INDIVIDUAL SITE AGREEMENT
(JOINDER TO MASTER CLINICAL TRIAL AGREEMENT)
Site Number: 002 Site Name: Lakemont Medical Center
Reference Document: Master Clinical Trial Agreement dated June 28, 2023 (the "MCTA") by and between Penterra Pharmaceuticals Corp. ("Sponsor") and Veridian Health Research Network, Inc. ("Network")
Protocol: PPC-4871-III — CLARION (Clinical Assessment of Response with Longitudinal Investigation in ONcology)
Investigational Product: Penterafenib (PPC-4871)
Date of this Individual Site Agreement: June 28, 2023
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RECITALS
WHEREAS, Penterra Pharmaceuticals Corp., a corporation organized and existing under the laws of the State of Delaware, with its principal offices located at 200 Biopharma Boulevard, Suite 1400, Princeton, New Jersey 08540 (the "Sponsor" or "Penterra"), and Veridian Health Research Network, Inc., a Delaware 501(c)(3) nonprofit corporation with its principal offices located at 750 Research Parkway, 8th Floor, Philadelphia, Pennsylvania 19104 (the "Network" or "Veridian"), have entered into that certain Master Clinical Trial Agreement dated June 28, 2023 (the "MCTA"), governing the conduct of a Phase III, randomized, double-blind, placebo-controlled clinical trial of the investigational product penterafenib (PPC-4871) in patients with advanced hepatocellular carcinoma under Protocol PPC-4871-III, entitled CLARION (Clinical Assessment of Response with Longitudinal Investigation in ONcology), registered under ClinicalTrials.gov Identifier NCT05928174, pursuant to Investigational New Drug Application No. 157823 filed with the United States Food and Drug Administration (the "FDA");
WHEREAS, the MCTA provides, among other things, that each participating site institution within the Veridian Health Research Network that desires to participate in the CLARION trial shall execute an Individual Site Agreement substantially in the form attached as Exhibit C to the MCTA, thereby becoming a "Participating Site Institution" under the MCTA and assuming all rights, benefits, and obligations applicable to such designation;
WHEREAS, Lakemont Medical Center ("Site Institution" or "Lakemont"), an Illinois nonprofit corporation organized and existing under the laws of the State of Illinois, located at 4400 North Michigan Drive, Chicago, Illinois 60611, is a duly authorized member institution of the Veridian Health Research Network and desires to participate as Site 002 in the CLARION trial in accordance with the terms and conditions of the MCTA and this Individual Site Agreement;
WHEREAS, Dr. Howard Matsuoka, M.D., Associate Professor of Hepatology & Oncology at Lakemont Medical Center, has been designated as the Co-Principal Investigator for Site 002, and has agreed to assume the responsibilities and obligations of a Co-Principal Investigator under Protocol PPC-4871-III, applicable regulations, and the Co-Principal Investigator Agreement to be executed concurrently herewith or prior to the effective date of this Individual Site Agreement; and
WHEREAS, all capitalized terms used herein and not otherwise defined shall have the meanings ascribed to them in the MCTA.
NOW, THEREFORE, in consideration of the mutual promises and covenants contained herein and in the MCTA, and for other good and valuable consideration, the receipt and sufficiency of which are hereby acknowledged, the parties agree as follows:
ARTICLE 1 — JOINDER AND INCORPORATION BY REFERENCE
Section 1.1 — Joinder to MCTA
By executing this Individual Site Agreement, Lakemont Medical Center hereby agrees to be bound by and to perform all obligations of a "Participating Site Institution" as that term is defined and used in the MCTA, as if Lakemont were an original signatory to the MCTA. Without limiting the generality of the foregoing, Lakemont assumes all rights, benefits, and obligations of a Participating Site Institution under the MCTA, including but not limited to: (a) indemnification protections set forth in the MCTA and this Individual Site Agreement; (b) insurance requirements applicable to Participating Site Institutions; (c) confidentiality obligations with respect to all Confidential Information (as defined in the MCTA and Exhibit F thereto); (d) data protection provisions, including compliance with the Health Insurance Portability and Accountability Act of 1996, as amended ("HIPAA"), and its implementing regulations; (e) regulatory compliance covenants, including compliance with all applicable provisions of the Federal Food, Drug, and Cosmetic Act and the regulations promulgated thereunder; and (f) publication rights as set forth in the MCTA and Exhibit G thereto.
Lakemont acknowledges that it has received, reviewed, and had the opportunity to obtain legal counsel with respect to the MCTA and all Exhibits and Schedules thereto, and that its execution of this Individual Site Agreement constitutes its voluntary agreement to be bound by the terms and conditions thereof. Lakemont further acknowledges that its participation as a Participating Site Institution is subject to the ongoing satisfaction of the conditions and obligations set forth in the MCTA and this Individual Site Agreement.
Section 1.2 — Incorporation by Reference
The MCTA and all Exhibits and Schedules thereto, specifically Exhibits A through K and Schedule 1, are hereby incorporated by reference into this Individual Site Agreement with the same force and effect as if set forth in full herein. For the avoidance of doubt, the following Exhibits to the MCTA are incorporated by reference and shall apply to the conduct of the CLARION trial at Site 002:
(a) Exhibit A — Protocol PPC-4871-III (CLARION);
(b) Exhibit B — Budget and Payment Schedule;
(c) Exhibit C — Form of Individual Site Agreement;
(d) Exhibit D — Indemnification Provisions;
(e) Exhibit E — Insurance Requirements;
(f) Exhibit F — Confidentiality Provisions;
(g) Exhibit G — Publication Rights and Academic Collaboration Framework;
(h) Exhibit H — Regulatory Compliance Representations and Covenants;
(i) Exhibit I — Form of Investigator Undertaking;
(j) Exhibit J — Safety Reporting Procedures;
(k) Exhibit K — Approved Subcontractors and Third-Party Service Providers; and
(l) Schedule 1 — Site Activation Checklist and Timeline.
In the event of a conflict between any provision of this Individual Site Agreement and any provision of the MCTA, the terms of this Individual Site Agreement shall control with respect to site-specific matters pertaining exclusively to Site 002 and the conduct of the trial at Lakemont Medical Center. In all other respects, the MCTA shall govern. To the extent a conflict exists between a provision of this Individual Site Agreement and a provision of any Exhibit or Schedule to the MCTA, the parties shall endeavor to resolve such conflict in a manner consistent with the overall intent and objectives of the MCTA and this Individual Site Agreement, with the MCTA taking precedence in the event of an irreconcilable inconsistency on non-site-specific matters.
Section 1.3 — Effective Date
This Individual Site Agreement shall become effective upon the latest to occur of the following: (a) execution of this Individual Site Agreement by all parties hereto (including acknowledgment by the Co-Principal Investigator); (b) satisfaction of the conditions precedent to site activation set forth in Article 6 of this Individual Site Agreement; and (c) the effective date of the MCTA, which is July 18, 2023 (the "Effective Date"). For the avoidance of doubt, the date of execution set forth on the signature page of this Individual Site Agreement reflects the date of signing, which may precede the Effective Date. No obligations shall arise under this Individual Site Agreement until the Effective Date, except as expressly provided herein with respect to preparatory activities required as conditions precedent to site activation.
ARTICLE 2 — SITE-SPECIFIC INFORMATION
Section 2.1 — Site Identification
The following information identifies Site 002 for purposes of the MCTA and this Individual Site Agreement:
Lakemont represents and warrants that the information set forth in this Section 2.1 is true and correct as of the date of execution of this Individual Site Agreement, and Lakemont shall promptly notify Penterra and Veridian in writing of any changes to such information during the term of this Individual Site Agreement.
Section 2.2 — Principal Investigator Designation
The Co-Principal Investigator for Site 002 under Protocol PPC-4871-III (CLARION) shall be:
Name: Dr. Howard Matsuoka, M.D.
Title: Associate Professor of Hepatology & Oncology
Institutional Affiliation: Lakemont Medical Center, Department of Hepatology & Oncology, 4400 North Michigan Drive, Chicago, Illinois 60611
Dr. Matsuoka has executed, or will execute prior to the Effective Date of this Individual Site Agreement, a separate Co-Principal Investigator Agreement with Penterra Pharmaceuticals Corp. in the form prescribed by the MCTA, and an Investigator Undertaking in the form of Exhibit I to the MCTA. The Co-Principal Investigator Agreement shall set forth the specific duties, responsibilities, and compensation of Dr. Matsuoka in connection with the conduct of the CLARION trial at Site 002.
Prior to site activation, Dr. Matsuoka shall complete and submit to Penterra (or its designee, Meridian CRO) a fully executed FDA Form 1572 (Statement of Investigator) listing all sub-investigators and the clinical trial site facilities, as well as a Financial Disclosure Certification in compliance with 21 C.F.R. Part 54. Dr. Matsuoka shall promptly update the FDA Form 1572 and Financial Disclosure Certification as required to reflect any changes in sub-investigators, facilities, or financial interests during the term of this Individual Site Agreement.
Lakemont shall not replace Dr. Matsuoka as Co-Principal Investigator without the prior written consent of Penterra, which consent shall not be unreasonably withheld, conditioned, or delayed. In the event that Dr. Matsuoka is unable to continue serving as Co-Principal Investigator for any reason (including but not limited to departure from Lakemont, illness, or regulatory action), Lakemont shall promptly notify Penterra and Veridian in writing and shall propose a replacement Co-Principal Investigator for Penterra's approval. Enrollment at Site 002 shall be suspended until a replacement Co-Principal Investigator has been approved by Penterra, has executed all required agreements and regulatory documents, and has been approved by the Veridian Central IRB.
Section 2.3 — Sub-Investigators and Key Site Personnel
Lakemont shall identify all sub-investigators and key research personnel participating in the conduct of the CLARION trial at Site 002 on FDA Form 1572 and/or a curriculum vitae listing maintained in the site regulatory binder. Such listing shall be maintained and updated as required by 21 C.F.R. § 312.53 and shall be provided to Penterra (or its designee, Meridian CRO) promptly upon request.
All sub-investigators listed on FDA Form 1572 shall, prior to their participation in any trial-related activities, execute the Investigator Undertaking in the form of Exhibit I to the MCTA and complete a Financial Disclosure Certification in compliance with 21 C.F.R. Part 54. Each sub-investigator shall also complete protocol-specific training and Good Clinical Practice (GCP) training as required by the Protocol and applicable regulations.
A listing of the initial sub-investigators, research coordinators, pharmacists, and other key site personnel for Site 002 is set forth in Appendix 2 to this Individual Site Agreement. Lakemont shall promptly notify Penterra and Meridian CRO of any additions, deletions, or changes to the site investigator list during the term of this Individual Site Agreement.
Section 2.4 — Site Facilities and Capabilities
Lakemont represents and warrants that it possesses adequate clinical facilities, qualified staff, equipment, and other resources necessary to conduct the CLARION trial at Site 002 in accordance with Protocol PPC-4871-III, ICH E6(R2) GCP Guidelines, and all applicable federal, state, and local laws and regulations. Without limitation, Lakemont confirms the availability of the following facilities and capabilities at its principal site location:
(a) Clinical Facilities. Lakemont maintains a dedicated oncology and hepatology clinical research unit with private examination rooms, treatment bays, and consultation areas adequate for the screening, enrollment, and follow-up of trial subjects in accordance with the Protocol.
(b) Pharmacy. Lakemont's investigational drug pharmacy is staffed by licensed pharmacists with experience in the management, storage, dispensing, and accountability of investigational products in clinical trials. The pharmacy maintains temperature-controlled storage facilities capable of meeting the storage requirements for penterafenib (PPC-4871) as specified in the investigator's brochure and Protocol.
(c) Infusion Center. To the extent that Protocol PPC-4871-III requires intravenous administration of any study medications or supportive care agents, Lakemont's outpatient infusion center is available and appropriately equipped, staffed, and certified for such administration.
(d) Laboratory. Lakemont maintains a CAP-accredited and CLIA-certified clinical laboratory capable of performing local safety laboratory assessments as specified in the Protocol. Central laboratory analyses, including pharmacokinetic/pharmacodynamic (PK/PD) assays, biomarker analyses, and specified safety laboratory panels, shall be performed by Northbridge Bioanalytical Laboratories, Inc., as set forth in Exhibit K to the MCTA.
(e) Imaging. Lakemont has access to diagnostic imaging services, including computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) scanning, as required for tumor assessments under Protocol PPC-4871-III and the RECIST v1.1 response criteria specified therein.
(f) Emergency and Supportive Care. Lakemont operates a fully equipped emergency department and inpatient hospital capable of managing adverse events, including serious adverse events, that may arise in connection with the administration of penterafenib or participation in the CLARION trial.
Lakemont shall promptly notify Penterra and Veridian of any material changes to its facilities, equipment, or staffing that could affect its ability to conduct the trial in accordance with the Protocol and applicable regulatory requirements.
ARTICLE 3 — INSTITUTIONAL REVIEW BOARD
Section 3.1 — IRB of Record
The Institutional Review Board of record for Site 002 shall be the Veridian Central Institutional Review Board (the "Veridian Central IRB"), which serves as the central IRB for all Veridian Health Research Network member sites located outside the Commonwealth of Pennsylvania. The Veridian Central IRB is registered with the Office for Human Research Protections (OHRP) and holds a current Federal Wide Assurance (FWA).
Lakemont agrees to rely on the Veridian Central IRB for the initial and continuing ethical review and approval of Protocol PPC-4871-III, the informed consent form, recruitment materials, and all other study-related documents requiring IRB review. Lakemont's reliance on the Veridian Central IRB shall be governed by an IRB Authorization Agreement executed between Lakemont Medical Center and the Veridian Central IRB, consistent with the requirements of the revised Common Rule (45 C.F.R. Part 46, as amended effective January 21, 2019) and applicable FDA regulations at 21 C.F.R. Parts 50 and 56.
Lakemont represents that it has executed, or will execute prior to the Effective Date, the IRB Authorization Agreement referenced in this Section 3.1, and that a copy of such agreement has been or will be provided to Penterra and Meridian CRO for the site regulatory binder.
Section 3.2 — IRB Approval as Condition Precedent
Enrollment of subjects at Site 002 shall not commence, and no trial-related activities involving human subjects shall be conducted at Site 002, until the Veridian Central IRB has reviewed and approved the following documents:
(a) Protocol PPC-4871-III (CLARION), including any protocol amendments applicable at the time of initial review;
(b) The informed consent form, including any site-specific modifications approved by Penterra and the Veridian Central IRB;
(c) Any subject recruitment materials, including advertisements, flyers, website postings, and other materials intended for use in the recruitment and screening of potential trial subjects at Site 002; and
(d) The investigator's brochure for penterafenib (PPC-4871), current version.
Evidence of IRB approval, including a copy of the Veridian Central IRB's written approval letter specifying the approved documents, the approval date, and the date of the next scheduled continuing review, shall be provided to Penterra and Meridian CRO prior to site activation. Lakemont and the Co-Principal Investigator shall not enroll any subjects until written confirmation of IRB approval has been received by Penterra and all other conditions precedent set forth in Article 6 have been satisfied.
Section 3.3 — Continuing IRB Obligations
Throughout the term of this Individual Site Agreement, Lakemont and the Co-Principal Investigator shall ensure compliance with all continuing review requirements, amendment submission procedures, and adverse event reporting obligations established by the Veridian Central IRB and applicable regulations. Without limitation:
(a) Continuing Review. The Co-Principal Investigator shall submit a continuing review application to the Veridian Central IRB at least annually, or more frequently if required by the IRB, and shall provide documentation of continuing IRB approval to Penterra and Meridian CRO promptly upon receipt.
(b) Protocol Amendments. Any amendments to Protocol PPC-4871-III shall require review and approval by the Veridian Central IRB prior to implementation at Site 002, except when the amendment is necessary to eliminate an apparent immediate hazard to subjects, in which case the amendment may be implemented immediately, with prompt notification to the IRB and Penterra.
(c) Adverse Event Reporting. The Co-Principal Investigator shall report unanticipated problems involving risks to subjects or others, and any serious or continuing noncompliance, to the Veridian Central IRB in accordance with the IRB's reporting requirements and applicable regulations.
(d) Informed Consent Revisions. Any revisions to the informed consent form, whether initiated by Penterra, the Veridian Central IRB, or the Co-Principal Investigator, shall require IRB approval prior to use with subjects. Subjects enrolled under a prior version of the informed consent form shall be re-consented with the revised form as required by the IRB and applicable regulations.
Lakemont acknowledges that failure to maintain current IRB approval for the Protocol and informed consent form constitutes a material breach of this Individual Site Agreement and may result in immediate suspension of enrollment at Site 002.
ARTICLE 4 — BUDGET AND PAYMENT
Section 4.1 — Site-Specific Budget Allocation
The budget for Site 002 shall be in accordance with Exhibit B to the MCTA (Budget and Payment Schedule), as specifically allocated to this Site in the site-specific budget appendix attached hereto as Appendix 1 (the "Site Budget"). The Site Budget sets forth the detailed financial terms applicable to the conduct of the CLARION trial at Lakemont Medical Center, including the following principal budget components:
(a) Start-Up Fee. Lakemont shall receive a one-time start-up fee of Seventy-Five Thousand Dollars ($75,000), payable in two equal installments: (i) Thirty-Seven Thousand Five Hundred Dollars ($37,500) upon site activation (defined as completion of all conditions precedent set forth in Article 6 and written confirmation of activation by Penterra or Meridian CRO); and (ii) Thirty-Seven Thousand Five Hundred Dollars ($37,500) upon enrollment and randomization of the first subject at Site 002.
(b) Per-Patient Site Fee. For each subject enrolled and randomized at Site 002, Lakemont shall receive a per-patient site fee of Fifty-Two Thousand Dollars ($52,000), payable in four equal milestone installments of Thirteen Thousand Dollars ($13,000) each, as follows:
(i) Thirteen Thousand Dollars ($13,000) upon randomization of the subject;
(ii) Thirteen Thousand Dollars ($13,000) upon completion of the Week 12 assessment visit;
(iii) Thirteen Thousand Dollars ($13,000) upon completion of the Week 24 assessment visit; and
(iv) Thirteen Thousand Dollars ($13,000) upon completion of the study completion visit or final follow-up visit for such subject, whichever is later.
(c) Annual Site Maintenance Fee. Lakemont shall receive an annual site maintenance fee of Forty Thousand Dollars ($40,000) per year, payable in advance on each anniversary of the site activation date, for the duration of Site 002's participation in the CLARION trial. Based on the estimated average study duration of approximately three and one-half (3.5) years per site, the total estimated site maintenance fee for Site 002 is One Hundred Forty Thousand Dollars ($140,000). The annual site maintenance fee shall be prorated for any partial year of participation.
(d) Investigator Grants for Academic Publication Support. Lakemont and the Co-Principal Investigator shall be eligible to receive an allocated share of investigator grants for academic publication support, as applicable and in accordance with the terms set forth in Exhibit G to the MCTA. The amount and timing of such grants shall be determined by Penterra in its sole discretion, subject to the terms of Exhibit G and applicable fair market value requirements.
Section 4.2 — Invoicing and Payment Terms
Lakemont shall submit invoices to Penterra (or its designee, Meridian CRO) in accordance with the invoicing procedures set forth in Exhibit B to the MCTA and this Section 4.2. All invoices shall be submitted in a format reasonably acceptable to Penterra and shall include, at a minimum, the following information:
(a) The site number (002) and the protocol number (PPC-4871-III);
(b) The invoice date and a unique invoice number assigned by Lakemont;
(c) A description of the services performed or milestone achieved, including the applicable milestone description from Section 4.1 above;
(d) For per-patient milestone payments, the subject identification number(s) for which payment is being requested and confirmation that the applicable milestone has been completed;
(e) The dollar amount requested for each line item and the total invoice amount; and
(f) Lakemont's remittance instructions, including bank name, account number, routing number, and any other information necessary for electronic funds transfer.
Payment of properly submitted and undisputed invoices shall be made by Penterra (or its designee) within forty-five (45) calendar days following receipt of a proper invoice ("Net 45"). If Penterra disputes any portion of an invoice, Penterra shall notify Lakemont in writing within fifteen (15) business days of receipt of such invoice, specifying the nature of the dispute, and shall pay the undisputed portion of the invoice within the Net 45 payment period. The parties shall use commercially reasonable efforts to resolve any invoice disputes promptly and in good faith.
Section 4.3 — Fair Market Value and Regulatory Compliance
All payments to Lakemont and to the Co-Principal Investigator under this Individual Site Agreement and the MCTA represent fair market value for the services rendered, as determined by Penterra's independent fair market value analysis conducted in accordance with industry standards and applicable legal requirements. Such payments are not intended to serve, and shall not be construed as, an inducement for the referral of patients or subjects to Penterra or for the prescription, recommendation, or use of penterafenib (PPC-4871) or any other Penterra product.
Lakemont acknowledges and agrees that all payments made to Lakemont and to the Co-Principal Investigator under this Individual Site Agreement and the MCTA shall be reported as required under the Physician Payments Sunshine Act (Section 6002 of the Affordable Care Act, codified at 42 U.S.C. § 1320a-7h) and the Centers for Medicare & Medicaid Services (CMS) Open Payments program. Lakemont shall cooperate with Penterra in providing any information necessary for such reporting.
All payments under this Individual Site Agreement are structured to comply with applicable safe harbors under the federal Anti-Kickback Statute (42 U.S.C. § 1320a-7b(b)), including but not limited to the personal services and management contracts safe harbor (42 C.F.R. § 1001.952(d)). Lakemont represents and warrants that it shall not take any action with respect to the payments received under this Individual Site Agreement that would cause Penterra to be in violation of the Anti-Kickback Statute or any applicable state anti-kickback or self-referral laws.
ARTICLE 5 — SITE OBLIGATIONS
Section 5.1 — Conduct of the Trial
Lakemont and the Co-Principal Investigator shall conduct the CLARION trial at Site 002 in strict accordance with Protocol PPC-4871-III, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline E6(R2) for Good Clinical Practice (GCP), and all applicable federal, state, and local laws and regulations, including without limitation 21 C.F.R. Parts 11 (Electronic Records; Electronic Signatures), 50 (Protection of Human Subjects), 54 (Financial Disclosure by Clinical Investigators), 56 (Institutional Review Boards), and 312 (Investigational New Drug Application).
Lakemont shall ensure that penterafenib (PPC-4871) and matching placebo are received, stored, dispensed, administered, and accounted for only in accordance with the Protocol, the investigator's brochure, and the Sponsor's written instructions regarding investigational product handling. The investigational product shall be stored in a secure, access-controlled area within the site pharmacy, at the temperature conditions specified in the Protocol, and shall be dispensed only to subjects enrolled in the CLARION trial by authorized site personnel. Lakemont shall maintain accurate and complete investigational product accountability records, including records of receipt, dispensing, return, and destruction of all investigational product at Site 002.
Lakemont shall ensure that all study procedures, assessments, and visits are conducted in accordance with the schedule of assessments set forth in the Protocol, and that all protocol-required evaluations are performed by qualified and appropriately trained site personnel. Lakemont acknowledges that adherence to the Protocol is essential to the scientific integrity of the CLARION trial and to the safety of trial subjects.
Section 5.2 — Enrollment
Lakemont shall use commercially reasonable efforts to enroll subjects in the CLARION trial at Site 002 at rates consistent with the enrollment targets set forth in Appendix 1 to this Individual Site Agreement. Lakemont acknowledges that timely enrollment is critical to the success of the CLARION trial and agrees to implement appropriate recruitment strategies, approved by the Veridian Central IRB, to achieve the enrollment targets.
The overall planned enrollment for the CLARION trial across all thirty-eight (38) Veridian Health Research Network participating sites is approximately one thousand two hundred (1,200) subjects, randomized in a 2:1 ratio (penterafenib to placebo), yielding approximately eight hundred (800) subjects in the penterafenib treatment arm and four hundred (400) subjects in the placebo arm. The target date for first patient in (FPI) across all participating sites is August 14, 2023, with projected last patient in (LPI) anticipated in February 2027. The total estimated study duration is approximately sixty (60) months, consisting of a forty-two (42) month enrollment period and an eighteen (18) month follow-up period.
In the event that enrollment at Site 002 falls materially below the enrollment targets set forth in Appendix 1, Penterra reserves the right, upon thirty (30) days' written notice to Lakemont and Veridian, to: (a) request a corrective action plan from Lakemont; (b) reduce the enrollment target for Site 002 and reallocate subjects to other participating sites; or (c) terminate this Individual Site Agreement in accordance with Article 10 if enrollment deficiencies are not remedied within a reasonable period. Any such action by Penterra shall be taken in good faith and in consultation with Veridian.
Section 5.3 — Safety Reporting
Lakemont and the Co-Principal Investigator shall comply with the safety reporting procedures set forth in Exhibit J to the MCTA and applicable regulations, including 21 C.F.R. § 312.32 and ICH E6(R2). Without limiting the foregoing:
(a) Serious Adverse Event (SAE) Reporting. All serious adverse events, as defined in the Protocol and ICH E2A guidelines, must be reported by the Co-Principal Investigator to Penterra and Meridian CRO within twenty-four (24) hours of the site becoming aware of the event. SAE reports shall be submitted using the SAE reporting forms and procedures specified in Exhibit J to the MCTA. Follow-up reports providing additional information on previously reported SAEs shall be submitted promptly as new information becomes available.
(b) IND Safety Reports. The Sponsor (Penterra) shall be responsible for the preparation and submission of IND safety reports to the FDA in accordance with 21 C.F.R. § 312.32, including seven (7) calendar day reports for fatal or life-threatening suspected adverse reactions and fifteen (15) calendar day reports for all other reportable events. Penterra shall provide copies of IND safety reports to the Co-Principal Investigator and the Veridian Central IRB as required by applicable regulations.
(c) Pregnancy Reporting. Any pregnancies occurring in female subjects of childbearing potential, or in the female partners of male subjects, during the trial or within ninety (90) days of the last dose of investigational product, shall be reported to Penterra and Meridian CRO within twenty-four (24) hours of the site becoming aware of the pregnancy.
Lakemont acknowledges that compliance with safety reporting obligations is essential to the protection of trial subjects and to Penterra's regulatory obligations, and that failure to comply with the safety reporting requirements set forth in this Section 5.3 and Exhibit J to the MCTA may constitute a material breach of this Individual Site Agreement.
Section 5.4 — Data Collection and Electronic Data Capture
Lakemont shall enter all trial data generated at Site 002 into the electronic data capture (EDC) platform provided by Pinnacle Data Solutions, Inc. (the "EDC System"), in accordance with the data entry procedures specified in the Protocol, the EDC user guide, and 21 C.F.R. Part 11. Data entry shall be performed by authorized site personnel who have completed training on the EDC System and have been assigned individual user credentials and access rights.
Lakemont shall ensure that data entered into the EDC System is accurate, complete, legible, and timely, and that all data queries generated by Meridian CRO or Penterra are resolved within the timeframes specified in the Protocol and the EDC user guide. Lakemont shall not alter, delete, or modify any data entered into the EDC System except through the audit trail functionality of the EDC System, which records the date, time, identity of the individual making the change, and the reason for the change.
Central laboratory analyses, including pharmacokinetic/pharmacodynamic (PK/PD) assays, biomarker analyses, and specified safety laboratory panels, shall be performed by Northbridge Bioanalytical Laboratories, Inc. in accordance with the laboratory manual provided by Penterra. Lakemont shall collect, process, label, and ship laboratory specimens in accordance with the procedures specified in the Protocol and the laboratory manual, and shall ensure that specimen integrity is maintained throughout the collection and shipping process.
Source documents, including but not limited to medical records, laboratory reports, imaging reports, pharmacy records, informed consent forms, and other original records documenting the conduct of the trial at Site 002, must be maintained at the Site in a secure location and must be available for review during monitoring visits by Meridian CRO and during audits and inspections by Penterra and regulatory authorities, including the FDA.
Section 5.5 — Monitoring, Audit, and Inspection
Lakemont shall permit and facilitate monitoring visits by Meridian CRO, audits by Penterra (or its designees), and inspections by the FDA and other regulatory authorities at such times as may be reasonably requested, upon reasonable prior notice (except in the case of regulatory inspections, for which prior notice may not be required or feasible). Without limitation, Lakemont shall:
(a) Provide reasonable access to site facilities, including clinical areas, pharmacy, laboratory, and administrative offices, as necessary for the conduct of monitoring visits, audits, and inspections;
(b) Make available to monitors, auditors, and inspectors all study records, source documents, investigational product accountability logs, IRB correspondence, regulatory filings, and other documents relevant to the conduct of the trial at Site 002;
(c) Ensure that the Co-Principal Investigator and key site personnel are available to meet with monitors, auditors, and inspectors during monitoring visits, audits, and inspections;
(d) Cooperate in good faith with Meridian CRO, Penterra, and regulatory authorities in connection with any findings, corrective actions, or follow-up activities arising from monitoring visits, audits, or inspections; and
(e) Promptly implement any corrective and preventive actions (CAPAs) identified as a result of monitoring visits, audits, or inspections, and provide documentation of such implementation to Penterra and Meridian CRO.
Section 5.6 — Record Retention
Lakemont shall retain all source documents, study records, site files, regulatory correspondence, and other documents related to the conduct of the CLARION trial at Site 002 for a minimum of fifteen (15) years following the completion of the trial (including the follow-up period), or for such longer period as may be required by applicable federal, state, or local law or regulation, or by the terms of the MCTA. For the avoidance of doubt, "completion of the trial" means the date on which all trial activities at all participating sites have been completed and the final clinical study report has been submitted to the FDA.
Lakemont shall store all retained records in a secure, access-controlled location and shall ensure that such records are protected against loss, damage, unauthorized access, and deterioration. Lakemont shall not destroy or dispose of any study records without the prior written consent of Penterra, which consent may be withheld in Penterra's sole discretion. In the event that Lakemont desires to transfer responsibility for record retention to a third party (for example, in connection with a corporate reorganization, dissolution, or sale of assets), Lakemont shall provide Penterra with at least ninety (90) days' prior written notice and shall ensure that the third-party custodian agrees in writing to comply with the record retention obligations set forth in this Section 5.6.
Section 5.7 — Subcontractors
Lakemont shall not subcontract, delegate, or outsource any material portion of the trial work to be performed at Site 002 under this Individual Site Agreement without the prior written consent of Penterra. For purposes of this Section, "material portion" includes, without limitation, subject screening and enrollment, administration of investigational product, collection and entry of trial data, and safety reporting.
The following subcontractors and third-party service providers have been approved by Penterra in connection with the conduct of the CLARION trial and are listed in Exhibit K to the MCTA:
(a) Meridian Clinical Research Organization, LLC ("Meridian CRO") — providing monitoring, data management, safety reporting, and biostatistical services;
(b) Pinnacle Data Solutions, Inc. — providing the electronic data capture (EDC) platform; and
(c) Northbridge Bioanalytical Laboratories, Inc. — providing central laboratory services.
Any additional subcontractors or third-party service providers engaged by Lakemont in connection with the trial at Site 002 must be approved in writing by Penterra prior to the commencement of any subcontracted work. All approved subcontractors shall be required to comply with the confidentiality, data protection, and regulatory compliance obligations set forth in the MCTA and this Individual Site Agreement, and Lakemont shall be responsible for the acts and omissions of its subcontractors to the same extent as if such acts and omissions were those of Lakemont.
ARTICLE 6 — CONDITIONS PRECEDENT TO SITE ACTIVATION
Section 6.1 — Conditions to Activation
Site 002 shall not be activated, and no enrollment of subjects shall commence at Lakemont Medical Center, until each of the following conditions precedent has been satisfied or waived in writing by Penterra:
(a) Execution of Individual Site Agreement. This Individual Site Agreement shall have been fully executed by all parties hereto, including acknowledgment by the Co-Principal Investigator.
(b) IRB Approval. The Veridian Central IRB shall have reviewed and approved Protocol PPC-4871-III, the informed consent form (including any site-specific modifications), all recruitment materials, and the investigator's brochure, and evidence of such approval shall have been provided to Penterra and Meridian CRO.
(c) Co-Principal Investigator Agreement. Dr. Howard Matsuoka shall have executed the Co-Principal Investigator Agreement with Penterra in the form prescribed by the MCTA.
(d) FDA Form 1572 and Financial Disclosure Certifications. Dr. Howard Matsuoka and all sub-investigators shall have completed and submitted FDA Form 1572 (Statement of Investigator) and Financial Disclosure Certifications in compliance with 21 C.F.R. Part 54.
(e) Investigator Undertakings. All investigators participating in the trial at Site 002 (including the Co-Principal Investigator and all sub-investigators) shall have executed the Investigator Undertaking in the form of Exhibit I to the MCTA.
(f) Site Initiation Visit. A site initiation visit shall have been completed by Meridian CRO, and any findings or corrective actions identified during the site initiation visit shall have been resolved to the satisfaction of Meridian CRO and Penterra.
(g) Investigational Product Delivery. An initial shipment of investigational product (penterafenib/PPC-4871 and matching placebo) shall have been delivered to the site pharmacy at Lakemont Medical Center, and the site pharmacy shall have confirmed receipt and proper storage of the investigational product.
(h) Certificate of Insurance. Lakemont shall have delivered to Penterra a certificate of insurance demonstrating that Lakemont maintains the insurance coverage required by Section 7.4 of this Individual Site Agreement and Exhibit E to the MCTA.
(i) Effective Date of MCTA. The MCTA shall have become effective in accordance with its terms (effective date: July 18, 2023).
Penterra shall provide written confirmation of site activation to Lakemont, Veridian, and Meridian CRO promptly upon satisfaction of all conditions precedent set forth in this Section 6.1. The date of such written confirmation shall be the "Site Activation Date" for Site 002.
ARTICLE 7 — INDEMNIFICATION AND INSURANCE
Section 7.1 — Sponsor Indemnification
As set forth in the MCTA (Article 12 and Exhibit D thereto), and subject to the terms, conditions, and limitations set forth therein and in this Section 7.1, Penterra shall defend, indemnify, and hold harmless Lakemont Medical Center, the Co-Principal Investigator (Dr. Howard Matsuoka, M.D.), all sub-investigators, research coordinators, and other site staff involved in the conduct of the CLARION trial at Site 002 (collectively, the "Site Indemnitees"), from and against any and all claims, demands, actions, suits, losses, damages, liabilities, judgments, settlements, penalties, fines, costs, and expenses (including reasonable attorneys' fees and costs of litigation or arbitration) (collectively, "Losses") arising from or in connection with:
(a) Any injury, illness, or death of a trial subject caused by penterafenib (PPC-4871) when administered in accordance with the Protocol and the Sponsor's written instructions;
(b) Any defect in the design, manufacture, labeling, packaging, storage, or shipping of the investigational product (penterafenib/PPC-4871 and matching placebo) that exists at the time of delivery to the site pharmacy;
(c) Any breach by Penterra of its obligations under the MCTA, the Protocol, or this Individual Site Agreement; and
(d) Any negligence or willful misconduct of Penterra, its officers, directors, employees, agents, or contractors (excluding the Site Indemnitees) in connection with the CLARION trial.
Carve-Outs to Sponsor Indemnification. Notwithstanding the foregoing, Penterra's indemnification obligations under this Section 7.1 shall not apply to Losses to the extent arising from or attributable to:
(i) The negligence or willful misconduct of Lakemont, the Co-Principal Investigator, any sub-investigator, or any other site personnel in the conduct of the trial at Site 002;
(ii) Protocol deviations at Site 002 that were not authorized by Penterra in writing and were not required for the immediate safety of trial subjects; or
(iii) Any breach by Lakemont of its obligations under the MCTA, this Individual Site Agreement, or applicable law.
Subject Medical Care. In addition to and without limiting the foregoing indemnification obligations, Penterra agrees to cover reasonable and customary medical costs for the diagnosis and treatment of study-related injuries sustained by trial subjects enrolled at Site 002, to the extent such costs are not covered by the subject's own health insurance or other third-party coverage. Penterra's obligation to cover subject medical costs under this provision shall be subject to a per-subject cap of Five Hundred Thousand Dollars ($500,000) and an aggregate cap across all participating sites of Fifteen Million Dollars ($15,000,000). The determination of whether an injury is "study-related" shall be made jointly by Penterra and the Co-Principal Investigator, with disputes resolved in accordance with the dispute resolution procedures set forth in Article 11.
Notice Requirement. Lakemont shall provide written notice to Penterra within thirty (30) calendar days of becoming aware of any claim, demand, action, suit, or other proceeding for which indemnification may be sought under this Section 7.1. Such notice shall include a description of the claim, the identity of the claimant, and all available information regarding the circumstances giving rise to the claim. Failure by Lakemont to provide timely notice shall not relieve Penterra of its indemnification obligations under this Section 7.1, except to the extent that Penterra demonstrates that it has been materially prejudiced by such failure.
Section 7.2 — Site/Investigator Indemnification
As set forth in the MCTA, Lakemont shall defend, indemnify, and hold harmless Penterra, its officers, directors, employees, agents, and contractors (the "Sponsor Indemnitees") from and against any and all Losses arising from or in connection with:
(a) The negligence or willful misconduct of Lakemont, the Co-Principal Investigator, any sub-investigator, or any other site personnel in the conduct of the trial at Site 002;
(b) Protocol deviations at Site 002 that were not authorized by Penterra in writing and were not required for the immediate safety of trial subjects; and
(c) Any breach by Lakemont of its obligations under the MCTA, this Individual Site Agreement, or applicable law.
Lakemont's indemnification obligations under this Section 7.2 shall be subject to a per-occurrence cap of Five Million Dollars ($5,000,000) per site and an aggregate cap of Twenty Million Dollars ($20,000,000) across all Veridian Health Research Network participating sites for the duration of the CLARION trial.
Section 7.3 — Sponsor Insurance
Penterra represents that it maintains clinical trial liability insurance through Briarcliff Mutual Insurance Company, under Policy No. BM-CTL-2023-04182, providing the following coverage:
Lakemont Medical Center, the Co-Principal Investigator (Dr. Howard Matsuoka, M.D.), and all sub-investigators and site personnel identified on FDA Form 1572 are named as additional insureds under the Briarcliff Mutual Insurance Company policy referenced above, as required by Exhibit E to the MCTA. A certificate of insurance evidencing such coverage and additional insured status has been, or shall be, delivered to Lakemont within fifteen (15) business days of execution of the MCTA.
Penterra shall maintain such clinical trial liability insurance coverage throughout the term of the CLARION trial and for a period of not less than three (3) years following the completion of all trial activities, or such longer period as reasonably necessary to cover the statute of limitations for claims arising from the trial. Penterra shall provide Lakemont with at least thirty (30) days' prior written notice of any material change in, cancellation of, or failure to renew such coverage, and shall promptly provide updated certificates of insurance upon request.
Section 7.4 — Site Insurance
Lakemont shall maintain, at its own expense, throughout the term of this Individual Site Agreement and for a period of not less than three (3) years following the expiration or termination of this Individual Site Agreement, general liability and professional liability (medical malpractice) insurance coverage with limits of not less than Five Million Dollars ($5,000,000) per occurrence and Ten Million Dollars ($10,000,000) in the aggregate, issued by an insurance carrier with an A.M. Best rating of not less than "A-" (Excellent), Financial Size Category VII or higher.
Lakemont shall deliver a certificate of insurance evidencing such coverage to Penterra within fifteen (15) business days of execution of this Individual Site Agreement, and annually thereafter upon request. The certificate of insurance shall identify Penterra Pharmaceuticals Corp. as an additional insured and shall include a provision requiring the insurer to provide at least thirty (30) days' prior written notice to Penterra of any material change in, cancellation of, or failure to renew such coverage.
In the event that Lakemont's insurance coverage lapses or falls below the minimum limits specified in this Section 7.4, Penterra may, at its option and upon written notice to Lakemont, suspend enrollment at Site 002 until satisfactory evidence of adequate coverage is provided, or terminate this Individual Site Agreement in accordance with Article 10.
ARTICLE 8 — CONFIDENTIALITY AND DATA PROTECTION
Section 8.1 — Confidentiality
Lakemont acknowledges and agrees to be bound by the confidentiality provisions set forth in the MCTA and Exhibit F thereto, which are incorporated herein by reference. Without limiting the generality of such provisions, Lakemont agrees that:
(a) All Confidential Information (as defined in the MCTA) disclosed by Penterra or its agents to Lakemont or any of its employees, agents, or contractors in connection with the CLARION trial shall be maintained in strict confidence and shall not be disclosed to any third party except as expressly permitted by the MCTA, this Individual Site Agreement, or applicable law.
(b) The confidentiality obligations set forth in this Section 8.1 and in the MCTA shall remain in effect for a period of ten (10) years from the date of disclosure of each item of Confidential Information, regardless of the expiration or termination of this Individual Site Agreement.
(c) The scope of Confidential Information includes, without limitation, all Protocol-related information, investigational product specifications (including chemical structure, formulation, and manufacturing information), preclinical and clinical study data, regulatory strategy and submissions, financial terms (including the Site Budget), and all other information designated as confidential by Penterra or that a reasonable person would understand to be confidential given the nature of the information and the circumstances of disclosure.
(d) Permitted disclosures of Confidential Information include disclosures: (i) to the Veridian Central IRB in connection with IRB submissions and reviews; (ii) to regulatory authorities in connection with regulatory inspections, filings, or inquiries; (iii) to Lakemont's legal counsel, under an obligation of confidentiality, for the purpose of obtaining legal advice; and (iv) as otherwise required by applicable law or legal process, provided that Lakemont gives Penterra prompt written notice of any such required disclosure (to the extent permitted by law) and cooperates with Penterra in seeking a protective order or other appropriate remedy.
Lakemont shall ensure that all employees, agents, contractors, and sub-investigators who have access to Confidential Information are bound by obligations of confidentiality no less restrictive than those set forth in this Section 8.1 and the MCTA.
Section 8.2 — HIPAA Compliance
Lakemont shall comply with the Health Insurance Portability and Accountability Act of 1996, as amended, and its implementing regulations at 45 C.F.R. Parts 160 and 164 (collectively, "HIPAA"), with respect to all protected health information ("PHI") of trial subjects enrolled at Site 002. Without limitation:
(a) Lakemont shall obtain valid research authorizations from each trial subject, in accordance with 45 C.F.R. § 164.508, as part of the informed consent process approved by the Veridian Central IRB, prior to the use or disclosure of such subject's PHI for research purposes.
(b) Lakemont shall implement appropriate administrative, physical, and technical safeguards to protect the privacy and security of subjects' PHI in accordance with HIPAA and applicable state privacy laws.
(c) To the extent that Lakemont discloses PHI to Penterra, Meridian CRO, or other parties in connection with the trial, such disclosures shall be made in accordance with the minimum necessary standard and the terms of any applicable business associate agreement or data use agreement.
Section 8.3 — Data Ownership
Penterra retains exclusive ownership of all clinical trial data generated at Site 002 in connection with the CLARION trial, including but not limited to all data entered into the EDC System, all case report forms (whether electronic or paper), all central laboratory data, all biomarker and PK/PD data, and all other data collected pursuant to the Protocol (collectively, "Study Data"). Lakemont acknowledges and agrees that all Study Data are the sole and exclusive property of Penterra and that Lakemont shall have no right, title, or interest in or to the Study Data, except as expressly provided in the MCTA and this Individual Site Agreement (including publication rights under Article 9).
For the avoidance of doubt, Lakemont retains ownership of its own medical records and source documents relating to the medical care of trial subjects, which are maintained by Lakemont in the ordinary course of its clinical practice. However, Lakemont grants Penterra, Meridian CRO, and applicable regulatory authorities the right to access and review such source documents as necessary for the conduct of monitoring visits, audits, inspections, and regulatory proceedings.
ARTICLE 9 — INTELLECTUAL PROPERTY AND PUBLICATION RIGHTS
Section 9.1 — Pre-Existing intellectual Property
Each party retains all right, title, and interest in and to its respective pre-existing intellectual property, including but not limited to patents, patent applications, trade secrets, know-how, copyrights, trademarks, and other proprietary rights that exist as of the Effective Date or that are developed independently of the CLARION trial. Nothing in this Individual Site Agreement or the MCTA shall be construed as granting to any party a license or other right in or to any pre-existing intellectual property of another party, except as expressly provided herein or in the MCTA.