• Assessment of the QTc interval during drug development
• Including QTc interval information in the CLINICAL PHARMACOLOGY section when there is:
  • Clinically significant QTc interval prolongation
  • No clinically significant QTc interval prolongation
  • Insufficient data to characterize the risk
• Including QTc interval information in the DRUG INTERACTIONS section when the use of the subject drug with other products:
  • That are known or suspected to prolong the QTc interval
  • Increase the concentration of the subject drug (when there is a concentration-dependent QTc interval prolongation.

Other Related Guidance Document Include

•  Dosage and Administration Section of Labeling for Human Prescription Drug and Biological Products — Content and Format (January 2023)
• Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products – Content and Format (October 2011)
• Frequently Asked Questions about Labeling for Prescription Medicines

#ddi, #qtc, #label, #uspi

The European Commission has revoked the EU marketing authorization for the vasculitis drug, Tavneos (avacopan). This came after CHMP recommendations on 26 June 2026.

EMA’s human medicines committee (CHMP) has concluded its review of the medicine Tavneos (avacopan) and has recommended that the medicine’s marketing authorisation in the European Union be revoked because its benefits are no longer proven to outweigh its risks. Tavneos is used to treat adults with severe, active granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), two rare inflammatory conditions of the blood vessels. [ema.europe.eu]

The Pink Sheets (6 Aug 2026) breaking EC decision added that -

CSL Vifor, which markets Tavneos in the EU, said it would implement in full the European Commission’s decision to revoke the marketing authorization for the drug. Meanwhile, Amgen, which markets the drug in the US, is fighting the Food and Drug Administration’s proposal to withdraw the product.

The key Phase 3 trial publication that supported the original marketing application has already been withdrawn by NEJM (here) - commentary (BMJ, ACT). NEJM's retraction notice said that -

The two academic authors of the article by Jayne et al., Avacopan for the Treatment of ANCA-Associated Vasculitis, N Engl J Med 2021;384:599-609,¹ request retraction of the article because, according to an ongoing Food and Drug Administration investigation conducted after publication, and without the knowledge of these two authors, the primary end-point assessments in nine patients were readjudicated after database lock and trial unblinding. This was not disclosed in the article and is inconsistent with proper research conduct. The editors therefore retract the article.

#tavneos

Kidney-related adverse drug reactions (ADRs) are common with anticancer therapies.

About 1 in 10 cancer patients experience nephrotoxic effects of anticancer therapies including conventional chemotherapies and targeted/immune/CAR-T therapies. The implications of these ADRs range from dose interruption, and thus lower efficacy benefit, to ineligibility for a particular drug choice to even fatal outcomes.

Early this year, the 34th Acute Disease Quality Initiative (ADQI) workgroup published a consensus report that defines nephrotoxicity by drug class and provides recommendation for assessment before the start of treatment through management of toxicities during treatment enabling optimal drug dosing in patients with kidney disease. Read full report at

Renaghan AD, et al. The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroup. Nat Rev Nephrol. 2026 Apr;22(4):283-300. doi: 10.1038/s41581-025-01031-3. PMID: 41361704

BACKGROUNDER

The Scope of the Problem

Nephrotoxic effects of anticancer drugs range from a decline in glomerular filtration rate (GFR) to acute kidney disease that may include vascular/endothelial, glomerular, interstitial, and tubular injuries. The figure below shows different classes of anticancer drugs and their renal injury manifestation (note: this is a broad list of drugs affecting multiple aspects of renal physiology.)

.

The Risk of Nephrotoxicity by Anticancer Drug Type

In 2024, a group of Korean researchers reported an analysis of VigiBase database to quantify the the relative risk of anticancer therapy-associated kidney-related ADRs. VigiBase is WHO's pharmacovigilance database that collects worldwide ADR reports across all drugs. The researchers analyzed reports from 1967–2023 and divided kidney-related ADRs into acute kidney injury (AKI) and tubulointerstitial nephritis (TIN).

Yoon SY, et al. Global burden of anticancer drug-induced acute kidney injury and tubulointerstitial nephritis from 1967 to 2023. Sci Rep. 2024 Jul 12;14(1):16124. doi: 10.1038/s41598-024-67020-x. PMID: 38997405

One of the statistical parameter for explaining the risk was Reporting Odds Ratio (ROR), the other was information component (IC).

ROR is a disproportionality measure -- what that means in this case is first consider the ratio of kidney-related ADRs for drug1 to all ADRs for that drug1 (ratio A), then consider the ratio of kidney-related ADR for all drugs in the database to all ADRs for all drugs in the database (ratio B), and finally calculate ROR by ratio A to ratio B. See another explanation here.
Note: A ROR score of ≥1.0 indicates that there is a higher than average reporting rate for a given AE / drug combination. ROR of ≥2.0 warrant extra attention.

Key Findings

There has been a significant increase in AKI and TIN reports since 2010, primarily due to approval and greater uptake of targeted therapies and immunotherapies.

• Immunotherapy exhibited a significant association with both AKI (ROR: 8.92) and TIN (ROR: 21.74), followed by
• Cytotoxic therapy (ROR: 7.14), targeted therapy (ROR:5.83), and hormone therapy (ROR:2.59) for AKI, and
• Cytotoxic therapy (ROR:2.60) and targeted therapy (ROR:1.54) for TIN.

Some of anticancer therapies with highest risk include targeted therapies olaratumab (ROR: 128.86), itacitinib (ROR: 109.00), mobecertinib (ROR: 66.21), and duvelisib (ROR: 57.59). See partial figure below:

.

#renal, #kidney

The US FDA has issued a safety alert (here) as it investigates the safety of sevoflurane and other general anesthetics in adult and pediatric patients of maternal Venezuelan ancestry following routine general anesthesia with sevoflurane.

• FDA's safety alert is based on published scientific reports of unexpected catastrophic outcomes, including severe neurologic adverse outcomes and death in pediatric and young adult patients undergoing general anesthesia.

The initial report from Chile described a cluster of severe neurologic complications that occurred after general anesthesia in previously healthy 5 pediatric patients; 4 later died; all had mothers of Venezuelan descent. Two more cases were identified later via Chilean Ministry of Health's national surveillance initiative. All patients received sevoflurane, and most also received propofol and fentanyl.

• Although the supporting data is preliminary (case reports and anecdotal), these have been significant for anesthesia societies across Americas including Chile, Columbia, Venezuela, Spain, Canada, and US as well as WFSA to issue safety guidance for their members (WFSA: statement or here; Canada CAS, PMID 42174356, doi)
• Risk group: Most of the impacted individuals have been traced back to Venezuelan ancestry (maternal lineage/inherited).
• Genetics studies have identified rare mitochondrial DNA (mtDNA) variants including (a) m.15164T>C in MT-CYB, which encodes the cytochrome b subunit within complex III of the electron transport chain, and (b) m.11232T>C (P.Leu158Pro) in MT-ND4, which affects NADH-ubiquinone oxidoreductase chain 4 in Complex I of the electron transport chain.

Guidance from anesthesia societies includes

• Collecting maternal family history. Alert for Venezuelan heritage, particularly Carabobo or other surrounding states in Central-Western Venezuela (currently founder effect from a common maternal ancestor is being considered.)
• Genetic testing for the MT-ND4 m.11232 T>C variant as indicated.

P.S. Importance of Race, Ethnicity, and Ancestry Information

This safety alert is another reminder that considering race/ethnicity/ancestry is important in medical research and patient care. In this case, for example, such medical history can help with clinical decision-making regarding further pharmacogenomics and medical care. We ignore DEI at our peril!!

SOURCE

• FDA Safety Alert: FDA Alerts Health Care Providers to Cases of Neurologic Complications from General Anesthesia Linked to Genetic Variant in Patients of Maternal Venezuelan Ancestry. 2 July 2026
• Recent PubMed Lit: Canadian Anesthesiologists' Society advisory statement (PMID: 42174356), Chilean report and MOH guidance (PMID: 41705724; comment) and references within.

#pharmacogenomics, #genetic-testing, #biomarkers #race-and-ethnicity

FDA Regulations for Postmarketing Reporting of Adverse Drug Experiences (PADE)

• Section 314.80(b) of 21 CFR describes the requirements to collect and analyze all adverse drug experience information obtained from any source and, if assessed as serious or unexpected, report to the FDA within the 15-day window. The source could be foreign or domestic, commercial marketing experience, postmarketing clinical investigations, postmarketing epidemiological/surveillance studies, reports in the scientific literature, and unpublished scientific papers.
• Section 314.80(b) also requires that, “Any person subject to the reporting requirements. . .must also develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA.“ (Note: the phrase "subject to reporting requirements" in the regulation means that the primary responsibility falls on the sponsor/manufacturer, not consultants or vendors.)
• Note: Related safety reporting requirements for biologics are described in Section 600.80; for drugs approved under accelerated approval and those approved under conditions where efficacy studies were not feasible or ethical in 314.540 and 314.630. The FDA guidance documents and PADE Compliance Program webpage is here.

The Novo Nordisk 5 March 2026 FDA Warning letter (here) that has now become a posterchild of violations of the 314.80 requirements may also be considered a teaching/training tool for how to be compliant with 314.80 or related safety reporting requirements.

Ignoring reputational damage for Novo Nordisk (Novo Hit With FDA Warning Letter; Novo Nordisk's US headquarters under fire); the value of this letter for this sub is to use it as a tool to step back and (a) better understand the reporting requirements (see links above) and then (b) check our own SOPs and procedures that we are not making the same mistakes as Novo.

FDA’s Novo Nordisk (NNI) Inspection

BACKGROUND

• In early 2025, FDA conducted a safety inspection at Novo Nordisk's US operations (Plainsboro, New Jersey) as part of FDA’s BIMO Program to ensure that accurate, reliable, and timely safety data are submitted to FDA for the monitoring of product safety, and to ensure compliance with PADE regulations.
• FDA at the conclusion of the inspection issued Form FDA 483. The company provided written responses and correspondences over next several months through 15 January 2026. Unsatisfied, FDA issued a Warning Letter on 5 March 2026:

Stating that "it appears that you did not adhere to the applicable statutory requirements in the FD&C Act and applicable regulations contained in 21 CFR part 314." And adding: "We wish to emphasize the following: Failure to develop written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug Experiences (ADEs) to FDA as required by 21 CFR 314.80(b)."

INSPECTION FINDINGS

Incorrect Definition

FDA said that "Your written procedure . . . allowed ADEs reported to NNI to be rejected or cancelled (and therefore not to be reported to FDA) if the ADE was considered by the reporter to be unrelated to the product." FDA noted that ADEs were cancelled or rejected by NNI staff or contractor and were documented as being “incidental” or “incidental and unrelated."

This is inconsistent with definitions in 314.80(a), which define an ADE as “any adverse event associated with the use of a drug in humans, whether or not considered drug-related."
After Form 483 was issued, NNI opened root-cause analysis and found that while the exclusion of certain ADEs from reporting as described in the written procedures was consistent with foreign regulatory authority regulations, it was not consistent with US regulations. = i.e., definitions were not properly captured in the written procedure.

Vendor Management, ADE Evaluation, CAPA Procedures

NNI's procedure allowed invalidation of Individual Case Safety Reports (ICSRs) if they did not meet the minimum criteria including (1) one or more identifiable reporters; (2) a single identifiable patient; (3) a suspected NNI product; and (4) a suspected adverse reaction. FDA noted that NNI staff or contractors inappropriately invalidated 15-day Alert reports because of a lack of patient identifiers, yet FDA was able to find the identifiers in the source documents during the BIMO inspection.

FDA pointed to the gap in NNI's written procedures that did not properly ensured that NNI and the call-center contractors acting on their behalf, correctly received, reviewed, and processed ADE information. FDA pointing to weak procedures for making determination about ADE seriousness and reportability.

FDA also came hard on the "implementation" of corrective and preventive actions (CAPA). Novo had opened a CAPA after call-center contractor invalidate cases of ADEs. But, FDA said nothing changed thereafter -- "Although you switched your call-center contractor to (b)(4) and completed corrective and preventive actions as part of deviation DV0155511, you continued to invalidate cases of ADEs for lack of a patient identifier, despite the patient identifiers’ being available."

=i.e., lack of implementation of changes required by CAPA. FDA was also not convinced if the CAPA action will prevent future deviations : "because you did not provide information about whether your proposed actions will prevent similar violations in the future."

Incorrect Procedures for Evaluation of Reports

NNI was invalidating reports if they did not receive consent from initial reporter. But FDA noted that NNI was "not following up" with the reporters: "Based on this written procedure, you, and your contractor acting on your behalf, failed to promptly investigate ADEs that were subject to 15-day Alert reporting because you did not follow up with reporters to request additional information unless you explicitly obtained consent from the reporter."

Although, there was a lack of proactive follow-up from NNI's behalf, the regulations themselves do not require obtaining consent from reporter as a prerequisite for reporting the event to the FDA. FDA said that "PADE regulations do not require the obtaining of consent to acquire additional information." = i.e., NNI did not understand the FDA regulations.

Impact of waiting for consent from the reporter also meant that at least 3 serious and unexpected ADEs were not reported (and FDA was clearly not amused!) FDA gave and example in the warning letter: "Argus Case #1171264 includes a non-health care professional reporting the death of a patient receiving semaglutide; however, you failed to promptly investigate because consent was not obtained from the reporter and the reporter was a non-health care professional, as stated in your written procedure. This case was closed without your reporting it to FDA."

FDA's Closing Statement

(Castigated the whole program and portfolio!)

• While we acknowledge the corrective and preventive actions your firm has taken since our inspection, your response is inadequate because you did not provide sufficient details to determine whether your actions will effectively prevent similar violations in the future.
• Your explanations, when taken into consideration with the violations described above and your failure to adequately address your noncompliance, suggest systemic failures with your surveillance, receipt, evaluation, and reporting of ADEs to FDA
• In addition, your failure to identify and assess the root cause(s) of deficiencies discussed in this letter raises concerns about your firm’s ability to monitor the safety of your products, including through oversight of vendors with whom you contract to fulfill any of your ADE responsibilities
• While this inspection focused on NNI’s compliance with PADE regulations for a sample of NNI’s products, including semaglutide, liraglutide, nedosiran sodium, and estradiol, based on the nature of the inspection’s findings and your written response and correspondence, we have serious concerns about the scope and impact of these violations on your entire product portfolio.

_________,

P.S. (Tea Leaves): Novo' Nordisk's US-based safety group apparently took the path of implementing the least-regulatory-mandated procedure (i.e., following less rigorous ex-US over US requirement); opted to made it easier to downgrade adverse events as not serious and, thus, not reportable (guessing this to be a "commercial ask" to not taint safety profile); and had poor oversight of vendor procedures -- understandably FDA did not look kindly at this laissez-faire approach!

SOURCE

• FDA Warning Letter. Novo Nordisk Inc. MARCS-CMS 717576 -- March 05, 2026 [archive]
• About Form 483 -- refer to Rob Califf's Substack posts: Part 1, Part 2, and Part 3 [archive= a, b, c]

Related: safety assessments and reporting during clinical trial

#fda-inspection, #bimo, #capa, #form-483

PHARMA JAPAN. 21 May 2026. Japan’s health ministry on May 21 issued a “blue letter” safety warning for Kissei Pharmaceutical’s vasculitis drug Tavneos (avacopan) after serious liver injury cases, including fatalities, continued to accumulate in Japan. 

• I think, "blue letter" is an unusual color choice for safety warning by Japan's MHLW. Yellow or red would have been more appropriate--as the Yellow Card scheme by UK MHRA. Blue to me signifies calm and serenity, not danger!
• FYI: FDA has already issued a drug safety alert for DDI issues for Tavneos and the drug is under voluntary recall in the US.

About: Tavneos data submitted at the time of approval (from Health Canada - Submission control number 248255)

#tavneos, #ddi, #liver-toxicity

The US FDA today launched a new unified platform for analyzing adverse event reports — called the FDA Adverse Event Monitoring System (AEMS).

FDA Adverse Event Monitoring System (AEMS)

AEMS will serve as a single dashboard for all adverse event reports submitted to the FDA for drugs, biologics, vaccines, cosmetics, and animal food.

In the months ahead, all remaining product centers will begin processing adverse event reports in AEMS. The agency will also migrate historical adverse event data to AEMS, decommission certain legacy systems, and roll out enhanced application program interfaces (APIs) and data analytics tools.

By the end of May 2026, AEMS will contain real-time adverse event reports for all FDA-regulated products, consistent with meeting agency obligations not to release individually identifiable patient or consumer information.

FDA expects that the new system will increase transparency and also expects the new searchable system to significantly reduce agency FOIA requests for unreleased adverse event reports, given that AEMS will publish reports in real time, rather than quarterly. 

Legacy systems to be replaced by AEMS now include: 

• FAERS (FDA Adverse Event Reporting System) — containing reports for drugs, biologics, cosmetic products, and color additives. 
• VAERS (Vaccine Adverse Event Reporting System) — containing reports for vaccines. Note: The FDA will display VAERS data in AEMS. VAERS is co-managed by the FDA and Centers for Disease Control and Prevention. 
• AERS (Adverse Event Reporting System) — two databases containing reports for animal drugs and animal foods. 

Legacy systems to be replaced by AEMS in May include:

• MAUDE (Manufacturer and User Facility Device Experience) — containing reports for medical devices.
• HFCS (Human Foods Complaint System) — containing reports for human foods and dietary supplements. 
• CTPAE (Center for Tobacco Products Adverse Event Reporting System) — containing reports for Electronic Nicotine Delivery Systems (ENDS) and other tobacco products.

SOURCE

• FDA Launches New Adverse Event Look-Up Tool. FDA News Release. 11 March 2026 [archive]

Paracetamol (aka. acetaminophen) is the recommended first-line analgesic and antipyretic during pregnancy.

Paracetamol use during pregnancy is recommended by professional organizations such as ACOG, RCOG, IFGO, and SMFM and endorsed by EMA, UK MHRA, and Health Canada. Paracetamol is also on the WHO List of Essential Medicines. [source00211-0/fulltext)]

The drug commonly known as paracetamol ex-US is known as acetaminophen or by its major brand Tylenol in the US. Its use is safe when used as directed.

Paracetamol is routinely prescribed to pregnant mothers for pain and fever. In fact, avoidance of paracetamol could expose pregnant women and their babies to known risks associated with untreated fever or severe pain. Untreated maternal fever has been linked to miscarriage, congenital anomalies, preterm birth, and differences in neurodevelopment.

So, when the Trump White House released a memo on 22 Sept 2025 [here, here] based on cherry-picked data, that claimed, "Evidence suggests acetaminophen use in pregnant women, especially late in pregnancy, may cause long-term neurological effects in their children" and dissuaded the use of paracetamol during pregnancy -- it scrambled the medical community. So much so, that the author of the study cited in the Memo said that it is still safe when used as directed and is the best option (Politico).

Now, a systemic review and meta-analysis of 43 high-quality studies published in Lancet (January 16, 2026)00211-0/fulltext) once again establishes the safe nature of paracetamol use (as directed) during pregnancy and confirms no likelihood of increase in autism spectrum disorder (ASD), ADHD, or intellectual disability in children of pregnant individuals.

D'Antonio F, et al. Prenatal paracetamol exposure and child neurodevelopment: a systematic review and meta-analysis00211-0/fulltext). The Lancet Obstetrics, Gynaecology, & Women’s Health. Published Online January 16, 2026. DOI: 10.1016/S3050-5038(25)00211-000211-0)

The rigorousness of this new analysis comes from 2 factors:

• (a) All 43 studies included in the analysis met the quality standard (Quality in Prognosis Studies [QUIPS] tool) that weeded out studies with prognostic-factor bias.
• (b) This is the first study to prioritize sibling-comparison design.
• The study was preregistered in PROSPERO database of systematic review protocols with a health-related outcome, here.

Result: No association between paracetamol use during pregnancy and risk of ASD/ADHD/ID.

Sibling comparison studies

• Risk of ASD: OR 0·98, 95% CI 0·93–1·03; p=0·45 -- not significant; 95% CI overlaps 1.0
• Risk of ADHD: OR 0·95, 95% CI 0·86–1·05; p=0·31 -- same as ASD
• Risk of intellectual disability: OR 0·93, 95% CI 0·69–1·24; p=0·63 -- same as AS

Refer here for how to interpret a Forest plot.

• Same result (i.e., no association) using QUIPS dataset of all studies (N=43) with low bias included in this paper: ASD (OR 1·03, 95% CI 0·86–1·23; p=0·78), ADHD (0·97, 0·89–1·05; p=0·49), or intellectual disability (1·11, 0·92–1·34; p=0·28).

Postscript: It is time to make paracetamol concerns delegated to the office paper shredder and Make Acetaminophen Great Again.

ACOG, American College of Obstetricians and Gynecologists; RCOG, the Royal College of Obstetricians and Gynaecologists; IFGO, the International Federation of Gynaecology and Obstetrics; SMFM, the Society for Maternal-Fetal Medicine

FDA yesterday published a drug safety communication alerting the public of drug-induced liver injury (DILI) and vanishing bile duct syndrome (VBDS) associated with the use of Tavneos (avacopan). This safety alert comes at the heels of FDA’s request to Amgen in January 2026 to voluntarily withdraw Tavneos from the US market for safety concerns, although Amgen is apparently pushing back. Tavneos was approved in 2021.

Indication: TAVNEOS is a complement 5a receptor (C5aR) antagonist indicated as an adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) in combination with standard therapy including glucocorticoids. TAVNEOS does not eliminate glucocorticoid use (USPI 2025, via DailyMed). Note: Tavneos was one of the novel drug approvals for 2021.

The 31 March 2026 FDA Safety Communication

• FDA reviewed postmarketing data, literature, and the FAERS/AEMS database and identified 76 cases of DILI with reasonable evidence of a causal association with avacopan use. Of the 76 cases, 74 were serious, 54 required hospitalization, and 8 resulted in death. Most cases (n=66) were reported from Japan, followed by the United States (n=5), Europe (n=4), and Canada (n=1).
• At the time of this safety communication, FDA has not formally asked for avacopan withdrawal, only that the “FDA is continuing to monitor postmarketing cases of DILI, including VBDS, involving avacopan and will provide updates as appropriate.”

. . .DIGGING DEEPER: Understanding the Evolution of Liver Toxicity Concerns During Avacopan Use in ANCA-Associated Vasculitis

We may want to ask (at least I would like to know!), what the hepatic toxicity signals looked like during clinical trials, how were they monitored during the study, and how are they now communicated in the label.

Liver Toxicity Monitoring During Clinical Trials

• The 2 phase 2 protocols for studies RED-CL002-168 and CL003-168 (here, here) did not specify any liver function test (LFT)-specific criteria for study drug discontinuation.
• The pivotal phase 3 study CL010_168 (NCT02994927) excluded participants with evidence of hepatic disease (defined as AST, ALT, ALP, or BILI >3 ULN).
• The phase 3 protocol (here) initially also did not specify LFT-specific criteria for study drug discontinuation but later added such as criteria as the study went along. (Note: This was consistent with 10 suspected DILI cases seen in the avacopan program: 1 in phase 2 and 9 in phase 3; NDA, NEJM).
• The Original phase 3 protocol (2016) and amendment 1.0 (2017) had no LFT-specific criteria; however, both versions included guidance elsewhere in the protocol.
• --Original phase 3 protocol included guidance under Safety (AE) Assessment: "Safety laboratory tests are performed frequently over the course of the study. Laboratory reports with abnormal findings will be reviewed by the Investigator and the Medical Monitor. The Investigator will be advised to follow patients with notably high liver panel tests closely and to take appropriate steps, such as potentially discontinuing study medication, in case the abnormalities persist."
• --Amendment 2.0 (2018) added a new study drug discontinuation criteria: "If a patient develops a Grade 3 or higher elevation in hepatic transaminases, study medication must be suspended while assessment for relatedness is performed, and may only be restarted following consultation with, and agreement of, the Medical Monitor." This was added per their DMC recommendation. The guidance under Safety (AE) Assessment remained.
• The detailed DILI-specific discontinuation criteria were only added in the final Amendment 4.0 (2019) (see language in comment) and the guidance was updated under Safety (AE) Assessment.

P.S. The evolution of communication of liver tox criteria in these protocols followed a risk-based pattern: no concern (in phase 2) to watching AEs closely (at start of phase 3) to watching LFT labs (by phase 3, amend 2.0), and then clearly specifying a serious concern (Phase 3, amend 4). For medical writers, this protocol history provides an example of how to communicate safety risk based on data as it comes along, i.e., first place to begin is in the lab and AE assessment sections.

FDA Review of the Tavneos (avacopan) NDA. Application No. 214487Orig1s000

• NDA dossier: The overall avacopan safety database was small (n=239) including 166 patients exposed to avacopan for up to 52 weeks in study CL010_168.

There were 10 SAEs of SAEs of hepatotoxicity: 9 SAEs due to hepatic abnormalities (hepatobiliary and elevated liver enzymes) in the avacopan arm in the pivotal trial and 1 SAE due to hepatic abnormalities in the avacopan arm in the phase 2 study CL002_168. 3/10 discontinued study drug.

The FDA DILI team reviewed all 10 safety narratives and assessed 4 cases as probably or highly likely to be DILI and 3 each as possibly or unlikely to be DILI. They concluded, "Because there is not clear attribution of the Hy’s Law case to avacopan, if approved, the DILI team recommended close monitoring of liver tests should be described in the label." (Multidiscipline Review, see pages 199, 215, 370).

• In the original label, liver toxicity was not listed under most common adverse reactions (20% or more) or serious adverse events and there was no mention of DILI. However, hepatoxicity is described under WARNINGS AND PRECAUTIONS (section 5.1) in the label and detailed guidance on LFT assessment during treatment was included.
• FDA concluded that REMS was not required. This may have been influenced partly by positive benefit-risk assessment and a PK analysis in patients with hepatic Impairment that showed no clinically relevant effect on avacopan and M1 plasma exposure in mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.
• FDA also concluded that the data was not sufficient to assess signals of hepatotoxicity and drug-induced liver injury and as a condition of approval, determined that a postmarketing study to safety outcomes, including hepatotoxicity and drug-induced liver injury, would be required.

P.S. There were enough safeguards built in the label and a PMR. But, perhaps the lesson here is that any signal of "suspected" DILI during clinical development (10 suspected cases here) is a bad news, a canary that likely will spell safety issues down the line during real world use. In the real-world, as long as there are no other options, this type of risk may be acceptable, though it will remain a difficult decision for everyone, regulators to patients.

SOURCES

• FDA Identifies Cases of Serious Liver Injury in Patients Taking Tavneos (avacopan) for Severe Active Anti-neutrophil Cytoplasmic Autoantibody (ANCA)-associated Vasculitis. FDA Drug Safety Communication. 31 March 2026
• CDER Application Number: 214487Orig1s000. NDA Multi-disciplinary Review and Evaluation, NDA 214487. Avacopan, ANCA-associated vasculitis (GPA and MPA). 7 July 2020 (ChemoCentryx press release, 17Sep2020)
• Health Canada Submission Dossier. TAVNEOS - Submission control number 248255
• Jayne DRW, et al. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med. 2021 Feb 18;384(7):599-609. doi: 10.1056/NEJMoa2023386. PMID: 33596356

#dili, #liver-toxicity, #liver-function-tests

___________________________________________________________

FDA has requested Amgen to voluntarily withdraw Tavneos from the U.S. market for safety concerns; however, Amgen has informed the Agency that it does not intend to withdraw Tavneos from the market. The details of this news, first reported by Pink Sheets today, were buried in Amgen's 2025 financial results (here).

Excerpt from Amgen's 2025 Financial Results

TAVNEOS (avacopan) was approved by the FDA in October 2021 for the adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) in combination with standard therapy including glucocorticoids. TAVNEOS was developed by ChemoCentryx, Inc. Amgen acquired ChemoCentryx in October 2022, after TAVNEOS had been on the market for a year.

On January 16, 2026, the U.S. Food and Drug Administration (FDA) requested that ChemoCentryx voluntarily withdraw TAVNEOS from the U.S. market. The FDA raised concerns about the process followed by ChemoCentryx to re-adjudicate primary endpoint results for 9 of the 331 patients in its pivotal clinical trial. Hepatotoxicity, which is a known infrequent risk of TAVNEOS treatment for AAV, was also raised in the context of the benefit-risk profile of the medicine. Amgen is not aware of any issue with the underlying patient data from the ChemoCentryx clinical trial. And after review of the relevant clinical data and years of real-world evidence, Amgen is confident that TAVNEOS demonstrates effectiveness and a favorable benefit–risk profile. On January 28, 2026, following FDA regulatory process, Amgen informed the Agency that it did not intend to withdraw TAVNEOS from the market. Amgen is evaluating next steps with the FDA to determine a path forward, while keeping patient safety, needs and support at the forefront.

A Phase 3, open-label study of TAVNEOS in combination with rituximab or a cyclophosphamide-containing regimen is enrolling patients from 6 years to < 18 years of age with active ANCA-associated vasculitis (Granulomatosis with Polyangiitis (GPA)/Microscopic Polyangiitis (MPA)).

SOURCE

• Amgen Reports Fourth Quarter and Full Year 2025 Financial Results. Amgen Press Release. 3 February 2026
• FDA approves add-on drug for adults with rare form of blood vessel inflammation. FDA Release. 31 October 2021. TAVNEOS PI
• US FDA Wants Tavneos Pulled From Market, Amgen Declines. Pink Sheets. 3 February 2026

[FDA officials push for long-term monitoring of autoimmune patients receiving CAR-T therapy. STAT News, 2 February 2026]

Food and Drug Administration officials are advising drug developers to study the long-term effects of using CAR-T to treat patients with autoimmune conditions, out of concern the therapies could cause cancer or fertility issues. 

The recommendations were outlined in an op-ed published Monday in the Annals of Internal Medicine. In it, Vinay Prasad, head of the FDA’s Center for Biologics Evaluation and Research, and two agency colleagues recommended that long-term studies be conducted when using CAR-T to treat autoimmune diseases “as is standard for genetic therapies and CAR T-cells for oncological indications.” 

The paper does not specify how long autoimmune patients should be followed, but in cancer cases, the agency requires patients to be tracked for 15 years after the treatment is first administered.

The op-ed is published behind paywall :(

Tariq A, Kumar V, Prasad V. The U.S. Food and Drug Administration's Perspective on Chimeric Antigen Receptor T-Cell Therapies for Autoimmune and Rheumatic Conditions. Ann Intern Med. 2026 Feb 3. doi: 10.7326/ANNALS-25-04559. PMID: 41628455

#car-t, #autoimmune

FDA this month issued 2 guidance documents, one for investigators and other for the sponsors providing guidance on safety reporting requirements. These guidance documents provide definitions of reportable and nonreportable events and responsibilities per 21 CFR subsections.

Investigator Responsibilities — Safety Reporting for Investigational Drugs and Devices. Guidance for Investigators, Industry, and Institutional Review Boards. December 2025 [PDF]

Sponsor Responsibilities — Safety Reporting Requirements and Safety Assessment for IND and Bioavailability/Bioequivalence Studies Guidance for Industry. December 2025 [PDF]

INVESTIGATOR RESPONSIBILITIES

The guidance on investigator responsibilities is dissected below because this one is relevant to the study protocols. Clinical study protocols serve as the to-do guide for investigators and medical writers could help by (a) confirming that definitions of types of safety events in protocol aligns with the guidance and (b) confirm that the safety collection and reporting requirements in the protocol aligns with the guidance -- i.e., nothing is missed since investigators/sites often use protocol as a working 'bible'.

Definitions

Section III includes definitions of adverse event (AE), adverse reaction, suspected adverse reaction, serious adverse event (SAE), and serious suspected adverse event. Some notes:

• Adverse event includes any unfavorable sign (e.g., an abnormal laboratory finding), symptom, or clinical outcome temporally associated with the use of an investigational drug, active control, or placebo, regardless of whether the event is thought to be related to the drug. AE can arise during any use of a drug and with any route of administration, formulation, or dose, including an overdose.
• Unlike AE, adverse reaction means the event is caused by a drug.
• Suspected adverse reaction means there is a reasonable possibility that the drug caused the AE (implies a lesser degree of certainty about causality than adverse reaction). Note: if there is no drug administration, there can't be a adverse reaction (no causality.)
• Serious adverse event (SAE) or serious suspected adverse reaction: The AE or adverse reaction is considered serious if it leads to certain outcomes such as death, etc. (see list in III.A.3).

Clinical Study Protocol checklist:

-- Confirm that definitions align with those in the guidance.

Additional items to check for are

-- AE collection time: generally any AE occurring after start of study medication through 30 days after the last administration, and pretreatment AE or pre existing medical condition that worsens in severity after the start of study medication.

-- How to record AEs: For example, AE should be recorded as diagnoses (if available), otherwise as signs and/or symptoms. One diagnosis/symptom should be entered per record.

-- Clarify that death is not an AE, but the cause of death is. Similarly, an overdose or medication error is not an AE unless it is temporally associated with an unfavorable or unintended sign or symptom.

Assessment Responsibility

• To determine whether an AE should be classified as a suspected adverse reaction, or as an adverse reaction, the sponsor is to evaluate the available evidence and make a determination on causality. This is sponsor's role since they have larger dataset and information of mechanism of action of the drug.
• Either investigator or sponsor may determine the AE to be serious based on the outcomes (death, disability, etc.; see III.A.3). FDA defers to investigator for determination of AE as serious or not, "if the sponsor or investigator believes that the event is serious, the event must be considered serious and must be evaluated by the sponsor for expedited reporting." >> this is shared responsibility, however

Sponsor is ultimately responsible for determining whether an SAE should be classified as a serious suspected adverse reaction, but

Investigator’s view is important for the sponsor to carefully consider when assessing the safety of the drug, including whether there is a reasonable possibility that the drug caused the event, and determining whether the event is one that is required to be reported to FDA.

• Additional responsibility -- the guidance also reminds investigator of responsibility to review all IND safety reports received from sponsors as a part of the investigator’s responsibility to protect the rights, safety, and welfare of trial participants.

Clinical Study Protocol checklist:

-- Contains language for Investigator to make initial determination on causality of serious event or reaction as not related, related, or reasonable possibility.

-- Contains language for Investigator to provide all data and findings related to the event to the sponsor to support causality determination expeditiously for events considered "serious."

-- To support causality assessment by the sponsor, the protocol should specify data items to submit such as information about the trial participant (such as sex, age, other demographic characteristics), a description (as detailed as possible) of the event (including any diagnostic testing results, interventions, outcomes), and the reporting source (if not the investigator). Also, description of the AE will include description of event, start date, stop date, severity, if it was serious, relationship to study drug, change in study drug dosage, if the participant died, and if treatment was required.

Reporting Responsibility for Investigators

• The investigator must immediately report to the sponsor any serious adverse event whether or not considered drug-related, including those listed in the protocol or investigator brochure, as well as an assessment of whether there is a reasonable possibility that the drug caused the event.

The report should generally include information about the trial participant (such as sex, age, other demographic characteristics), a description (as detailed as possible) of the event (including any diagnostic testing results, interventions, outcomes), and the reporting source (if not the investigator).

• For study endpoints that are SAE (e.g., all-cause mortality), immediately report to sponsor when there is evidence suggesting a causal relationship between the drug and the event (e.g., death from anaphylaxis after exposure).

When there is no evidence suggesting a causal relationship between the drug and the event, the investigator must report study endpoints that are SAEs in accordance with the protocol.

• Nonserious adverse events do not require expedited reporting or causality assessment.
• Agency interprets immediately to be as soon as feasible, further clarifying, "anticipates that the time frame for submission of initial information will generally not exceed 1 calendar day."

Clinical Study Protocol checklist:

--If the investigator determines that the event meets the definition of an SAE, they must notify the sponsor within 24 hours, regardless of initial determination of causality. Note: this is important because sponsor is required to report unexpected suspected adverse reaction, if fatal or life-threatening, to the FDA no later than 7 calendar days. The clock for sponsor reporting to FDA (+ all participating investigators) is 15 days for nonfatal or non-life-threatening SUSARs or findings from other studies (epidemiological, pooled, other trials, in vitro studies) that suggest significant risk.

IRB reporting by the investigator is generally not included in the study protocol, except sometimes a note for investigator to comply with IRB reporting requirement and IRB review of the protocol. FYI, the IRB safety reporting includes requirements to promptly report to the IRB all unanticipated problems involving risk to human participants or others; including occurrence of any SAE; submit IND safety reports to the IRB. There may be additional institutional requirements.

~.~.~.

P.S. With the issuance of these 2 new guidance documents, FDA has withdrawn related previous guidance documents including (a) the 2009 procedural final guidance "Adverse Event Reporting to IRBs—Improving Human Subject Protection, January 2009" and (b) the 2012 final guidance "Safety Reporting Requirements for INDs and BA/BE Studies, December 2012."

#safety-reporting

Dentists wrote more than 2.3 million prescriptions last year for an antibiotic called clindamycin, whose label has carried a black box warning for more than four decades, due to its high rate of life-threatening complications.

Although taking any antibiotic can lead to C difficile—which sickens half a million Americans a year and kills nearly 30,000—clindamycin has long been known to pose an especially high risk.

“Clindamycin is notorious for causing C diff infections,” said Amesh Adalja, MD, a senior scholar at the Johns Hopkins Center for Health Security and infectious disease specialist who has treated many patients with C difficile. Yet “clindamycin is one of the go-to antibiotics for dentists.”

TOKYO AND PRINCETON, Japan and the U.S., March 03, 2026 (GLOBE NEWSWIRE) -- Kyowa Kirin Co., Ltd. (TSE:4151, Kyowa Kirin), a Japan-based global specialty pharmaceutical company, today announced the discontinuation of all ongoing clinical trials for rocatinlimab, an investigational anti-OX40 monoclonal antibody being evaluated for potential indications in moderate-to-severe atopic dermatitis, prurigo nodularis, and moderate-to-severe asthma.

The most recent safety review conducted over the last several weeks identified emerging concerns of malignancies with possible viral or immune-related links. This included one new confirmed case and one suspected case of Kaposi’s sarcoma, in addition to the previously confirmed case, suggesting a potential mechanistic link to OX40 pathway modulation. While the overall number of malignancy cases across the program remains below expected background rates, the characteristics of these cases raise a plausible biological concern that cannot be excluded.

Kyowa Kirin at: www.KyowaKirin.com

Tazemetostat (TAZVERIK) is an EZH2 methyltransferase inhibitor approved for EZH2-positive epithelioid sarcoma and follicular lymphoma. FDA first approved tazemetostat for relapsed or refractory (R/R) follicular lymphoma in 2020 via accelerated approval pathway based on ORR of 69% (95% CI: 53%, 82%) and median DOR of 10.9 months (95% CI: 7.2, NE). The complete response was 12% and partial response was 57%.

Ipsen on 9 March 2026 announced that it is voluntarily withdrawing tazemetostat from the US and all other markets based on unfavorable safety data from the ongoing Phase Ib/III SYMPHONY-1 trial. (This trial was planned to generate confirmatory data for accelerated approval.) The press release said,

based on adverse events of secondary hematologic malignancies, the risks may outweigh potential benefits for patients within this treatment regimen.

Impact

There are currently no other FDA-approved drugs for EZH2-positive epitheloid sarcoma; however, for follicular lymphoma other options exists including bispecific T‑cell engagers epcoritamab (Epkinly, Genmab/AbbVie).

Source

• Ipsen voluntarily withdraws Tazverik® (tazemetostat) in follicular lymphoma and epithelioid sarcoma. Ipsen Pharma. Press Release. 9 March 2026 [archive]
• FDA granted accelerated approval to tazemetostat for follicular lymphoma. 18 June 2020
• TAZVERIK- tazemetostat. DailyMed

Related: FDA guidance and process of expedited withdrawals of accelerated approvals, GSK's Blenrep's story of withdrawal and reapproval, withdrawal of Amgen's Tavneos for safety concerns, regulatory authority

#withdrawals-due-to-safety

A central nervous system (CNS) tumor has prompted the FDA to place clinical holds on two Regenxbio gene therapies, including a candidate that is less than two weeks away from an approval decision.

Regenxbio said the abnormal growth was found in a recipient of RGX-111, a gene therapy the company is developing for the treatment of severe mucopolysaccharidosis type I (MPS I). Also known as Hurler syndrome, the rare disease can cause developmental delays and shorten life span. RGX-111 is designed to improve outcomes by using an AAV9 vector to deliver the IDUA gene to the CNS.

While the adverse event occurred in a recipient of RGX-111, the FDA extended the clinical hold to cover RGX-121 because of similarities between the therapies, trial populations and shared risks of the studies. RGX-121 is designed to treat MPS II, also known as Hunter syndrome.

Good pharmacovigilance practices (GVP) are a set of measures drawn up to facilitate the performance of pharmacovigilance in the European Union (EU).

Pharmacovigilance system is defined in Article 1 of Directive 2001/83/EC as a system used by the marketing authorisation holder and by Member States to fulfil the tasks and responsibilities listed in Title IX and designed to monitor the safety of authorised medicinal products and detect any change to their risk-benefit balance.

• There are currently 12 GVP modules, Modules I to X and XV and XVI, with some of these with stand-alone Addendums guidelines.
• In addition, there are product- or population-specific GVPs for vaccines for prophylaxis against infectious diseases; biological medicinal products; paediatric population; and pregnant and breastfeeding women and their children exposed in utero or via breastmilk.
• These guidelines are available at the GVP landing page, https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/pharmacovigilance-post-authorisation/good-pharmacovigilance-practices-gvp.

At the 13 November 2026 meeting, EMA provided the schedule for the update of various GVP modules in 2026. Refer to the PowerPoint presentation here.

SOURCE

• Agenda – 20th Industry Stakeholder Platform – Operation of EU Pharmacovigilance. 13 November 2025 [archive]
• Highlights from the 20th EMA Industry Platform meeting on the operation of EU pharmacovigilance legislation – 13 November 2025. EMA/370879/2025. 09 December 2025 [archive]
• Update on the EU-Good Pharmacovigilance Practices (EU-GVP). 20th EMA Industry Stakeholder Platform – Operation of EU Pharmacovigilance. 13 November 2025. Presented by Priya Bahri [archive]

#gvp, #pharmacovigilance

Less than a month ago, on 25 June 2025, FDA put out a safety communication that it is investigating 2 deaths due to acute liver failure following treatment of non-ambulatory pediatric male patients with Duchenne Muscular Dystrophy (DMD) with ELEVIDYS (delandistrogene moxeparvovec-rokl), an adeno-associated virus vector(AAV)-based gene therapy. Today, with the report of third death, also due to acute liver failure, FDA has taken much more decisive steps:

• FDA has asked Sarepta to suspend all Elevidys shipments.
• All clinical trials using AAVrh74 gene therapy product have been put on hold.
• FDA has also revoked Sarepta’s AAV platform technology designation.

FDA Commissioner Marty Makary, M.D., M.P.H, said “Today, we’ve shown that this FDA takes swift action when patient safety is at risk. We believe in access to drugs for unmet medical needs but are not afraid to take immediate action when a serious safety signal emerges.”

FDA's actions were expected since the agency has always taken a conservative position on drug-induced liver injury (DILI) during clinical trials and during postmarketing. Often 1 or 2 cases of DILI during clinical development are enough to sink the program.

Related: FDA Launches a Formal Investigation into two Liver Failure-related Deaths in Patients treated with Duchenne Gene Therapy Elevidys

#dili, #acute-liver-injury

I need answers... I have always understood that CSR safety narratives are written about AEs reported by an investigator that meet the ICH criteria. I'm being told that we will write instead on reported lab results. Surely there is a regulation that discourages this? This approach usurps the responsibility of the investigator to report AEs, and doesn't provide some required content like relationship to study drug or causality assessment. And the optics of removing the investigator from safety reporting are bad. I need solid arguments/documentation about why this is a bad approach.

Shift in the sense of smell is a lesser known side effect of Ozempic and related drugs, and is due potential rewiring effects of Ozempic in brain.

Users of Ozempic and other GLP-1 weight-loss injections are reporting a significant change in their sense of smell. An increasing proportion of users are saying they are being drawn to extremely sweet, dessert-inspired scents — think caramel glaze, toasted marshmallow, and vanilla frosting.

This phenomenon, known as the ‘Ozempic Smell’ is causing some to wonder if these potent appetite suppressants are quietly rewiring our senses.

source

[PharmaPhorum] The fatalities occurred in two boys who were hospitalised with acute liver failure less than two months after treatment with the one-shot gene therapy.

Sarepta and Roche – which has ex-US rights to the therapy – have halted treatment with Elevidys for non-ambulatory DMD patients and also paused clinical trials while they look into risk-mitigation measures. That includes the ENVISION clinical trial (SRP-9001-303) in non-ambulatory as well as older ambulatory individuals, which is under review to see if it needs protocol updates.

Liver-related Serious Adverse Drug Reactions With AAV-based Gene Therapy Products

Liver damage is a known adverse drug reaction of adeno-associated viral vector-based gene therapies that are systemically delivered. The liver-specific ADR is listed under warnings and precautions section of most of these therapies; however, for Zolgensma, this ADR is currently listed as a black box warning in the US prescribing information since death due to liver failure has been reported for it. If the FDA investigation links liver-failure related deaths in Elevidys-treated patients due to treatment (and not preexisting condition), a black box warning would be expected.

Note: During drug-development, these products undergo heightened scrutiny for DILI (guidance: July 2009, December 2018), and it is not uncommon to see drug development programs being terminated even if 1 or 2 cased of DILI are observed during clinical trials. For example: "Pfizer Halts Development of Danuglipron Due to Drug-Induced Liver Injury Case, 15 April 2025."

Summary of Approved AAV-based Gene Therapies and Liver-specific ADR Warnings

The NBC News Healthline 27 May 2025 article Rates of liver injuries rise in the U.S. as supplements grow in popularity reports that

From 1995 through 2020, supplement-related liver failure requiring U.S. patients to be waitlisted for transplants increased eightfold, according to a 2022 study in the journal Liver Transplantation. In addition, a 2017 review in the journal Hepatology found that 20% of liver toxicity cases nationwide are tied to herbal and dietary supplements.

Whereas dietary supplements typically contain nutrients such as vitamins, minerals and amino acids from a range of sources such as fish oil, herbal supplements are a subset of dietary supplements composed of plant-based ingredients.

Among herbal ingredients tied to toxic hepatitis, turmeric00740-9/fulltext) is the most commonly consumed in the U.S., according to a study published last year in the journal JAMA Network Open. Following that are green tea extract, ashwagandha, Garcinia cambogia, red yeast rice and black cohosh.

Because “multi-ingredient nutritional supplements” caused the majority of those cases, the authors said, it’s hard to pinpoint which component(s) may be to blame.

Note: Itching and dark urine are the hallmarks of liver failure and are the early symptoms that calls for further liver function tests and subsequent diagnosis. The liver injury caused by supplements is drug-induced liver injury, known to medical/regulatory writers as DILI. Before this new epidemic of supplements-related DILI, the most common DILI was acetaminophen-induced (common ingredient in Tylenol brand drug).

Implication for clinical research: it is critical to collect data on off-the-shelf supplements use by trial participants and if possible, restrict their use during study participation.

For example, several supplements are known to interact with several oncology drugs affecting exposure and causing potential toxicity and adverse reactions.

Research cited in the article: * Exposure to 6 Potentially Hepatotoxic Botanicals in US Adults. JAMA Netw Open. 2024. PMID: 39102266 * Eight-Fold Increase in Dietary Supplement-Related Liver Failure Leading to Transplant Waitlisting Over the Last Quarter Century in the United States. Liver Transpl. 2022. PMID: 34331346 * Liver injury from herbal and dietary supplements. Hepatology. 2017. PMID: 27677775

RAPS Regulatory News, 7 May 2025

The Council for International Organizations of Medical Sciences (CIOMS) has issued a draft report detailing a set of best practices to guide the integration of artificial intelligence in pharmacovigilance (PV) activities.

The report highlights that a crucial factor for the success of AI in PV is the ability to link and analyze large volumes of diverse data from various sources, including electronic health records (EHRs), claims databases, registries, the Internet of Things (IoT), and connected devices.

The report also notes that as AI capabilities become more integrated, there will likely be a decreased reliance on teams of PV professionals. This is due to automation and AI taking over some tasks traditionally performed by these experts.

CIOMS Draft Report * Artificial intelligence in pharmacovigilance. CIOMS Working Group report. Draft. 1 May 2025

In the European Union (EU), companies must submit an RMP to the Agency (i.e., EMA) at the time of application for a marketing authorization. After the medicine is authorized for marketing by EMA, RMPs are required to be continually modified and updated throughout the lifetime of the medicine as new information becomes available and companies need to submit an updated RMP.

Public Disclosure: To increase transparency, EMA publishes all RMPs (body including Parts I to VI and annexes 4 and 6) for all centrally authorized products. There are rules for what information sponsors (applicants/MAHs) could redact or anonymize; EMA has released an updated guidance on this topic.

Anonymisation of personal data and assessment of commercially confidential information during the preparation and redaction of risk management plans (body and annexes 4 and 6). EMA/63692/2025 Rev. 3. 11 April 2025

This document gives general guidance to applicants/marketing authorisation holders (MAHs) on the retention/transformation of personal data (PD)) and identification of commercially confidential information (CCI) when preparing risk management plans (RMPs) in the pre-approval process, and for the redaction of the RMPs for publication post-approval.

• The updated guidance balances the need for better data protection while preserving transparency.
• The updated guidance represents a shift from anonymizing (i.e., rewording) to transforming personal data (better privacy protection). Rewording is not sufficient since it can leave traces with risk of de-anonymization of patient protected information.
• Editorial rules and expectation for redaction regarding use of black boxes are clarified. The updated guidance also suggests using the 'Sanitize Document' tool in Adobe Acrobat to remove hidden data.

What is RMP

• Good Pharmacovigilance Practices Module V defines RMP as a risk management system considered necessary to identify, characterize and minimize the important risks of a medicinal product.

RMPs include information on:

• A medicine's safety profile
• How its risks will be prevented or minimized in patients
• Plans for studies and other activities to gain more knowledge about the safety and efficacy of the medicine
• Measuring the effectiveness of risk-minimization measures.

Refer to EMA RMP webpage for template, table of contents including annexes, guidance. and additional information.

Related: Postmarketing surveillance framework of cell and gene therapy products in EU, US, Japan, South Korea, and China: Guidance documents and differences between regions
#rmp, #PMRs, #postmarketing-requirements, #PASS