📚 Part of the TILA-278 Regulatory Dossier — Reader's Guide. This article shows the live document; edits to the source appear here automatically.

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Safety Management Plan (TILA278-201)

Field	Value
Document ID	TMF-006
Version	1.0
Compound	TILA-278 (anti-TL1A antagonist / IL-22R agonist bispecific)
Standard	ICH E2A / E6(R3)
Confidentiality	Confidential

Trial Master File operational document for Study TILA278-201.

Change History

Version	Date	Author	Summary
1.0	2026-07-08	Clinical Operations	Initial issue

1. Introduction, Scope, and Purpose

1.1 Purpose

This Safety Management Plan (SMP) defines the operational and regulatory framework for the identification, documentation, assessment, collection, expedited reporting, and ongoing evaluation of safety information generated during Study TILA278-201, a Phase 2b induction study of TILA-278 in subjects with moderate-to-severe ulcerative colitis (UC). It establishes the conventions for adverse event (AE) and serious adverse event (SAE) handling, the Reference Safety Information (RSI) against which expectedness is judged, the causality and expectedness assessment process, the expedited reporting of suspected unexpected serious adverse reactions (SUSARs), pregnancy and lactation reporting, and the aggregate signal-management activities that support continuous benefit-risk surveillance.

This plan is a controlled Trial Master File (TMF) document and is cross-referenced by the study protocol, the Investigator's Brochure (IB), the pharmacovigilance agreement(s), and the Data Safety Monitoring Board (DSMB) charter. In the event of a discrepancy between this SMP and the clinical study protocol with respect to a subject's medical management or the required reporting of a specific event, the protocol prevails and the SMP is to be reconciled at the next amendment.

1.2 Applicable standards

Safety management for TILA278-201 is conducted in accordance with:

• ICH E2A — Clinical Safety Data Management: Definitions and Standards for Expedited Reporting
• ICH E2B(R3) — Electronic Transmission of Individual Case Safety Reports (ICSRs)
• ICH E2D — Definitions and standards for post-approval safety data (definitional alignment)
• ICH E2F — Development Safety Update Report (DSUR)
• ICH E6(R3) — Good Clinical Practice (investigator and sponsor safety responsibilities)
• ICH M1 — MedDRA terminology (coding dictionary version 29.0, upversioned per the coding SOP)
• CIOMS I/V/VI working-group conventions for ICSR content and aggregate reporting

Regional expedited-reporting obligations (US 21 CFR 312.32 IND safety reporting; EU Regulation (EU) No 536/2014 with submission to EudraVigilance; and the corresponding requirements of other participating regions) are met through the timelines and processes described in Section 7. Where a regional requirement is more stringent than the ICH baseline, the more stringent requirement governs.

1.3 Product and study context

TILA-278 is a recombinant humanized IgG1 bispecific monoclonal antibody administered subcutaneously (SC). One antigen-binding arm is an antagonist of TL1A (TNFSF15); the second is an agonist of the IL-22 receptor. The intended pharmacology couples dampening of TH1/TH17-driven mucosal inflammation and fibrosis (TL1A antagonism) with promotion of epithelial regeneration and mucosal-barrier repair (IL-22 receptor agonism). The molecule is a large protein therapeutic with pharmacokinetics dominated by target-mediated drug disposition and an elimination half-life in the range typical of an IgG1 antibody (approximately 2 to 4 weeks); this half-life governs the duration of the post-treatment safety observation and contraception windows defined in Sections 3 and 8.

Study TILA278-201 is a randomized, double-blind, placebo-controlled, parallel-group, 12-week induction study. Of 1700 subjects screened, 900 were randomized 1:1:1 to TILA-278 High (n=299), TILA-278 Low (n=300), or Placebo (n=301), stratified by baseline modified Mayo severity and prior biologic exposure, with scheduled visits at Weeks 0, 2, 4, 8, and 12.

1.4 Governance and responsibilities

Function	Responsibility
Sponsor (Virtual Biopharma Inc.) Pharmacovigilance (PV)	Overall accountability for safety surveillance; expectedness determination; SUSAR/expedited reporting; DSUR authoring; maintenance of the RSI and safety database.
Sponsor Medical Monitor	Medical review of all SAEs and AESIs; sponsor causality assessment; emergency medical advice to sites; benefit-risk interpretation.
Contract PV / safety-database vendor	ICSR intake, MedDRA coding, case processing, regulatory gateway submission (E2B(R3)), reconciliation support.
Investigator	Subject safety; AE/SAE ascertainment, documentation, initial (investigator) causality and severity; immediate SAE reporting to sponsor; compliance with local IRB/EC reporting.
Safety Review Team (SRT)	Blinded/unblinded periodic aggregate review and signal management (Section 10).
Data Safety Monitoring Board (DSMB)	Independent oversight of subject safety through periodic review of accumulating unblinded safety data per its charter.

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2. Definitions

The following definitions (ICH E2A/E2D) govern all safety activities in TILA278-201.

Term	Definition
Adverse Event (AE)	Any untoward medical occurrence in a subject administered a pharmaceutical product, which does not necessarily have a causal relationship with the treatment. An AE can be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the product, whether or not considered related to it.
Adverse Drug Reaction (ADR) / Adverse Reaction	An AE for which a causal relationship between the study drug and the event is at least a reasonable possibility, i.e., the relationship cannot be ruled out.
Serious Adverse Event (SAE) / Serious Adverse Reaction	Any AE/ADR that at any dose: results in death; is life-threatening (subject at immediate risk of death at the time of the event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an other medically important event that may jeopardize the subject or require intervention to prevent one of the outcomes above (medical and scientific judgement, e.g., anaphylaxis, or suspected transmission of an infectious agent).
Unexpected Adverse Reaction	An adverse reaction the nature, severity, specificity, or outcome of which is not consistent with the applicable Reference Safety Information (Section 5).
Suspected Unexpected Serious Adverse Reaction (SUSAR)	An adverse reaction that is simultaneously serious, unexpected per the RSI, and assessed as at least reasonably possibly related to study drug by the investigator and/or the sponsor.
Adverse Event of Special Interest (AESI)	A noteworthy event (serious or non-serious) for the product/class that warrants enhanced ascertainment, expedited internal notification, and targeted follow-up, per Section 9.
Severity	Intensity of a specific event (mild/moderate/severe), graded per Section 3.4. Severity is distinct from seriousness.
Seriousness	A regulatory outcome-based classification per the SAE criteria above; used to determine reporting obligations. A severe event is not necessarily serious.

Note on terminology: "life-threatening" refers to an event in which the subject was at immediate risk of death at the time of the event, not to an event that hypothetically might have caused death had it been more severe.

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3. Adverse Event Collection and Documentation

3.1 Reporting periods

• Medical history and baseline conditions are recorded at screening and are not AEs unless they worsen after the start of study-drug exposure.
• Non-serious AEs are collected from the first administration of study drug through the End-of-Study/Safety Follow-up Visit (Week 20, approximately 8 weeks after the final scheduled dose).
• SAEs are collected from the time the subject signs the informed consent form (ICF) through the Safety Follow-up Visit. Any SAE occurring after ICF signature but before first dose is reported and assessed for relatedness to study procedures.
• After the reporting period, the investigator reports to the sponsor any SAE assessed as related to study drug that comes to the investigator's attention, without a time limit (Section 4.4).

The extended post-treatment window reflects the prolonged systemic exposure of an IgG1 antibody and ensures capture of delayed reactions, including delayed hypersensitivity and infection.

3.2 Ascertainment method

At each scheduled and unscheduled visit, and during any contact prompted by the subject, AEs are elicited using non-leading, open-ended questioning (e.g., "How have you been feeling since your last visit?"). Subjects are additionally instructed to report injection-site symptoms and signs of infection or hypersensitivity between visits. All spontaneously reported and observed events are recorded.

3.3 Recording conventions

• A single unifying diagnosis is recorded in preference to individual signs and symptoms whenever a diagnosis is available; if no diagnosis has been established, each sign/symptom is recorded as a separate AE.
• Each AE is recorded with verbatim term, onset and resolution dates, severity, seriousness, investigator causality, action taken with study drug, other action/treatment, and outcome. Verbatim terms are coded to the current MedDRA version.
• Pre-existing conditions are recorded as AEs only if they worsen in frequency or severity after first dose.
• Clinically significant abnormal laboratory values, vital signs, or ECG findings are recorded as AEs if they meet at least one of the following: are associated with clinical signs/symptoms; require diagnostic evaluation or intervention (including study-drug modification); or are judged clinically significant by the investigator. Isolated abnormal values without these features are not recorded as AEs but are captured in the laboratory dataset.

3.4 Severity grading

AEs are graded as:

• Mild — awareness of a sign/symptom that is easily tolerated and does not interfere with usual activity.
• Moderate — sufficient discomfort to interfere with usual activity.
• Severe — incapacitating, preventing usual activity.

Selected protocol-defined events (e.g., laboratory abnormalities, injection-site reactions) are additionally graded using CTCAE v5.0. Changes in severity are captured as follow-up information on the original AE where the event is continuous; a resolved event that recurs is recorded as a new AE.

3.5 Handling of the disease under study (worsening UC)

Worsening of ulcerative colitis (the indication under study) is recorded as an AE (or SAE if serious). Because UC exacerbation is an anticipated disease-related outcome, pre-specified UC-progression events (e.g., disease-related hospitalization or colectomy for refractory UC) that are documented in the protocol as anticipated are recorded and reported as SAEs when serious, but are exempted from expedited SUSAR handling as isolated cases and are instead monitored in aggregate by the SRT and DSMB and reported in the DSUR (ICH E2F approach to disease-related outcomes). In TILA278-201, worsening UC was more frequently reported in the placebo arm, consistent with the observed efficacy gradient.

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4. Serious Adverse Event Reporting (Site to Sponsor)

4.1 Immediate reporting obligation

Consistent with ICH E6(R3), the investigator reports every SAE to the sponsor immediately and no later than 24 hours of first becoming aware of the event, except for those pre-specified disease-related outcomes identified in the protocol as not requiring immediate individual reporting (Section 3.5). Reporting is by completion and transmission of the SAE form to the sponsor safety mailbox/gateway.

4.2 Minimum criteria for a valid report

A report is actionable once it contains an identifiable reporter, an identifiable subject, a suspect product (TILA-278 or placebo; blinded designation as applicable), and at least one event/outcome meeting a seriousness criterion. Incomplete reports are followed up promptly to secure the missing elements.

4.3 Follow-up and outcome

The investigator provides follow-up information as it becomes available until the event resolves, stabilizes, or is otherwise medically explained, or the subject is lost to follow-up. For fatal events, a copy of any available death certificate and, where performed, the autopsy/post-mortem report are provided. All follow-up reports carry the original case identifier.

4.4 SAEs after the reporting period

Any SAE assessed by the investigator as related to study drug that occurs after the end of the defined reporting period is reported to the sponsor without a time limit and is processed as an ICSR.

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5. Reference Safety Information (RSI)

5.1 Definition and location

The RSI is the single, version-controlled listing of expected serious adverse reactions used exclusively for the expectedness assessment that determines SUSAR status. For TILA278-201, the RSI is a clearly demarcated section of the current Investigator's Brochure (IB Edition 3.0, RSI Section 6.3), titled to identify it unambiguously as the RSI. The RSI in force at the time the sponsor first receives the minimum information for a case is the version applied to that case; the applied RSI version is documented on each expedited report.

5.2 Content

The RSI lists only expected serious adverse reactions, by MedDRA Preferred Term, together with the qualifier(s) (nature/severity/specificity/outcome) that define the boundary of what is expected. Non-serious expected reactions are not part of the RSI and do not bear on expectedness for expedited-reporting purposes.

Expected serious adverse reaction (RSI)	Basis
Injection-site reaction, severe	Class effect of SC-administered biologics; observed drug-attributable finding in TILA278-201.
Hypersensitivity reaction, including anaphylaxis	Class effect of therapeutic proteins; potential immunogenicity-mediated.
Serious infection	Anticipated risk of an immunomodulatory (TL1A-antagonist) mechanism.

5.3 Version control

Changes to the RSI (additions, deletions, or re-characterizations of expected reactions) are made only through a controlled IB update with documented medical and regulatory sign-off. RSI changes are prospectively applied; cases already assessed are not retrospectively re-classified unless a regional authority requires it. The safety database records the RSI version applicable to every case.

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6. Causality and Expectedness Assessment

6.1 Investigator causality

For every AE, the investigator provides a binary causality assessment relative to study drug — Related (a reasonable possibility of a causal relationship exists) or Not Related (no reasonable possibility). In reaching this judgement the investigator considers: the temporal relationship between exposure and event; the plausibility given the known pharmacology of TL1A antagonism and IL-22 receptor agonism; the presence of a plausible alternative etiology (concomitant disease, concomitant medication, UC itself); the response to dechallenge and, where applicable, rechallenge; and consistency with the known safety profile of the product and class. An event is assessed as Related if the causal relationship cannot be reasonably excluded. Absence of a positive dechallenge does not by itself establish non-relatedness for a long-acting antibody.

6.2 Sponsor causality

The sponsor (Medical Monitor) performs an independent causality assessment for all SAEs. For the purpose of expedited reporting, an event is treated as a suspected adverse reaction if either the investigator or the sponsor assesses a reasonable possibility of a causal relationship; a downgrade by the sponsor does not override an investigator's assessment of relatedness.

6.3 Expectedness

Expectedness is determined by the sponsor only, by comparing the event (nature, severity, specificity, and outcome) against the applicable RSI (Section 5). An event more severe or more specific than what the RSI describes is unexpected even if a less severe form is listed (e.g., a fatal or anaphylactic hypersensitivity reaction is unexpected if the RSI describes only non-serious or uncomplicated hypersensitivity). The investigator does not assess expectedness.

6.4 SUSAR determination

An event qualifies as a SUSAR, and triggers expedited reporting, when all three conditions are met:

1. Serious — meets at least one SAE criterion (Section 2);
2. Suspected — assessed as at least reasonably possibly related by the investigator and/or sponsor (Section 6.1/6.2);
3. Unexpected — not consistent with the RSI per the sponsor's expectedness assessment (Section 6.3).

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7. Expedited Reporting (SUSAR)

7.1 Clock start

The reporting clock (Day 0) starts on the calendar date the sponsor (or any sponsor-designated party) first receives the minimum information for a valid case (Section 4.2) that, on initial assessment, qualifies as a SUSAR. Newly significant follow-up information on a previously reported SUSAR starts a new clock for the follow-up report.

7.2 Timelines

SUSAR category	Initial report	Follow-up
Fatal or life-threatening	As soon as possible, no later than 7 calendar days after the sponsor is first aware	Any relevant follow-up information within a further 8 calendar days (i.e., complete report by Day 15)
All other (non-fatal, non-life-threatening)	As soon as possible, no later than 15 calendar days after the sponsor is first aware	Relevant follow-up as soon as available

Where a case is initially non-life-threatening but later meets the fatal/life-threatening criterion, the 7-day clock applies from the date the seriousness-upgrading information is received.

7.3 Recipients

Expedited reports are submitted to the competent regulatory authorities of the participating regions (including the US FDA and, via EudraVigilance, the EU authorities), to the responsible IRBs/IECs in accordance with local requirements, and are communicated to participating investigators (either as individual reports or through periodic line listings, per regional convention). Local IRB/EC reporting by investigators is performed per local requirements and timelines.

7.4 Format, coding, and transmission

ICSRs are prepared in the ICH E2B(R3) format, coded in MedDRA (current version), and transmitted electronically through the qualified safety gateway. Case narratives follow CIOMS conventions and present a coherent clinical account, including relevant history, concomitant medications, time course, treatment, outcome, and the assessor's causality reasoning.

7.5 Blinding and unblinding for expedited reporting

Blinding is preserved to the fullest extent possible. For a case that requires expedited reporting, the sponsor unblinds only that subject's treatment assignment, and only where the treatment identity is necessary for the report (for SUSARs assessed against the active-product RSI). Personnel involved in the conduct and analysis of the study remain blinded. Where the sponsor and DSMB agree that maintaining the blind for a particular expedited report does not compromise subject safety, blinded expedited reporting may be used per protocol. Events occurring in placebo subjects are handled per the protocol/regional convention and are generally not reported as SUSARs unless attributable to a study procedure or excipient.

7.6 Other events requiring expedited handling

The following are treated with the urgency of an expedited report irrespective of individual SUSAR classification: any finding that could materially alter the benefit-risk assessment or warrant a change to product administration or study conduct; a clinically important increase in the rate or severity of an expected serious adverse reaction; suspected transmission of an infectious agent via the product; and lack of efficacy for a life-threatening condition (not applicable to the UC indication of this study).

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8. Pregnancy and Lactation Reporting

8.1 Prevention

Because the reproductive and developmental safety of TILA-278 has not been established, and because IgG1 antibodies undergo active FcRn-mediated placental transfer that increases through the second and third trimesters, pregnancy is an exclusion and women of childbearing potential (WOCBP) must use highly effective contraception from screening through approximately 20 weeks after the last dose (based on 5 half-lives). Nonclinical support for this labeling comprises repeat-dose SC toxicology in the cynomolgus monkey and tissue cross-reactivity assessment; a dedicated enhanced pre-/post-natal development study is not available at this stage.

8.2 Pregnancy reporting

Any pregnancy in a study subject that occurs after the first dose and up to the end of the contraception window is not in itself an AE, but is reported by the investigator to the sponsor within 24 hours of awareness on the dedicated pregnancy report form. Study drug is discontinued. Each pregnancy is followed to outcome (live birth, spontaneous abortion, elective termination, ectopic pregnancy, or stillbirth), and the infant is followed for congenital anomalies and for developmental status through 12 months given the expected persistence of transferred antibody in the neonate.

8.3 Events reported as SAEs

The following pregnancy outcomes are reported as SAEs on the SAE pathway (Section 4): spontaneous abortion, stillbirth, congenital anomaly/birth defect, ectopic pregnancy, and any serious maternal or neonatal complication. A congenital anomaly is additionally assessed for expectedness and may qualify as a SUSAR.

8.4 Partner pregnancies and lactation

Pregnancy in the partner of a male subject is reported (with the partner's separate consent for follow-up) and followed to outcome. Breastfeeding is not permitted during treatment and through the post-treatment window; any exposure via breast milk is recorded and any resulting infant event is captured as an AE/SAE.

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9. Adverse Events of Special Interest (AESI)

AESIs are defined a priori from the pharmacology of dual TL1A antagonism / IL-22 receptor agonism, the biologic/SC modality, and the UC population. Each AESI is subject to enhanced ascertainment, notification to the Medical Monitor within 24 hours (as for an SAE, whether or not serious), and targeted follow-up (including immunogenicity sampling where relevant).

AESI	Rationale
Serious and opportunistic infections (including tuberculosis reactivation and viral hepatitis reactivation)	Immunomodulation via TL1A (TNFSF15) antagonism; standard class concern for immunomodulatory biologics.
Injection-site reactions	SC administration; the principal drug-attributable finding observed in TILA278-201.
Systemic hypersensitivity, including anaphylaxis and serum-sickness-like reactions	Therapeutic-protein immunogenicity; assessed alongside anti-drug antibody (ADA) status via the tiered immunogenicity assay.
Malignancy, including colorectal dysplasia/neoplasia	Chronic immunomodulation, plus theoretical epithelial-proliferative risk of IL-22 receptor agonism in the chronically inflamed colon.
Hepatic events (transaminase elevation, hepatocellular injury)	IL-22 hepatic tropism and epithelial-proliferative signaling; standard DILI monitoring conventions apply.
Immunogenicity-associated loss of effect or PK alteration	ADA formation may affect exposure, efficacy, and safety; captured through the tiered ADA assay and PK.

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10. Signal Management and Aggregate Safety Review

10.1 Continuous surveillance

The sponsor maintains ongoing safety surveillance throughout the study. Individual cases are reviewed by the Medical Monitor on receipt. In parallel, cumulative and interval safety data are reviewed periodically to detect quantitative signals (imbalances in frequency, severity, or seriousness between arms) and qualitative signals (clustering of related terms, unexpected severity, new AESIs, or events suggesting a previously unrecognized risk).

10.2 Safety Review Team (SRT)

The SRT — comprising sponsor clinical, pharmacovigilance, biostatistics, and clin-pharm representatives — meets on a defined cadence (e.g., monthly, and ad hoc on trigger) to review blinded aggregate data and, where the DSMB has released it, unblinded summaries. Signal-management decisions (validation, prioritization, assessment, and any resulting action such as protocol amendment, IB/RSI update, or informed-consent revision) are documented in a signal-tracking log retained in the TMF.

10.3 Data Safety Monitoring Board (DSMB)

An independent DSMB provides ongoing oversight of subject safety and reviews accumulating unblinded safety data — including deaths, serious adverse events, adverse events leading to discontinuation, injection-site reactions, and laboratory safety parameters — at pre-specified intervals. The DSMB operates under a charter that defines its composition (independent clinical experts and an independent statistician), meeting schedule, review scope, statistical monitoring conventions, and communication pathway to the sponsor; its role is confined to safety oversight, and no formal interim efficacy analysis for early stopping is planned. Unblinded safety reports are prepared by an independent statistical group functionally separate from the blinded sponsor study team, preserving the integrity of the double-blind. Based on its benefit-risk assessment, the DSMB may recommend continuation, modification, temporary suspension, or termination of the study, and the sponsor implements DSMB recommendations affecting subject safety without unblinding the study team beyond what is necessary.

10.4 Development Safety Update Report (DSUR)

An annual DSUR is prepared in accordance with ICH E2F, integrating clinical-trial safety data across the TILA-278 development program, cumulative and interval line listings and summary tabulations, an evaluation of the ongoing benefit-risk, and any actions taken for safety reasons. Disease-related outcomes handled per Section 3.5 are presented in aggregate in the DSUR.

10.5 Emergency unblinding

Treatment assignment may be unblinded for an individual subject when knowledge of the assignment is essential to the subject's clinical management. Emergency unblinding is performed via the controlled system, is available at all times to the treating investigator, and is documented (who, when, why). Unblinding for individual medical management is distinct from, and does not trigger, study-wide unblinding.

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11. Study Safety Experience — TILA278-201

The safety population (Safety Analysis Set) comprises all randomized subjects who received at least one dose of study drug and had at least one post-baseline safety assessment (TILA-278 High N=284; TILA-278 Low N=283; Placebo N=273; 840 treated). Of the 900 randomized subjects, 60 (High 15, Low 17, Placebo 28) were not dosed or lacked a post-baseline assessment and are excluded from this set. The observed treatment-emergent safety profile is summarized below (n [%] of the Safety Analysis Set).

Parameter	TILA-278 High (N=284)	TILA-278 Low (N=283)	Placebo (N=273)
Subjects with >=1 TEAE	109 (38.4)	131 (46.3)	130 (47.6)
Subjects with >=1 SAE	3 (1.1)	0 (0.0)	4 (1.5)
Deaths (all assessed unrelated)	2 (0.7)	0 (0.0)	1 (0.4)
Discontinuations (any cause)	17 (6.0)	17 (6.0)	29 (10.6)

The most frequently reported AEs were nasopharyngitis, headache, worsening UC (more frequent on placebo), anaemia, arthralgia, upper respiratory tract infection, injection-site reaction (more frequent on active SC drug), and nausea. No dose-dependent safety signal was identified across the High and Low active arms. Injection-site reactions were the principal drug-attributable finding, consistent with SC administration of a therapeutic protein and with the RSI. All deaths were assessed by the investigator and confirmed on independent review by the sponsor Medical Monitor and the DSMB as unrelated to study drug. The higher discontinuation count in the placebo arm was driven by lack of efficacy rather than by adverse events, consistent with the pronounced efficacy gradient favouring active treatment (clinical remission at Week 12: High 37.3%, Low 16.2%, Placebo 0.7%).

Interpretation. Treatment-emergent adverse events were not more frequent on active treatment than on placebo (38.4% High and 46.3% Low vs 47.6% placebo), and no dose-dependent trend was evident between the High and Low arms. Serious adverse events were infrequent and numerically fewer in the combined active arms than on placebo (3 and 0 subjects vs 4), with none reported at the Low dose. The three deaths (2 High, 0 Low, 1 Placebo) were each adjudicated unrelated to study drug; their small absolute number, the absence of dose-ordering, the lack of temporal clustering, and the absence of a common aetiology or mechanistic link to TL1A antagonism or IL-22 receptor agonism indicate that their distribution reflects background mortality risk in a moderate-to-severe UC population rather than a treatment-related signal. No new safety signal that would warrant a change to the RSI was identified on the basis of this study, and the aggregate benefit-risk in the induction setting remains favourable and supports continued development.

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12. Records, Reconciliation, Training, and TMF

12.1 Data reconciliation

SAE information held in the safety database is reconciled against the clinical database at defined intervals and prior to database lock, with discrepancies resolved and documented. MedDRA coding is quality-controlled and, on dictionary upversioning, the coded data are re-coded per the coding SOP.

12.2 Training

Site and sponsor personnel are trained on this SMP, the SAE/pregnancy forms, the AESI list, and the reporting timelines prior to first-subject-first-visit and on material updates. Training is documented in the TMF.

12.3 Filing

This SMP and its supporting records — SAE and pregnancy source and processed cases, expedited-report acknowledgements, the RSI version history, SRT signal logs, DSMB outputs, DSURs, and reconciliation records — are filed and retained in the TMF in accordance with ICH E6(R3) and applicable regional record-retention requirements.

12.4 Version control of this plan

This SMP is version-controlled; substantive changes are made by controlled amendment with documented review and approval by the sponsor Medical Monitor and Pharmacovigilance, and the effective version is recorded in the TMF.