INDIVIDUAL SITE AGREEMENT (JOINDER)
Site Number: 003
Site Name: Haverford Regional Medical Center
Joinder to the Master Clinical Trial Agreement dated June 28, 2023, by and between Penterra Pharmaceuticals Corp. and Veridian Health Research Network, Inc.
Protocol PPC-4871-III "CLARION — Clinical Assessment of Response with Longitudinal Investigation in ONcology"
Investigational Product: Penterafenib (PPC-4871)
Date of Execution: June 28, 2023
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PREAMBLE
This Individual Site Agreement (this "Agreement" or "ISA") is entered into as of June 28, 2023 (the "Effective Date"), by and among:
Penterra Pharmaceuticals Corp. ("Sponsor" or "Penterra"), a corporation organized and existing under the laws of the State of Delaware, with its principal place of business at 200 Biopharma Boulevard, Suite 1400, Princeton, New Jersey 08540;
Veridian Health Research Network, Inc. ("Network" or "Veridian"), a not-for-profit corporation organized and existing under the laws of the State of Delaware and exempt from federal income taxation under Section 501(c)(3) of the Internal Revenue Code, with its principal place of business at 750 Research Parkway, 8th Floor, Philadelphia, Pennsylvania 19104; and
Haverford Regional Medical Center ("Site" or "Institution"), a Veridian Network member institution located in Boston, Massachusetts, designated as Site 003 under the MCTA (as defined below).
Each of Sponsor, Network, and Site may be referred to individually as a "Party" and collectively as the "Parties."
RECITALS
WHEREAS, Sponsor and Network 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), an oral multi-kinase inhibitor, in adult subjects with advanced hepatocellular carcinoma who have received prior systemic therapy, under Protocol PPC-4871-III (the "CLARION" trial), ClinicalTrials.gov Identifier NCT05928174, IND Application No. 157823 filed with the United States Food and Drug Administration (the "FDA");
WHEREAS, the MCTA provides that each participating clinical trial site within the Veridian Health Research Network shall execute an Individual Site Agreement in substantially the form attached as Exhibit C to the MCTA, to evidence such site's agreement to be bound by the terms and conditions of the MCTA and to set forth site-specific information, including identification of the principal investigator, enrollment allocation, budget parameters, and applicable institutional review board information;
WHEREAS, Haverford Regional Medical Center is a member institution in good standing of the Veridian Health Research Network and desires to participate as Site 003 in the CLARION trial in accordance with the terms of the MCTA and this Agreement;
WHEREAS, the total value of the MCTA across all thirty-eight (38) participating Veridian Network sites is approximately Eighty Million Dollars ($80,000,000) over the projected life of the CLARION trial, encompassing site fees, per-patient payments, investigator grants, network coordination fees, technology integration costs, and operational costs over a projected forty-two (42)-month enrollment period and an approximate sixty (60)-month total study duration; and
WHEREAS, the Parties desire to memorialize the terms under which Haverford Regional Medical Center shall participate as Site 003 in the CLARION trial and to set forth the site-specific information applicable thereto.
NOW, THEREFORE, in consideration of the mutual covenants and agreements set forth 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
Haverford Regional Medical Center hereby joins the MCTA as a participating Site and agrees to be bound by all terms, conditions, representations, warranties, covenants, and obligations of the MCTA applicable to a "Site" or "Institution" thereunder, as if Haverford Regional Medical Center were an original signatory party thereto. By executing this Agreement, the Site confirms that it has received, reviewed, and understands the MCTA in its entirety, including all Exhibits and Schedules attached thereto and incorporated therein. The MCTA, together with all Exhibits (A through M) and Schedules (1 through 5) thereto, is hereby incorporated by reference in its entirety as though fully set forth herein. This Agreement shall be deemed a part of the MCTA for all purposes and shall be subject to all of the terms and provisions thereof, except as expressly modified or supplemented by the site-specific terms set forth in the Appendices to this Agreement.
Section 1.2 — Defined Terms
Capitalized terms used but not otherwise defined in this Agreement shall have the meanings ascribed to such terms in the MCTA. For the avoidance of doubt, all definitions set forth in Article I of the MCTA, including but not limited to the definitions of "Adverse Event," "Confidential Information," "Good Clinical Practice" or "GCP," "Informed Consent Form," "Investigational Product," "Protocol," "Serious Adverse Event," "Study Data," and "Subject," are incorporated herein by reference and shall apply to this Agreement as though set forth in full. All references to the "Site" or "Institution" in this Agreement shall mean Haverford Regional Medical Center, unless the context otherwise requires.
Section 1.3 — Order of Precedence
In the event of any conflict, inconsistency, or ambiguity between the terms and conditions of this Agreement and the MCTA, the terms and conditions of the MCTA shall control and take precedence; provided, however, that where such conflict or inconsistency pertains to site-specific information set forth in Appendices A, B, C, or D to this Agreement—including, without limitation, site contact information, investigator identification, enrollment allocation, budget parameters, and IRB information—the site-specific terms set forth in the applicable Appendix shall control to the extent of such conflict. In no event shall a site-specific provision be construed to alter, amend, or waive any material obligation, representation, warranty, indemnification provision, or limitation of liability set forth in the MCTA without the express prior written consent of all Parties.
ARTICLE 2 — SITE INFORMATION
Section 2.1 — Site Identification
The following information identifies the Site for all purposes under the MCTA and this Agreement:
All correspondence, investigational product shipments, regulatory documentation, and monitoring visit communications shall be directed to the addresses and contacts identified in Appendix A, unless otherwise specified in writing by the Site.
Section 2.2 — Site Principal Investigator
The principal investigator assigned to Site 003 for the conduct of the CLARION trial (the "Principal Investigator" or "PI") is identified in Appendix B attached hereto. The Principal Investigator shall be responsible for the overall conduct of the CLARION trial at the Site, including supervision of all sub-investigators and study personnel, compliance with the Protocol, and the accuracy and completeness of all data collected at the Site. The Principal Investigator shall hold and maintain at all times during the term of this Agreement: (a) an active and unrestricted license to practice medicine in the Commonwealth of Massachusetts; and (b) board certification(s) in medical oncology, hematology/oncology, gastroenterology, or another specialty relevant to the diagnosis and treatment of hepatocellular carcinoma, as appropriate to the Principal Investigator's qualifications and the requirements of the Protocol. The Principal Investigator shall have executed, or shall execute prior to the enrollment of the first subject at the Site, a completed Form FDA 1572 (Statement of Investigator) listing Site 003 as the clinical trial site and identifying all sub-investigators. In addition, the Principal Investigator shall have completed, or shall complete prior to the enrollment of the first subject at the Site, a Financial Disclosure Certification in compliance with 21 C.F.R. Part 54, disclosing any financial interests, arrangements, or affiliations that could be affected by the outcome of the CLARION trial.
Section 2.3 — Sub-Investigators and Key Site Personnel
A complete list of all sub-investigators and key study personnel at Site 003, including study coordinators, research nurses, pharmacists responsible for investigational product accountability, and other essential personnel, is set forth in Appendix B. Each sub-investigator identified in Appendix B shall execute an Investigator Undertaking in the form set forth in Exhibit I to the MCTA, pursuant to which each sub-investigator shall agree to be bound by the obligations applicable to investigators under the MCTA, the Protocol, and applicable law and regulations. Financial Disclosure Certifications in accordance with 21 C.F.R. Part 54 are required from all investigators and sub-investigators identified on the Form FDA 1572 and shall be completed and provided to the Sponsor prior to the enrollment of the first subject at the Site. The Site shall promptly notify the Sponsor and Meridian Contract Research Organization, Inc. (the "CRO") in writing of any changes in the list of sub-investigators or key site personnel during the term of this Agreement and shall ensure that any replacement personnel meet the qualifications and credentialing requirements set forth in the MCTA and the Protocol.
Section 2.4 — Site Facilities and Capabilities
Haverford Regional Medical Center hereby confirms that it possesses the physical facilities, clinical equipment, laboratory capabilities, qualified medical and research staff, and access to a sufficient patient population necessary to conduct the CLARION trial in accordance with Protocol PPC-4871-III, the MCTA, applicable regulations, and Good Clinical Practice guidelines. Without limiting the generality of the foregoing, the Site confirms that it has the ability to recruit and enroll subjects with advanced hepatocellular carcinoma (Barcelona Clinic Liver Cancer Stage B or C) who have received at least one prior line of systemic therapy, consistent with the second-line indication that is the focus of the CLARION trial. The Site further confirms that it has adequate pharmacy facilities for the secure storage, dispensing, accountability, and return or destruction of the investigational product in accordance with the Protocol and applicable regulatory requirements. The Site shall permit the Sponsor, the CRO, and applicable regulatory authorities to conduct qualification, initiation, interim monitoring, and close-out visits at the Site in accordance with the monitoring plan set forth in the MCTA.
ARTICLE 3 — IRB APPROVAL AND REGULATORY REQUIREMENTS
Section 3.1 — Institutional Review Board
The Institutional Review Board ("IRB") of Record for Site 003 shall be the Veridian Central IRB, which serves as the central IRB for all non-Pennsylvania Veridian Network member institutions participating in the CLARION trial. The Site shall rely upon the Veridian Central IRB for initial and continuing ethical review of Protocol PPC-4871-III, the informed consent form, recruitment materials, and all protocol amendments, pursuant to an IRB Authorization Agreement (also referred to as an IRB Reliance Agreement) executed between Haverford Regional Medical Center and the Veridian Central IRB. Such reliance arrangement is consistent with the requirements of the 2018 revised Common Rule (45 C.F.R. Part 46, Subpart A, as revised effective January 21, 2019), which mandates single-IRB review for cooperative research conducted at multiple domestic sites, and with FDA guidance applicable to multi-site clinical investigations. For the avoidance of doubt, the Veridian Central IRB designation for Site 003 is distinguished from the IRB arrangements applicable to certain other participating sites within the Veridian Network. For example, Graystone University Medical Center (Site 001), serving as a lead enrollment site within the CLARION trial, utilizes its own institutional IRB—the Graystone University Institutional Review Board (IRB Registration No. IRB00012847, IORG No. IORG0009763)—as its IRB of Record. The Site's reliance on the Veridian Central IRB does not relieve the Site of any institutional obligations to comply with local institutional requirements, institutional biosafety committee approvals, radiation safety committee approvals, or other institutional review or approval requirements applicable at Haverford Regional Medical Center.
Section 3.2 — IRB Approval as Condition Precedent
The Site shall not screen, enroll, randomize, or administer investigational product to any subject until: (a) the Veridian Central IRB has granted written approval of Protocol PPC-4871-III (including any applicable amendments), the informed consent form (in the version applicable to Site 003), and all subject-facing recruitment materials; and (b) a copy of the IRB approval letter or notification has been provided to the Sponsor and to Meridian Contract Research Organization, Inc. (the "CRO"). Receipt of IRB approval documentation by the Sponsor and the CRO is a condition precedent to site activation and to the release of investigational product for shipment to the Site. The Site shall promptly provide to the Sponsor and the CRO copies of all continuing review approvals, amendments, and any correspondence from the Veridian Central IRB relating to the CLARION trial, including without limitation any modifications to the informed consent form or conditions imposed by the IRB.
Section 3.3 — Regulatory Compliance
The Site shall conduct the CLARION trial and all activities under this Agreement in full compliance with all applicable federal, state, and local laws, rules, and regulations, including without limitation the following:
(a) 21 C.F.R. Part 11 (Electronic Records; Electronic Signatures);
(b) 21 C.F.R. Part 50 (Protection of Human Subjects);
(c) 21 C.F.R. Part 54 (Financial Disclosure by Clinical Investigators);
(d) 21 C.F.R. Part 56 (Institutional Review Boards);
(e) 21 C.F.R. Part 312 (Investigational New Drug Application);
(f) The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline E6(R2) — Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice (November 2016);
(g) The Health Insurance Portability and Accountability Act of 1996, as amended ("HIPAA"), and its implementing regulations at 45 C.F.R. Parts 160 and 164;
(h) The Anti-Kickback Statute, 42 U.S.C. § 1320a-7b, and applicable safe harbor regulations at 42 C.F.R. § 1001.952;
(i) The Physician Payments Sunshine Act (Section 6002 of the Affordable Care Act, codified at 42 U.S.C. § 1320a-7h), and the Open Payments reporting requirements of the Centers for Medicare & Medicaid Services; and
(j) All applicable Commonwealth of Massachusetts state laws and regulations governing the conduct of clinical research and the protection of human subjects.
The Site shall ensure that all compensation paid to investigators and other study personnel at the Site in connection with the CLARION trial reflects fair market value for the services rendered and is not conditioned upon or influenced by the volume or value of referrals of subjects to the CLARION trial or any other arrangement. The Site shall make all required regulatory submissions and filings applicable to its participation in the CLARION trial and shall maintain all regulatory documentation at the Site in an organized and accessible manner, available for inspection by the Sponsor, the CRO, the FDA, and other applicable regulatory authorities.
Section 3.4 — IND and Sponsor Obligations
Penterra Pharmaceuticals Corp. is the holder of IND Application No. 157823 filed with the FDA for penterafenib (PPC-4871) and retains all IND-related regulatory responsibilities, including without limitation the obligation to submit IND annual reports, IND amendments, and IND safety reports to the FDA. The Site acknowledges and agrees that the Sponsor bears sole responsibility for: (a) submitting IND safety reports to the FDA within seven (7) calendar days of initial receipt of information for events that are both serious and unexpected and are fatal or life-threatening (as required by 21 C.F.R. § 312.32(c)(2)); and (b) submitting IND safety reports to the FDA within fifteen (15) calendar days of initial receipt of information for all other reportable events meeting the criteria set forth in 21 C.F.R. § 312.32(c)(1). The Site shall cooperate with the Sponsor in the preparation and submission of such safety reports by providing timely, complete, and accurate information regarding adverse events occurring at the Site.
ARTICLE 4 — PROTOCOL CONDUCT AND SAFETY REPORTING
Section 4.1 — Protocol Compliance
The Site shall conduct the CLARION trial in strict accordance with Protocol PPC-4871-III (including all amendments thereto approved by the IRB and the Sponsor), the approved informed consent form, all applicable federal, state, and local laws and regulations, and the ICH E6(R2) Good Clinical Practice guidelines. The Site shall not implement any change to, or deviation from, the Protocol without the prior written agreement of the Sponsor, except where such deviation is necessary to eliminate an immediate hazard to a study subject. Any protocol deviation, whether intentional or unintentional, must be documented by the Site and reported to the Sponsor and to the CRO (Meridian Contract Research Organization, Inc.) in accordance with the deviation reporting procedures set forth in the MCTA. Deviations that are medically necessary to protect the safety, rights, or welfare of a study subject are permitted without prior Sponsor approval and must be reported to the Sponsor and the CRO within twenty-four (24) hours of occurrence, with a full written description of the deviation, the reason therefor, and any corrective and preventive actions taken. The Site acknowledges that repeated or significant protocol deviations may constitute grounds for termination of the Site's participation in the CLARION trial in accordance with the termination provisions of the MCTA.
Section 4.2 — Study Conduct
The CLARION trial is a Phase III, randomized, double-blind, placebo-controlled, multi-center clinical trial evaluating the efficacy and safety of penterafenib (PPC-4871) compared to placebo in adult subjects with advanced hepatocellular carcinoma who have received at least one prior line of systemic therapy. The study employs a two-to-one (2:1) randomization ratio, with subjects randomized to receive either penterafenib or matching placebo administered orally in continuous twenty-eight (28)-day treatment cycles. The primary efficacy endpoint is overall survival ("OS"). Key secondary endpoints include progression-free survival ("PFS"), objective response rate ("ORR") as assessed by independent central radiological review per RECIST v1.1 criteria, and duration of response ("DOR"). Additional exploratory endpoints are set forth in the Protocol.
The investigational product, penterafenib (PPC-4871), is an oral multi-kinase inhibitor targeting VEGFR-2, FGFR-1/2, and c-MET signaling pathways. The Site is responsible for the proper receipt, inspection, storage (at controlled room temperature of 20°C to 25°C, with permitted excursions to 15°C to 30°C), dispensing, drug accountability (including maintenance of investigational product accountability logs), and return or destruction of all investigational product in accordance with the Protocol, the Pharmacy Manual provided by the Sponsor, and applicable regulations. The Site shall designate a licensed pharmacist to serve as the investigational product custodian at the Site, as identified in Appendix B.
Section 4.3 — Safety Reporting
The Site shall report all Serious Adverse Events ("SAEs") to the Sponsor and to Meridian Contract Research Organization, Inc. (9200 Corporate Boulevard, Raleigh, North Carolina 27615) within twenty-four (24) hours of the time at which the Site (including the Principal Investigator or any sub-investigator) first becomes aware of the event, in accordance with the Safety Reporting Procedures set forth in Exhibit J to the MCTA. Initial SAE reports shall be submitted via the electronic safety reporting system provided by Meridian CRO, with follow-up reports submitted within five (5) calendar days of receipt of additional information. The Site shall cooperate fully with the Sponsor in the preparation and submission of IND safety reports to the FDA and in the communication of safety information to the Veridian Central IRB and other applicable regulatory authorities. All non-serious adverse events shall be recorded in the electronic data capture system in accordance with the data entry timelines specified in the Protocol. The Site shall promptly inform the Sponsor and the CRO of any safety signals, trends, or concerns identified at the Site that may affect subject safety or the benefit-risk profile of the investigational product.
Section 4.4 — Electronic Data Capture
The Site shall enter all clinical trial data, including but not limited to subject demographic information, efficacy assessments, laboratory results, adverse event reports, concomitant medication records, and protocol deviation reports, into the electronic data capture ("EDC") platform provided by Pinnacle Data Solutions, Inc. (6000 Clearwater Drive, San Diego, California 92121) in accordance with the data entry timelines specified in the Protocol and the Data Management Plan. The Site shall ensure that all data entries and electronic signatures comply with the requirements of 21 C.F.R. Part 11 governing electronic records and electronic signatures. The Site shall designate appropriately trained study personnel to serve as authorized users of the EDC system and shall ensure that all such personnel complete the EDC training program provided by Pinnacle Data Solutions, Inc. prior to entering any data. The Site shall resolve all data queries issued through the EDC system within the timeframes specified in the Data Management Plan.
Section 4.5 — Central Laboratory
All pharmacokinetic ("PK"), pharmacodynamic ("PD"), biomarker, and safety laboratory analyses required under Protocol PPC-4871-III shall be performed by Northbridge Bioanalytical Laboratories, Inc. (2900 Commerce Way, Baltimore, Maryland 21224), which has been designated as the central laboratory for the CLARION trial, unless otherwise specified in the Protocol or the Laboratory Manual. The Site shall collect, process, and ship all laboratory specimens in accordance with the specimen collection, handling, and shipping procedures set forth in the Laboratory Manual provided by Northbridge Bioanalytical Laboratories, Inc. The Site acknowledges that local laboratory results may be used for clinical management of subjects at the discretion of the Principal Investigator, but that central laboratory results will be used for all efficacy and safety analyses in the CLARION trial database.
Section 4.6 — Approved Subcontractors
The Site acknowledges and agrees that the following entities have been approved by the Sponsor as subcontractors for the performance of specified functions in connection with the CLARION trial, as set forth in Exhibit K to the MCTA:
(a) Meridian Contract Research Organization, Inc. (9200 Corporate Boulevard, Raleigh, North Carolina 27615) — serving as the contract research organization responsible for clinical monitoring, site management, safety data management, and regulatory support;
(b) Pinnacle Data Solutions, Inc. (6000 Clearwater Drive, San Diego, California 92121) — providing the electronic data capture (EDC) platform, data management services, and biostatistical programming support; and
(c) Northbridge Bioanalytical Laboratories, Inc. (2900 Commerce Way, Baltimore, Maryland 21224) — serving as the central laboratory for PK/PD, biomarker, and safety laboratory analyses.
The Site shall not subcontract any of its obligations under this Agreement or the MCTA to any third party without the prior written approval of the Sponsor. Any request for subcontracting approval shall be submitted in writing to the Sponsor and shall include the identity of the proposed subcontractor, a description of the functions to be subcontracted, and evidence of the proposed subcontractor's qualifications and compliance with applicable regulatory requirements.
ARTICLE 5 — BUDGET AND PAYMENT TERMS
Section 5.1 — Site Budget Allocation
The per-patient site fee for the CLARION trial at Site 003 is Fifty-Two Thousand Dollars ($52,000) per subject (screen-to-completion), calculated to reflect fair market value for the investigator and institutional services required under Protocol PPC-4871-III. This per-patient fee covers all study-related procedures, investigator and coordinator time, institutional overhead, and other costs associated with the conduct of the trial at the Site, except as otherwise specified in this Article 5. The Site's enrollment allocation—representing Site 003's proportional share of the total planned enrollment of one thousand two hundred (1,200) subjects across the thirty-eight (38) participating Veridian Network sites—is set forth in Appendix C attached hereto.
Section 5.2 — Payment Milestones (Per Patient)
The per-patient site fee of $52,000 shall be paid in four (4) equal milestone installments as follows:
For purposes of this Section 5.2, "study completion / final visit" means the completion of all Protocol-required assessments for the subject, including the end-of-treatment visit and the safety follow-up visit, or, if applicable, the subject's withdrawal from the study after completion of all required end-of-study procedures. In the event a subject withdraws from the study or is discontinued from treatment prior to reaching a milestone, the Site shall be entitled to payment for all milestones achieved prior to such withdrawal or discontinuation. Partial milestone payments shall not be made except as expressly provided in the MCTA.
Section 5.3 — Start-Up Fees
The total start-up fee payable to Site 003 is Seventy-Five Thousand Dollars ($75,000), intended to cover the costs of site qualification, regulatory submissions, staff training, systems setup, and other start-up activities associated with the initiation of the CLARION trial at the Site. The start-up fee shall be paid in two (2) equal installments as follows:
(a) Fifty percent (50%), in the amount of Thirty-Seven Thousand Five Hundred Dollars ($37,500), payable upon site activation (defined as the date on which the Site has met all activation criteria, including receipt of IRB approval, execution of this Agreement, completion of site initiation visit, and receipt of investigational product); and
(b) Fifty percent (50%), in the amount of Thirty-Seven Thousand Five Hundred Dollars ($37,500), payable upon enrollment of the first subject at the Site.
Section 5.4 — Annual Site Maintenance Fees
In addition to the per-patient fees and start-up fees set forth above, the Sponsor shall pay to the Site an annual site maintenance fee of Forty Thousand Dollars ($40,000) per year, payable annually in advance on each anniversary of site activation. The annual site maintenance fee is intended to cover ongoing institutional overhead, research infrastructure costs, regulatory maintenance, and personnel costs associated with the Site's continued participation in the CLARION trial. Based on an estimated average site participation period of approximately three and one-half (3.5) years, the total estimated site maintenance fees payable to Site 003 over the life of the trial are approximately One Hundred Forty Thousand Dollars ($140,000), subject to adjustment based on the actual duration of Site participation. Proration shall apply for any partial year of participation, calculated on a pro rata basis.
Section 5.5 — Payment Terms
All payments due from the Sponsor to the Site under this Agreement shall be made on a Net Forty-Five (45) days basis from the date of the Sponsor's receipt of a proper, complete, and undisputed invoice from the Site. Invoices shall be submitted to Penterra's Clinical Contracts department at the following address and to the attention of the following individual:
Penterra Pharmaceuticals Corp. Clinical Contracts Department 200 Biopharma Boulevard, Suite 1400 Princeton, New Jersey 08540
Attn: Samantha Novak, Director, Clinical Contracts
Email: s.novak@penterra.com
All invoices shall reference the MCTA, this Agreement, the Site Number (003), the Protocol Number (PPC-4871-III), and the applicable milestone or fee category. The Sponsor reserves the right to withhold payment of any invoice that is incomplete, inaccurate, or in dispute, provided that the Sponsor shall notify the Site in writing of the basis for any such withholding within fifteen (15) business days of receipt of the invoice and shall promptly pay all undisputed amounts.
Section 5.6 — Network Coordination Fee
The Site acknowledges that Veridian Health Research Network, Inc. receives a network coordination and administrative fee in the total amount of Four Million Two Hundred Thousand Dollars ($4,200,000), calculated at a rate of Three Hundred Thousand Dollars ($300,000) per quarter over fourteen (14) quarters, paid directly by the Sponsor to the Veridian central office. The network coordination fee compensates Veridian for centralized administrative support, protocol development assistance, site recruitment and qualification, regulatory coordination, network-wide training, quality assurance oversight, and other network-level services. This fee is separate from and in addition to all Site-specific payments set forth in this Article 5 and is not deducted from or offset against any amounts payable to the Site.
Section 5.7 — Technology/EDC Integration Costs
The costs associated with the integration, configuration, licensing, and ongoing maintenance of the electronic data capture platform provided by Pinnacle Data Solutions, Inc. are covered under the MCTA's technology/EDC integration allocation of One Million Two Hundred Thirty Thousand Dollars ($1,230,000) and are paid directly by the Sponsor to Pinnacle Data Solutions, Inc. These costs are not charged separately to the Site, and the Site shall not be responsible for any EDC platform fees, user license fees, or system integration costs in connection with the CLARION trial, except for the costs of Site-owned hardware (e.g., computers, monitors, internet connectivity) used to access the EDC platform.
ARTICLE 6 — INDEMNIFICATION
Section 6.1 — Sponsor Indemnification of Site and Investigators
Subject to the terms, conditions, and limitations set forth in this Article 6 and in the MCTA, Penterra Pharmaceuticals Corp. shall defend, indemnify, and hold harmless Haverford Regional Medical Center, its officers, directors, trustees, employees, agents, investigators, sub-investigators, and site staff (collectively, the "Site Indemnitees") from and against any and all claims, demands, actions, suits, proceedings, losses, damages, liabilities, judgments, settlements, penalties, fines, costs, and expenses (including reasonable attorneys' fees and costs of litigation) (collectively, "Losses") to the extent arising out of or resulting from:
(a) Personal injury, illness, or death of a study subject caused by the investigational product (penterafenib / PPC-4871) when such investigational product was administered in accordance with Protocol PPC-4871-III and the instructions of the Sponsor;
(b) Any defect in the design, manufacture, labeling, packaging, or distribution of the investigational product, including any failure of the investigational product to conform to the specifications set forth in the Investigator's Brochure;
(c) Any breach by Penterra of its representations, warranties, covenants, or obligations under the MCTA or the Protocol; and
(d) Any negligent act or omission, recklessness, or willful misconduct of Penterra, its employees, agents, or representatives in connection with the CLARION trial.
Section 6.2 — Carve-Outs from Sponsor Indemnification
Notwithstanding Section 6.1, Penterra's indemnification obligations under this Article 6 shall not apply to any Losses to the extent such Losses arise out of or result from:
(i) The negligence, recklessness, or willful misconduct of the Site, the Principal Investigator, any sub-investigator, or any member of the Site's study personnel;
(ii) Protocol deviations committed by the Site, the Principal Investigator, or any sub-investigator that were not authorized by Penterra and were not required for the immediate protection of a study subject's safety, rights, or welfare; or
(iii) Any breach by the Site of its representations, warranties, covenants, or obligations under the MCTA, this Agreement, or applicable law.
To the extent that Losses result from the concurrent fault of both Penterra and one or more Site Indemnitees, the indemnification obligation of Penterra under this Article 6 shall be reduced in proportion to the relative fault of the Site Indemnitees, as determined by agreement of the Parties or, if the Parties cannot agree, by a trier of fact in a proceeding conducted in accordance with Article 11.
Section 6.3 — Subject-Injury Medical Care
In addition to the indemnification obligations set forth in Section 6.1, Penterra shall pay or reimburse the reasonable and customary medical costs incurred for the treatment of study-related injuries sustained by subjects enrolled at Site 003, to the extent such costs are not covered by the subject's own health insurance or other third-party coverage. For purposes of this Section 6.3, "study-related injuries" means injuries, illnesses, or adverse events that are directly attributable to the administration of the investigational product or to Protocol-required study procedures, as determined by Penterra's medical monitor in consultation with the Principal Investigator. Penterra's obligation under this Section 6.3 is subject to the following caps:
(a) Per-subject cap: Five Hundred Thousand Dollars ($500,000) per subject;
(b) Aggregate cap across all participating sites in the CLARION trial: Fifteen Million Dollars ($15,000,000).
Notwithstanding the foregoing caps, claims arising from defects in the investigational product (as described in Section 6.1(b)) shall be subject to uncapped indemnification, subject only to Penterra's overall financial capacity and applicable insurance coverage.
Section 6.4 — Site/Investigator Indemnification of Sponsor
Subject to the terms, conditions, and limitations set forth in this Article 6 and in the MCTA, Haverford Regional Medical Center shall defend, indemnify, and hold harmless Penterra Pharmaceuticals Corp., its officers, directors, employees, agents, and representatives (collectively, the "Sponsor Indemnitees") from and against any and all Losses to the extent arising out of or resulting from:
(a) The negligence, recklessness, or willful misconduct of the Site, the Principal Investigator, any sub-investigator, or any member of the Site's study personnel in the performance of the CLARION trial at Site 003;
(b) Protocol deviations committed by the Site, the Principal Investigator, or any sub-investigator that were not authorized by Penterra and were not required for the immediate protection of a study subject's safety, rights, or welfare; and
(c) Any breach by the Site of its representations, warranties, covenants, or obligations under the MCTA or this Agreement.
The Site's indemnification obligations under this Section 6.4 are subject to the following caps:
(i) Five Million Dollars ($5,000,000) per site per occurrence; and
(ii) Twenty Million Dollars ($20,000,000) in the aggregate across all Veridian Network sites participating in the CLARION trial.
Section 6.5 — Notice Requirements
The Party seeking indemnification (the "Indemnified Party") shall provide written notice to the Party from which indemnification is sought (the "Indemnifying Party") within thirty (30) calendar days of the date on which the Indemnified Party first becomes aware of any claim, demand, action, suit, or proceeding for which indemnification may be sought under this Article 6. Such notice shall include a reasonably detailed description of the claim, the factual basis therefor (to the extent known), and the estimated amount of Losses (if ascertainable). The failure of the Indemnified Party to provide timely notice in accordance with this Section 6.5 shall not relieve the Indemnifying Party of its indemnification obligations under this Article 6, except to the extent that the Indemnifying Party demonstrates that it has been materially prejudiced by such failure to provide timely notice.
Section 6.6 — Defense and Settlement
The Indemnifying Party shall have the right, at its expense, to assume and control the defense of any claim for which indemnification is sought under this Article 6, including the right to select counsel, direct the litigation strategy, and negotiate and effectuate settlement, provided that the Indemnifying Party shall keep the Indemnified Party reasonably informed of the progress of such defense. The Indemnified Party shall cooperate with the Indemnifying Party and its counsel in the defense of any such claim, including providing access to relevant documents, records, and witnesses. The Indemnifying Party shall not consent to the entry of any judgment or enter into any settlement with respect to any indemnified claim without the prior written consent of the Indemnified Party, which consent shall not be unreasonably withheld, conditioned, or delayed. The Indemnified Party shall have the right to participate in the defense of any indemnified claim at its own expense and with counsel of its own selection.
ARTICLE 7 — INSURANCE
Section 7.1 — Sponsor Insurance
Penterra Pharmaceuticals Corp. represents and warrants that it maintains clinical trial liability insurance through Briarcliff Mutual Insurance Company (55 Constitution Plaza, Hartford, Connecticut 06103), under Policy No. BM-CTL-2023-04182, with the following coverage limits:
The current policy period is April 1, 2023 through March 31, 2024, and the policy is renewable annually for the duration of the CLARION trial. Penterra shall maintain such insurance coverage, or substantially equivalent coverage, in full force and effect throughout the term of the MCTA and for a period of not less than three (3) years following the completion or termination of the CLARION trial. Haverford Regional Medical Center, its officers, directors, trustees, employees, and investigators are named as additional insureds under the policy with respect to claims arising from the conduct of the CLARION trial at Site 003. Penterra shall provide a certificate of insurance evidencing such coverage to the Site upon request and shall notify the Site in writing at least thirty (30) days prior to any material change in, cancellation of, or non-renewal of such insurance coverage.
Section 7.2 — Site Insurance
Haverford Regional Medical Center shall obtain and maintain, at its own expense, the following minimum insurance coverage during the term of this Agreement and for a period of not less than three (3) years following the completion or termination of the CLARION trial at Site 003:
(a) Commercial General Liability Insurance with a per-occurrence limit of not less than Five Million Dollars ($5,000,000) and an aggregate limit of not less than Ten Million Dollars ($10,000,000); and
(b) Professional Liability (Medical Malpractice) Insurance with a per-occurrence limit of not less than Five Million Dollars ($5,000,000) and an aggregate limit of not less than Ten Million Dollars ($10,000,000).
The Site shall provide a certificate of insurance evidencing such coverage to the Sponsor within fifteen (15) business days of the execution of this Individual Site Agreement. Evidence of coverage shall be provided annually thereafter during the term of the MCTA and upon the Sponsor's reasonable request. The Site shall notify the Sponsor in writing at least thirty (30) days prior to any material change in, cancellation of, or non-renewal of such insurance coverage.
Section 7.3 — Certificate Exchange
The Parties shall exchange certificates of insurance evidencing the coverage required under Sections 7.1 and 7.2 within fifteen (15) business days of the execution of this Agreement and annually thereafter during the term of the MCTA. Each Party shall promptly notify the other Parties in writing of any material change in, cancellation of, or non-renewal of any required insurance coverage.
ARTICLE 8 — DATA OWNERSHIP, CONFIDENTIALITY, AND RECORDS
Section 8.1 — Clinical Trial Data Ownership
Penterra Pharmaceuticals Corp. shall retain exclusive ownership of all clinical trial data, case report forms (whether electronic or paper), databases, analyses, reports, and other data and information generated under Protocol PPC-4871-III at the Site (collectively, "Study Data"). The Site shall have no right, title, or interest in or to the Study Data, except as expressly provided in the MCTA or this Agreement. Notwithstanding the foregoing, the Site shall retain ownership of the original source documents (e.g., medical records, nursing notes, laboratory records) maintained at the Site in the ordinary course of patient care, subject to the Sponsor's right to access and copy such source documents in accordance with the monitoring and audit provisions of the MCTA and applicable regulations. The Site hereby grants to Penterra a perpetual, irrevocable, worldwide, royalty-free license to access, use, copy, and reference source documents to the extent necessary for the Sponsor's regulatory, research, and commercial purposes.
Section 8.2 — Site Record Retention
The Site shall maintain and retain all source documents, regulatory files, investigational product accountability records, IRB correspondence, signed informed consent forms, and all other study records relating to the conduct of the CLARION trial at Site 003 for a minimum period of fifteen (15) years following the completion of the CLARION trial at the Site (projected study completion: approximately August 2028) or for such longer period as may be required by applicable federal, state, or local law, whichever is longer. The Site shall not destroy any study records without the prior written consent of the Sponsor. In the event the Site is unable to continue maintaining study records (e.g., due to institutional closure or reorganization), the Site shall notify the Sponsor at least ninety (90) days in advance and shall transfer custody of all study records to the Sponsor or to a designee specified by the Sponsor.
Section 8.3 — Confidentiality
All information disclosed by the Sponsor to the Site in connection with the CLARION trial, including without limitation the Protocol, the Investigator's Brochure, the investigational product specifications, manufacturing information, proprietary analytical methods, unpublished Study Data, financial terms of this Agreement and the MCTA, and any other information designated as confidential by the disclosing party (collectively, "Confidential Information"), shall be treated by the receiving party as confidential and proprietary. The confidentiality obligations set forth in this Section 8.3 shall remain in effect for a period of ten (10) years from the date of disclosure of the applicable Confidential Information, regardless of the expiration or termination of this Agreement or the MCTA.
The receiving party shall not disclose Confidential Information to any third party without the prior written consent of the disclosing party, except as follows:
(a) Disclosures to the IRB of Record or other institutional review bodies as required for the ethical review and oversight of the CLARION trial;
(b) Disclosures to the FDA or other regulatory authorities as required by applicable law or regulation;
(c) Disclosures to the receiving party's legal counsel, accountants, or auditors who have a need to know such information and who are bound by obligations of confidentiality no less restrictive than those set forth herein; and
(d) Disclosures required by court order, subpoena, or other compulsory legal process, provided that the receiving party provides prompt written notice to the disclosing party (to the extent legally permitted) and cooperates with the disclosing party's efforts to obtain a protective order or other appropriate remedy.
Section 8.4 — HIPAA Compliance
The Site shall comply with all applicable provisions of HIPAA (45 C.F.R. Parts 160 and 164) in all handling, use, and disclosure of protected health information ("PHI") in connection with the CLARION trial. The Site shall obtain valid HIPAA research authorizations from each study subject, or shall obtain an IRB-approved waiver of authorization, prior to using or disclosing any PHI for research purposes. The Site shall implement appropriate administrative, physical, and technical safeguards to protect the privacy and security of PHI in accordance with the HIPAA Privacy Rule and the HIPAA Security Rule. The relationship between the Sponsor and the Site with respect to PHI shall be governed by the Business Associate Agreement or equivalent provisions set forth in the MCTA, as applicable.
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 pre-existing intellectual property, including without limitation patents, patent applications, copyrights, trademarks, trade secrets, and know-how owned or controlled by such Party prior to the Effective Date or developed independently of the CLARION trial. Nothing in this Agreement or the MCTA shall be construed to grant to any other Party any license or right in or to any pre-existing intellectual property of the owning Party, except as expressly set forth herein or in the MCTA.
Section 9.2 — Joint Inventions
Any inventions, discoveries, improvements, or other intellectual property jointly conceived or first reduced to practice by employees, agents, or investigators of two or more Parties in the course of or as a result of the conduct of the CLARION trial ("Joint Inventions") shall be owned and managed in accordance with the terms and conditions set forth in the intellectual Property Side Letter (the "IP Side Letter") executed concurrently with the MCTA on June 28, 2023, by and between Penterra Pharmaceuticals Corp. and Veridian Health Research Network, Inc., which IP Side Letter is incorporated herein by reference. The Site agrees to be bound by the terms of the IP Side Letter with respect to any Joint Inventions to which the Site's investigators or personnel contribute.
Section 9.3 — Publication Rights
The Site's investigators shall have the right to publish the results of the CLARION trial in peer-reviewed journals, at scientific conferences, and in other academic publications, subject to the following conditions:
(a) Sponsor Review. The Site shall submit to the Sponsor a copy of any proposed publication or presentation at least sixty (60) days prior to the anticipated date of submission or presentation. The Sponsor shall have the right to review such proposed publication or presentation solely for the purpose of identifying any Confidential Information of the Sponsor and any patentable subject matter.
(b) Delay for Patent Filing. If the Sponsor determines in good faith that the proposed publication or presentation contains patentable subject matter, the Sponsor may request a delay in publication or presentation of up to an additional ninety (90) days beyond the initial sixty (60)-day review period to permit the filing of patent applications. The total delay shall not exceed one hundred fifty (150) days from the date of submission of the proposed publication to the Sponsor.
(c) Removal of Confidential Information. The Site shall remove any Confidential Information of the Sponsor identified during the review period, unless the Sponsor consents in writing to the inclusion of such information.
(d) Academic Freedom. The Parties acknowledge and agree that the publication review provisions of this Section 9.3 are intended to protect the legitimate intellectual property and business interests of the Sponsor while preserving the academic freedom and professional obligations of the Site's investigators, consistent with the principles negotiated and agreed upon by the Parties in Article XII of the MCTA.
ARTICLE 10 — TERM, TERMINATION, AND WIND-DOWN
Section 10.1 — Term
This Individual Site Agreement shall be effective as of the Effective Date and shall continue in full force and effect for the duration of the MCTA, including any extensions or renewals thereof, unless earlier terminated in accordance with this Article 10 or the termination provisions of the MCTA. The projected enrollment period for the CLARION trial is forty-two (42) months from the date of first patient in (target first patient in date: August 14, 2023). The projected total study duration, including enrollment, treatment, follow-up, and study close-out, is approximately sixty (60) months, with projected study completion on or about August 2028. These projections are estimates only and are subject to change based on enrollment rates, interim analysis results, regulatory requirements, and other factors.
Section 10.2 — Termination
Either Party may terminate this Agreement upon the occurrence of a material breach by another Party that remains uncured after the expiration of the applicable cure period set forth in the MCTA. All termination rights, notice requirements, and cure periods applicable to the Site's participation in the CLARION trial are governed by the termination provisions set forth in Article XV of the MCTA, which are incorporated herein by reference. Without limiting the foregoing, the Sponsor may terminate the Site's participation in the CLARION trial for cause, including without limitation:
(a) Failure by the Site to comply with the Protocol, applicable regulations, GCP guidelines, or the terms of this Agreement or the MCTA;
(b) Receipt by the Sponsor of a warning letter, Form FDA 483 (Inspectional Observations), or other regulatory action from the FDA or other regulatory authority relating to the Site's conduct of the CLARION trial;
(c) Inadequate enrollment at the Site, as determined by the Sponsor in its reasonable discretion based on enrollment milestones established in the MCTA;
(d) Loss by the Principal Investigator of medical licensure, board certification, or clinical privileges;
(e) Debarment, exclusion, or disqualification of the Site or any investigator under applicable federal or state law; or
(f) Termination or expiration of the MCTA.
Section 10.3 — Wind-Down
Upon termination or expiration of this Agreement or the Site's participation in the CLARION trial, a wind-down period of one hundred twenty (120) days shall apply to ensure the orderly transition and continued safety of all study subjects enrolled at Site 003. During the wind-down period:
(a) Subjects who are actively receiving treatment with the investigational product shall be transitioned to another qualified participating site within the Veridian Network, or, if no suitable alternative site is available, shall be permitted to complete their current treatment cycle at Site 003, subject to the approval of the Sponsor and the IRB;
(b) The Site shall continue to perform all safety reporting, adverse event follow-up, and regulatory reporting obligations under this Agreement, the MCTA, and applicable law;
(c) The Site shall cooperate with the Sponsor and the CRO in the orderly transfer of all study records, Study Data, and regulatory documentation;
(d) The Site shall return all unused investigational product, study supplies, and Sponsor-provided equipment to the Sponsor or the CRO in accordance with the Sponsor's instructions; and
(e) Payment for services rendered by the Site through and including the end of the wind-down period shall be made by the Sponsor in accordance with the payment terms set forth in Article 5 of this Agreement and the MCTA.
ARTICLE 11 — DISPUTE RESOLUTION
Section 11.1 — Governing Law
This Individual Site Agreement and the MCTA, and all claims, disputes, and controversies arising out of or relating to this Agreement or the MCTA, shall be governed by, construed in accordance with, and enforced under the laws of the State of New York, without giving effect to any choice-of-law or conflict-of-laws rules or provisions that would cause the application of the laws of any other jurisdiction.
Section 11.2 — Dispute Escalation
Any dispute, controversy, or claim arising out of or relating to this Agreement or the MCTA, or the breach, termination, or validity thereof (a "Dispute"), shall be resolved in accordance with the following escalation procedure:
(a) Negotiation. The Parties shall first attempt to resolve the Dispute through good-faith negotiation between designated senior representatives of each Party. Such representatives shall meet (in person or by videoconference) within ten (10) business days of written notice of the Dispute and shall endeavor to resolve the Dispute within thirty (30) days of such initial meeting.
(b) Mediation. If the Dispute is not resolved through negotiation within the thirty (30)-day period, the Parties shall submit the Dispute to mediation administered by the American Arbitration Association ("AAA") under the AAA Commercial Mediation Procedures then in effect. The mediation shall be conducted in New York, New York, and shall be completed within sixty (60) days of the commencement of mediation, unless the Parties mutually agree to extend such period. The costs of mediation shall be shared equally by the Parties.
(c) Binding Arbitration. If the Dispute is not resolved through mediation within the sixty (60)-day period, the Dispute shall be finally and exclusively resolved by binding arbitration administered by the AAA under the AAA Commercial Arbitration Rules then in effect. The arbitration shall be conducted in New York, New York, before a panel of three (3) arbitrators, each of whom shall have substantial experience in pharmaceutical or biotechnology litigation or clinical trial disputes. Each Party shall select one (1) arbitrator, and the two (2) Party-selected arbitrators shall select the third arbitrator, who shall serve as the chairperson of the arbitration panel. The arbitration award shall be final and binding on the Parties and may be entered and enforced in any court of competent jurisdiction. The arbitrators shall not have the authority to award punitive or exemplary damages except to the extent such damages are expressly authorized by applicable law.
Section 11.3 — Injunctive Relief
Notwithstanding the dispute resolution provisions set forth in Section 11.2, any Party may seek temporary, preliminary, or permanent injunctive relief, specific performance, or other equitable relief from the state and federal courts located in New York County, New York, without first exhausting the negotiation, mediation, and arbitration procedures set forth in Section 11.2, where such relief is necessary to prevent irreparable harm, including without limitation breaches of confidentiality, misappropriation of intellectual property, or unauthorized disclosure of Study Data. Each Party irrevocably submits to the exclusive jurisdiction and venue of such courts for the purpose of any such proceeding and waives any objection to such jurisdiction and venue on the grounds of inconvenient forum or otherwise.
ARTICLE 12 — REPRESENTATIONS AND WARRANTIES
Section 12.1 — Site Representations
Haverford Regional Medical Center hereby represents and warrants to the Sponsor and the Network as follows, as of the Effective Date and continuing throughout the term of this Agreement:
(a) Organization and Existence. The Site is a duly organized and validly existing institution under the laws of the Commonwealth of Massachusetts and has all requisite power and authority to own its properties and to carry on its operations as currently conducted.
(b) Network Membership. The Site is a member in good standing of the Veridian Health Research Network, Inc. and has satisfied all membership requirements and obligations applicable to its participation in the CLARION trial.
(c) Authority. The Site has the full corporate or institutional authority to execute, deliver, and perform this Agreement and to consummate the transactions contemplated hereby. The execution, delivery, and performance of this Agreement by the Site have been duly authorized by all necessary institutional action, and this Agreement constitutes a valid and binding obligation of the Site, enforceable against the Site in accordance with its terms.
(d) Investigator Qualifications. All investigators and sub-investigators identified in Appendix B are properly qualified, credentialed, and licensed to conduct clinical research and to practice medicine in the Commonwealth of Massachusetts, and possess the training and experience necessary to conduct the CLARION trial in accordance with the Protocol and applicable regulations.
(e) Non-Debarment. Neither the Site nor any of its officers, directors, employees, agents, investigators, or sub-investigators has been debarred, excluded, suspended, proposed for debarment, or otherwise made ineligible to participate in federal healthcare programs under 42 U.S.C. § 1320a-7, 42 U.S.C. § 1320a-7a, or 21 U.S.C. § 335a, or any similar federal or state law. The Site shall promptly notify the Sponsor in writing if any such debarment, exclusion, or disqualification occurs during the term of this Agreement.