📚 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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Clinical Trial Agreement & IRB/IEC Approvals (TILA278-201)

Document ID: TMF-013
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH E6(R3)

Clinical Trial Agreement & IRB/IEC Approvals — TILA278-201

The executed clinical trial agreement framework for TILA278-201 and the record of Institutional Review Board / Independent Ethics Committee approvals of the protocol, informed consent, and related documents prior to enrollment. ICH E6(R3).

1. Purpose and scope

This Trial Master File (TMF) document consolidates the contractual and ethics-approval foundation for Study TILA278-201, a Phase 2b, randomized, double-blind, placebo-controlled, parallel-group, 12-week induction study of TILA-278 in adults with moderately to severely active ulcerative colitis (UC). TILA-278 (Virtual Biopharma Inc.) is a humanized IgG1 bispecific monoclonal antibody that combines TL1A (TNFSF15) antagonism with interleukin-22 receptor (IL-22R) agonism, produced by Chinese hamster ovary (CHO) cell culture and administered subcutaneously (SC). The antagonist arm dampens TL1A-driven TH1/TH17 inflammation and pro-fibrotic signaling, while the agonist arm engages IL-22R to promote intestinal epithelial and mucosal healing.

The document has two functions. First, it records the executed Clinical Trial Agreement (CTA) framework governing the legal, financial, and compliance relationship among the sponsor, the contract research organization (CRO), each participating institution, and each principal investigator (PI). Second, it maintains the register of IRB/IEC approvals — of the protocol, the informed consent form (ICF), the current Investigator's Brochure (IB), and all subject-facing materials — obtained for each site before any subject is screened or randomized.

The study is conducted at approximately 130 sites across approximately 15 countries, screening 1700 subjects to randomize 900 in a 1:1:1 ratio to TILA-278 High (299), TILA-278 Low (300), and placebo (301). No site may screen or enroll a subject until both (a) the site-specific CTA is fully executed and (b) the governing IRB/IEC has issued written approval of the current protocol version and the site-specific ICF. This gating rule is verified at the Site Initiation Visit (SIV) and is a release condition for investigational product (IP) shipment.

2. Regulatory and ethical framework

The CTA and ethics-approval processes are conducted in accordance with:

• ICH E6(R3) Good Clinical Practice, including the principles governing sponsor and investigator responsibilities, essential-document management, ethics-committee review, and the proportionate, risk-based conduct of the trial.
• Declaration of Helsinki (current version) and the Council for International Organizations of Medical Sciences (CIOMS) international ethical guidelines.
• United States: 21 CFR Part 50 (protection of human subjects and informed consent), Part 54 (financial disclosure by clinical investigators), Part 56 (Institutional Review Boards), and Part 312 (Investigational New Drug application). TILA-278 is a biologic developed toward a Biologics License Application (BLA) under 21 CFR Part 601; the investigational use is authorized under an IND in effect under 21 CFR Part 312.
• European Union / other regions: Regulation (EU) No 536/2014 (Clinical Trials Regulation) and national ethics-committee and competent-authority requirements, and the corresponding local statutes in each participating country.
• ICH E8(R1) (general considerations for clinical studies) and ICH E2A (expedited safety-reporting definitions and standards), which govern the safety information flowing to ethics committees during the trial.
• Investigational-product context reviewed within the IB. Because TILA-278 is a biotechnology-derived monoclonal antibody, the nonclinical and quality information that ethics committees review within the IB reflects ICH S6(R1) (preclinical safety evaluation of biotechnology-derived pharmaceuticals) and ICH Q5A(R2)/Q5C/Q6B (viral safety, stability, and specifications). Consistent with S6(R1), the cynomolgus monkey is the sole pharmacologically relevant toxicology species, and a standard genotoxicity, carcinogenicity, and safety-pharmacology (for example, hERG or thorough-QT) battery is not warranted for a monoclonal antibody; ethics committees are advised of this scientifically justified nonclinical scope so the benefit–risk assessment is not misread as an omission.

Where a regional requirement is more stringent than this framework, the more stringent requirement governs at that site.

3. Clinical Trial Agreement framework

3.1 Contracting structure and parties

Contracting follows a two-tier structure. A Master Services Agreement (MSA) and associated work orders govern the relationship between the sponsor (Virtual Biopharma Inc.) and the CRO to which operational conduct is delegated. Beneath this, a site-specific CTA is executed for each participating institution and its PI, with a consistent master template adapted for local law, institutional policy, and language. Where an academic medical center, its affiliated practice group, and the individual investigator are distinct legal entities, each necessary signatory is a party to, or is bound by, the executed agreement.

The parties and their principal accountabilities are: the sponsor, retaining overall accountability for trial quality, safety oversight, and regulatory obligations; the CRO, performing delegated activities under a documented delegation log; the institution, providing facilities, staff, and compliance infrastructure; and the PI, accountable for the conduct of the trial at the site and for the rights, safety, and well-being of enrolled subjects.

3.2 Key contractual provisions

Provision	Content specific to TILA278-201
Scope of work / protocol adherence	Conduct strictly per the current approved protocol; screening of 1700 and randomization of 900 subjects across the network, with site-level enrollment caps managed via the interactive response technology (IRT).
GCP and regulatory compliance	Compliance with ICH E6(R3), applicable regional GCP, and the sponsor's SOPs; cooperation with monitoring, audit, and inspection.
Delegation of duties	Only qualified, trained, and delegated staff perform study procedures; the site delegation log is maintained and current before activation.
Budget and payment terms	Fair-market-value, per-subject and per-procedure payments (including endoscopy and central-read logistics, SC administration visits, and PK/anti-drug antibody [ADA] sampling); milestone and pass-through costs defined; no payments contingent on a favorable outcome.
Investigational product handling	Cold-chain storage, accountability, and administration of the SC prefilled syringe/autoinjector at Weeks 0, 2, 4, and 8; return/destruction terms; prohibition on non-protocol use.
Subject injury and medical care	Sponsor responsibility for reasonable and customary costs of medical care for study-related injury, as detailed in Section 3.5 and reflected in the ICF.
Indemnification	Mutual indemnification allocating liability for negligence and for defects in the IP, subject to standard exclusions.
Insurance	Maintenance of clinical-trial and professional-liability insurance meeting or exceeding local minimums; certificates filed before activation.
Publication rights	Multi-center primary publication precedence; defined sponsor review window for confidentiality and IP protection; no suppression of results; registry disclosure obligations preserved.
Intellectual property	Sponsor ownership of study data and of inventions arising from use of the IP or confidential information; institution retains rights to pre-existing IP.
Confidentiality	Protection of protocol, IB, and sponsor confidential information; carve-outs for regulatory and ethics submissions and for subject-safety disclosures.
Data protection and privacy	Processing of personal data per Section 6; roles of controller/processor defined by region.
Records retention and access	Retention of essential documents and source records per Section 7; sponsor and authority access for monitoring, audit, and inspection.
Term and termination	Term tied to study completion; termination for cause, for safety, or for regulatory reasons; orderly wind-down and subject-safety continuity on termination.
Governing law and dispute resolution	Governing law and forum specified per site/region.

3.3 Sponsor–CRO delegation and vendor agreements

Delegation of operational activities to the CRO and to functional service providers is documented in the sponsor–CRO agreement, the delegation log, and quality/technical agreements (QTAs) as applicable. Vendors engaged under separate agreements include the IRT provider (randomization and IP management), the central safety laboratory, the central endoscopy reading facility (which centrally reads the endoscopy subscore of the modified Mayo score), the bioanalytical laboratory performing pharmacokinetic (PK) and immunogenicity (ADA) assays, the independent statistical group supporting the Data Safety Monitoring Board (DSMB), and biostatistics/programming. Each agreement specifies GCP/GCLP obligations, data-integrity and confidentiality terms, and the sponsor's right to audit. The sponsor retains oversight accountability notwithstanding delegation.

3.4 Financial arrangements and investigator financial disclosure

Site budgets are negotiated at fair market value and documented in the CTA payment schedule; no component of investigator compensation is tied to a particular study result or to the number of subjects reaching the primary endpoint. Consistent with 21 CFR Part 54, each investigator and sub-investigator provides financial-disclosure information before participation, certified on Form FDA 3454 (certification of absence of disclosable interests) or disclosed on Form FDA 3455 where applicable. Investigators undertake to report changes in relevant financial interests during the study and for one year following completion, and these records are maintained in the TMF to support the eventual marketing application.

3.5 Insurance, indemnification, and subject-injury compensation

Clinical-trial insurance is maintained in each participating country to the required limits, with certificates filed before site activation and renewed as needed to remain current throughout the study. The sponsor undertakes to pay the reasonable and customary costs of medical treatment for injuries determined to be caused by the correct administration of TILA-278 or by protocol-mandated procedures, and no-fault compensation is provided where local law or ethics-committee requirements mandate it. The compensation and injury provisions, and the corresponding contact route, are described in plain language in the ICF. Anticipated product-related risks reflected in these provisions and in the consent materials include injection-site reactions (the principal drug-attributable finding on active SC drug), hypersensitivity and infusion-type/injection reactions, immunogenicity (ADA formation, which may affect PK, efficacy, and safety), and serious or opportunistic infections associated with modulation of TL1A-driven TH1/TH17 immunity.

4. IRB/IEC review and approvals

4.1 Documents submitted for ethics review

For each site, the following are submitted to the governing IRB/IEC and their approval or favorable opinion is obtained and filed before enrollment:

• the current protocol and any amendments;
• the master ICF and each site-specific/localized and translated ICF, including any assent or partner/pregnancy-related consent materials;
• the current edition of the Investigator's Brochure and any IB updates;
• subject recruitment and advertising materials and any subject-facing instruments (for example, symptom diaries capturing stool frequency and rectal bleeding subscores);
• the PI's qualifications (current CV, medical licensure) and those of key sub-investigators, and documentation of GCP training;
• the clinical-trial insurance certificate and, where required, the subject compensation arrangements;
• the safety-reporting plan and the arrangements for communicating expedited safety information and DSMB outputs to the committee.

4.2 Central and local IRB/IEC model

Where permitted, a central IRB is used to review and approve the protocol and master consent for multiple sites (including single-IRB arrangements in the United States), while local ethics committees provide review where national law or institutional policy requires it. Country- and site-level committees review localized consent and any local-context items. The model applied at each site, and the identity of the reviewing committee of record, are documented in the approval register.

4.3 Approvals obtained before enrollment

The register below is maintained as a living record; each entry is supported by the dated written approval filed in the TMF. Enrollment at a site is authorized only when its row is complete and current, and when the corresponding competent-authority authorization (IND in effect, or regional clinical-trial authorization) is confirmed.

Register field	Content maintained per site
Region / country	Country of the participating site (network spans approximately 15 countries).
Site / institution	Institution and PI (network comprises approximately 130 sites).
Reviewing IRB/IEC	Central IRB or local ethics committee of record.
Documents approved	Protocol version, ICF version(s)/translations, IB edition, recruitment materials.
Approval type / date	Initial approval / favorable opinion, with date, preceding first screening.
Authorization linkage	Confirmation of IND-in-effect / regional clinical-trial authorization.
Status	Active, pending amendment approval, or suspended.

It is attested that, for every enrolling site, initial IRB/IEC approval of the protocol and the site-specific ICF was in place before the first subject was screened or randomized.

4.4 Continuing review, amendments, and safety reporting to IRB/IEC

Continuing review is obtained at the interval required by each committee (for example, at least annually, or more frequently where specified), and approval is maintained without lapse for the duration of the site's participation. Substantial protocol and ICF amendments are submitted and approved before implementation, except where a change is necessary to eliminate an immediate hazard to subjects, in which case the deviation is implemented and reported to the committee promptly per ICH E6(R3). Expedited safety reports (including suspected unexpected serious adverse reactions), periodic safety reporting (the Development Safety Update Report), and relevant DSMB recommendations affecting subject safety or the conduct of the trial are transmitted to the IRB/IEC on the applicable timelines. Re-consent of enrolled subjects is obtained when a new consent version is approved and the change is relevant to subjects continuing in the study.

5. Essential documents and pre-enrollment gating

Site activation is gated on a defined set of essential documents, verified and filed in the TMF before the site may screen or enroll. The core gating checklist is:

Gating item	Status required before enrollment
Executed site-specific CTA	Fully signed by all necessary parties.
IRB/IEC approval — protocol	Written approval of the current protocol version.
IRB/IEC approval — ICF	Written approval of the site-specific/translated ICF version.
Investigator's Brochure	Current edition received and acknowledged by the PI.
Regulatory authorization	IND in effect (US) / regional clinical-trial authorization confirmed.
Financial disclosure	Form FDA 3454/3455 collected for PI and sub-investigators.
Insurance	Valid clinical-trial insurance certificate on file.
Delegation log and training	Delegation log current; GCP and protocol training documented.
Laboratory documentation	Central/local certifications, accreditations, and normal ranges on file.
IP release conditions	Cold-chain and site-readiness conditions met for IP shipment.

A site is released for enrollment only when every applicable item is complete and current; any subsequent lapse (for example, an expired continuing-review approval) suspends new enrollment at that site until reinstated.

6. Data protection and confidentiality

Personal data are processed under the applicable regional frameworks (for example, the EU General Data Protection Regulation and, in the United States, HIPAA where applicable), with controller/processor roles, lawful basis, and cross-border transfer mechanisms defined in the CTA and supporting data-processing agreements. Subject data are pseudonymized using the subject identifier assigned at screening; the subject identification list linking codes to identities is held at the site under the PI's control. Biological samples collected for PK and immunogenicity (ADA) testing are handled and retained under the consent obtained, with the scope of any exploratory or retained-sample use, and the applicable retention period, specified in the ICF and honored in the vendor agreements.

7. Records, retention, version control, and TMF filing

All CTA and ethics-approval documents — executed agreements and amendments, the delegation and financial-disclosure records, and the dated IRB/IEC approvals and continuing-review correspondence — are filed contemporaneously in the TMF and are maintained inspection-ready. Essential documents are retained per ICH E6(R3) and the applicable regional requirements (for example, at least 25 years under EU Regulation No 536/2014, or longer where local law or institutional policy requires), and are not destroyed without sponsor notification. This document is version-controlled; material changes to the contracting framework or the approval status are recorded and re-issued under change control.

8. Approval

This document and the underlying CTA and IRB/IEC approval framework are approved on behalf of the sponsor, Virtual Biopharma Inc., and, for delegated activities, the CRO. Controlled signatures and dates are maintained in the signed version filed in the TMF.