INDIVIDUAL SITE AGREEMENT (JOINDER)
Site 001 — Graystone University Medical Center
Pursuant to the Master Clinical Trial Agreement dated June 28, 2023
Protocol PPC-4871-III (CLARION — Clinical Assessment of Response with Longitudinal Investigation in ONcology)
Among:
PENTERRA PHARMACEUTICALS CORP. ("Sponsor")
VERIDIAN HEALTH RESEARCH NETWORK, INC. ("Network")
GRAYSTONE UNIVERSITY MEDICAL CENTER ("Site" or "Institution")
Execution Date: June 28, 2023
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INDIVIDUAL SITE AGREEMENT (JOINDER)
This Individual Site Agreement (this "Agreement" or "ISA") is entered into as of June 28, 2023 (the "Execution Date"), by and among:
PENTERRA PHARMACEUTICALS CORP., a Delaware corporation, with its principal offices at 200 Biopharma Boulevard, Suite 1400, Princeton, New Jersey 08540 (the "Sponsor" or "Penterra");
VERIDIAN HEALTH RESEARCH NETWORK, INC., a Delaware 501(c)(3) tax-exempt research organization, with its principal offices at 750 Research Parkway, 8th Floor, Philadelphia, Pennsylvania 19104 (the "Network" or "Veridian");
GRAYSTONE UNIVERSITY MEDICAL CENTER, a Pennsylvania nonprofit corporation, with its principal offices at 1200 University Avenue, Philadelphia, Pennsylvania 19104 (the "Site" or "Institution" or "Graystone"); and
DR. CATHERINE ALDRIDGE, M.D., Ph.D., in her capacity as Principal Investigator and Global Principal Investigator for Protocol PPC-4871-III, at Graystone University Medical Center, 1200 University Avenue, Philadelphia, Pennsylvania 19104 (the "Principal Investigator" or "PI").
Each of the foregoing is sometimes referred to individually as a "Party" and collectively as the "Parties."
RECITALS
WHEREAS (A), Penterra Pharmaceuticals Corp., a corporation organized and existing under the laws of the State of Delaware and headquartered at 200 Biopharma Boulevard, Suite 1400, Princeton, New Jersey 08540, is the sponsor of a Phase III, randomized, double-blind, placebo-controlled clinical trial of penterafenib (PPC-4871), an oral multi-kinase inhibitor, for the treatment of advanced hepatocellular carcinoma ("HCC") in the second-line setting after prior systemic therapy, conducted pursuant to Protocol PPC-4871-III, commonly referred to as the "CLARION" trial (Clinical Assessment of Response with Longitudinal Investigation in ONcology), under Investigational New Drug Application No. 157823 filed with the United States Food and Drug Administration (the "FDA"), and registered under ClinicalTrials.gov Identifier NCT05928174;
WHEREAS (B), Veridian Health Research Network, Inc., a Delaware 501(c)(3) tax-exempt research organization headquartered at 750 Research Parkway, 8th Floor, Philadelphia, Pennsylvania 19104, operates a collaborative network of thirty-eight (38) academic medical centers and affiliated research institutions located across fourteen (14) states throughout the United States, and serves as the coordinating entity for multi-site clinical research conducted within its member institutions;
WHEREAS (C), the Sponsor and the Network have entered into that certain Master Clinical Trial Agreement dated June 28, 2023 (as may be amended from time to time, the "MCTA"), with a total deal value of Eighty Million Dollars ($80,000,000), governing the conduct of the CLARION trial across the Network's participating sites, including the establishment of general terms and conditions applicable to all participating institutions within the Veridian Health Research Network;
WHEREAS (D), Graystone University Medical Center, a Pennsylvania nonprofit corporation located at 1200 University Avenue, Philadelphia, Pennsylvania 19104, is a duly constituted member institution of the Veridian Health Research Network in good standing, and has been designated as Site 001 and the lead enrollment site for the CLARION trial, based upon its demonstrated clinical capabilities, patient population, and the qualifications of its investigative staff;
WHEREAS (E), the Graystone University Institutional Review Board (IRB Registration Number: IRB00012847, registered with the Office for Human Research Protections of the U.S. Department of Health and Human Services) will serve as the Institutional Review Board of record for this Site, providing independent ethical oversight of the conduct of the CLARION trial at Graystone University Medical Center;
WHEREAS (F), Dr. Catherine Aldridge, M.D., Ph.D., Professor of Oncology at Graystone University Medical Center, a physician-scientist with extensive experience in the conduct of clinical trials in hepatocellular carcinoma and hepatobiliary malignancies, will serve as the Global Principal Investigator for Protocol PPC-4871-III across all participating Veridian Network sites, and simultaneously as the Site Principal Investigator for Site 001 at Graystone University Medical Center; and
WHEREAS (G), this Individual Site Agreement constitutes a joinder to the MCTA in accordance with Section 3.2 thereof, and, together with the MCTA and its Exhibits A through K and Schedule 1, and the Appendices attached hereto, sets forth the complete terms and conditions governing the conduct of the CLARION trial at this Site.
NOW, THEREFORE, in consideration of the mutual promises, covenants, and agreements set forth herein, and for other good and valuable consideration, the receipt and sufficiency of which are hereby acknowledged, the Parties agree as follows:
ARTICLE 1 — DEFINITIONS AND INCORPORATION BY REFERENCE
Section 1.1 — Definitions
All capitalized terms used but not otherwise defined in this Individual Site Agreement shall have the respective meanings ascribed to such terms in the MCTA. In addition to the defined terms set forth in Article 1 of the MCTA, the following terms shall have the meanings set forth below for purposes of this Individual Site Agreement:
(a) "Effective Date" means July 18, 2023, which is the effective date of the MCTA upon the satisfaction of all conditions precedent set forth in Section 2.4 of the MCTA, including receipt of all executed joinder agreements, evidence of IRB approval, and delivery of certificates of insurance by the requisite number of participating sites.
(b) "Institution" or "Site" means Graystone University Medical Center, a Pennsylvania nonprofit corporation, located at 1200 University Avenue, Philadelphia, Pennsylvania 19104.
(c) "Site Number" means Site 001, as designated by the Sponsor in the Site Designation Table attached as Schedule 1 to the MCTA.
(d) "Principal Investigator" or "PI" means Dr. Catherine Aldridge, M.D., Ph.D., Professor of Oncology, Graystone University Medical Center. Dr. Aldridge also serves as the Global Principal Investigator for Protocol PPC-4871-III.
(e) "IRB" means the Graystone University Institutional Review Board, bearing IRB Registration Number IRB00012847, as registered with the Office for Human Research Protections of the U.S. Department of Health and Human Services.
(f) "Protocol" means Protocol PPC-4871-III (CLARION — Clinical Assessment of Response with Longitudinal Investigation in ONcology), including all amendments thereto approved by the Sponsor, the IRB, and the FDA, as applicable.
(g) "Investigational Product" means penterafenib (PPC-4871), an oral multi-kinase inhibitor, supplied by or on behalf of the Sponsor for use in connection with the CLARION trial, and any matching placebo manufactured for use in the trial.
(h) "CRO" means Meridian Contract Research Organization, Inc., the contract research organization engaged by the Sponsor to provide monitoring, data management, safety reporting, biostatistical, and related services in connection with the CLARION trial.
(i) "EDC Platform" means the electronic data capture and eClinical system provided by Pinnacle Data Solutions, Inc. for the collection, management, and transmission of clinical trial data generated at participating sites under the CLARION trial.
(j) "Central Laboratory" means Northbridge Bioanalytical Laboratories, Inc., the central laboratory services provider engaged by the Sponsor to perform pharmacokinetic, pharmacodynamic, biomarker, and safety laboratory analyses for the CLARION trial.
Section 1.2 — Incorporation of MCTA
The terms and conditions of the Master Clinical Trial Agreement dated June 28, 2023, by and between Penterra Pharmaceuticals Corp. and Veridian Health Research Network, Inc., including without limitation all Exhibits A through K and Schedule 1 attached thereto and incorporated therein, are hereby incorporated by reference in their entirety into this Individual Site Agreement as if fully set forth herein. The Parties acknowledge and agree that this Individual Site Agreement is a joinder instrument as contemplated by Section 3.2 of the MCTA and that, upon execution and delivery of this Agreement by all Parties hereto, the Institution shall be bound by all terms and conditions of the MCTA applicable to a "Participating Site" or "Site" thereunder.
In the event of any conflict or inconsistency between any provision of this Individual Site Agreement and any provision of the MCTA, the terms and conditions of the MCTA shall control and govern, except where this Individual Site Agreement contains site-specific provisions that are expressly stated to supersede or modify the corresponding general terms of the MCTA with respect to this Site only. Any such site-specific superseding provision shall be clearly identified as such in this Agreement and shall apply solely to Site 001 and shall not affect the rights or obligations of any other participating site under the MCTA.
ARTICLE 2 — SITE DESIGNATION AND SCOPE OF WORK
Section 2.1 — Site Designation
Graystone University Medical Center is hereby designated as Site 001 under the MCTA, serving as the lead enrollment site for the CLARION trial. The Institution's principal site address for the conduct of all trial-related activities under Protocol PPC-4871-III is:
Graystone University Medical Center 1200 University Avenue Philadelphia, Pennsylvania 19104
All clinical trial activities at this Site shall be conducted at the facilities of the Institution at the above address, or at such other facilities of the Institution as may be approved in writing by the Sponsor from time to time. The Institution shall not relocate trial activities to any facility outside the Institution's campus without the prior written consent of the Sponsor and, where applicable, approval of the IRB.
Section 2.2 — Scope of Work
The Institution shall conduct the CLARION trial at Site 001 in strict accordance with Protocol PPC-4871-III, as the same may be amended from time to time in accordance with the MCTA, and in compliance with all applicable regulatory requirements, including without limitation the requirements of ICH E6(R2) GCP Guidelines, Title 21 of the United States Code of Federal Regulations, and the conditions of the IRB approval. The scope of work to be performed by the Institution at Site 001 includes, without limitation, the following activities:
(a) Screening and Enrollment. Identification, screening, and enrollment of subjects meeting the eligibility criteria set forth in the Protocol, including completion of all screening assessments, documentation of informed consent, and assessment of inclusion and exclusion criteria.
(b) Randomization. Randomization of eligible subjects through the interactive response technology ("IRT") system designated by the Sponsor, in accordance with the randomization schedule set forth in the Protocol.
(c) Treatment Administration. Dispensing and administration of the Investigational Product (penterafenib or matching placebo) to enrolled subjects in accordance with the dosing regimen, schedule, and instructions set forth in the Protocol, including management of dose modifications and interruptions as specified therein.
(d) Follow-Up Assessments. Conduct of all protocol-specified study visits, assessments, and procedures, including but not limited to physical examinations, vital signs, electrocardiograms, laboratory assessments, tumor imaging, patient-reported outcomes, and survival follow-up.
(e) Data Collection and Entry. Collection of all required clinical data and timely entry of such data into the EDC Platform provided by Pinnacle Data Solutions, Inc., in accordance with the data management plan and data entry guidelines established by the CRO.
(f) Specimen Collection and Shipment. Collection, processing, and shipment of biological specimens (blood, tissue, and other samples) to the Central Laboratory (Northbridge Bioanalytical Laboratories, Inc.) in accordance with the laboratory manual and specimen handling guidelines provided by the Sponsor.
(g) Safety Monitoring and Reporting. Ongoing monitoring of subject safety, identification and documentation of adverse events and serious adverse events, and timely reporting in accordance with the safety reporting procedures set forth in Article 10 of this Agreement and Exhibit J of the MCTA.
(h) Investigational Product Accountability. Receipt, storage, dispensing, return, and destruction of the Investigational Product in accordance with the Protocol and the Investigational Product handling instructions, including maintenance of accurate drug accountability records.
(i) Regulatory Document Maintenance. Maintenance of a complete and current Investigator Site File ("ISF") and regulatory binder, including all essential documents required by ICH E6(R2) GCP Guidelines and applicable regulatory authorities.
The CLARION trial is a Phase III, randomized, double-blind, placebo-controlled study with a planned total enrollment of one thousand two hundred (1,200) subjects randomized in a 2:1 ratio (penterafenib to placebo), resulting in approximately eight hundred (800) subjects in the treatment arm and four hundred (400) subjects in the placebo arm across all thirty-eight (38) participating Veridian Network sites. The enrollment allocation for Site 001 is specified in the Site-Specific Enrollment Schedule attached hereto as Appendix A.
The study timelines applicable to this Site are as follows:
• Target First Patient In (FPI): August 14, 2023
• Projected Enrollment Period: Forty-two (42) months from FPI
• Post-Enrollment Follow-Up Period: Eighteen (18) months following the end of the enrollment period
• Total Estimated Study Duration: Sixty (60) months from FPI
The primary efficacy endpoint of the CLARION trial is overall survival ("OS"), defined as the time from the date of randomization to the date of death from any cause. The key secondary endpoints are: progression-free survival ("PFS"), defined as the time from randomization to the date of first documented disease progression per RECIST v1.1 or death from any cause, whichever occurs first; objective response rate ("ORR"), defined as the proportion of subjects with a confirmed complete response or partial response per RECIST v1.1; and duration of response ("DOR"), defined as the time from first documented response to first documented disease progression or death from any cause.
Section 2.3 — Lead Site Responsibilities
In addition to the general obligations applicable to all participating sites under the MCTA, the Institution, in its capacity as the lead enrollment site (Site 001) for the CLARION trial, shall have the following additional responsibilities:
(a) Protocol Training. The Institution shall serve as the primary site for the conduct of investigator meetings and protocol training sessions for all participating sites within the Veridian Health Research Network. The Principal Investigator shall lead or participate in protocol training activities, including presentation of the scientific rationale, study design, and operational procedures to investigators and study coordinators at all Network sites.
(b) Monitor Qualification Visits. The Institution shall serve as the primary site for the conduct of monitor qualification visits ("MQVs") by the CRO (Meridian Contract Research Organization, Inc.), including demonstration of site procedures, source document practices, and regulatory compliance processes that may serve as templates for other Network sites.
(c) Best-Practice Dissemination. The Institution and the Principal Investigator shall collaborate with the Sponsor, the Network, and the CRO to develop and disseminate best practices, standard operating procedures, and operational guidance to all participating sites, with the objective of promoting consistency, quality, and efficiency in the conduct of the trial across the Network.
(d) Coordination with Sponsor and CRO. The Principal Investigator, in her capacity as Global Principal Investigator for Protocol PPC-4871-III, shall coordinate with the Sponsor's Senior Vice President, Clinical Development (Dr. Marcus Yun, M.D.) and Vice President, Clinical Operations (Jennifer Holt) on all protocol-level matters, including protocol amendments, interim analyses, and data safety monitoring board communications. The Principal Investigator shall further coordinate with the CRO (Meridian Contract Research Organization, Inc., Chief Executive Officer Thomas Hartwell) on all matters relating to monitoring, data management, and safety reporting.
The Institution acknowledges and agrees that its designation as the lead enrollment site carries additional responsibilities beyond those of a standard participating site, and that the compensation structure set forth in Article 5 and Appendix B hereto reflects the fair market value of such additional responsibilities.
ARTICLE 3 — PRINCIPAL INVESTIGATOR
Section 3.1 — Identification and Qualifications
The Principal Investigator for the conduct of the CLARION trial at Site 001 is Dr. Catherine Aldridge, M.D., Ph.D., Professor of Oncology at Graystone University Medical Center. Dr. Aldridge holds an M.D. from the University of Pennsylvania Perelman School of Medicine and a Ph.D. in Molecular Pharmacology from the same institution. She is board-certified in Medical Oncology and Hematology by the American Board of Internal Medicine.
Dr. Aldridge has served as a principal investigator on more than forty (40) interventional clinical trials in hepatocellular carcinoma and other hepatobiliary malignancies, including multiple Phase II and Phase III registrational studies. She has published extensively in peer-reviewed journals on the treatment of advanced HCC and the development of multi-kinase inhibitors in solid tumors.
In addition to her role as Site Principal Investigator for Site 001, Dr. Aldridge has been appointed by the Sponsor to serve as the Global Principal Investigator for Protocol PPC-4871-III across all participating sites within the Veridian Health Research Network. A copy of Dr. Aldridge's curriculum vitae and medical license documentation is on file with the Sponsor and the CRO and is maintained in the Investigator Site File at Site 001.
Section 3.2 — PI Obligations
The Principal Investigator shall perform her duties and obligations under this Agreement, the MCTA, and the Protocol with the degree of skill, care, and diligence expected of a qualified investigator conducting a clinical trial in accordance with applicable professional standards and regulatory requirements. Without limiting the generality of the foregoing, the Principal Investigator shall:
(a) Conduct the trial at Site 001 in strict accordance with Protocol PPC-4871-III, the ICH E6(R2) Good Clinical Practice Guidelines, and all applicable regulations of the United States Food and Drug Administration, including without limitation Title 21, Code of Federal Regulations, 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).
(b) Execute and maintain a current FDA Form 1572 (Statement of Investigator) listing the Principal Investigator's qualifications, the sub-investigators and study staff authorized to perform trial-related procedures, and the facilities and laboratories used in the conduct of the trial. The PI shall update Form 1572 promptly upon any change to the information contained therein and shall provide updated copies to the Sponsor and the CRO within ten (10) business days of any such change.
(c) Complete and submit to the Sponsor a Financial Disclosure Certification in accordance with the requirements of 21 C.F.R. Part 54, disclosing any financial interests or arrangements that could affect the objectivity of the trial, including equity interests, significant payments, and proprietary interests in the Investigational Product. The PI shall update such certification promptly upon any material change in her financial interests during the course of the trial and for one (1) year following the completion of the trial.
(d) Execute the Form of Investigator Undertaking attached as Exhibit I to the MCTA, acknowledging and agreeing to the PI's responsibilities and obligations under the Protocol, the MCTA, this Agreement, and applicable law.
(e) Ensure that all sub-investigators and study staff listed on the delegation of authority log are appropriately qualified by education, training, and experience to perform the protocol-specified procedures delegated to them, and that all such personnel have completed all required training, including but not limited to Good Clinical Practice training (within the preceding thirty-six (36) months), protocol-specific training, EDC system training, and training on the Institution's standard operating procedures for clinical research.
(f) Personally supervise the conduct of the trial at Site 001 and maintain adequate time and resources to fulfill her obligations as both Site PI and Global PI for the duration of the study.
(g) Ensure that informed consent is obtained from each subject (or the subject's legally authorized representative, where applicable) prior to the subject's participation in any study-related procedures, in accordance with 21 C.F.R. Part 50, the IRB-approved informed consent form, and the Protocol.
Section 3.3 — Replacement of PI
The Institution shall not replace the Principal Investigator without the prior written consent of the Sponsor, which consent shall not be unreasonably withheld, conditioned, or delayed, provided that the proposed replacement investigator meets the Sponsor's qualification requirements as set forth in the Protocol and the MCTA. In the event of the Principal Investigator's unavailability for any reason (including, without limitation, illness, disability, leave of absence, change of employment, death, or regulatory disqualification), the Institution shall:
(a) Notify the Sponsor and the CRO in writing within five (5) business days of becoming aware of the PI's unavailability or anticipated unavailability;
(b) Designate a qualified interim sub-investigator to assume responsibility for the day-to-day conduct of the trial at Site 001 pending the identification and approval of a replacement PI;
(c) Propose a replacement Principal Investigator who meets the Sponsor's qualification requirements, and provide the Sponsor with such replacement investigator's curriculum vitae, medical license documentation, Form 1572, and Financial Disclosure Certification within thirty (30) calendar days of the PI's unavailability; and
(d) Cooperate with the Sponsor and the CRO in all respects necessary to effect a smooth transition of PI responsibilities, including execution of updated regulatory documents and notification of the IRB and, where applicable, the FDA.
The Parties acknowledge that replacement of the Global Principal Investigator will require additional coordination with the Sponsor, the Network, and all participating sites, and the Sponsor reserves the right to designate a replacement Global PI from among the qualified investigators at any participating Veridian Network site.
ARTICLE 4 — IRB APPROVAL AND REGULATORY COMPLIANCE
Section 4.1 — IRB of Record
The Graystone University Institutional Review Board (IRB Registration Number: IRB00012847) shall serve as the Institutional Review Board of record for the conduct of the CLARION trial at Site 001. The Parties acknowledge that Graystone University Medical Center requires individual institutional IRB approval for all clinical research conducted at its facilities and does not rely upon the Veridian Central IRB or any other central or external IRB for the review and approval of research protocols conducted at Graystone. Accordingly, notwithstanding any provision of the MCTA contemplating reliance on a central IRB for participating sites, the Graystone University IRB shall serve as the sole IRB of record for this Site.
Section 4.2 — IRB Approval as Condition Precedent
IRB approval of Protocol PPC-4871-III, the informed consent form (including any site-specific modifications approved by the Sponsor), and all subject-facing materials (including recruitment materials, subject diaries, and patient information sheets) by the Graystone University IRB is a condition precedent to the enrollment of any subject at Site 001. No screening or enrollment activities shall commence at this Site until the Institution has provided the Sponsor and the CRO with a copy of the IRB's written approval letter, together with the IRB-approved versions of the Protocol, informed consent form, and all subject-facing materials.
The Parties acknowledge that documentation of IRB approval for Protocol PPC-4871-III at Site 001 was delivered to the Sponsor as part of the closing conditions under Section 2.4 of the MCTA on July 5, 2023, and that such condition precedent has been satisfied.
Section 4.3 — Ongoing IRB Compliance
The Institution and the Principal Investigator shall maintain continuous IRB approval throughout the entire duration of the conduct of the CLARION trial at Site 001, from the date of initial approval through the completion of all trial-related activities, including the follow-up period and the final data lock. Without limiting the foregoing, the Institution and PI shall:
(a) Submit timely applications for continuing review of the Protocol in accordance with the Graystone University IRB's policies and procedures and applicable federal regulations, such that there is no lapse in IRB approval at any time during the conduct of the trial;
(b) Submit all Protocol amendments to the IRB for review and approval prior to implementation at the Site, except where an 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;
(c) Submit all IND safety reports, annual safety reports (Development Safety Update Reports), and other safety information provided by the Sponsor to the IRB in accordance with the IRB's requirements and applicable federal regulations;
(d) Submit reports of all unanticipated problems involving risks to subjects or others, protocol deviations, and non-compliance events to the IRB in accordance with the IRB's requirements and 21 C.F.R. Part 56;
(e) Promptly notify the Sponsor and the CRO (Meridian Contract Research Organization, Inc.) of any IRB actions affecting the conduct of the trial at this Site, including without limitation suspension or termination of IRB approval, conditional approval, required modifications to the Protocol or informed consent form, or any other restrictions imposed by the IRB; and
(f) Provide the Sponsor and the CRO with copies of all IRB correspondence, including approval letters, continuing review approval letters, amendment approval letters, and any letters reflecting IRB conditions, restrictions, or other actions, within five (5) business days of receipt by the Institution.
Section 4.4 — Regulatory Compliance Representations
The Institution represents and warrants to the Sponsor and the Network that the Institution and the Principal Investigator are, and throughout the term of this Agreement shall remain, in compliance with all applicable federal, state, and local laws, regulations, and guidelines governing the conduct of clinical trials, including without limitation:
(a) Title 21, Code of Federal Regulations, Part 11 (Electronic Records; Electronic Signatures);
(b) Title 21, Code of Federal Regulations, Part 50 (Protection of Human Subjects);
(c) Title 21, Code of Federal Regulations, Part 54 (Financial Disclosure by Clinical Investigators);
(d) Title 21, Code of Federal Regulations, Part 56 (Institutional Review Boards);
(e) Title 21, Code of Federal Regulations, 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;
(g) The Health Insurance Portability and Accountability Act of 1996, as amended ("HIPAA"), and its implementing regulations at Title 45, Code of Federal Regulations, Parts 160 and 164, including the Privacy Rule, the Security Rule, and the Breach Notification Rule;
(h) The Federal Anti-Kickback Statute (42 U.S.C. § 1320a-7b(b)) and the regulations promulgated thereunder, including the safe harbor provisions at 42 C.F.R. § 1001.952; and
(i) The Physician Payments Sunshine Act (42 U.S.C. § 1320a-7h), commonly referred to as "Open Payments," including the requirement that the Sponsor report payments and other transfers of value to covered recipients.
The Institution further represents and warrants that all compensation payable to the Institution, the Principal Investigator, and site personnel under this Agreement and the MCTA reflects fair market value for the services to be rendered and has been determined through an arm's-length negotiation process, and that such compensation does not constitute or involve any payment, remuneration, or consideration intended to induce or reward the referral of subjects or the ordering of items or services reimbursable by any federal or state healthcare program.
The Institution's detailed regulatory compliance representations and covenants are set forth in Exhibit H (Regulatory Compliance Representations and Covenants) to the MCTA, which is incorporated herein by reference. The Institution acknowledges that it has reviewed Exhibit H and confirms its compliance therewith as of the Execution Date.
ARTICLE 5 — BUDGET AND PAYMENT
Section 5.1 — Site-Specific Budget
The financial terms applicable to the conduct of the CLARION trial at Site 001 are set forth in Exhibit B (Budget and Payment Schedule) to the MCTA and in the Site-Specific Budget Schedule attached hereto as Appendix B, which are incorporated herein by reference. In the event of any conflict between the general budget provisions of Exhibit B to the MCTA and the site-specific provisions of Appendix B hereto, the site-specific provisions of Appendix B shall control with respect to this Site.
The per-patient site fee for each subject enrolled and randomized at Site 001 under Protocol PPC-4871-III shall be Fifty-Two Thousand Dollars ($52,000) per subject, payable in four (4) milestone-based installments of Thirteen Thousand Dollars ($13,000) each, as follows:
(a) Milestone 1 — Randomization: Twenty-five percent (25%) of the per-patient site fee, equal to Thirteen Thousand Dollars ($13,000), shall be payable upon randomization of the subject through the IRT system and confirmation of the subject's eligibility;
(b) Milestone 2 — Week 12 Assessment: Twenty-five percent (25%) of the per-patient site fee, equal to Thirteen Thousand Dollars ($13,000), shall be payable upon completion of the subject's Week 12 assessment visit and entry of all required data into the EDC Platform;
(c) Milestone 3 — Week 24 Assessment: Twenty-five percent (25%) of the per-patient site fee, equal to Thirteen Thousand Dollars ($13,000), shall be payable upon completion of the subject's Week 24 assessment visit and entry of all required data into the EDC Platform; and
(d) Milestone 4 — Study Completion/Final Visit: Twenty-five percent (25%) of the per-patient site fee, equal to Thirteen Thousand Dollars ($13,000), shall be payable upon completion of the subject's final study visit (including the end-of-treatment visit, safety follow-up visit, or survival follow-up visit, as applicable) and resolution of all outstanding data queries for such subject.
For subjects who discontinue study treatment or withdraw from the trial prior to completion of all milestone visits, payment shall be made for each milestone that has been completed as of the date of discontinuation or withdrawal. No partial milestone payments shall be made for milestones that are not completed.
Section 5.2 — Start-Up Fees
The Sponsor shall pay the Institution a non-refundable start-up fee of Seventy-Five Thousand Dollars ($75,000) in connection with the initiation of the CLARION trial at Site 001. The start-up fee shall cover all costs associated with site preparation, IRB submission and review, staff training, source document template preparation, pharmacy set-up, and other pre-enrollment activities. The start-up fee shall be payable in two (2) installments as follows:
(a) First Installment: Fifty percent (50%) of the start-up fee, equal to Thirty-Seven Thousand Five Hundred Dollars ($37,500), shall be payable upon site activation, defined as the date on which the Site has satisfied all conditions for activation as set forth in the Site Activation Checklist provided by the CRO, including receipt of IRB approval, execution of this Agreement, completion of the site initiation visit, and confirmation of drug shipment receipt; and
(b) Second Installment: Fifty percent (50%) of the start-up fee, equal to Thirty-Seven Thousand Five Hundred Dollars ($37,500), shall be payable upon enrollment of the first subject at Site 001 (i.e., the date on which the first subject is randomized through the IRT system).
Section 5.3 — Annual Site Maintenance Fees
In addition to the per-patient site fees and start-up fees described above, the Sponsor shall pay the Institution an annual site maintenance fee of Forty Thousand Dollars ($40,000) per year during the term of this Agreement. The annual site maintenance fee shall cover the Institution's ongoing overhead costs, including site infrastructure, regulatory document maintenance, IRB continuing review fees, study coordinator time for non-visit-specific activities, and general administrative support for the trial.
The annual site maintenance fee shall be paid in advance on each anniversary of the site activation date. The first annual maintenance payment shall be due within forty-five (45) days of site activation, and subsequent annual payments shall be due within forty-five (45) days of each anniversary thereafter. Based on the estimated average site participation period of three and one-half (3.5) years, the total estimated site maintenance fees payable to the Institution over the life of the trial are One Hundred Forty Thousand Dollars ($140,000).
Section 5.4 — Payment Terms
All payments to the Institution under this Agreement shall be made within forty-five (45) calendar days of the Sponsor's receipt of a proper invoice submitted by the Institution (Net 45 days). Each invoice shall set forth in reasonable detail the basis for the payment requested, including the applicable milestone, the subject identification number(s) (where applicable), and the amount due. The Institution shall submit all invoices in writing (including by electronic mail) to:
Samantha Novak Director, Clinical Contracts Penterra Pharmaceuticals Corp. 200 Biopharma Boulevard, Suite 1400 Princeton, New Jersey 08540
Email: s.novak@penterra.com
The Sponsor reserves the right to dispute any invoice or portion thereof that it reasonably believes to be inaccurate or not in accordance with the terms of this Agreement. In the event of a good-faith dispute, the Sponsor shall pay the undisputed portion of the invoice within the applicable payment period and shall notify the Institution in writing of the disputed amount and the basis for the dispute within fifteen (15) business days of receipt of the invoice. The Parties shall use good-faith efforts to resolve any invoice dispute within thirty (30) calendar days.
All payments shall be made in United States Dollars by wire transfer to the Institution's designated bank account, the details of which shall be provided by the Institution to the Sponsor in writing prior to the first payment.
Section 5.5 — Network Coordination Fee
The Parties acknowledge that the network coordination and administrative fee payable by the Sponsor to the Veridian Health Research Network in the aggregate amount of Four Million Two Hundred Thousand Dollars ($4,200,000), payable in quarterly installments of Three Hundred Thousand Dollars ($300,000) each over fourteen (14) quarters, is governed exclusively by the terms of the MCTA and is not separately invoiced by this Site. The network coordination fee compensates the Network for central coordination services, including site selection and qualification, central data management oversight, network-wide training, regulatory support, and administrative coordination. The Institution shall not include any charges for network coordination services in its invoices to the Sponsor under this Agreement.
Section 5.6 — Investigator Grants
Investigator grants for academic publication support and dissemination of scientific findings, in the aggregate amount of One Million Five Hundred Thousand Dollars ($1,500,000) across all participating Veridian Network sites, shall be disbursed upon acceptance of manuscripts for publication in peer-reviewed scientific journals, in accordance with the terms and conditions set forth in Exhibit G (Intellectual Property and Publication Rights) of the MCTA and the Principal Investigator Agreement executed by Dr. Aldridge. The amount of any individual investigator grant shall be determined based on the nature and scope of the publication (e.g., primary endpoint analysis, subgroup analysis, ancillary study) and the role of the investigator as lead or co-author, as set forth in the publication plan agreed upon by the Sponsor and the Steering Committee. Applications for investigator grants shall be submitted to the Sponsor's Medical Affairs department and are subject to the Sponsor's review and approval.
ARTICLE 6 — INDEMNIFICATION
Section 6.1 — Sponsor Indemnification of Site and Investigators
Subject to the terms and conditions of this Article 6 and Exhibit D (Subject-Injury Indemnification Provisions) of the MCTA, Penterra Pharmaceuticals Corp. shall defend, indemnify, and hold harmless the Institution, the Principal Investigator, all sub-investigators, and all study staff at Site 001 (collectively, the "Site Indemnitees") from and against any and all claims, demands, actions, suits, proceedings, losses, damages, liabilities, judgments, settlements, costs, and expenses (including reasonable attorneys' fees, expert witness fees, and costs of litigation) (collectively, "Losses") arising from or in connection with:
(a) Any bodily injury, illness, or death of a subject enrolled in the CLARION trial at Site 001 to the extent caused by the administration of the Investigational Product (penterafenib/PPC-4871 or matching placebo) when such Investigational Product is administered in accordance with the Protocol and the Investigator's Brochure;
(b) Any defect in the design, manufacture, formulation, labeling, packaging, storage, or distribution of the Investigational Product, including any failure to meet applicable specifications or any contamination, adulteration, or mislabeling of the Investigational Product;
(c) Any breach by the Sponsor of its representations, warranties, covenants, or obligations under the MCTA, this Agreement, or the Protocol; and
(d) Any negligent act or omission or willful misconduct of the Sponsor, its employees, agents, or contractors (other than the Institution and its personnel) in connection with the CLARION trial.
Section 6.2 — Carve-Outs from Sponsor Indemnification
Notwithstanding anything to the contrary in Section 6.1, the Sponsor's indemnification obligations under this Article 6 shall not extend to, and the Sponsor shall have no obligation to defend, indemnify, or hold harmless any Site Indemnitee with respect to, any Losses to the extent arising from or attributable to:
(i) The negligence, gross negligence, recklessness, or willful misconduct of the Institution, the Principal Investigator, any sub-investigator, or any member of the site staff in the conduct of the CLARION trial, including but not limited to errors in the administration of the Investigational Product, failure to obtain proper informed consent, and failure to follow standard medical practice;
(ii) Any Protocol deviation committed by the Institution, the Principal Investigator, or site staff that was not authorized or directed by the Sponsor and was not reasonably necessary to protect the safety, rights, or welfare of subjects enrolled in the trial; or
(iii) Any breach by the Institution, the Principal Investigator, or site staff of any representation, warranty, covenant, or obligation under the MCTA, this Agreement, or applicable law, including but not limited to breaches of regulatory compliance obligations, data integrity requirements, or confidentiality obligations.
In the event that Losses are attributable to the combined fault of the Sponsor and one or more Site Indemnitees, the Parties shall allocate responsibility for such Losses in proportion to their respective degrees of fault, as determined by mutual agreement or, failing agreement, by the dispute resolution procedures set forth in Article 15 of this Agreement.
Section 6.3 — Subject Medical Care Costs
In addition to its indemnification obligations under Section 6.1, Penterra shall reimburse or pay directly the reasonable and customary medical costs incurred for the diagnosis and treatment of study-related injuries sustained by subjects enrolled in the CLARION trial at Site 001, to the extent that such costs are not covered by the subject's health insurance or other third-party coverage. For purposes of this Section 6.3, "study-related injury" means any bodily injury, illness, or adverse health condition that is determined by the Sponsor's medical monitor (or, in the event of dispute, by an independent medical reviewer mutually agreed upon by the Parties) to be causally related to the administration of the Investigational Product or the conduct of a protocol-specified procedure.
The Sponsor's obligation to reimburse or pay subject medical care costs under this Section 6.3 is subject to the following caps:
(a) Per-Subject Cap: The maximum amount payable by the Sponsor for medical care costs attributable to study-related injuries for any single subject shall be Five Hundred Thousand Dollars ($500,000); and
(b) Aggregate Cap: The maximum aggregate amount payable by the Sponsor for medical care costs attributable to study-related injuries across all participating sites in the CLARION trial shall be Fifteen Million Dollars ($15,000,000).
Section 6.4 — Product Defect Claims
Notwithstanding the caps set forth in Section 6.3, the Sponsor's indemnification obligations with respect to Losses arising from defects in the Investigational Product (as described in Section 6.1(b)) shall not be subject to any per-subject cap or aggregate cap. The Sponsor's liability for product defect claims shall be unlimited in amount, and the Sponsor shall fully indemnify, defend, and hold harmless the Site Indemnitees from and against all Losses arising from such defects, regardless of the total amount of such Losses.
Section 6.5 — Site/Institution Indemnification of Sponsor
Subject to the terms and conditions of this Article 6 and Exhibit D of the MCTA, the Institution (acting through the Network, to the extent required by the MCTA) shall defend, indemnify, and hold harmless Penterra Pharmaceuticals Corp., its officers, directors, employees, agents, and affiliates (collectively, the "Sponsor Indemnitees") from and against any and all Losses arising from or in connection with:
(a) Any negligent act or omission, gross negligence, recklessness, or willful misconduct of the Institution, the Principal Investigator, any sub-investigator, or any member of the site staff at Site 001 in the conduct of the CLARION trial;
(b) Any Protocol deviation committed by the Institution, the Principal Investigator, or site staff at Site 001 that was not authorized or directed by Penterra and was not reasonably necessary to protect the safety, rights, or welfare of subjects enrolled in the trial; and
(c) Any breach by the Institution, the Principal Investigator, or site staff of any representation, warranty, covenant, or obligation under the MCTA, this Agreement, or applicable law.
The Institution's indemnification obligations under this Section 6.5 shall be subject to the following caps:
• Per-Site, Per-Occurrence Cap: Five Million Dollars ($5,000,000) per site per occurrence; and
• Aggregate Cap: Twenty Million Dollars ($20,000,000) in the aggregate across all participating Veridian Network sites for all occurrences during the term of the MCTA.
Section 6.6 — Notice Requirements
The Party seeking indemnification (the "Indemnified Party") shall provide written notice to the Party from whom indemnification is sought (the "Indemnifying Party") within thirty (30) calendar days of becoming aware of any claim, demand, action, suit, or proceeding for which indemnification may be sought under this Article 6. Such notice shall include a description of the claim in reasonable detail, copies of any relevant documents (including pleadings, correspondence, and demand letters), and an estimate of the Losses involved, to the extent known.
The failure of the Indemnified Party to provide timely notice as required by this Section 6.6 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. The Indemnifying Party shall have the right to assume the defense of any claim for which indemnification is sought, subject to the Indemnified Party's right to participate in such defense with its own counsel at its own expense.
Section 6.7 — Cross-Reference
The detailed indemnification provisions governing the CLARION trial, including the procedures for defense, settlement, and payment of claims, are set forth in Exhibit D (Subject-Injury Indemnification Provisions) to the MCTA, which is incorporated herein by reference. In the event of any conflict between this Article 6 and Exhibit D, Exhibit D shall control.
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, under Policy No. BM-CTL-2023-04182, providing coverage for claims arising from the conduct of the CLARION trial, with the following coverage limits:
• Per-Occurrence Limit: Twenty-Five Million Dollars ($25,000,000)
• Aggregate Limit: Seventy-Five Million Dollars ($75,000,000)
• Subject-Injury Sublimit: Ten Million Dollars ($10,000,000) per occurrence / Fifty Million Dollars ($50,000,000) aggregate
• Policy Period: April 1, 2023 through March 31, 2024, renewable annually upon payment of premium
Graystone University Medical Center, its officers, directors, employees, agents, and the Principal Investigator are named as additional insureds under the Briarcliff policy with respect to claims arising from the conduct of the CLARION trial at Site 001, to the extent of the Sponsor's indemnification obligations under this Agreement and the MCTA. The Sponsor shall maintain such coverage in full force and effect throughout the term of this Agreement and for a period of not less than three (3) years following the completion or termination of the trial at this Site.
The Sponsor shall provide the Institution with a certificate of insurance evidencing the foregoing coverage within fifteen (15) business days of execution of this Agreement and annually thereafter upon renewal of the policy. The Sponsor shall provide the Institution with not less than thirty (30) days' prior written notice of any material change in, cancellation of, or non-renewal of such coverage.
Section 7.2 — Site Insurance
The Institution shall maintain, at its own expense and throughout the term of this Agreement, general liability and professional liability (medical malpractice) insurance coverage with limits of not less than:
• Per-Occurrence Limit: Five Million Dollars ($5,000,000)
• Aggregate Limit: Ten Million Dollars ($10,000,000)
Such insurance shall be obtained from a carrier or carriers rated A- (Excellent) or better by A.M. Best Company and shall provide coverage for claims arising from the Institution's and the Principal Investigator's conduct of the CLARION trial at Site 001, including coverage for medical professional liability, clinical trial liability, and general premises liability.
Evidence of the foregoing coverage, in the form of a certificate of insurance issued by the Institution's insurance carrier or broker, shall be provided to the Sponsor within fifteen (15) business days of execution of this Agreement and annually thereafter upon renewal of the policy. The Institution shall provide the Sponsor with not less than thirty (30) days' prior written notice of any material change in, cancellation of, or non-renewal of such coverage.
Section 7.3 — Certificate Exchange
The requirements for insurance certificates, the form of certificates, and the procedures for the exchange of insurance documentation are set forth in Exhibit E (Insurance Requirements and Certificate Forms) to the MCTA, which is incorporated herein by reference.
ARTICLE 8 — DATA OWNERSHIP, RECORDS, AND CONFIDENTIALITY
Section 8.1 — Data Ownership
The Institution acknowledges and agrees that Penterra Pharmaceuticals Corp. retains exclusive ownership of all clinical trial data generated at Site 001 under Protocol PPC-4871-III, including without limitation all case report form data (whether entered into the EDC Platform or recorded on paper source documents), laboratory data, imaging data, pharmacokinetic and pharmacodynamic data, biomarker data, safety data, efficacy data, patient-reported outcome data, and any and all analyses, compilations, and summaries thereof (collectively, "Study Data"). The Institution shall not use, disclose, or otherwise exploit the Study Data for any purpose other than the conduct of the CLARION trial at Site 001 and as permitted under this Agreement, the MCTA, and applicable law, without the prior written consent of the Sponsor.