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EXHIBIT J

SAFETY REPORTING PROCEDURES

Attached to and forming part of the Master Clinical Trial Agreement dated June 28, 2023 (the "MCTA")

by and between

PENTERRA PHARMACEUTICALS CORP. ("Sponsor" or "Penterra")

and

VERIDIAN HEALTH RESEARCH NETWORK, INC. ("Veridian" or "Site Network")

Protocol: PPC-4871-III CLARION — Clinical Assessment of Response with Longitudinal Investigation in ONcology

Investigational Product: Penterafenib (PPC-4871)

IND Number: IND 157823

ClinicalTrials.gov Identifier: NCT05928174

Sponsor's Contract Research Organization: Meridian Contract Research Organization, Inc. ("Meridian CRO")

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Section 1: Purpose and Scope

1.1 This Exhibit J (these "Safety Reporting Procedures") sets forth the procedures applicable to the identification, documentation, assessment, reporting, and follow-up of adverse events, serious adverse events, and other safety information arising during the conduct of the Phase III clinical trial conducted under Protocol PPC-4871-III, known as the CLARION trial (Clinical Assessment of Response with Longitudinal Investigation in ONcology), evaluating the investigational product penterafenib (PPC-4871). These Safety Reporting Procedures apply to all thirty-eight (38) Veridian Health Research Network participating clinical sites located across fourteen (14) states in the United States.

1.2 The purpose of these Safety Reporting Procedures is to ensure timely, accurate, and regulatory-compliant reporting of all adverse events ("AEs"), serious adverse events ("SAEs"), suspected unexpected serious adverse reactions ("SUSARs"), adverse events of special interest ("AESIs"), pregnancies, deaths, and other safety information arising in subjects enrolled in the CLARION trial, so as to protect the safety and well-being of trial subjects and to satisfy the obligations of the Sponsor, the Site Network, and each participating investigator under applicable federal regulations and international guidelines.

1.3 These Safety Reporting Procedures apply to all principal investigators, sub-investigators, clinical research coordinators, study nurses, pharmacists, and other site staff at each participating institution within the Veridian Network who are involved in any aspect of the identification, assessment, documentation, or reporting of safety information in connection with the CLARION trial. Compliance with these procedures is a material obligation of each participating site and its personnel under the MCTA and applicable site-specific agreements.

1.4 These Safety Reporting Procedures supplement, and are intended to be read in conjunction with, the safety reporting provisions contained in Protocol PPC-4871-III (including all appendices and amendments thereto) and the Investigator's Brochure for penterafenib (PPC-4871), as updated from time to time. In the event of any perceived inconsistency between these Safety Reporting Procedures and the Protocol, the Protocol shall govern unless applicable law or regulation requires otherwise. These Safety Reporting Procedures do not replace the safety provisions contained in the Protocol or the Investigator's Brochure.

1.5 These Safety Reporting Procedures have been developed in accordance with, and are governed by, the following regulatory framework:

(a) Title 21, Code of Federal Regulations, Part 312 — Investigational New Drug Application (IND regulations);

(b) Title 21, Code of Federal Regulations, Section 312.32 — IND Safety Reporting;

(d) Title 21, Code of Federal Regulations, Part 56 — Institutional Review Boards;

(e) Title 21, Code of Federal Regulations, Part 11 — Electronic Records; Electronic Signatures;

(f) Title 45, Code of Federal Regulations, Part 46 — Protection of Human Subjects (Common Rule);

(g) The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ("ICH") Guideline E6(R2) — Guideline for Good Clinical Practice; and

(h) ICH Guideline E2A — Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.

1.6 Penterra Pharmaceuticals Corp. is the holder of IND 157823, filed with the United States Food and Drug Administration ("FDA") for penterafenib (PPC-4871), and bears ultimate responsibility for all IND safety reporting obligations to the FDA arising from the conduct of the CLARION trial and all other clinical studies conducted under IND 157823.

1.7 Meridian Contract Research Organization, Inc. ("Meridian CRO") serves as the Sponsor's contract research organization for the CLARION trial pursuant to the Master Services Agreement dated January 15, 2023, between Penterra and Meridian CRO (the "MSA"). Under the MSA, Meridian CRO has been delegated certain responsibilities related to clinical monitoring, data management, safety reporting processing, pharmacovigilance support, and biostatistics, as further described in Section 3.2 of these Safety Reporting Procedures. The delegation of such responsibilities to Meridian CRO does not relieve Penterra of its regulatory responsibilities as the IND holder.

Section 2: Definitions

For purposes of these Safety Reporting Procedures, the following terms shall have the meanings set forth below. Capitalized terms not defined in this Section 2 shall have the meanings ascribed to them in the MCTA or, if not defined therein, in Protocol PPC-4871-III.

2.1 Adverse Event ("AE"). Any untoward medical occurrence in a clinical trial subject who has been administered the investigational product (penterafenib / PPC-4871) or placebo, whether or not considered by the investigator to be causally related to the study treatment. An adverse event can therefore be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of the investigational product or placebo, without any judgment about causation. An adverse event includes, without limitation, any clinically significant worsening of a pre-existing condition, any intercurrent illness, any drug interaction, and any abnormal laboratory value or diagnostic test result that the investigator considers clinically significant.

2.2 Serious Adverse Event ("SAE"). An adverse event occurring at any dose of the investigational product or placebo that results in any of the following outcomes:

(a) Death;

(b) A life-threatening event (i.e., an event that, in the view of the investigator, places the subject at immediate risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe);

(c) Inpatient hospitalization or prolongation of existing hospitalization (excluding hospitalizations planned before informed consent was signed or hospitalizations for elective procedures not related to worsening of an underlying condition);

(d) Persistent or significant disability or incapacity (i.e., a substantial disruption of the subject's ability to conduct normal life functions);

(e) A congenital anomaly or birth defect in the offspring of a study subject; or

(f) Any other medically important event or condition that, in the judgment of the investigator, may jeopardize the subject or may require medical or surgical intervention to prevent one of the outcomes listed in (a) through (e) above.

The definition of "serious adverse event" set forth herein is consistent with the definitions in 21 C.F.R. § 312.32(a) and ICH Guideline E2A. The determination of whether an event is "serious" is distinct from the assessment of "severity" (mild, moderate, or severe), which describes the intensity of the event.

2.3 Suspected Adverse Reaction. An adverse event for which there is a reasonable possibility that the investigational product (penterafenib) caused the adverse event. "Reasonable possibility" means that there is evidence to suggest a causal relationship between the investigational product and the adverse event; it does not require certainty of causation. A suspected adverse reaction implies a lesser degree of certainty about causality than the term "adverse reaction," which denotes a known causal relationship.

2.4 Unexpected Adverse Event. An adverse event, the nature, severity, or frequency of which is not consistent with information contained in the current version of the Investigator's Brochure for penterafenib (PPC-4871). For purposes of this definition, an adverse event is considered "unexpected" if: (a) the event is not listed in the Investigator's Brochure; (b) the event is listed in the Investigator's Brochure but occurs at a greater severity or frequency than described therein; or (c) the event manifests in a clinically distinct presentation not described in the Investigator's Brochure.

2.5 Suspected Unexpected Serious Adverse Reaction ("SUSAR"). A serious adverse event that is both: (a) suspected to be related to the investigational product (penterafenib) (i.e., meets the definition of a suspected adverse reaction); and (b) unexpected, as defined in Section 2.4 above (i.e., not listed in nature, severity, or frequency in the current version of the Investigator's Brochure). SUSARs are subject to expedited IND safety reporting by the Sponsor to the FDA under 21 C.F.R. § 312.32.

2.6 IND Safety Report. A report submitted by the Sponsor (Penterra) to the FDA and to all participating investigators under 21 C.F.R. § 312.32, notifying them of safety findings that require expedited reporting. IND Safety Reports may include reports of SUSARs (both fatal/life-threatening and non-fatal/non-life-threatening), findings from epidemiological or pooled analyses suggesting significant risks, clinically important increases in the rate of a known serious suspected adverse reaction, and findings from animal or in vitro testing suggesting a significant risk to human subjects.

2.7 Protocol Deviation. Any departure from the approved Protocol PPC-4871-III that is not prospectively authorized by the Sponsor or required to eliminate an apparent immediate hazard to the subject. Protocol deviations include, without limitation, deviations from inclusion or exclusion criteria, dosing schedules, visit windows, required assessments, and safety monitoring procedures. As used herein, the term "protocol deviation" encompasses both minor deviations and major deviations (i.e., those that may significantly affect the completeness, accuracy, or reliability of the study data, or the rights, safety, or well-being of the subjects). For the avoidance of doubt, medically necessary protocol deviations implemented by the investigator to protect the immediate safety of a subject are permitted and must be documented and reported promptly to the Sponsor, Meridian CRO, and the applicable IRB, as further described in Section 9 of the MCTA.

2.8 Study Treatment Period. The period commencing on the date of the first dose of investigational product (penterafenib) or placebo administered to a given study subject and continuing through thirty (30) calendar days after the last dose of investigational product or placebo, or such longer period as may be required by the Protocol for safety follow-up. As set forth in Protocol PPC-4871-III, the total anticipated study duration is approximately sixty (60) months, comprising an estimated forty-two (42)-month enrollment period and an eighteen (18)-month follow-up period. Safety reporting obligations as set forth in these Safety Reporting Procedures apply throughout the Study Treatment Period and, where specified in the Protocol, during the post-treatment follow-up period.

Section 3: Roles and Responsibilities

3.1 Sponsor (Penterra Pharmaceuticals Corp.)

Penterra, as the holder of IND 157823, bears overall responsibility for IND safety reporting and pharmacovigilance for the investigational product penterafenib (PPC-4871) across all clinical studies conducted under the IND, including the CLARION trial. Penterra's safety reporting responsibilities include, without limitation, the following:

(a) IND Safety Reporting to the FDA. Submission of all IND safety reports to the FDA in accordance with the timelines and requirements of 21 C.F.R. § 312.32, including seven (7)-calendar-day reports for fatal or life-threatening SUSARs and fifteen (15)-calendar-day reports for all other reportable safety findings, as further described in Section 5 of these Safety Reporting Procedures.

(b) Distribution of IND Safety Reports. Distribution of all IND safety reports submitted to the FDA to all participating investigators at the thirty-eight (38) Veridian Network sites, coordinated through Meridian CRO and the Veridian central office, within the timelines required by 21 C.F.R. § 312.32(c)(1)(iii) and (c)(2).

(c) Global Safety Database. Maintenance and oversight of a global safety database for penterafenib, which aggregates safety data from all clinical studies conducted under IND 157823, including the CLARION trial and any other ongoing or completed studies.

(d) Aggregate Safety Analysis. Review and assessment of aggregate safety data on a periodic basis, including signal detection activities, periodic safety analyses, and preparation of annual IND safety reports under 21 C.F.R. § 312.33.

(e) Medical Safety Oversight. Coordination with the Penterra Chief Medical Officer, Dr. Elaine Whitford, M.D., and the Senior Vice President, Clinical Development, Dr. Marcus Yun, M.D., M.P.H., for all medical safety decisions, including causality assessment at the Sponsor level, benefit-risk evaluation, decisions regarding dose modifications or protocol amendments for safety, and communications with the Data Safety Monitoring Board.

(f) Oversight of Meridian CRO. Oversight and supervision of Meridian CRO's delegated safety data management and pharmacovigilance functions, including periodic audits and review of quality metrics related to safety data processing.

(g) Notification of Regulatory Actions. Notification to the Veridian central office, specifically the Senior Vice President, Research Administration, Dr. Lena Marchetti, Ph.D., and to all participating investigators, of any regulatory action, clinical hold, or safety-related protocol amendment affecting the CLARION trial, within twenty-four (24) hours of the Sponsor's receipt of such information from the FDA or other regulatory authority.

3.2 Contract Research Organization (Meridian CRO)

Meridian Contract Research Organization, Inc. (headquarters: 9200 Corporate Boulevard, Raleigh, North Carolina 27615; Chief Executive Officer: Thomas Hartwell) serves as the Sponsor's contract research organization for the CLARION trial. Under the Master Services Agreement dated January 15, 2023, between Penterra and Meridian CRO, Meridian CRO has been delegated the following responsibilities related to safety reporting and pharmacovigilance:

(a) Receipt and Processing of SAE Reports. Receipt of all initial and follow-up SAE reports from the thirty-eight (38) Veridian Network sites, including quality review for completeness, accuracy, and consistency with source documentation.

(b) Data Entry into Global Safety Database. Entry of all SAE data into the global safety database within one (1) business day of receipt by the Meridian CRO Safety Department, as further described in Section 7.1 of these Safety Reporting Procedures.

(c) Medical Coding. Medical coding of all adverse events and serious adverse events using the Medical Dictionary for Regulatory Activities ("MedDRA"), current version.

(d) Draft IND Safety Reports. Preparation of draft IND safety reports (seven-day and fifteen-day reports) for Sponsor review, approval, and submission to the FDA.

(e) Signal Detection and Aggregate Analysis. Support for signal detection activities and aggregate safety analyses, including generation of periodic safety data listings, tabulations, and line listings for review by the Sponsor's medical monitor and the DSMB.

(f) Clinical Monitoring. Conduct of routine and for-cause clinical monitoring visits at each of the thirty-eight (38) Veridian Network sites to verify compliance with safety reporting procedures, as further described in Section 8.3 of these Safety Reporting Procedures.

(g) Coordination with Pinnacle Data Solutions, Inc. Coordination with Pinnacle Data Solutions, Inc. (headquarters: 6000 Clearwater Drive, San Diego, California 92121), the vendor responsible for the electronic data capture ("EDC") platform used in the CLARION trial, to ensure integration of safety data between the EDC system and the global safety database, including system validation, data reconciliation, and compliance with 21 C.F.R. Part 11.

(h) Coordination with Northbridge Bioanalytical Laboratories, Inc. Coordination with Northbridge Bioanalytical Laboratories, Inc. (central laboratory; headquarters: 2900 Commerce Way, Baltimore, Maryland 21224) for receipt and integration of safety laboratory data, including flagging of abnormal laboratory values that meet pre-specified criteria for investigator review and potential SAE reporting.

The delegation of the foregoing responsibilities to Meridian CRO does not relieve Penterra of its regulatory obligations as the IND holder. Penterra retains responsibility for oversight of all delegated functions and for all IND safety reporting submissions to the FDA.

3.3 Site Network (Veridian Health Research Network, Inc.)

Veridian Health Research Network, Inc. (central office: 750 Research Parkway, 8th Floor, Philadelphia, Pennsylvania 19104) serves as the site network organization coordinating the participation of thirty-eight (38) clinical trial sites in the CLARION trial. Veridian's responsibilities related to safety reporting include the following:

(a) Central Coordination. Central coordination of safety reporting activities across all participating sites within the Veridian Network, including dissemination of safety communications, IND safety reports, and protocol amendments to site personnel.

(b) Training and Compliance. Ensuring that each participating site has trained personnel capable of timely and accurate identification, documentation, and reporting of safety events in accordance with these Safety Reporting Procedures, the Protocol, and applicable regulatory requirements.

(c) Communication Hub. The Veridian central office serves as the primary communication hub for distribution of IND safety reports and safety-related communications from the Sponsor and Meridian CRO to Veridian Network sites. The Veridian central office will maintain records of distribution and acknowledgment of receipt by each site.

(d) Central Safety Contacts. The Vice President, Legal & Compliance, Gregory Callahan, Esq., and the Senior Vice President, Research Administration, Dr. Lena Marchetti, Ph.D., serve as the designated central safety contacts for the Veridian Network. All safety-related escalation communications from the Sponsor or Meridian CRO directed to the Veridian Network at the organizational level should be addressed to these individuals.

3.4 Principal Investigators and Site Staff

Each site principal investigator, including without limitation the Global Principal Investigator, Dr. Catherine Aldridge, M.D., Ph.D., at Graystone University Medical Center (Site 001, 1200 University Avenue, Philadelphia, Pennsylvania 19104), and the Co-Principal Investigator, Dr. Howard Matsuoka, M.D., at Lakemont Medical Center (Site 002, 4400 North Michigan Drive, Chicago, Illinois 60611), bears the following responsibilities with respect to safety reporting at his or her respective site:

(a) Identification and Documentation. Identifying, documenting, and recording all adverse events occurring in study subjects at the site, from the date of informed consent (for pre-treatment events, as required by the Protocol) and throughout the Study Treatment Period and the post-treatment follow-up period.

(b) Assessment. Determining the seriousness (serious or non-serious), severity (mild, moderate, or severe), and causality (relationship to study treatment: unrelated, unlikely, possibly, probably, or definitely related) of each adverse event, using clinical judgment and the guidance provided in the Protocol and the Investigator's Brochure.

(c) Timely Reporting. Reporting all SAEs to the Sponsor and Meridian CRO within the timelines specified in Section 4 of these Safety Reporting Procedures (i.e., within twenty-four (24) hours of the site's awareness of the SAE for initial reports, with follow-up reports within five (5) calendar days of receipt of new information).

(d) Source Documentation. Ensuring the completeness and accuracy of source documentation for all adverse events and serious adverse events, including medical records, laboratory reports, hospital records, discharge summaries, pathology reports, radiology reports, and any other relevant clinical documents.

(e) IRB Reporting. Reporting SAEs, SUSARs, IND safety reports, and unanticipated problems involving risks to subjects to the applicable Institutional Review Board in accordance with IRB policies and applicable regulations. For the Graystone University Medical Center site (Site 001), the applicable IRB is the Graystone University Institutional Review Board (IRB Registration: IRB00012847). For the Lakemont Medical Center site (Site 002) and other non-Pennsylvania Veridian sites, the applicable IRB is the Veridian Central IRB, unless otherwise specified under applicable IRB reliance or authorization agreements.

(f) Regulatory Compliance. Compliance with the obligations of Form FDA 1572 (Statement of Investigator) filed by each investigator in connection with IND 157823, including the obligation to report adverse experiences to the Sponsor. Compliance with 21 C.F.R. Part 54 financial disclosure requirements. Compliance with all applicable federal, state, and institutional requirements related to the protection of human subjects.

(g) Subject Safety. Maintaining the safety and well-being of study subjects as the paramount obligation. In the event that the investigator determines that an immediate deviation from the Protocol is necessary to protect the safety of a subject, the investigator must implement such deviation and promptly report it to the Sponsor, Meridian CRO, and the applicable IRB, documenting the circumstances and the actions taken.

Section 4: Site Reporting of Adverse Events and Serious Adverse Events

4.1 Adverse Event Reporting (Non-Serious)

All adverse events, whether or not considered by the investigator to be related to the investigational product (penterafenib) or placebo, must be identified, assessed, and recorded by the site investigator or designee. Non-serious adverse events must be entered into the electronic case report form ("eCRF") via the Pinnacle Data Solutions EDC platform within five (5) business days of the site's initial awareness of the event.

The documentation of each non-serious adverse event in the eCRF must include, at a minimum, the following information:

(a) Date of onset and date of resolution (or notation that the event is ongoing);

(b) Description of the event, including the specific diagnosis or signs and symptoms if a diagnosis has not been established;

(c) Severity, graded as mild (easily tolerated, causing minimal discomfort), moderate (sufficiently discomforting to interfere with usual activities), or severe (preventing normal daily activities);

(d) Relationship to study treatment, assessed by the investigator as: unrelated, unlikely related, possibly related, probably related, or definitely related;

(e) Action taken with study drug (none, dose reduced, dose interrupted, drug permanently discontinued, not applicable);

(f) Treatment or corrective action taken for the adverse event;

(g) Outcome (recovered/resolved, recovering/resolving, not recovered/not resolved, recovered with sequelae, fatal, unknown); and

(h) Whether the event meets the criteria for an adverse event of special interest as defined in the Protocol.

4.2 Serious Adverse Event Reporting — Initial Report

Sites must report all SAEs to the Sponsor (Penterra) and Meridian CRO within twenty-four (24) hours of the site becoming aware of the event. The twenty-four (24)-hour reporting clock begins at the moment any qualified site personnel (investigator, sub-investigator, clinical research coordinator, or study nurse) first becomes aware that the event meets the criteria for a serious adverse event, regardless of the day of the week or time of day.

The initial SAE report must be submitted via the designated SAE reporting form, using one of the following methods:

(a) Preferred method: Electronic submission through the Pinnacle EDC SAE module;

(b) Backup method (in the event of EDC system unavailability): Submission of a completed SAE reporting form by fax or encrypted email to the Meridian CRO Safety Department, using the contact information set forth in the Study Reference Manual (see Section 13 of these Safety Reporting Procedures).

The initial SAE report must include, at a minimum, the following information:

(a) Subject identification number (as assigned in the EDC system);

(b) Site number and institution name;

(d) Date the site became aware of the event;

(e) Description of the event, including the specific diagnosis or signs and symptoms;

(f) Seriousness criteria met (death, life-threatening, hospitalization or prolongation of hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, other medically important event);

(g) Severity (mild, moderate, or severe);

(h) Investigator's assessment of causality (relationship to study treatment);

(i) Current status of the subject at the time of the report;

(j) Any immediate actions taken, including actions taken with the study drug and any emergency treatment administered; and

(k) Investigator name and signature (electronic signature is acceptable for submissions via the Pinnacle EDC SAE module).

If complete information is not available within the twenty-four (24)-hour reporting window, the site must nonetheless submit the initial report with all information available at that time and clearly indicate that the report is preliminary and that follow-up information will be provided. Incomplete information does not excuse or delay submission of the initial report.

4.3 Serious Adverse Event Reporting — Follow-Up Reports

Follow-up SAE reports must be submitted within five (5) calendar days of receipt of new or updated information regarding a previously reported SAE. Each follow-up report must include all previously reported information, updated and supplemented with newly available findings, including but not limited to:

(a) Updated clinical status of the subject;

(b) Relevant laboratory data, including results from Northbridge Bioanalytical Laboratories (central laboratory) and local laboratory results, as applicable;

(d) Pathology reports and biopsy results;

(e) Autopsy findings, if applicable;

(f) Hospital discharge summaries;

(g) Consultant reports and subspecialty evaluations;

(h) Updated concomitant medication information;

(i) Updated investigator assessment of causality, if the assessment has changed based on new information;

(j) Final outcome of the event (recovered/resolved, recovered with sequelae, not recovered, ongoing, fatal); and

(k) Any revised diagnosis, if the initial report was based on symptoms only and a definitive diagnosis has since been established.

Follow-up reports must continue to be submitted as new information becomes available until the event is resolved, has stabilized (i.e., no further change in status is expected), or the subject has been lost to follow-up. Each follow-up report must clearly reference the initial SAE report and include the date of the initial report and the subject identification number.

4.4 Reporting of Deaths

Any death occurring during the study or within thirty (30) calendar days of the last dose of study treatment (investigational product or placebo) must be reported as a serious adverse event within twenty-four (24) hours of the site's awareness, using the SAE reporting procedures described in Section 4.2 above.

In addition to the standard SAE reporting requirements, the investigator must provide the following information as soon as it becomes available:

(a) A death narrative, describing the circumstances leading to the subject's death, including the clinical course, treatments administered, and temporal relationship to study drug administration;

(b) The cause of death, as determined by the investigator or as documented on the death certificate;

(c) Autopsy results, if an autopsy was performed (the investigator should make reasonable efforts to obtain autopsy results when available); and

(d) The investigator's assessment of the relationship of the death to the investigational product, placebo, and/or the underlying disease or condition under study.

Deaths occurring more than thirty (30) calendar days after the last dose of study treatment that the investigator believes are reasonably possibly related to the investigational product must also be reported as SAEs within twenty-four (24) hours of the site's awareness, using the same procedures.

4.5 Pregnancy Reports

Any pregnancy occurring in a female study subject or in the female partner of a male study subject during the study (from the date of first dose through thirty (30) calendar days after the last dose, or during the follow-up period if specified by the Protocol) must be reported to the Sponsor and Meridian CRO within twenty-four (24) hours of the site's awareness, using the designated pregnancy reporting form provided in the Study Reference Manual.

Pregnancies are not themselves classified as adverse events; however, each pregnancy must be followed to outcome (including live birth, spontaneous abortion, elective termination, stillbirth, or ectopic pregnancy). Any adverse pregnancy outcome, including but not limited to spontaneous abortion, stillbirth, congenital anomaly, or neonatal complications, must be reported as a serious adverse event in accordance with the procedures set forth in Section 4.2 of these Safety Reporting Procedures. Study drug must be immediately discontinued upon confirmation of pregnancy in a female study subject, and the investigator must consult with the Sponsor's medical monitor regarding any additional safety measures.

4.6 Adverse Events of Special Interest (AESIs)

Protocol PPC-4871-III designates certain categories of adverse events as adverse events of special interest ("AESIs") based on the known or suspected pharmacological profile of penterafenib and the safety signals identified in earlier clinical development. The following events are designated as AESIs for the CLARION trial:

(a) Hepatotoxicity (including elevated transaminases, drug-induced liver injury, hepatic failure);

(b) QTc prolongation (including clinically significant changes from baseline in the QTcF interval);

(c) Severe dermatologic reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [DRESS]);

(d) Thromboembolic events (including deep vein thrombosis, pulmonary embolism, arterial thrombosis); and

(e) Such other events as may be designated by the Sponsor from time to time through protocol amendment or safety letter.

All AESIs must be reported to the Sponsor and Meridian CRO within twenty-four (24) hours of the site's awareness, regardless of whether the event meets the criteria for a serious adverse event. AESIs that do not meet SAE criteria must nonetheless be reported using the SAE reporting pathway (i.e., through the Pinnacle EDC SAE module or the backup fax/encrypted email method described in Section 4.2). This enhanced reporting requirement ensures that the Sponsor can evaluate potential safety signals in real time, even for events that might not individually satisfy seriousness criteria.

Section 5: Sponsor IND Safety Reporting to the FDA

5.1 Seven (7)-Day Reports — Fatal or Life-Threatening SUSARs

In accordance with 21 C.F.R. § 312.32(c)(2), the Sponsor (Penterra) must report to the FDA any SUSAR that is fatal or life-threatening within seven (7) calendar days of the Sponsor's initial receipt of the information. For purposes of this requirement, the date of "initial receipt" is the date on which the Sponsor (or Meridian CRO, as the Sponsor's delegated agent for safety data processing) first receives information sufficient to identify the event as a SUSAR that is fatal or life-threatening.

The seven (7)-day report must be submitted to the FDA via FDA Form 3500A (MedWatch Adverse Event Report) or through the FDA Safety Reporting Portal (electronic submission), as applicable. The initial seven (7)-day report may be submitted with incomplete information if a complete report cannot be assembled within the reporting timeframe; however, the Sponsor must submit a follow-up report within eight (8) additional calendar days (i.e., within a total of fifteen (15) calendar days from the date of initial receipt of the information), providing all available updated and supplementary information.

The Sponsor's medical monitor, Dr. Marcus Yun, M.D., M.P.H., or designee, will review each potentially qualifying event and confirm the classification as a SUSAR that is fatal or life-threatening before submission of the seven (7)-day report, provided that such review does not delay submission beyond the regulatory deadline.

5.2 Fifteen (15)-Day Reports — All Other IND Safety Reports

In accordance with 21 C.F.R. § 312.32(c)(1), the Sponsor (Penterra) must report to the FDA all other reportable safety findings within fifteen (15) calendar days of the Sponsor's initial receipt of the information. Reportable safety findings subject to fifteen (15)-day reporting include, without limitation:

(a) Any SUSAR that does not qualify for seven (7)-day reporting (i.e., SUSARs that are not fatal or life-threatening);

(b) Any finding from clinical trials, epidemiological studies, or pooled analyses of multiple studies that suggests a significant risk to human subjects exposed to the investigational product, including any clinically meaningful change in the benefit-risk profile of penterafenib;

(c) Any clinically important increase in the rate of a known serious suspected adverse reaction over the rate previously identified in the Investigator's Brochure or in prior IND safety reports; and

(d) Any finding from animal or in vitro testing that suggests a significant risk to human subjects, including reports of mutagenicity, teratogenicity, carcinogenicity, or significant organ toxicity at clinically relevant exposure levels.

All fifteen (15)-day reports must be submitted to the FDA via FDA Form 3500A (MedWatch) or through the FDA Safety Reporting Portal, in the format required by applicable FDA guidance. Each report must include a narrative assessment of the clinical significance of the finding and the Sponsor's assessment of the impact, if any, on the ongoing conduct of the CLARION trial.

5.3 Annual IND Safety Reports

Penterra will prepare and submit annual IND safety reports ("IND Annual Reports") to the FDA in accordance with 21 C.F.R. § 312.33, summarizing all IND safety information accumulated during each reporting period. The IND Annual Report will include, without limitation:

(a) A narrative summary of the most significant safety findings during the reporting period, including any new safety signals identified;

(b) Individual case narratives for all SUSARs reported to the FDA during the reporting period;

(c) Tabulations and summary tables of all SAEs and SUSARs, organized by System Organ Class (SOC) and Preferred Term (PT) per MedDRA coding conventions;

(d) Aggregate safety analyses, including incidence rates, exposure-adjusted rates, and comparisons between treatment arms, as appropriate;

(e) A description of any actions taken during the reporting period for safety reasons, including dose modifications, protocol amendments, changes to the informed consent form, trial suspension, or early termination of any study under the IND; and

(f) An updated benefit-risk assessment for penterafenib, including any new information from preclinical studies, published literature, or post-marketing experience (if applicable) that is relevant to the safety profile of the investigational product.

5.4 Distribution of IND Safety Reports to Investigators

All IND safety reports submitted to the FDA by Penterra (including seven (7)-day reports, fifteen (15)-day reports, and follow-up reports) must be distributed to all participating investigators at the thirty-eight (38) Veridian Network sites within the timelines required by 21 C.F.R. § 312.32(c)(1)(iii) and (c)(2). Specifically:

(a) For seven (7)-day reports: distribution to all investigators concurrently with or promptly after submission to the FDA;

(b) For fifteen (15)-day reports: distribution to all investigators within the fifteen (15)-calendar-day reporting timeframe or promptly thereafter.

Distribution will be coordinated through Meridian CRO and the Veridian central office (750 Research Parkway, 8th Floor, Philadelphia, Pennsylvania 19104). Meridian CRO will transmit IND safety reports to the Veridian central office, which will in turn distribute the reports to all network sites and confirm receipt. Alternatively, Meridian CRO may distribute reports directly to individual site investigators with simultaneous notification to the Veridian central office.

Upon receipt of an IND safety report, each principal investigator must promptly review the report and assess whether the information affects the benefit-risk profile for subjects enrolled at the investigator's site. Each investigator must submit the IND safety report to the applicable IRB — the Graystone University Institutional Review Board (IRB Registration: IRB00012847) for the Graystone University Medical Center site (Site 001), or the Veridian Central IRB for non-Pennsylvania sites — in accordance with IRB policies and the requirements of 21 C.F.R. Part 56 and ICH E6(R2).

Section 6: IRB Notification and Reporting

6.1 Site IRB Reporting Obligations

Each principal investigator participating in the CLARION trial must report SAEs, SUSARs, IND safety reports, and any other safety information requiring IRB notification to the applicable Institutional Review Board in a timely manner, in accordance with:

(a) The policies and procedures of the applicable IRB;

(b) 21 C.F.R. § 56.108(b), which requires IRBs to have procedures for ensuring prompt reporting of changes in research activities and unanticipated problems;

(c) 21 C.F.R. § 312.66, which requires investigators to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others;

(d) ICH E6(R2) GCP Guidelines, Section 4.11, which requires the investigator to report to the IRB/IEC all SAEs that are both serious and unexpected, and any findings that could adversely affect the safety of subjects.

The IRB reporting structure for the CLARION trial is as follows:

(a) Graystone University Medical Center (Site 001): The applicable IRB is the Graystone University Institutional Review Board (IRB Registration Number: IRB00012847; Office of Human Research Protections [OHRP] assurance: FWA00018293). Dr. Catherine Aldridge, M.D., Ph.D., as the Global Principal Investigator and the site principal investigator, is responsible for all IRB submissions and communications with the Graystone University IRB for this site.

(b) Lakemont Medical Center (Site 002) and other non-Pennsylvania Veridian sites: The applicable IRB is the Veridian Central IRB, which serves as the IRB of record pursuant to applicable IRB reliance agreements and IRB authorization agreements executed between Veridian Central IRB and each participating institution. Dr. Howard Matsuoka, M.D., as the Co-Principal Investigator at Site 002, is responsible for ensuring compliance with Veridian Central IRB requirements at the Lakemont site.

(c) Lead sites (Graystone University Medical Center and Lakemont Medical Center): These lead sites require individual IRB approval from their respective institutional IRBs (Graystone University IRB for Site 001; Veridian Central IRB or the local institutional IRB for Site 002, as applicable under the relevant reliance agreement). All remaining Veridian Network sites may rely on the Veridian Central IRB under executed IRB Authorization Agreements, unless a participating institution requires use of its own institutional IRB, in which case the site-specific agreement will specify the applicable IRB.

Each investigator must retain copies of all IRB correspondence, submissions, and approvals related to safety reporting in the site's investigator site file.

6.2 Unanticipated Problems Involving Risks to Subjects

Any event, incident, experience, or outcome that meets the definition of an "unanticipated problem involving risk to subjects or others" as set forth in 45 C.F.R. § 46.108(a)(4) and applicable FDA guidance must be reported by the investigator to the applicable IRB and to the Sponsor (Penterra) and Meridian CRO within the timeframes specified by the IRB's policies and applicable federal regulations.

An "unanticipated problem involving risk to subjects or others" generally includes any incident, experience, or outcome that meets all of the following criteria: (i) is unexpected (in terms of nature, severity, or frequency) given the procedures described in the Protocol and the characteristics of the study population; (ii) is related or possibly related to participation in the research; and (iii) suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

Reporting of unanticipated problems to the IRB typically must occur within the timeframes specified in the IRB's policies, which in most cases require notification within five (5) to ten (10) business days, or sooner for events that are also SAEs. The investigator must also report such events to Meridian CRO through the standard SAE reporting pathway if the event qualifies as an SAE, or through a separate report to the Meridian CRO Safety Department if the unanticipated problem does not otherwise meet SAE criteria.

Section 7: Data Management and Safety Database

7.1 Global Safety Database

Penterra maintains a global safety database for penterafenib (PPC-4871) under IND 157823 (the "Global Safety Database"). The Global Safety Database aggregates safety data from all clinical studies conducted under the IND, including the CLARION trial and any other ongoing or completed studies involving penterafenib. The Global Safety Database is the authoritative repository for all individual case safety reports ("ICSRs") related to penterafenib.

Meridian CRO is responsible for data entry, medical coding (using MedDRA, current version), quality control, and day-to-day database maintenance under the Master Services Agreement dated January 15, 2023. All SAE data received from the thirty-eight (38) Veridian Network sites will be entered into the Global Safety Database within one (1) business day of receipt by the Meridian CRO Safety Department. Meridian CRO must perform quality control review of each database entry, including verification of medical coding accuracy, completeness of data fields, and consistency with source documentation.

Penterra retains oversight of the Global Safety Database and reserves the right to audit database entries, query resolution timelines, and quality metrics at any time. Penterra's pharmacovigilance team will conduct periodic reviews of the Global Safety Database to support signal detection activities, aggregate safety analyses, and regulatory reporting obligations.

7.2 Electronic Data Capture Integration

SAE data entered by site personnel via the Pinnacle Data Solutions EDC platform will be interfaced with the Global Safety Database maintained by Meridian CRO through validated electronic data transfer mechanisms. The integration between the Pinnacle EDC system and the Global Safety Database must be validated to ensure accurate, complete, and timely transfer of safety data.

System validation and data reconciliation procedures must be established and documented, and must include the following:

(a) Validation of the electronic interface between the Pinnacle EDC system and the Global Safety Database, including verification that all required data fields are accurately mapped and transferred;

(b) Periodic reconciliation of SAE records between the EDC system and the Global Safety Database, performed at a frequency of no less than monthly, to identify and resolve any discrepancies;

(c) Audit trails for all safety data entries, modifications, and deletions in both the EDC system and the Global Safety Database; and

(d) Backup and disaster recovery procedures for both systems to prevent data loss.

All electronic safety data systems used in connection with the CLARION trial must comply with 21 C.F.R. Part 11 requirements for electronic records and electronic signatures, including requirements for system validation, access controls, audit trails, and data integrity.

EXHIBIT J
SAFETY REPORTING PROCEDURES
Attached to and forming part of the Master Clinical Trial Agreement dated June 28, 2023 (the "MCTA")
by and between
PENTERRA PHARMACEUTICALS CORP. ("Sponsor" or "Penterra")
and
VERIDIAN HEALTH RESEARCH NETWORK, INC. ("Veridian" or "Site Network")
Protocol: PPC-4871-III CLARION — Clinical Assessment of Response with Longitudinal Investigation in ONcology
Investigational Product: Penterafenib (PPC-4871)
IND Number: IND 157823
ClinicalTrials.gov Identifier: NCT05928174
Sponsor's Contract Research Organization: Meridian Contract Research Organization, Inc. ("Meridian CRO")
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Section 1: Purpose and Scope
1.1 This Exhibit J (these "Safety Reporting Procedures") sets forth the procedures applicable to the identification, documentation, assessment, reporting, and follow-up of adverse events, serious adverse events, and other safety information arising during the conduct of the Phase III clinical trial conducted under Protocol PPC-4871-III, known as the CLARION trial (Clinical Assessment of Response with Longitudinal Investigation in ONcology), evaluating the investigational product penterafenib (PPC-4871). These Safety Reporting Procedures apply to all thirty-eight (38) Veridian Health Research Network participating clinical sites located across fourteen (14) states in the United States.
1.2 The purpose of these Safety Reporting Procedures is to ensure timely, accurate, and regulatory-compliant reporting of all adverse events ("AEs"), serious adverse events ("SAEs"), suspected unexpected serious adverse reactions ("SUSARs"), adverse events of special interest ("AESIs"), pregnancies, deaths, and other safety information arising in subjects enrolled in the CLARION trial, so as to protect the safety and well-being of trial subjects and to satisfy the obligations of the Sponsor, the Site Network, and each participating investigator under applicable federal regulations and international guidelines.
1.3 These Safety Reporting Procedures apply to all principal investigators, sub-investigators, clinical research coordinators, study nurses, pharmacists, and other site staff at each participating institution within the Veridian Network who are involved in any aspect of the identification, assessment, documentation, or reporting of safety information in connection with the CLARION trial. Compliance with these procedures is a material obligation of each participating site and its personnel under the MCTA and applicable site-specific agreements.
1.4 These Safety Reporting Procedures supplement, and are intended to be read in conjunction with, the safety reporting provisions contained in Protocol PPC-4871-III (including all appendices and amendments thereto) and the Investigator's Brochure for penterafenib (PPC-4871), as updated from time to time. In the event of any perceived inconsistency between these Safety Reporting Procedures and the Protocol, the Protocol shall govern unless applicable law or regulation requires otherwise. These Safety Reporting Procedures do not replace the safety provisions contained in the Protocol or the Investigator's Brochure.
1.5 These Safety Reporting Procedures have been developed in accordance with, and are governed by, the following regulatory framework:
(a) Title 21, Code of Federal Regulations, Part 312 — Investigational New Drug Application (IND regulations);
(b) Title 21, Code of Federal Regulations, Section 312.32 — IND Safety Reporting;
(c) Title 21, Code of Federal Regulations, Part 50 — Protection of Human Subjects;
(d) Title 21, Code of Federal Regulations, Part 56 — Institutional Review Boards;
(e) Title 21, Code of Federal Regulations, Part 11 — Electronic Records; Electronic Signatures;
(f) Title 45, Code of Federal Regulations, Part 46 — Protection of Human Subjects (Common Rule);
(g) The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ("ICH") Guideline E6(R2) — Guideline for Good Clinical Practice; and
(h) ICH Guideline E2A — Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.
1.6 Penterra Pharmaceuticals Corp. is the holder of IND 157823, filed with the United States Food and Drug Administration ("FDA") for penterafenib (PPC-4871), and bears ultimate responsibility for all IND safety reporting obligations to the FDA arising from the conduct of the CLARION trial and all other clinical studies conducted under IND 157823.
1.7 Meridian Contract Research Organization, Inc. ("Meridian CRO") serves as the Sponsor's contract research organization for the CLARION trial pursuant to the Master Services Agreement dated January 15, 2023, between Penterra and Meridian CRO (the "MSA"). Under the MSA, Meridian CRO has been delegated certain responsibilities related to clinical monitoring, data management, safety reporting processing, pharmacovigilance support, and biostatistics, as further described in Section 3.2 of these Safety Reporting Procedures. The delegation of such responsibilities to Meridian CRO does not relieve Penterra of its regulatory responsibilities as the IND holder.
Section 2: Definitions
For purposes of these Safety Reporting Procedures, the following terms shall have the meanings set forth below. Capitalized terms not defined in this Section 2 shall have the meanings ascribed to them in the MCTA or, if not defined therein, in Protocol PPC-4871-III.
2.1 Adverse Event ("AE"). Any untoward medical occurrence in a clinical trial subject who has been administered the investigational product (penterafenib / PPC-4871) or placebo, whether or not considered by the investigator to be causally related to the study treatment. An adverse event can therefore be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of the investigational product or placebo, without any judgment about causation. An adverse event includes, without limitation, any clinically significant worsening of a pre-existing condition, any intercurrent illness, any drug interaction, and any abnormal laboratory value or diagnostic test result that the investigator considers clinically significant.
2.2 Serious Adverse Event ("SAE"). An adverse event occurring at any dose of the investigational product or placebo that results in any of the following outcomes:
(a) Death;
(b) A life-threatening event (i.e., an event that, in the view of the investigator, places the subject at immediate risk of death at the time of the event; it does not refer to an event that hypothetically might have caused death if it were more severe);
(c) Inpatient hospitalization or prolongation of existing hospitalization (excluding hospitalizations planned before informed consent was signed or hospitalizations for elective procedures not related to worsening of an underlying condition);
(d) Persistent or significant disability or incapacity (i.e., a substantial disruption of the subject's ability to conduct normal life functions);
(e) A congenital anomaly or birth defect in the offspring of a study subject; or
(f) Any other medically important event or condition that, in the judgment of the investigator, may jeopardize the subject or may require medical or surgical intervention to prevent one of the outcomes listed in (a) through (e) above.
The definition of "serious adverse event" set forth herein is consistent with the definitions in 21 C.F.R. § 312.32(a) and ICH Guideline E2A. The determination of whether an event is "serious" is distinct from the assessment of "severity" (mild, moderate, or severe), which describes the intensity of the event.
2.3 Suspected Adverse Reaction. An adverse event for which there is a reasonable possibility that the investigational product (penterafenib) caused the adverse event. "Reasonable possibility" means that there is evidence to suggest a causal relationship between the investigational product and the adverse event; it does not require certainty of causation. A suspected adverse reaction implies a lesser degree of certainty about causality than the term "adverse reaction," which denotes a known causal relationship.
2.4 Unexpected Adverse Event. An adverse event, the nature, severity, or frequency of which is not consistent with information contained in the current version of the Investigator's Brochure for penterafenib (PPC-4871). For purposes of this definition, an adverse event is considered "unexpected" if: (a) the event is not listed in the Investigator's Brochure; (b) the event is listed in the Investigator's Brochure but occurs at a greater severity or frequency than described therein; or (c) the event manifests in a clinically distinct presentation not described in the Investigator's Brochure.
2.5 Suspected Unexpected Serious Adverse Reaction ("SUSAR"). A serious adverse event that is both: (a) suspected to be related to the investigational product (penterafenib) (i.e., meets the definition of a suspected adverse reaction); and (b) unexpected, as defined in Section 2.4 above (i.e., not listed in nature, severity, or frequency in the current version of the Investigator's Brochure). SUSARs are subject to expedited IND safety reporting by the Sponsor to the FDA under 21 C.F.R. § 312.32.
2.6 IND Safety Report. A report submitted by the Sponsor (Penterra) to the FDA and to all participating investigators under 21 C.F.R. § 312.32, notifying them of safety findings that require expedited reporting. IND Safety Reports may include reports of SUSARs (both fatal/life-threatening and non-fatal/non-life-threatening), findings from epidemiological or pooled analyses suggesting significant risks, clinically important increases in the rate of a known serious suspected adverse reaction, and findings from animal or in vitro testing suggesting a significant risk to human subjects.
2.7 Protocol Deviation. Any departure from the approved Protocol PPC-4871-III that is not prospectively authorized by the Sponsor or required to eliminate an apparent immediate hazard to the subject. Protocol deviations include, without limitation, deviations from inclusion or exclusion criteria, dosing schedules, visit windows, required assessments, and safety monitoring procedures. As used herein, the term "protocol deviation" encompasses both minor deviations and major deviations (i.e., those that may significantly affect the completeness, accuracy, or reliability of the study data, or the rights, safety, or well-being of the subjects). For the avoidance of doubt, medically necessary protocol deviations implemented by the investigator to protect the immediate safety of a subject are permitted and must be documented and reported promptly to the Sponsor, Meridian CRO, and the applicable IRB, as further described in Section 9 of the MCTA.
2.8 Study Treatment Period. The period commencing on the date of the first dose of investigational product (penterafenib) or placebo administered to a given study subject and continuing through thirty (30) calendar days after the last dose of investigational product or placebo, or such longer period as may be required by the Protocol for safety follow-up. As set forth in Protocol PPC-4871-III, the total anticipated study duration is approximately sixty (60) months, comprising an estimated forty-two (42)-month enrollment period and an eighteen (18)-month follow-up period. Safety reporting obligations as set forth in these Safety Reporting Procedures apply throughout the Study Treatment Period and, where specified in the Protocol, during the post-treatment follow-up period.
Section 3: Roles and Responsibilities
3.1 Sponsor (Penterra Pharmaceuticals Corp.)
Penterra, as the holder of IND 157823, bears overall responsibility for IND safety reporting and pharmacovigilance for the investigational product penterafenib (PPC-4871) across all clinical studies conducted under the IND, including the CLARION trial. Penterra's safety reporting responsibilities include, without limitation, the following:
(a) IND Safety Reporting to the FDA. Submission of all IND safety reports to the FDA in accordance with the timelines and requirements of 21 C.F.R. § 312.32, including seven (7)-calendar-day reports for fatal or life-threatening SUSARs and fifteen (15)-calendar-day reports for all other reportable safety findings, as further described in Section 5 of these Safety Reporting Procedures.
(b) Distribution of IND Safety Reports. Distribution of all IND safety reports submitted to the FDA to all participating investigators at the thirty-eight (38) Veridian Network sites, coordinated through Meridian CRO and the Veridian central office, within the timelines required by 21 C.F.R. § 312.32(c)(1)(iii) and (c)(2).
(c) Global Safety Database. Maintenance and oversight of a global safety database for penterafenib, which aggregates safety data from all clinical studies conducted under IND 157823, including the CLARION trial and any other ongoing or completed studies.
(d) Aggregate Safety Analysis. Review and assessment of aggregate safety data on a periodic basis, including signal detection activities, periodic safety analyses, and preparation of annual IND safety reports under 21 C.F.R. § 312.33.
(e) Medical Safety Oversight. Coordination with the Penterra Chief Medical Officer, Dr. Elaine Whitford, M.D., and the Senior Vice President, Clinical Development, Dr. Marcus Yun, M.D., M.P.H., for all medical safety decisions, including causality assessment at the Sponsor level, benefit-risk evaluation, decisions regarding dose modifications or protocol amendments for safety, and communications with the Data Safety Monitoring Board.
(f) Oversight of Meridian CRO. Oversight and supervision of Meridian CRO's delegated safety data management and pharmacovigilance functions, including periodic audits and review of quality metrics related to safety data processing.
(g) Notification of Regulatory Actions. Notification to the Veridian central office, specifically the Senior Vice President, Research Administration, Dr. Lena Marchetti, Ph.D., and to all participating investigators, of any regulatory action, clinical hold, or safety-related protocol amendment affecting the CLARION trial, within twenty-four (24) hours of the Sponsor's receipt of such information from the FDA or other regulatory authority.
3.2 Contract Research Organization (Meridian CRO)
Meridian Contract Research Organization, Inc. (headquarters: 9200 Corporate Boulevard, Raleigh, North Carolina 27615; Chief Executive Officer: Thomas Hartwell) serves as the Sponsor's contract research organization for the CLARION trial. Under the Master Services Agreement dated January 15, 2023, between Penterra and Meridian CRO, Meridian CRO has been delegated the following responsibilities related to safety reporting and pharmacovigilance:
(a) Receipt and Processing of SAE Reports. Receipt of all initial and follow-up SAE reports from the thirty-eight (38) Veridian Network sites, including quality review for completeness, accuracy, and consistency with source documentation.
(b) Data Entry into Global Safety Database. Entry of all SAE data into the global safety database within one (1) business day of receipt by the Meridian CRO Safety Department, as further described in Section 7.1 of these Safety Reporting Procedures.
(c) Medical Coding. Medical coding of all adverse events and serious adverse events using the Medical Dictionary for Regulatory Activities ("MedDRA"), current version.
(d) Draft IND Safety Reports. Preparation of draft IND safety reports (seven-day and fifteen-day reports) for Sponsor review, approval, and submission to the FDA.
(e) Signal Detection and Aggregate Analysis. Support for signal detection activities and aggregate safety analyses, including generation of periodic safety data listings, tabulations, and line listings for review by the Sponsor's medical monitor and the DSMB.
(f) Clinical Monitoring. Conduct of routine and for-cause clinical monitoring visits at each of the thirty-eight (38) Veridian Network sites to verify compliance with safety reporting procedures, as further described in Section 8.3 of these Safety Reporting Procedures.
(g) Coordination with Pinnacle Data Solutions, Inc. Coordination with Pinnacle Data Solutions, Inc. (headquarters: 6000 Clearwater Drive, San Diego, California 92121), the vendor responsible for the electronic data capture ("EDC") platform used in the CLARION trial, to ensure integration of safety data between the EDC system and the global safety database, including system validation, data reconciliation, and compliance with 21 C.F.R. Part 11.
(h) Coordination with Northbridge Bioanalytical Laboratories, Inc. Coordination with Northbridge Bioanalytical Laboratories, Inc. (central laboratory; headquarters: 2900 Commerce Way, Baltimore, Maryland 21224) for receipt and integration of safety laboratory data, including flagging of abnormal laboratory values that meet pre-specified criteria for investigator review and potential SAE reporting.
The delegation of the foregoing responsibilities to Meridian CRO does not relieve Penterra of its regulatory obligations as the IND holder. Penterra retains responsibility for oversight of all delegated functions and for all IND safety reporting submissions to the FDA.
3.3 Site Network (Veridian Health Research Network, Inc.)
Veridian Health Research Network, Inc. (central office: 750 Research Parkway, 8th Floor, Philadelphia, Pennsylvania 19104) serves as the site network organization coordinating the participation of thirty-eight (38) clinical trial sites in the CLARION trial. Veridian's responsibilities related to safety reporting include the following:
(a) Central Coordination. Central coordination of safety reporting activities across all participating sites within the Veridian Network, including dissemination of safety communications, IND safety reports, and protocol amendments to site personnel.
(b) Training and Compliance. Ensuring that each participating site has trained personnel capable of timely and accurate identification, documentation, and reporting of safety events in accordance with these Safety Reporting Procedures, the Protocol, and applicable regulatory requirements.
(c) Communication Hub. The Veridian central office serves as the primary communication hub for distribution of IND safety reports and safety-related communications from the Sponsor and Meridian CRO to Veridian Network sites. The Veridian central office will maintain records of distribution and acknowledgment of receipt by each site.
(d) Central Safety Contacts. The Vice President, Legal & Compliance, Gregory Callahan, Esq., and the Senior Vice President, Research Administration, Dr. Lena Marchetti, Ph.D., serve as the designated central safety contacts for the Veridian Network. All safety-related escalation communications from the Sponsor or Meridian CRO directed to the Veridian Network at the organizational level should be addressed to these individuals.
3.4 Principal Investigators and Site Staff
Each site principal investigator, including without limitation the Global Principal Investigator, Dr. Catherine Aldridge, M.D., Ph.D., at Graystone University Medical Center (Site 001, 1200 University Avenue, Philadelphia, Pennsylvania 19104), and the Co-Principal Investigator, Dr. Howard Matsuoka, M.D., at Lakemont Medical Center (Site 002, 4400 North Michigan Drive, Chicago, Illinois 60611), bears the following responsibilities with respect to safety reporting at his or her respective site:
(a) Identification and Documentation. Identifying, documenting, and recording all adverse events occurring in study subjects at the site, from the date of informed consent (for pre-treatment events, as required by the Protocol) and throughout the Study Treatment Period and the post-treatment follow-up period.
(b) Assessment. Determining the seriousness (serious or non-serious), severity (mild, moderate, or severe), and causality (relationship to study treatment: unrelated, unlikely, possibly, probably, or definitely related) of each adverse event, using clinical judgment and the guidance provided in the Protocol and the Investigator's Brochure.
(c) Timely Reporting. Reporting all SAEs to the Sponsor and Meridian CRO within the timelines specified in Section 4 of these Safety Reporting Procedures (i.e., within twenty-four (24) hours of the site's awareness of the SAE for initial reports, with follow-up reports within five (5) calendar days of receipt of new information).
(d) Source Documentation. Ensuring the completeness and accuracy of source documentation for all adverse events and serious adverse events, including medical records, laboratory reports, hospital records, discharge summaries, pathology reports, radiology reports, and any other relevant clinical documents.
(e) IRB Reporting. Reporting SAEs, SUSARs, IND safety reports, and unanticipated problems involving risks to subjects to the applicable Institutional Review Board in accordance with IRB policies and applicable regulations. For the Graystone University Medical Center site (Site 001), the applicable IRB is the Graystone University Institutional Review Board (IRB Registration: IRB00012847). For the Lakemont Medical Center site (Site 002) and other non-Pennsylvania Veridian sites, the applicable IRB is the Veridian Central IRB, unless otherwise specified under applicable IRB reliance or authorization agreements.
(f) Regulatory Compliance. Compliance with the obligations of Form FDA 1572 (Statement of Investigator) filed by each investigator in connection with IND 157823, including the obligation to report adverse experiences to the Sponsor. Compliance with 21 C.F.R. Part 54 financial disclosure requirements. Compliance with all applicable federal, state, and institutional requirements related to the protection of human subjects.
(g) Subject Safety. Maintaining the safety and well-being of study subjects as the paramount obligation. In the event that the investigator determines that an immediate deviation from the Protocol is necessary to protect the safety of a subject, the investigator must implement such deviation and promptly report it to the Sponsor, Meridian CRO, and the applicable IRB, documenting the circumstances and the actions taken.
Section 4: Site Reporting of Adverse Events and Serious Adverse Events
4.1 Adverse Event Reporting (Non-Serious)
All adverse events, whether or not considered by the investigator to be related to the investigational product (penterafenib) or placebo, must be identified, assessed, and recorded by the site investigator or designee. Non-serious adverse events must be entered into the electronic case report form ("eCRF") via the Pinnacle Data Solutions EDC platform within five (5) business days of the site's initial awareness of the event.
The documentation of each non-serious adverse event in the eCRF must include, at a minimum, the following information:
(a) Date of onset and date of resolution (or notation that the event is ongoing);
(b) Description of the event, including the specific diagnosis or signs and symptoms if a diagnosis has not been established;
(c) Severity, graded as mild (easily tolerated, causing minimal discomfort), moderate (sufficiently discomforting to interfere with usual activities), or severe (preventing normal daily activities);
(d) Relationship to study treatment, assessed by the investigator as: unrelated, unlikely related, possibly related, probably related, or definitely related;
(e) Action taken with study drug (none, dose reduced, dose interrupted, drug permanently discontinued, not applicable);
(f) Treatment or corrective action taken for the adverse event;
(g) Outcome (recovered/resolved, recovering/resolving, not recovered/not resolved, recovered with sequelae, fatal, unknown); and
(h) Whether the event meets the criteria for an adverse event of special interest as defined in the Protocol.
4.2 Serious Adverse Event Reporting — Initial Report
Sites must report all SAEs to the Sponsor (Penterra) and Meridian CRO within twenty-four (24) hours of the site becoming aware of the event. The twenty-four (24)-hour reporting clock begins at the moment any qualified site personnel (investigator, sub-investigator, clinical research coordinator, or study nurse) first becomes aware that the event meets the criteria for a serious adverse event, regardless of the day of the week or time of day.
The initial SAE report must be submitted via the designated SAE reporting form, using one of the following methods:
(a) Preferred method: Electronic submission through the Pinnacle EDC SAE module;
(b) Backup method (in the event of EDC system unavailability): Submission of a completed SAE reporting form by fax or encrypted email to the Meridian CRO Safety Department, using the contact information set forth in the Study Reference Manual (see Section 13 of these Safety Reporting Procedures).
The initial SAE report must include, at a minimum, the following information:
(a) Subject identification number (as assigned in the EDC system);
(b) Site number and institution name;
(c) Date of onset of the serious adverse event;
(d) Date the site became aware of the event;
(e) Description of the event, including the specific diagnosis or signs and symptoms;
(f) Seriousness criteria met (death, life-threatening, hospitalization or prolongation of hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, other medically important event);
(g) Severity (mild, moderate, or severe);
(h) Investigator's assessment of causality (relationship to study treatment);
(i) Current status of the subject at the time of the report;
(j) Any immediate actions taken, including actions taken with the study drug and any emergency treatment administered; and
(k) Investigator name and signature (electronic signature is acceptable for submissions via the Pinnacle EDC SAE module).
If complete information is not available within the twenty-four (24)-hour reporting window, the site must nonetheless submit the initial report with all information available at that time and clearly indicate that the report is preliminary and that follow-up information will be provided. Incomplete information does not excuse or delay submission of the initial report.
4.3 Serious Adverse Event Reporting — Follow-Up Reports
Follow-up SAE reports must be submitted within five (5) calendar days of receipt of new or updated information regarding a previously reported SAE. Each follow-up report must include all previously reported information, updated and supplemented with newly available findings, including but not limited to:
(a) Updated clinical status of the subject;
(b) Relevant laboratory data, including results from Northbridge Bioanalytical Laboratories (central laboratory) and local laboratory results, as applicable;
(c) Imaging results (radiographs, CT scans, MRI, PET scans, etc.);
(d) Pathology reports and biopsy results;
(e) Autopsy findings, if applicable;
(f) Hospital discharge summaries;
(g) Consultant reports and subspecialty evaluations;
(h) Updated concomitant medication information;
(i) Updated investigator assessment of causality, if the assessment has changed based on new information;
(j) Final outcome of the event (recovered/resolved, recovered with sequelae, not recovered, ongoing, fatal); and
(k) Any revised diagnosis, if the initial report was based on symptoms only and a definitive diagnosis has since been established.
Follow-up reports must continue to be submitted as new information becomes available until the event is resolved, has stabilized (i.e., no further change in status is expected), or the subject has been lost to follow-up. Each follow-up report must clearly reference the initial SAE report and include the date of the initial report and the subject identification number.
4.4 Reporting of Deaths
Any death occurring during the study or within thirty (30) calendar days of the last dose of study treatment (investigational product or placebo) must be reported as a serious adverse event within twenty-four (24) hours of the site's awareness, using the SAE reporting procedures described in Section 4.2 above.
In addition to the standard SAE reporting requirements, the investigator must provide the following information as soon as it becomes available:
(a) A death narrative, describing the circumstances leading to the subject's death, including the clinical course, treatments administered, and temporal relationship to study drug administration;
(b) The cause of death, as determined by the investigator or as documented on the death certificate;
(c) Autopsy results, if an autopsy was performed (the investigator should make reasonable efforts to obtain autopsy results when available); and
(d) The investigator's assessment of the relationship of the death to the investigational product, placebo, and/or the underlying disease or condition under study.
Deaths occurring more than thirty (30) calendar days after the last dose of study treatment that the investigator believes are reasonably possibly related to the investigational product must also be reported as SAEs within twenty-four (24) hours of the site's awareness, using the same procedures.
4.5 Pregnancy Reports
Any pregnancy occurring in a female study subject or in the female partner of a male study subject during the study (from the date of first dose through thirty (30) calendar days after the last dose, or during the follow-up period if specified by the Protocol) must be reported to the Sponsor and Meridian CRO within twenty-four (24) hours of the site's awareness, using the designated pregnancy reporting form provided in the Study Reference Manual.
Pregnancies are not themselves classified as adverse events; however, each pregnancy must be followed to outcome (including live birth, spontaneous abortion, elective termination, stillbirth, or ectopic pregnancy). Any adverse pregnancy outcome, including but not limited to spontaneous abortion, stillbirth, congenital anomaly, or neonatal complications, must be reported as a serious adverse event in accordance with the procedures set forth in Section 4.2 of these Safety Reporting Procedures. Study drug must be immediately discontinued upon confirmation of pregnancy in a female study subject, and the investigator must consult with the Sponsor's medical monitor regarding any additional safety measures.
4.6 Adverse Events of Special Interest (AESIs)
Protocol PPC-4871-III designates certain categories of adverse events as adverse events of special interest ("AESIs") based on the known or suspected pharmacological profile of penterafenib and the safety signals identified in earlier clinical development. The following events are designated as AESIs for the CLARION trial:
(a) Hepatotoxicity (including elevated transaminases, drug-induced liver injury, hepatic failure);
(b) QTc prolongation (including clinically significant changes from baseline in the QTcF interval);
(c) Severe dermatologic reactions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [DRESS]);
(d) Thromboembolic events (including deep vein thrombosis, pulmonary embolism, arterial thrombosis); and
(e) Such other events as may be designated by the Sponsor from time to time through protocol amendment or safety letter.
All AESIs must be reported to the Sponsor and Meridian CRO within twenty-four (24) hours of the site's awareness, regardless of whether the event meets the criteria for a serious adverse event. AESIs that do not meet SAE criteria must nonetheless be reported using the SAE reporting pathway (i.e., through the Pinnacle EDC SAE module or the backup fax/encrypted email method described in Section 4.2). This enhanced reporting requirement ensures that the Sponsor can evaluate potential safety signals in real time, even for events that might not individually satisfy seriousness criteria.
Section 5: Sponsor IND Safety Reporting to the FDA
5.1 Seven (7)-Day Reports — Fatal or Life-Threatening SUSARs
In accordance with 21 C.F.R. § 312.32(c)(2), the Sponsor (Penterra) must report to the FDA any SUSAR that is fatal or life-threatening within seven (7) calendar days of the Sponsor's initial receipt of the information. For purposes of this requirement, the date of "initial receipt" is the date on which the Sponsor (or Meridian CRO, as the Sponsor's delegated agent for safety data processing) first receives information sufficient to identify the event as a SUSAR that is fatal or life-threatening.
The seven (7)-day report must be submitted to the FDA via FDA Form 3500A (MedWatch Adverse Event Report) or through the FDA Safety Reporting Portal (electronic submission), as applicable. The initial seven (7)-day report may be submitted with incomplete information if a complete report cannot be assembled within the reporting timeframe; however, the Sponsor must submit a follow-up report within eight (8) additional calendar days (i.e., within a total of fifteen (15) calendar days from the date of initial receipt of the information), providing all available updated and supplementary information.
The Sponsor's medical monitor, Dr. Marcus Yun, M.D., M.P.H., or designee, will review each potentially qualifying event and confirm the classification as a SUSAR that is fatal or life-threatening before submission of the seven (7)-day report, provided that such review does not delay submission beyond the regulatory deadline.
5.2 Fifteen (15)-Day Reports — All Other IND Safety Reports
In accordance with 21 C.F.R. § 312.32(c)(1), the Sponsor (Penterra) must report to the FDA all other reportable safety findings within fifteen (15) calendar days of the Sponsor's initial receipt of the information. Reportable safety findings subject to fifteen (15)-day reporting include, without limitation:
(a) Any SUSAR that does not qualify for seven (7)-day reporting (i.e., SUSARs that are not fatal or life-threatening);
(b) Any finding from clinical trials, epidemiological studies, or pooled analyses of multiple studies that suggests a significant risk to human subjects exposed to the investigational product, including any clinically meaningful change in the benefit-risk profile of penterafenib;
(c) Any clinically important increase in the rate of a known serious suspected adverse reaction over the rate previously identified in the Investigator's Brochure or in prior IND safety reports; and
(d) Any finding from animal or in vitro testing that suggests a significant risk to human subjects, including reports of mutagenicity, teratogenicity, carcinogenicity, or significant organ toxicity at clinically relevant exposure levels.
All fifteen (15)-day reports must be submitted to the FDA via FDA Form 3500A (MedWatch) or through the FDA Safety Reporting Portal, in the format required by applicable FDA guidance. Each report must include a narrative assessment of the clinical significance of the finding and the Sponsor's assessment of the impact, if any, on the ongoing conduct of the CLARION trial.
5.3 Annual IND Safety Reports
Penterra will prepare and submit annual IND safety reports ("IND Annual Reports") to the FDA in accordance with 21 C.F.R. § 312.33, summarizing all IND safety information accumulated during each reporting period. The IND Annual Report will include, without limitation:
(a) A narrative summary of the most significant safety findings during the reporting period, including any new safety signals identified;
(b) Individual case narratives for all SUSARs reported to the FDA during the reporting period;
(c) Tabulations and summary tables of all SAEs and SUSARs, organized by System Organ Class (SOC) and Preferred Term (PT) per MedDRA coding conventions;
(d) Aggregate safety analyses, including incidence rates, exposure-adjusted rates, and comparisons between treatment arms, as appropriate;
(e) A description of any actions taken during the reporting period for safety reasons, including dose modifications, protocol amendments, changes to the informed consent form, trial suspension, or early termination of any study under the IND; and
(f) An updated benefit-risk assessment for penterafenib, including any new information from preclinical studies, published literature, or post-marketing experience (if applicable) that is relevant to the safety profile of the investigational product.
5.4 Distribution of IND Safety Reports to Investigators
All IND safety reports submitted to the FDA by Penterra (including seven (7)-day reports, fifteen (15)-day reports, and follow-up reports) must be distributed to all participating investigators at the thirty-eight (38) Veridian Network sites within the timelines required by 21 C.F.R. § 312.32(c)(1)(iii) and (c)(2). Specifically:
(a) For seven (7)-day reports: distribution to all investigators concurrently with or promptly after submission to the FDA;
(b) For fifteen (15)-day reports: distribution to all investigators within the fifteen (15)-calendar-day reporting timeframe or promptly thereafter.
Distribution will be coordinated through Meridian CRO and the Veridian central office (750 Research Parkway, 8th Floor, Philadelphia, Pennsylvania 19104). Meridian CRO will transmit IND safety reports to the Veridian central office, which will in turn distribute the reports to all network sites and confirm receipt. Alternatively, Meridian CRO may distribute reports directly to individual site investigators with simultaneous notification to the Veridian central office.
Upon receipt of an IND safety report, each principal investigator must promptly review the report and assess whether the information affects the benefit-risk profile for subjects enrolled at the investigator's site. Each investigator must submit the IND safety report to the applicable IRB — the Graystone University Institutional Review Board (IRB Registration: IRB00012847) for the Graystone University Medical Center site (Site 001), or the Veridian Central IRB for non-Pennsylvania sites — in accordance with IRB policies and the requirements of 21 C.F.R. Part 56 and ICH E6(R2).
Section 6: IRB Notification and Reporting
6.1 Site IRB Reporting Obligations
Each principal investigator participating in the CLARION trial must report SAEs, SUSARs, IND safety reports, and any other safety information requiring IRB notification to the applicable Institutional Review Board in a timely manner, in accordance with:
(a) The policies and procedures of the applicable IRB;
(b) 21 C.F.R. § 56.108(b), which requires IRBs to have procedures for ensuring prompt reporting of changes in research activities and unanticipated problems;
(c) 21 C.F.R. § 312.66, which requires investigators to promptly report to the IRB all changes in the research activity and all unanticipated problems involving risk to human subjects or others;
(d) ICH E6(R2) GCP Guidelines, Section 4.11, which requires the investigator to report to the IRB/IEC all SAEs that are both serious and unexpected, and any findings that could adversely affect the safety of subjects.
The IRB reporting structure for the CLARION trial is as follows:
(a) Graystone University Medical Center (Site 001): The applicable IRB is the Graystone University Institutional Review Board (IRB Registration Number: IRB00012847; Office of Human Research Protections [OHRP] assurance: FWA00018293). Dr. Catherine Aldridge, M.D., Ph.D., as the Global Principal Investigator and the site principal investigator, is responsible for all IRB submissions and communications with the Graystone University IRB for this site.
(b) Lakemont Medical Center (Site 002) and other non-Pennsylvania Veridian sites: The applicable IRB is the Veridian Central IRB, which serves as the IRB of record pursuant to applicable IRB reliance agreements and IRB authorization agreements executed between Veridian Central IRB and each participating institution. Dr. Howard Matsuoka, M.D., as the Co-Principal Investigator at Site 002, is responsible for ensuring compliance with Veridian Central IRB requirements at the Lakemont site.
(c) Lead sites (Graystone University Medical Center and Lakemont Medical Center): These lead sites require individual IRB approval from their respective institutional IRBs (Graystone University IRB for Site 001; Veridian Central IRB or the local institutional IRB for Site 002, as applicable under the relevant reliance agreement). All remaining Veridian Network sites may rely on the Veridian Central IRB under executed IRB Authorization Agreements, unless a participating institution requires use of its own institutional IRB, in which case the site-specific agreement will specify the applicable IRB.
Each investigator must retain copies of all IRB correspondence, submissions, and approvals related to safety reporting in the site's investigator site file.
6.2 Unanticipated Problems Involving Risks to Subjects
Any event, incident, experience, or outcome that meets the definition of an "unanticipated problem involving risk to subjects or others" as set forth in 45 C.F.R. § 46.108(a)(4) and applicable FDA guidance must be reported by the investigator to the applicable IRB and to the Sponsor (Penterra) and Meridian CRO within the timeframes specified by the IRB's policies and applicable federal regulations.
An "unanticipated problem involving risk to subjects or others" generally includes any incident, experience, or outcome that meets all of the following criteria: (i) is unexpected (in terms of nature, severity, or frequency) given the procedures described in the Protocol and the characteristics of the study population; (ii) is related or possibly related to participation in the research; and (iii) suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.
Reporting of unanticipated problems to the IRB typically must occur within the timeframes specified in the IRB's policies, which in most cases require notification within five (5) to ten (10) business days, or sooner for events that are also SAEs. The investigator must also report such events to Meridian CRO through the standard SAE reporting pathway if the event qualifies as an SAE, or through a separate report to the Meridian CRO Safety Department if the unanticipated problem does not otherwise meet SAE criteria.
Section 7: Data Management and Safety Database
7.1 Global Safety Database
Penterra maintains a global safety database for penterafenib (PPC-4871) under IND 157823 (the "Global Safety Database"). The Global Safety Database aggregates safety data from all clinical studies conducted under the IND, including the CLARION trial and any other ongoing or completed studies involving penterafenib. The Global Safety Database is the authoritative repository for all individual case safety reports ("ICSRs") related to penterafenib.
Meridian CRO is responsible for data entry, medical coding (using MedDRA, current version), quality control, and day-to-day database maintenance under the Master Services Agreement dated January 15, 2023. All SAE data received from the thirty-eight (38) Veridian Network sites will be entered into the Global Safety Database within one (1) business day of receipt by the Meridian CRO Safety Department. Meridian CRO must perform quality control review of each database entry, including verification of medical coding accuracy, completeness of data fields, and consistency with source documentation.
Penterra retains oversight of the Global Safety Database and reserves the right to audit database entries, query resolution timelines, and quality metrics at any time. Penterra's pharmacovigilance team will conduct periodic reviews of the Global Safety Database to support signal detection activities, aggregate safety analyses, and regulatory reporting obligations.
7.2 Electronic Data Capture Integration
SAE data entered by site personnel via the Pinnacle Data Solutions EDC platform will be interfaced with the Global Safety Database maintained by Meridian CRO through validated electronic data transfer mechanisms. The integration between the Pinnacle EDC system and the Global Safety Database must be validated to ensure accurate, complete, and timely transfer of safety data.
System validation and data reconciliation procedures must be established and documented, and must include the following:
(a) Validation of the electronic interface between the Pinnacle EDC system and the Global Safety Database, including verification that all required data fields are accurately mapped and transferred;
(b) Periodic reconciliation of SAE records between the EDC system and the Global Safety Database, performed at a frequency of no less than monthly, to identify and resolve any discrepancies;
(c) Audit trails for all safety data entries, modifications, and deletions in both the EDC system and the Global Safety Database; and
(d) Backup and disaster recovery procedures for both systems to prevent data loss.
All electronic safety data systems used in connection with the CLARION trial must comply with 21 C.F.R. Part 11 requirements for electronic records and electronic signatures, including requirements for system validation, access controls, audit trails, and data integrity.
7.3 Central Laboratory Safety Data
Safety laboratory data, including hematology, clinical chemistry, urinalysis, coagulation studies, and other protocol-specified laboratory assessments, will be generated by Northbridge Bioanalytical Laboratories, Inc. (central laboratory; headquarters: 2900 Commerce Way, Baltimore, Maryland 21224) and transmitted electronically to Meridian CRO for integration into the Pinnacle EDC platform and, as applicable, the Global Safety Database.
Northbridge Bioanalytical Laboratories will flag abnormal laboratory values that meet pre-specified criteria defined in the Protocol (including, without limitation, Grade 3 or Grade 4 laboratory abnormalities per the NCI Common Terminology Criteria for Adverse Events [CTCAE], current version, and protocol-specified liver chemistry stopping rules). Flagged values will be transmitted to the site investigator for clinical review and assessment as to whether the abnormal value represents an adverse event or serious adverse event requiring reporting under these Safety Reporting Procedures.
Local laboratory results obtained at the site in the course of routine clinical care or emergency assessment may also be clinically significant and must be assessed by the investigator for potential AE or SAE reporting, independent of central laboratory results.
7.4 Data Ownership
All safety data generated in connection with the CLARION trial, including but not limited to individual SAE reports, aggregate safety analyses, IND safety reports, and any derivative data, are the exclusive property of Penterra Pharmaceuticals Corp., as set forth in the MCTA and Exhibit G (Intellectual Property and Publication Rights) thereto. Neither Veridian nor any participating site shall acquire any ownership interest in safety data generated under the CLARION trial.
Site source documents (including medical records, hospital charts, laboratory reports, and other original clinical documentation) are maintained by and remain in the custody of the respective participating sites. Each site must retain all source documents related to the CLARION trial, including safety-related source documents, for a minimum of fifteen (15) years following study completion or as otherwise required by applicable federal, state, or institutional record retention requirements, whichever is longer. In the event that a site intends to destroy safety-related source documents at the conclusion of the retention period, the site must provide written notice to Penterra no less than sixty (60) days prior to destruction to afford Penterra the opportunity to request transfer of such records.
Section 8: Safety Monitoring and Oversight
8.1 Data Safety Monitoring Board (DSMB)
An independent Data Safety Monitoring Board ("DSMB") has been established for the CLARION trial to provide independent review and assessment of accumulating safety data during the course of the study. The DSMB operates under a separate DSMB Charter, which defines the composition, operating procedures, meeting schedule, data to be reviewed, and decision-making authority of the DSMB. The DSMB Charter is a standalone document and is not attached to this Exhibit J.
The DSMB will meet at pre-specified intervals (as defined in the DSMB Charter) and on an ad hoc basis if circumstances warrant. The DSMB has the authority to review unblinded safety data and may issue recommendations to the Sponsor, including but not limited to the following:
(a) Continuation of the trial without modification;
(b) Modification of the trial (e.g., dose adjustments, additional safety monitoring, revision of eligibility criteria);
(c) Temporary suspension of enrollment or dosing;
(d) Early termination of the trial for safety reasons; or
(e) Requests for additional data or analyses from the Sponsor.
Penterra's Chief Medical Officer, Dr. Elaine Whitford, M.D., will serve as the Sponsor's primary liaison to the DSMB. The Sponsor will provide all data and analyses requested by the DSMB in a timely manner and will give serious consideration to all DSMB recommendations. The final decision regarding trial conduct remains with the Sponsor, subject to applicable regulatory requirements.
8.2 Sponsor Medical Monitor
Penterra's Senior Vice President, Clinical Development, Dr. Marcus Yun, M.D., M.P.H., or his qualified designee, will serve as the medical monitor for the CLARION trial. The medical monitor's responsibilities include:
(a) Review of all SAE reports received from the thirty-eight (38) Veridian Network sites, including assessment of causality from the Sponsor's perspective (which is independent of, and may differ from, the investigator's causality assessment);
(b) Participation in signal detection activities, including review of aggregate safety data, line listings of SAEs and AESIs, and periodic safety analyses;
(c) Evaluation of individual case narratives for potential classification as SUSARs and determination of appropriate IND safety reporting;
(d) Consultation with site investigators regarding complex or unusual safety events;
(e) Availability twenty-four hours per day, seven days per week (24/7) for urgent safety consultations with investigators. Contact information for the medical monitor's 24/7 availability will be provided in the Study Reference Manual and will be updated as necessary; and
(f) Communication of safety findings and recommendations to the Sponsor's Chief Medical Officer and to the DSMB, as appropriate.
8.3 CRO Safety Monitoring
Meridian CRO clinical research associates ("CRAs") and senior monitors will conduct routine monitoring visits at each of the thirty-eight (38) Veridian Network sites, at a frequency determined by the monitoring plan (typically every four (4) to eight (8) weeks, depending on enrollment rate and risk assessment). In addition, for-cause monitoring visits may be conducted at any time if there are indications of non-compliance with safety reporting requirements or other significant protocol deviations.
Safety monitoring activities conducted during each visit will include, without limitation:
(a) Verification that all SAEs have been identified, documented, and reported within the timelines specified in these Safety Reporting Procedures;
(b) Source document verification to confirm the accuracy and completeness of SAE data entered in the eCRF and submitted on SAE reporting forms;
(c) Review of the timeliness of SAE reporting, including comparison of the date the site became aware of the event with the date of submission of the initial SAE report;
(d) Review of investigator causality assessments for medical plausibility;
(e) Verification that all SAEs, IND safety reports, and unanticipated problems have been reported to the applicable IRB;
(f) Review of source documentation for non-serious adverse events to confirm that all AEs have been identified and documented;
(g) Review of AESIs reporting for compliance with the enhanced twenty-four (24)-hour reporting requirement; and
(h) Verification that safety-related training documentation is current and maintained in the investigator site file.
Any findings of non-compliance with safety reporting requirements will be documented in the monitoring visit report and promptly escalated to the Sponsor, including specifically Jennifer Holt, Vice President, Clinical Operations, and to the Veridian central office, Dr. Lena Marchetti, Ph.D. Significant or repeated non-compliance may result in corrective action, additional training, increased monitoring frequency, or other measures, up to and including suspension or termination of the site's participation in the CLARION trial in accordance with the MCTA.
8.4 Regulatory Authority Communications
Penterra, as the holder of IND 157823, is the primary point of contact with the FDA and any other applicable regulatory authority for all safety-related regulatory communications arising from the CLARION trial or any other study conducted under the IND. Penterra's responsibilities in this regard include:
(a) Submission of all IND safety reports, annual reports, and other regulatory filings related to safety;
(b) Response to FDA requests for additional safety information or clarification;
(c) Notification to the FDA of any Sponsor-initiated safety actions (e.g., clinical hold requests, voluntary suspension of the trial, risk mitigation measures); and
(d) Communication with the FDA in the event of a regulatory inspection of any participating site related to the CLARION trial.
Penterra's regulatory counsel at Castleton & Hargrove LLP (Dr. Priya Sundaram, Esq.; 1100 Connecticut Avenue NW, Suite 900, Washington, D.C. 20036) may be consulted on regulatory strategy related to safety findings, clinical hold risk, IND maintenance, and responses to FDA communications. The involvement of regulatory counsel does not alter the Sponsor's regulatory obligations or reporting timelines.
In the event that the FDA issues a clinical hold order or takes any other regulatory action affecting the conduct of the CLARION trial (including partial clinical holds, requests for additional safety data, or imposition of new conditions on the IND), Penterra must notify the Veridian central office (Dr. Lena Marchetti, Ph.D., and Gregory Callahan, Esq.) and all participating investigators within twenty-four (24) hours of the Sponsor's receipt of such communication from the FDA. The notification must include a summary of the regulatory action and any instructions regarding the impact on ongoing study activities, including instructions regarding enrollment suspension, continued dosing of enrolled subjects, and safety monitoring requirements during the clinical hold period.
Section 9: Protocol Amendments and Safety-Related Actions
9.1 Safety-Related Protocol Amendments
If accumulating safety data from the CLARION trial, from other penterafenib studies under IND 157823, from the published literature, or from preclinical studies necessitate amendment of Protocol PPC-4871-III, Penterra will prepare the protocol amendment and distribute it to all participating sites and to Meridian CRO. Safety-related protocol amendments may include, without limitation:
(a) Modifications to dosing regimens (dose reductions, dose holds, dose escalation limitations);
(b) Addition of new safety monitoring requirements (additional laboratory tests, electrocardiograms, imaging studies, or clinical assessments);
(c) Revision of inclusion or exclusion criteria to exclude subjects at heightened risk for identified safety events;
(d) Addition of new stopping rules or dose modification algorithms;
(e) Changes to the informed consent form to reflect newly identified risks; and
(f) Changes to the list of adverse events of special interest.
Safety-related protocol amendments must be submitted to the applicable IRBs (Graystone University IRB, Veridian Central IRB, or other applicable institutional IRBs) for review and approval before implementation at the sites, except in circumstances where immediate implementation is necessary to eliminate an apparent immediate hazard to study subjects. In such cases, the amendment may be implemented immediately, with IRB notification and approval sought as soon as practicable thereafter, and in no event later than ten (10) business days after implementation.
The Sponsor must notify the FDA of any protocol amendment in accordance with 21 C.F.R. § 312.30, including submission of the amendment as part of an IND amendment (prior approval supplement, if applicable, or notification at the time of implementation for amendments that do not require prior FDA approval).
9.2 Investigator's Brochure Updates
The Investigator's Brochure for penterafenib (PPC-4871) will be updated at least annually, or more frequently if warranted by new safety information that materially affects the known safety profile of the investigational product. Updates may include new preclinical findings, safety data from other clinical studies under the IND, published literature reports, or regulatory authority communications.
Updated Investigator's Brochures will be distributed to all principal investigators at the thirty-eight (38) Veridian Network sites through Meridian CRO and the Veridian central office. Upon receipt of an updated Investigator's Brochure, each investigator must acknowledge receipt in writing (electronic acknowledgment is acceptable), review the updated safety information, and determine whether the new information necessitates re-consent of currently enrolled subjects or modification of site-level safety monitoring procedures. Copies of updated Investigator's Brochures must be maintained in the investigator site file.
9.3 Trial Suspension or Early Termination for Safety
Penterra reserves the right, in its sole discretion, to suspend or terminate the CLARION trial at any or all participating sites if safety data indicate that the risks to subjects outweigh the potential benefits of continued participation, or if the overall benefit-risk profile of penterafenib is determined to be unacceptable. Such a decision may be made by the Sponsor independently or in response to a recommendation from the DSMB, a regulatory authority action, or other circumstances.
In the event of trial suspension, Penterra will notify all participating investigators, Veridian central, and Meridian CRO in writing (including via electronic communication) within twenty-four (24) hours, specifying the reason for suspension, the scope of the suspension (all sites or specific sites), and instructions for the management of enrolled subjects during the suspension period, including whether subjects may continue on study treatment or must immediately discontinue dosing.
In the event of trial termination for safety reasons, the wind-down provisions set forth in the MCTA shall apply, including the one-hundred-twenty (120)-day wind-down period for subject safety. During the wind-down period, subjects who are actively receiving study treatment must be transitioned to standard-of-care therapy or, if clinically appropriate and with Sponsor approval, permitted to complete their current treatment cycle. The investigator must ensure that all subjects are informed of the trial termination, the reasons therefor (to the extent consistent with confidentiality obligations and regulatory requirements), and any recommended follow-up care.
Veridian and all site investigators must cooperate fully in implementing any safety-related trial suspension or termination, including compliance with Sponsor instructions regarding subject management, return or destruction of investigational product, and comple

EXHIBIT J

SAFETY REPORTING PROCEDURES

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